Clinical Topic A-Z Clinical Speciality

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease
D029424Pulmonary Disease, Chronic Obstructive
D029481Bronchitis, Chronic
D011656Pulmonary Emphysema
D008173Lung Diseases, Obstructive
Respiratory
2010-11-01Last revised in November 2010

Chronic obstructive pulmonary disease - Summary

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction which is usually progressive, not fully reversible, and does not change markedly over several months.

Tobacco smoking is the major risk factor for development of COPD.

There may be disability and impairment of quality of life.

A diagnosis of COPD can be made if the person meets all of the following criteria:

Age older than 35 years.

Presence of a risk factor (for example smoking, history of smoking, or an occupational exposure).

Typical symptoms.

Absence of clinical features of asthma.

Presence of airflow obstruction confirmed by post-bronchodilator spirometry.

Typical symptoms include:

Exertional breathlessness.

Chronic cough.

Regular sputum production.

Frequent 'winter bronchitis'.

Wheeze.

Other symptoms include weight loss, exercise intolerance, ankle swelling, fatigue, and chest pain or haemoptysis (rare).

Signs include hyperinflated chest, wheeze or quiet breath sounds, pursed lip breathing, use of accessory muscles, peripheral oedema, cyanosis, raised jugular venous pressure, and cachexia.

Post-bronchodilator spirometry should be measured to confirm the diagnosis of COPD.

Spirometry should be carried out 15–20 minutes after inhalation of salbutamol.

In COPD, the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) is less than 0.7.

Severity should be assessed in terms of:

The degree of airflow obstruction according to the reduction in forced expiratory volume in 1 second (FEV1).

The degree of breathlessness according to the Medical Research Council dyspnoea scale.

Presence of cor pulmonale.

The person's smoking history should be documented and encouragement given regarding stopping.

Anxiety or depression should be screened for in people who are hypoxic or have severe dyspnoea.

The full blood count should be checked, and other investigations arranged as appropriate.

The person should be offered inhaled treatment — strategies for stepping up inhaled treatments differ according to the reduction in FEV1.

Referral should be considered, when appropriate:

To a respiratory specialist, for assessment for oxygen therapy.

For pulmonary rehabilitation.

To a physiotherapist.

To social services and occupational therapy.

An annual influenza vaccination and a once-only pneumococcal vaccination should be advised.

A self-management plan that includes how to recognize the early signs of an exacerbation and respond appropriately should be discussed.

Acute exacerbations should be treated by prescribing:

Systemic corticosteroids for people with a significant increase in breathlessness.

Oral antibiotics for people with a history of more purulent sputum or clinical signs of pneumonia.

Advice should be offered on nutrition, medications, exercise, and flying.

Cor pulmonale should be managed, usually by referring the person to a respiratory specialist.

All people with COPD should be followed up; the frequency of follow up depends on the severity of disease.

End-of-life issues should be discussed when appropriate.

Have I got the right topic?

192months3060monthsBoth

This CKS topic covers the management of people with chronic obstructive pulmonary disease (COPD).

This CKS topic does not cover the management of asthma.

There are separate CKS topics on Asthma, Breathlessness, Chest infections - adult, Cough, Lung cancer - suspected, Palliative cancer care - cough, Palliative cancer care - dyspnoea, and Smoking cessation.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in November 2010

March 2014 — minor update. Links to the European Committee for Standardization have been removed (www.cen.eu/) as this no longer has text on the use of nebulisers.

July 2013 — minor update. Links to the DVLA website have been updated.

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic [BMA and NHS Employers, 2013].

March 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic [BMA and NHS Employers, 2012]. Issued in April 2012.

February 2012 — minor update. A recommendation to advise people inhaling terbutaline via a turbohaler to rinse their mouth after each use to minimize systemic adverse effects has been added, following an update to the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2011]. Issued in March 2012.

November 2011 — minor update. The black triangle has been removed from Serevent Evohaler® (salmeterol cfc-free inhaler); prescriptions have been amended to reflect this. Issues in December 2011.

September 2011 — minor update. NICE has recommended in its COPD Quality Standard document that people receiving long-term oxygen therapy should have a review at least once per year, which includes pulse oximetry [NICE, 2011]. Issued in October 2011.

September 2011 — minor update. Further evidence has been added from a recent systematic review and meta-analysis of randomized controlled trials which found that compared with placebo, Spiriva Respimat® 5 micrograms/day was associated with a statistically significant increased risk of mortality [Singh et al, 2011]. Issued in October 2011.

May 2011 — minor update. The 2011/2012 QOF indicators have been added to this topic [BMA and NHS Employers, 2011]. Issued in June 2011.

February 2011 — minor update. The range of long–acting beta2–agonist inhaler devices included as prescriptions has been updated. Issued in February 2011.

November 2010 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice that the Spiriva Respimat® formulation of tiotropium should be used with caution in people with known cardiac rhythm disorders [MHRA, 2010]. Issued in November 2010.

July to November 2010 — topic updated. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

Major changes to the recommendations that are relevant to primary healthcare professionals include:

Diagnosis

Spirometry should be measured post-bronchodilator to confirm the diagnosis of chronic obstructive pulmonary disease (COPD).

Assessment of severity

NICE recommend a new classification of the severity of airflow obstruction according to forced expiratory volume in one second (FEV1).

Drug treatment

Initial decisions about treatment with a long-acting beta-2 agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS) should be made according to whether FEV1 is less than, or greater than or equal to, 50% predicted.

In people with stable COPD who remain breathless or have exacerbations despite use of short-acting bronchodilators as required, NICE recommends the following as maintenance therapy:

If FEV1 is greater than or equal to 50% predicted: a LABA or LAMA.

If FEV1 is less than 50% predicted: LABA with an ICS in a combination inhaler, or a LAMA.

In people with stable COPD and an FEV1 greater than or equal to 50% who remain breathless or have exacerbations despite maintenance therapy with a LABA, NICE recommends a LABA plus an ICS in a combination inhaler (or a LAMA in addition to a LABA where an ICS is declined or not tolerated).

However, NICE recommends a LAMA in addition to a LABA plus ICS for people with COPD who remain breathless or have exacerbations despite taking a LABA plus ICS, regardless of their FEV1.

Pulmonary rehabilitation

In addition to people who consider themselves functionally disabled by COPD (usually Medical Research Council dyspnoea scale grade 3 and above), pulmonary rehabilitation should be made available to people who have had a recent hospitalization for an acute exacerbation.

End-stage COPD

Recommendations on when to discuss end-of-life issues, and on the identification and management of end-stage COPD have been strengthened, in line with a growing awareness of the palliative and information needs of people with end-stage COPD.

Previous changes

March 2010 — minor update. All strengths of Beclazone® inhalers have been discontinued. Prescriptions removed. Issued in March 2010.

January 2010 — minor update to text regarding drug interactions with theophylline. Issued in January 2010.

October 2009 — minor typographical error corrected. Issued in October 2009.

July 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice on the use of long-acting beta2-agonists and inhaled corticosteroids in chronic obstructive pulmonary disease [MHRA, 2009]. Issued in July 2009.

June 2009 — minor update. Broken link removed. Issued in June 2009.

May 2009 — minor update. A budesonide CFC-free pMDI has been launched, and a prescription has been added. The Nebuhaler® spacer device has been discontinued. This prescription has been replaced with the NebuChamber® spacer device. Issued in June 2009.

April 2009 — minor update. The Quality and Outcomes Framework (QOF) indicators for stopping smoking that apply to COPD have been added. Issued in May 2009.

March 2009 — minor update. The agreed changes to the QOF for 2009/2010 for COPD have been updated in the Goals and outcome measures section. Issued in April 2009.

May to August 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

April 2006 — updated. Prescriptions for CFC-free and salmeterol pressurized metered dose inhalers have replaced those for CFC-containing inhalers. Information on changing to CFC-free inhalers included in the Medicines management section. Issued in May 2006.

January 2006 — update to reflect the new supply arrangements for home oxygen. Oxygen prescriptions have been removed and changes to the text in management issues and the oxygen therapy scenario have been made. Volumatic® spacer device re-introduced and prescriptions included; terbutaline pressurized metered dose inhalers have been discontinued and prescriptions removed. Issued in February 2006.

October 2005 — minor update. Volumatic® spacer device discontinued and prescriptions removed; advice for using alternative spacer devices included. Issued in November 2005.

July 2005 — updated to incorporate the Referral guidelines for suspected cancer published by the National Institute for Health and Care Excellence. Issued in July 2005.

March 2004 — reviewed. Validated in May 2004 and issued in July 2004.

October 2000 — reviewed and updated to incorporate recommendations from the Royal College of Physicians 1999 report on domiciliary oxygen therapy services. Validated in November 2000 and issued in October 2001.

October 1997 — rewritten. Replaces guidance on Chronic bronchitis, Emphysema and Acute exacerbation of COAD.

Update

New evidence

NICE Evidence published an evidence update on chronic obstructive pulmonary disease in February 2012. [Free Full-text (pdf)]

Evidence-based guidelines

Evidence-based guidelines published since the last revision of this topic:

ICSI (2011) Diagnosis and management of chronic obstructive pulmonary disease (COPD). Institute for Clinical Systems Improvement. www.icsi.org [Free Full-text]

Qaseem, A., Wilt, T.J., Weinberger, S.E., et al. (2011) Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Annals of Internal Medicine 155(3), 179-191. [Abstract] [Free Full-text]

NICE have published evidence summaries on new medicines for COPD:

NICE (2013) ESNM8: Chronic obstructive pulmonary disease: aclidinium bromide. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2013) ESNM9: Chronic obstructive pulmonary disease: glycopyrronium bromide. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2013) ESNM21: Chronic obstructive pulmonary disease: fluticasone furoate plus vilanterol. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2014) ESNM33: Chronic obstructive pulmonary disease: indacaterol/glycopyrronim (Ultibro Breezhaler). National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

HTAs (Health Technology Assessments)

Technology appraisals published since the last revision of this topic:

NICE (2012) Roflumilast for the management of severe chronic obstructive pulmonary disease Technology Appraisal 244. National Institute for Health and Care Excellence www.nice.org.uk [Free Full-text]

Economic appraisals

No new economic appraisals relevant to England since 1 July 2010.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

An, X., Zhang, A.L., May, B.H., et al. (2012) Oral chinese herbal medicine for improvement of quality of life in patients with stable chronic obstructive pulmonary disease: a systematic review. Journal of Alternative and Complementary Medicine 18(8), 731-743. [Abstract]

An, X., Zhang, A.L., Yang, A.W., et al. (2010) Oral ginseng formulae for stable chronic obstructive pulmonary disease: a systematic review. Respiratory Medicine 105(2), 165-176. [Abstract]

Bartlett, Y.K., Sherran, P., and Hawley, M.S. (2014) Effective behaviour change techniques in smoking cessation interventions for people with chronic obstructive pulmonary disease: a meta-analysis. British Journal of Health Psychology 19(1), 181-203. [Abstract]

Bentsen, S.B., Langeland, E., and Holm, A.L. (2012) Evaluation of self-management interventions for chronic obstructive pulmonary disease. Journal of Nursing Management 20(6), 802-813. [Abstract]

Bossenbroek, L., de Greef, M.H., Wempe, J.B., et al. (2011) Daily physical activity in patients with chronic obstructive pulmonary disease: a systematic review. COPD 8(4), 306-319. [Abstract]

Cao, C., Wang, R., Wang, J., et al. (2012) Body mass index and mortality in chronic obstructive pulmonary disease: a meta-analysis. PLoS One 7(8), e43892. [Abstract] [Free Full-text]

Cheyne, L., Irvin-Sellers, M.J., and White, J. (2013) Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 9. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Chong, J., Karner, C., and Poole, P. (2012) Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease (Cochrane Review) The Cochrane Library. Issue 9. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Chong, J., Poole, P., Leung, B., and Black, P.N. (2011)Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 5. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Collins, P.F., Stratton, R.J., and Elia, M. (2012) Nutritional support in chronic obstructive pulmonary disease: a systematic review and meta-analysis. American Journal of Clinical Nutrition 95(6), 1385-1395. [Abstract]

Cope, S., Donohue, J.F., Jansen, J.P., et al. (2013) Comparative efficacy of long-acting bronchodilators for COPD - a network meta-analysis. Respiratory Research 14(1), 100. [Abstract]

COPD Working Group (2012) Long-term oxygen therapy for patients with chronic obstructive pulmonary disease (COPD): an evidence-based analysis. Ontario Health Technology Assessment Series 12(7), 1-64. [Abstract] [Free Full-text]

De Coster, D.A., Jones, M. and Thakrar, N. (2013) Beclometasone for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Donath, E., Chaudhry, A., Hernandez-Aya, L.F., and Lit, L. (2013) A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with chronic obstructive pulmonary disease. Respiratory Medicine 107(9), 1385-1392. [Abstract]

Dong, Y.H., Lin, H.H., Shau, W.Y., et al. (2013) Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax 68(1), 48-56.[Abstract]

Gershon, A., Croxford, R., Calzavara, A., et al. (2013) Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Internal Medicine 173(13), 1175-1185. [Abstract]

Giacomini, M., Dejean, D., Simeonov, D., and Smith, A. (2012) Experiences of living and dying with COPD: a systematic review and synthesis of the qualitative empirical literature. Ontario Health Technology Assessment Series 12(13), 1-47. [Abstract] [Free Full-text]

Halpin, D.M., Gray, J., Edwards, S.J., et al. (2011) Budesonide/formoterol vs. Salmeterol/fluticasone in COPD: systematic review and adjusted indirect comparison of pneumonia in randomised controlled trials. International Journal of Clinical Practice 65(7), 764-774. [Abstract]

Han, J., Dai, L., and Zhong, N. (2013) Indacateroil on dyspnea in chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized placebo-controlled trials. BMC Pulmonary Medicine 13(1), 26. [Abstract] [Free Full-text]

Herath, S.C., and Poole, P. (2013) Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) (Cochrane Review). The Cochrane Library. Issue 11. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Heneghan, N.R., Adab, P., Balanos, G.M., and Jordan, R.E. (2012) Manual therapy for chronic obstructive airways disease: a systematic review of current evidence. Manual Therapy 17(6), 507-518. [Abstract]

Holland, A.E., Hill, C.J., Jones, A.Y., and MacDonald, C.F. (2012) Breathing exercises for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Ides, K., Vissers, D., De Backer, L., et al. (2011) Airway clearance in COPD: need for a breath of fresh air? A systematic review. COPD 8(3), 196-205. [Abstract]

Jen, R., Rennard, S.I., and Sin, D.D. (2012) Effects of inhaled corticosteroids on airway inflammation in chronic obstructive pulmonary disease: a systematic review and meta-analysis. International Journal of Chronic Obstructive Pulmonary Disease 7, 587-595. [Abstract] [Free Full-text]

Jiang, F.M., Liang, Z.A., Zheng, Q.L., et al. (2013) Safety and efficacy of 12-week or longer indacaterol treatment in moderate-to-severe COPD patients: a systematic review. Lung 191(2), 135-46. [Abstract]

Jing, Z., Wei-Jie, Y., Nan, Z., et al. (2012) Hemoglobin targets for chronic kidney disease patients with anemia: a systematic review and meta-analysis. PLoS One 7(8), e43655. [Abstract] [Free Full-text]

Kaplan, A. (2010) Effect of tiotropium on quality of life in COPD: a systematic review. Primary Care Respiratory Journal 19(4), 315-325. [Abstract] [Free Full-text (pdf)]

Kamer, C., and Cates, C.J. (2011)Combination inhaled steroid and long-acting beta2-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 3. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Karner, C., and Cates, C.J. (2011) The effect of adding inhaled corticosteroids to tiotropium and long-acting beta2-agonists for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 9. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Karner, C. and Cates, C.J. (2012) Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 4. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Karner, C., Chong, J., and Poole, P. (2012) Tiotropium versus placebo for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 7. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Kew, K.M., Mavergames, C. and Walters, J.A.E. (2013) Long-acting beta2-agonists for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Kocks, J.W., Asijee, G.M., Tsiligianni, I.G., et al. (2011) Functional status measurement in COPD: a review of available methods and their feasibility in primary care. Primary Care Respiratory Journal 20(3), 269-275. [Abstract] [Free Full-text (pdf)]

Loke, Y.K., Cavallazzi, R., and Singh, S. (2011) Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 66(8), 699-708. [Abstract]

Lui, K.X., Xu, B., Wang, J., et al. (2014) Efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis and COPD: a systematic review and meta-analysis. Journal of Thoracic Disease 6(3), 221-229. [Abstract] [Free Full-text]

McNamara, R.J., McKeough, Z.J., McKenzie, D.K., and Alison, J.A. (2013) Water-based exercise training for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 12. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Ng, L.W., Mackney, J., Jenkins, S. and Hill, K. (2012) Does exercise training change physical activity in people with COPD? A systematic review and meta-analysis. Chronic Respiratory Disease 9(1), 17-26. [Abstract]

Nurmatov, U., Buckingham, S., Kendall, M., et al. (2012) Effectiveness of holistic interventions for people with severe chronic obstructive pulmonary disease: systematic review of controlled clinical trials. PLoS One 7(10), e46433. [Abstract] [Free Full-text]

Oba, Y. and Lone, N.A. (2013) Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Therapeutic Advances in Respiratory Disease 7(1), 13-24. [Abstract]

Osadnik, C.R., McDonald, C.F., Jones, A.P., and Holland, A.E. (2012) Airway clearance techniques for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 3. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Ram, F.S., Carvallho, C.R. and White, J. (2011) Clinical effectiveness of the Respimat inhaler device in managing chronic obstructive pulmonary disease: evidence when compared with other handheld inhaler devices. International Journal of Chronic Obstructive Pulmonary Disease 6, 129-139. [Abstract] [Free Full-text]

Rodrigo, G.J., Plaza, V., Castro-Rodriguez, J.A. (2012) Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review. Pulmonary Pharmacology and Therapeutics 25(1), 40-47. [Abstract]

Rutten-van Molken, M.P. and Goossens, L.M. (2012) Cost effectiveness of pharmacological maintenance treatment for chronic obstructive pulmonary disease: a review of the evidence and methodological issues. Pharmacoeconomics 30(4), 271-302. [Abstract]

Schou, L., Ostergaard, B., Rasmussen, L.S., et al. (2012) Cognitive dysfunction in patients with chronic obstructive pulmonary disease - a systematic review. Respiratory Medicine 106(8), 1071-1081. [Abstract]

Seidel, D., Cheung, A., Suh, E.S., et al. (2012) Physical inactivity and risk of hospitalisation for chronic obstructive pulmonary disease. International Journal of Tuberculosis and Lung Disease 16(8), 1015-1019. [Abstract]

Shi, J.X., Xu, J., Sun, W.K., et al. (2013) Effect of noninvasive, positive pressure ventilation on patients with severe, stable chronic obstructive pulmonary disease: a meta-analysis. Chinese Medical Journal 126(1), 140-146. [Abstract]

Singh, S., Loke, Y.K., Enright, P.L. and Furberg, C.D. (2011) Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ 342, d3215. [Abstract] [Free Full-text]

Smith, T.A., Davidson, P.M., Lam, L.T., et al. (2012) The use of non-invasive ventilation for the relief of dyspnoea in exacerbations of chronic obstructive pulmonary disease; a systematic review. Respirology 17(2), 300-307. [Abstract]

Spencer, S., Evans, D.J., Karner, C., and Cates, C.J. (2011) Inhaled corticosteroids versus long-acting beta2-agonists for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Strasser, B., Siebert, U., and Schobersberger, W. (2012) Effects of resistance training on respiratory function in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Sleep and Breathing 17(1), 217-226. [Abstract]

Thabane, M. and COPD Working Group (2012) Smoking cessation for patients with chronic obstructive pulmonary disease (COPD): an evidence-based analysis. Ontario Health Technology Assessment 12(4), 1-50. [Abstract] [Free Full-text]

Thorpe, O., Johnston, K., and Kumar, S. (2012) Barriers and enablers to physical activity participation in patients with COPD: a systematic review. Journal of Cardiopulmonary Rehabilitation and Prevention 32(6), 359-369. [Abstract]

Tsiligianni, I.G. and van der Molen, T. (2010) A systematic review of the role of vitamin insufficiencies and supplementation in COPD. Respiratory Research 11(171). [Abstract] [Free Full-text]

Tsiligianni, I., Kocks, J., Tzanakis, N., et al. (2011) Factors that influence disease-specific quality of life or health status in patients with COPD: a review and meta-analysis of Pearson correlations. Primary Care Respiratory Journal 20(3), 257-268. [Abstract] [Free Full-text (pdf)]

Uronis, H., McCrory, D.C., Samsa, G., et al. (2011) Symptomatic oxygen for non-hypoxaemic chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 6. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Usmani, Z.A., Carson, K.V., Cheng, J.N., et al. (2011) Pharmacological interventions for the treatment of anxiety disorders in chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 11. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Vollenweider, D.J., Jarrett, H., Steuer-Stey, C.A., et al. (2012) Antibiotics for exacerbations of chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 12. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Walters, J.A., Wang, W., Morley, C., et al. (2011) Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Wang, J., Jin, D., Zuo, P., et al. (2011) Comparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis. Respirology 16(2), 350-358. [Abstract]

Wang, J., Nie, B., Xiong, W., and Xu, Y. (2012) Effect of long-acting beta-agonists on the frequency of COPD exacerbations: a meta-analysis. Journal of Clinical Pharmacy and Therapeutics 37(2), 204-211. [Abstract]

Warnier, M.J., Riet, E.E., Rutten, F.H., et al. (2012) Smoking cessation strategies in patients with chronic obstructive pulmonary disease. European Respiratory Journal 41(3), 727-734. [Abstract]

Westwood, M., Bourbeau, J., Jones, P.W., et al. (2011) Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review. Respiratory Research 12, 40. [Abstract] [Free Full-text]

Wu, R., Fengjie, Z., Li, Y., et al. (2013) Modified dochengqi decoction combined with conventional treatment for treating acute exacerbation of chronic obstructive pulmonary disease: a systematic review based on randomized controlled trials. Evidence-base Complementary and Alternative Medicine 2013, 323715. [Abstract]

Yan, J.H., Gu, W.J. and Pan, L. (2014) Efficacy and safety of roflumilast in patients with stable chronic obstructive pulmonary disease: a meta-analysis. Pulmonary Pharmacology and Therapeutics27(1), 83-89. [Abstract]

Yohannes, A.M., Willgoss, T.G. and Vestbo, J. (2011) Tiotropium for treatment of stable COPD: a meta-analysis of clinically relevant outcomes. Respiratory Care 56(4), 477-487. [Abstract]

Zainuldin, R., Mackey, M.G. and Alison, J.A. (2011) Optimal intensity and type of leg exercise training for people with chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 11. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Zhang, M.W., Ho, R.C., Cheung, M.W., et al. (2011) Prevalence of depressive symptoms in patients with chronic obstructive pulmonary disease: a systematic review, meta-analysis and meta-regression. General Hospital Psychiatry 33(3), 217-223. [Abstract]

Primary evidence

Randomized controlled trials published since the last revision of this topic:

Albert, R.K., Connett, J., Bailey, W.C., et al. (2011) Azithromycin for prevention of exacerbations of COPD. New England Journal of Medicine 365(8), 689-698. [Abstract] [Free Full-text]

Austin, M.A., Wills,K.E., Blizzard,L. et al (2010) Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ 341, c5462. [Abstract] [Free Full-text]

Bischoff, E.W.M.A., Akkermans, R., Bourbeau, J., et al. (2012) Comprehensive self management and routine monitoring in chronic obstructive pulmonary disease patients in general practice: randomised controlled trial. BMJ 345, e7642. [Free Full-text]

Bucknall, C.E., Miller, G., Llloyd, S.M., et al. (2012) Glasgow supported self-management trial (GSuST) for patients with moderate to severe COPD: randomised controlled trial. BMJ 344, e1060. [Abstract] [Free Full-text]

Buhl, R., Dunn, L.J., Disdier, C., et al. (2011) Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. European Respiratory Journal 38(4), 797-803. [Abstract]

Calverley,P.M., Kuna,P., Monsó,E. et al (2010) Beclomethasone/formoterol in the management of COPD: A randomised controlled trial. Respiratory Medicine 104(12), 1858-1868. [Abstract]

Edwards, L., Shirtcliffe, P., Wadsworth, K., et al. (2013) Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial. Thorax 68(4), 338-343. [Abstract]

Lehouck, A., Mathieu, C., Carremans, C., et al. (2012) High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease. A randomized trial. Annals of Internal Medicine 156(20), 105-114. [Abstract] [Free Full-text]

Leuppi, J.D., Schuetz, P., Bingisser, R., et al. (2013) Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 309(21), 2223-2231. [Abstract]

Llor, C. Moragas, A., Hernandez, S., et al. (2012) Efficacy of antibiotic therapy for acute exacerbations of mild to moderate COPD. American Journal of Respiratory and Critical Care Medicine 186(8), 716-723. [Abstract]

Mahler, D.A., D'Urzo, A., Bateman, E.D., et al. (2012) Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax 67(9), 871-788. [Abstract]

Moore, R.P., Berlowitz, D.J., Denehy, L., et al. (2011) A randomized trial of domiciliary, ambulatory oxygen in patients with COPD and dyspnoea but without resting hypoxaemia. Thorax 66(1), 32-37. [Abstract]

Suzuki, M., Muro, S., Ando, Y., et al. (2012) A randomized, placebo-controlled trial of acupuncture in patients with chronic obstructive pulmonary disease (COPD). The COPD-Acupuncture Trial (CAT). Archives of Internal Medicine 172(11), 878-886. [Abstract]

Vogelmeirer, C., Glaab, T., Schmidt, H., et al. (2011) Tiotropium versus salmeterol for the prevention of exacerbations of COPD. New England Journal of Medicine 364(12), 1093-1103. [Abstract] [Free Full-text]

Zhou, Y., Hu, G., Wang, D., et al. (2010) Community based integrated intervention for prevention and management of chronic obstructive pulmonary disease (COPD) in Guangdong, China: cluster randomised controlled trial. BMJ 341, c6387. [Abstract] [Free Full-text]

Observational Studies published since the last revision of this topic:

Calderón-Larrañaga, A., Carney, L., Soljak, M., et al. (2011) Association of population and primary healthcare factors with hospital admission rates for chronic obstructive pulmonary disease in England: national cross-sectional study. Thorax 66(3), 191-196. [Abstract]

Feary, J.R., Rodrigues, L.C., Smith, C.J. et al (2010) Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax 65(11), 956-962. [Abstract]

Gershon, A.S., Warner, L., Cascagnette, P., et al. (2011) Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study. Lancet 378(9795), 991-996. [Abstract]

Jara, M., Wentworth III, C., and Lanes, S. (2012) A new user cohort study comparing the safety of long-acting inhaled bronchdilators in COPD. BMJ Open 2(3), e0000841. [Abstract] [Free Full-text]

Lapi, F., Kezouh, A., Suissa, S., and Ernst, P. (2013) The use of inhaled corticosteroids and the risk of adrenal insufficiency. European Respiratory Journal 42(1), 79-86. [Abstract]

Pinnock, H., Kendall, M., Murray, S.A., et al. (2011) Living and dying with severe chronic obstructive pulmonary disease: multi-perspective longitudinal qualitative study. BMJ 342, d142. [Abstract] [Free Full-text]

Short, P.M., Lipworth, S.I., Elder, D.H., et al. (2011) Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ 342, d2549. [Abstract] [Free Full-text]

New policies

No new national policies or guidelines since 1 July 2010.

New safety alerts

The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice on the Spiriva Respimat® formulation of tiotropium.

A recent safety study found a non-statistically significant increase in all cause mortality with the Spiriva Respimat® formulation. Conversely, a double-blind randomized controlled trial showed a non-statistically significant decrease in all-cause mortality with the Spiriva Handihaler®.

There were differences in the baseline characteristics of these study populations.

While further studies are ongoing to investigate these differences and whether there is a causal link, the MHRA advises that the Spiriva Respimat® should be used with caution in people with known cardiac disorders.

Reference: MHRA (2010) Tiotropium: safety studies of Spiriva Respimat [black triangle]. Drug Safety Update 4(4). H2. [Free Full-text (pdf)]

Changes in product availability

Roflumilast (Daxax® tablets) is a phosphodiesterase-4 inhibitor. It is indicated for the maintenance treatment of severe chronic obstructive pulmonary disease (forced expiratory volume in 1 second (FEV1) post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adults with a history of frequent exacerbations as add on to bronchodilator treatment. It is available as a 500 microgram tablet.

Indacaterol (Onbrez Breezhaler®) is a 24- hour, once daily, long-acting beta-2 agonist licenced for the treatment of adults with chronic obstructive pulmonary disease. It is available as hard capsules containing 150 or 300 micrograms of indacaterol inhalation powder.

Combivent® metered dose aerosol inhalers were discontinued in March 2009.

Goals and outcome measures

Goals

To support primary healthcare professionals:

To make an accurate diagnosis of chronic obstructive pulmonary disease (COPD)

To assess severity of disease

To refer people appropriately to specialist services

To refer people appropriately for pulmonary rehabilitation

To refer people appropriately to other members of the multidisciplinary team

To advise people on smoking cessation and offer treatment

To offer people appropriate treatment for managing breathlessness and preventing exacerbations

To provide people with a self-management plan for recognizing and managing exacerbations

To provide people with advice on exercise and flying

To manage acute exacerbations

To communicate effectively with people with end-stage COPD and offer effective palliative and terminal care

QOF indicators

Table 1 . Indicators related to chronic obstructive pulmonary disease (COPD) in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract.
Indicator Points Payment stages
COPD001 The contractor establishes and maintains a register of patients with COPD 3
COPD002 The percentage of all patients with COPD (diagnosed on or after 1 April 2011) in whom the diagnosis has been confirmed by post bronchodilator spirometry between 3 months before and 12 months after entering on to the register 5 45–80%
COPD004 The percentage of patients with COPD with a record of FEV1 in the preceding 12 months 7 40–75%
COPD006 The percentage of patients with COPD who have had influenza immunisation in the preceding 1 September to 31 March 6 57-97%
COPD005
The percentage of patients with COPD and Medical Research Council dyspnoea grade ≥3 at any time in the preceding 12 months, with a record of oxygen saturation value within the preceding 12 months
COPD003 The percentage of patients with COPD who have had a review, undertaken by a healthcare professional, including an assessment of breathlessness using the Medical Research Council dyspnoea scale in the preceding 12 months 9 50–90%
SMOKING 5 The percentage of patients with any or any combination of the following conditions: CHD, PAD, stroke or TIA, hypertension, diabetes, COPD, CKD, asthma, schizophrenia, bipolar affective disorder or other psychoses whose notes record smoking status in the preceding 12 months 25 50–90%
SMOKING 6 The percentage of patients with any or any combination of the following conditions: CHD, PAD, stroke or TIA, hypertension, diabetes, COPD, CKD, asthma, schizophrenia, bipolar affective disorder or other psychoses who are recorded as current smokers who have a record of an offer of support and treatment within the preceding 12 months 25 56–96%
Data from: [BMA and NHS Employers, 2013].

Background information

Definition

What is it?

Chronic obstructive pulmonary disease (COPD) is a treatable (but not curable) and largely preventable lung disease with symptoms such as cough, sputum, and increasing breathlessness [Qaseem et al, 2007; Eva et al, 2009].

It is characterized by airflow obstruction which is usually progressive, not fully reversible, and does not change markedly over several months [National Clinical Guideline Centre, 2010].

The obstruction is due to a combination of airway disease (obstructive bronchiolitis) and parenchymal damage (emphysema), and is associated with abnormal inflammatory response of the lungs, mainly to noxious particles, especially cigarette smoke [GOLD, 2009].

'COPD' is the preferred term for chronic bronchitis, emphysema, or chronic obstructive airways disease [National Clinical Guideline Centre, 2010].

Prevalence and incidence

How common is it?

In the United Kingdom, it is estimated that more than 3 million people currently have chronic obstructive pulmonary disease (COPD), and an estimated 2 million people have COPD which remains undiagnosed.

Among people with undiagnosed COPD, it is thought that 5.5% will have COPD at the mild end of the spectrum.

The incidence of COPD is difficult to determine because symptoms usually develop insidiously. Most people are not diagnosed with COPD until they are 50 years of age or older.

The prevalence of COPD increases with age and varies significantly by region. COPD is also more common in low socioeconomic groups; however, it is unclear whether this pattern reflects exposure to air pollutants, poor nutrition, crowding, or other factors related to low socioeconomic status [GOLD, 2009].

COPD is more common in men. However, over the past decade, the prevalence has reached a plateau in men but has increased in women. This reflects the increase in smoking amongst women.

A GP practice in the UK which cares for about 7000 people will have up to 200 people with COPD on its practice list (of whom many will be undiagnosed). This equates to around 1.4 million consultations with GPs each year, up to four times more than the number of consultations for angina.

In the UK, one in eight (130,000) emergency hospital admissions is for COPD, although only a small proportion of people with COPD are admitted to hospital yearly. This makes COPD the second largest cause of emergency admissions, and one of the most expensive inpatient conditions treated by the NHS.

[National Clinical Guideline Centre, 2010]

Risk factors

What are the risk factors?

Tobacco smoking

This is the major risk factor for development of chronic obstructive pulmonary disease (COPD).

Although COPD can occur in people who have never smoked, about 90% of cases are caused by cigarette smoking [Currie, 2007].

Pipe and cigar smokers also have a greater morbidity and mortality rate from COPD than do non-smokers. However, the rates are lower than for cigarette smokers.

Passive smoking increases the lung's total burden of inhaled particles and gases, and case-control studies have found a trend towards increased risk of COPD with passive smoking [Silverman and Speizer, 1996].

Smoking seems to enhance the effects of other risk factors (such as occupational exposure) on the development of COPD [Currie, 2007].

Occupational exposure

This is an important and under appreciated risk factor for COPD development.

Exposure to dust, chemicals, noxious gases, and particles (such as coal, grains, isocyanates, and cadmium) has been implicated in the development of COPD; the association is independent of smoking [Currie, 2007].

About 20% of diagnosed cases of COPD can be attributed to occupational exposure. In lifelong non-smokers, this increases to 30% [Currie, 2007; GOLD, 2009].

Air pollution

Indoor and outdoor air pollution may also contribute to the development of COPD [Silverman and Speizer, 1996].

Wood, animal dung, crop residues, and coal (burned in open fires or poorly functioning stoves), may lead to high levels of indoor air pollution.

In developing countries, air pollution from cooking and heating fuel (biomass) is major risk factor for COPD, especially in women.

In the UK, the role of outdoor air pollution in causing COPD seems to be small compared with that of smoking. However, air pollution from motor vehicles emission in cities is associated with a decrease in respiratory function.

Exposure to particulate and nitrogen dioxide has been associated with impaired ventilatory function in adults and reduced lung growth in children [Currie, 2007].

Genetics

The genetic risk of homozygous alpha1-antitrypsin deficiency accounts for less than 1% of COPD cases [American Thoracic Society, 1995]. However, it is the best-documented genetic risk factor for COPD [GOLD, 2009].

Severe alpha1-antitrypsin deficiency is linked with premature and accelerated development of COPD in smokers and non-smokers, but lung function decline occurs more rapidly in smokers [Currie, 2007].

Although no gene for COPD has been identified, there is likely to be a genetic influence in the development of the disease. A significant familial risk of airflow obstruction has been reported in smoking siblings of people with severe COPD [GOLD, 2009].

Prognosis

What is the prognosis?

The natural history of chronic obstructive pulmonary disease (COPD) varies among individuals. However, COPD is progressive, especially if the person's exposure to noxious agents continues. Stopping exposure to these agents may slow or halt the progression of the disease. However, once developed, it cannot be cured.

About 30,000 people each year in the UK die of COPD, accounting for 5% of all deaths [National Clinical Guideline Centre, 2010].

In 2004, 90% of deaths from COPD occurred in people older than 65 years of age.

The true mortality rate due to COPD is difficult to quantify, as many people with COPD die with the disease rather than because of it. Nevertheless, mortality from COPD increases with age, severity of disease, and socioeconomic deprivation.

The World Health Organization predicts that COPD will be the third most common cause of death in the world by 2020 [Efraimsson et al, 2008].

Exacerbations of COPD requiring hospital admission are associated with an inpatient mortality rate of 3–4%, which increases to 11–24% for people who require treatment in an intensive care unit [Bach et al, 2001].

[GOLD, 2009; National Clinical Guideline Centre, 2010]

Complications

What are the complications?

Disability and impairment of quality of life — chronic obstructive pulmonary disease (COPD) results in general disability and impairs the person's quality of life (for example the person may develop reduced mobility or become increasingly housebound).

Other complications include:

Depression and anxiety — these are two of the most common and least treated comorbidities of COPD [Maurer et al, 2008].

Cor pulmonale (right heart failure secondary to lung disease) — characterized by fluid retention, peripheral oedema, and raised venous pressure in people with COPD who have no other cause for ventricular dysfunction.

Frequent respiratory infections.

Polycythaemia.

Respiratory failure.

COPD may increase the risk of lung cancer. However, it is not clear whether this is due to common risk factors, such as smoking, involvement of susceptibility genes, or impaired clearance of carcinogens [GOLD, 2009].

[National Clinical Guideline Centre, 2010]

Diagnosis

Diagnosis

Diagnosis - COPD

Diagnosis of chronic obstructive pulmonary disease

192months3060monthsBoth2010-11-01

Diagnosis

How do I know my patient has it?

There is no single diagnostic test for chronic obstructive pulmonary disease (COPD).

Make a diagnosis of COPD if the person meets all of the following criteria:

Age older than 35 years.

Presence of a risk factor (for example smoking, history of smoking, or an occupational exposure).

Typical symptoms.

Absence of clinical features of asthma.

Presence of airflow obstruction confirmed by post-bronchodilator spirometry.

Individual physical signs are not diagnostic of COPD, and in some people there may be no abnormal physical signs.

Consider alternative diagnoses.

Consider the possibility of alpha1-antitrypsin deficiency if the person is younger than 40 years of age or has a family history of alpha1-antitrypsin deficiency.

If suspected, refer the person to a respiratory specialist for investigations and treatment.

Reconsider the diagnosis of COPD (and consider the possibility of asthma) if the person has a marked response to drug treatment, illustrated by either:

A marked improvement in symptoms, or

Return of forced expiratory volume in 1 second (FEV1) and FEV1/FVC (forced vital capacity) ratio to normal.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Symptoms

What symptoms suggest a diagnosis of COPD?

Typical symptoms of chronic obstructive pulmonary disease include:

Exertional breathlessness.

Chronic cough.

Regular sputum production.

Frequent 'winter bronchitis'.

Wheeze.

Other symptoms that may be present include:

Weight loss.

Exercise intolerance.

Ankle swelling.

Fatigue.

Chest pain or haemoptysis. These are uncommon, and their presence may indicate an alternative or concomitant diagnosis. For more information, see Differential diagnosis.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Physical signs

What physical signs may be present?

The following signs may be present:

Hyperinflated chest.

Wheeze or quiet breath sounds.

Pursed lip breathing.

Use of accessory muscles.

Peripheral oedema.

Cyanosis.

Raised jugular venous pressure.

Cachexia.

Basis for recommendation

Basis for recommendation

This information is based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Spirometry

When should I arrange spirometry, and how should I interpret the results?

Ensure that there is access to spirometry performed by an appropriately trained professional and supported by quality-control processes, and that the skills are available to interpret results.

Referral to a community or hospital spirometry service may be necessary.

Measure post-bronchodilator spirometry to confirm the diagnosis of chronic obstructive pulmonary disease (COPD).

Do spirometry 15–20 minutes after the person has inhaled salbutamol 200 micrograms delivered via a spacer device (terbutaline 500 micrograms may be an alternative). If ipratropium bromide is used, wait for 30 minutes before doing spirometry.

In COPD, the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) is less than 0.7.

Predicted normal values of FEV1 and FVC depend on age, height, and sex. These values may over diagnose COPD in elderly people and are not applicable in black and Asian populations.

The slow or relaxed vital capacity (SVC) may be used instead of FVC to calculate the ratio if either the SVC is higher than the FVC, or the person cannot perform a forced manoeuvre to full exhalation.

If the FEV1 is 80% predicted normal or greater, a diagnosis of COPD should be made only in the presence of respiratory symptoms, for example breathlessness or cough.

Assess the severity of airflow obstruction according to the reduction in FEV1 — see Assessment of severity.

Routine spirometric reversibility testing is not recommended unless COPD and asthma cannot be distinguished clinically (see Distinguishing COPD and asthma).

Repeat spirometry if the person has an exceptionally good response to treatment; reconsider the diagnosis if the FEV1/FVC ratio is 0.7 or greater at follow up.

Basis for recommendation

Basis for recommendation

These recommendations are mainly based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

The statement that referral to a community or hospital spirometry service may be necessary is based on expert opinion and evidence of low-quality delivery and interpretation of spirometry in primary care, discussed in guidelines on diagnostic spirometry in primary care by the GP Airways Group [Levy et al, 2009].

The recommendation that spirometry should be post-bronchodilator is new in the updated 2010 NICE guideline. This recommendation by NICE is based on limited evidence from a cross-sectional study and a case series study of increased diagnostic accuracy compared with pre-bronchodilator spirometry, and on the consensus of the guideline development group. The major limitation of the evidence is the lack of a gold (reference) standard for chronic obstructive pulmonary disease (COPD).

The recommendations on the choice, dose, and delivery of bronchodilator, and how long after inhalation spirometry should be done, are based on expert opinion from CKS reviewers and on extrapolations from recommendations in guidelines on diagnostic spirometry in primary care by the GP Airways Group on how to do reversibility testing using a short-acting bronchodilator [Levy et al, 2009].

The statement that a slow or relaxed vital capacity (SVC) may be used instead of forced vital capacity (FVC) to calculate the ratio if either the SVC is higher than the FVC, or the person cannot perform a forced manoeuvre to full exhalation, is derived from guidelines on diagnostic spirometry in primary care by the GP Airways Group [Levy et al, 2009] and a consensus statement in the NICE COPD guideline [National Clinical Guideline Centre, 2010].

Routine spirometric reversibility testing is not recommended by NICE on the basis of evidence from mainly observational studies and one randomized controlled trial indicating that:

Repeated measurements of the forced expiratory volume in 1 second (FEV1) can show small spontaneous fluctuations.

The results of a reversibility test performed on different occasions can be inconsistent and not reproducible.

Over reliance on a single reversibility test may be misleading unless the change in FEV1 is greater than 400 mL.

Response to long-term therapy is not predicted by acute reversibility testing.

Other recommendations by NICE are based on expert opinion or extrapolations from higher levels of evidence.

Differential diagnosis

What else might it be?

The differential diagnosis of chronic obstructive pulmonary disease (COPD) includes any condition that presents with breathlessness and/or cough. For example:

Asthma — consider if the person has a family history, has other atopic diseases or nocturnal or variable symptoms, is a non-smoker, or experienced onset of symptoms at younger than 35 years of age. For more information, see Distinguishing COPD and asthma and the CKS topic on Asthma.

Bronchiectasis — clinical features include copious sputum, frequent chest infections, a history of childhood pneumonia, and coarse lung crepitations.

Congestive cardiac failure — clinical features include breathlessness when lying flat, a history of ischaemic heart disease, and fine lung crepitations. See the CKS topic on Heart failure - chronic.

Lung cancer — consider if the person has haemoptysis, weight loss, or hoarseness. See the CKS topic on Lung cancer - suspected.

Interstitial lung disease (asbestosis, pneumoconiosis, fibrosing alveolitis, sarcoidosis) — clinical features include dry cough and fine crepitations.

Bronchopulmonary dysplasia — consider in a young adult with recurrent chest infections.

Anaemia. See the CKS topics on Anaemia - iron deficiency and Anaemia - B12 and folate deficiency.

Obstructive sleep apnoea. See the CKS topic on Sleep apnoea.

Tuberculosis. See the CKS topic on Tuberculosis.

These conditions may be present in addition to COPD.

For detailed information on the differential diagnosis of people with cough or breathlessness, see the CKS topics on Cough and Breathlessness.

Basis for recommendation

Basis for recommendation

This information is derived from the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], the Global strategy for diagnosis, management, and prevention of COPD [GOLD, 2009], a guideline on interstitial lung disease from the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society [Bradley et al, 2008], and a study of the validity of primary care diagnosis of COPD [Sichletidis et al, 2007].

Distinguishing COPD and asthma

How do I distinguish COPD and asthma?

Chronic obstructive pulmonary disease (COPD) and asthma can be difficult to distinguish and may coexist.

Compare clinical features.

If diagnostic doubt remains, one or more of the following strategies are recommended:

Do longitudinal observations of symptoms, peak flow, and/or spirometry.

Serial domiciliary peak expiratory flow measurements showing 20% or greater diurnal or day-to-day variability indicate asthma. Peak expiratory flow is not routinely recommended for the diagnosis or assessment of people with COPD, as it may significantly underestimate the degree of airflow obstruction, but it may help to distinguish COPD from asthma.

On spirometry, clinically significant COPD is not present if the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) increases to 0.7 or greater at follow up. Suspect asthma, in which airways obstruction is variable.

Perform reversibility testing using either inhaled bronchodilators or oral prednisolone. The following findings identify asthma:

A large (greater than 400 mL FEV1) response to inhaled bronchodilators.

A large (greater than 400 mL FEV1) response to 30 mg oral prednisolone given daily for 2 weeks.

Start drug treatment and arrange early follow up that includes repeat spirometry. Reconsider the diagnosis of COPD (and suspect asthma) if the person has a marked response to drug treatment, illustrated by either:

A marked improvement in symptoms, or

Return of FEV1 and the FEV1/FVC ratio to normal.

Refer the person to a respiratory specialist for more detailed investigations.

Clinical features differentiating COPD and asthma

Clinical features differentiating COPD and asthma

Table 1 . Clinical features differentiating chronic obstructive pulmonary disease (COPD) and asthma.
Clinical features COPD Asthma
Smoker or ex-smoker Nearly all Possibly
Age < 35 years Rare Often
Chronic productive cough Common Uncommon
Breathlessness Persistent and productive Variable
Night-time waking with breathlessness or wheeze Uncommon Common
Significant diurnal or day-to-day variation in symptoms Uncommon Common
Data from: [NICE, 2010]

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Chest X-ray

Is a chest X-ray needed?

Arrange a chest X-ray for all people with suspected chronic obstructive pulmonary disease to exclude other pathologies (see Differential diagnosis).

Basis for recommendation

Basis for recommendation

This recommendation is based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Treating when diagnosis uncertain

Can I treat whilst the diagnosis is being established?

Drug treatment can be started before the diagnosis has been confirmed, provided that spirometry has been performed and other assessments to exclude asthma have been undertaken.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Diagnosis - acute exacerbation

Diagnosis of acute exacerbation of chronic obstructive pulmonary disease

192months3060monthsBoth2010-11-01

Diagnosis

How do I diagnose an acute exacerbation of COPD?

An acute exacerbation of COPD is a sustained worsening of a person's symptoms from their usual stable state, which is beyond normal day-to-day variations and acute in onset. There is no single defining symptom of an exacerbation.

Commonly reported symptoms are:

Increased breathlessness.

Increased cough.

Increased sputum production and change in sputum colour.

Other symptoms may include:

Increased wheeze and chest tightness.

Upper respiratory tract symptoms (for example colds or sore throats).

Reduced exercise tolerance.

Fluid retention.

Increased fatigue.

Acute confusion.

Basis for recommendation

Basis for recommendation

This information is based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline, Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

The definition of an acute exacerbation is from NICE. However, NICE asserts that there is no agreed uniform definition.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines an exacerbation of COPD as 'an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication' [GOLD, 2009].

Differential diagnosis

What else might it be?

Conditions which present with symptoms similar to those of an acute exacerbation of chronic obstructive pulmonary disease include:

Pneumonia.

Pneumothorax.

Left ventricular failure/pulmonary oedema.

Pulmonary embolism.

Lung cancer.

Upper airway obstruction.

Pleural effusion.

Recurrent aspiration.

Basis for recommendation

Basis for recommendation

This information is based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Management

Management

Scenario: Stable COPD : covers the active management of people with persistent symptoms of COPD who are not experiencing an acute exacerbation, and who are not near the end of life. This scenario includes recommendations on when to refer.

Scenario: Acute exacerbation : covers the management of people experiencing an acute exacerbation of COPD, and includes recommendations on when to admit.

Scenario: End-stage COPD : covers the management of people with COPD that is very severe (forced expiratory volume in 1 second [FEV1] less than 30% predicted), unresponsive to usual medical treatment for COPD, and associated with a likely life expectancy of less than 6–12 months.

Scenario: Stable COPD

Scenario: Stable chronic obstructive pulmonary disease

192months3060monthsBoth

Overview

Overview of management

Assessment

Assess the severity of chronic obstructive pulmonary disease (COPD) according to the reduction in forced expiratory volume in 1 second (FEV1), degree of breathlessness according to the Medical Research Council dyspnoea scale, body mass index, and presence of cor pulmonale.

Document the person's smoking history, encourage smokers to stop, and offer smoking cessation treatment.

Assess for anxiety or depression in people who are hypoxic or have severe dyspnoea.

Check the full blood count, and arrange other investigations as appropriate.

Referral

Consider referral:

To a respiratory specialist, for assessment for oxygen therapy.

For pulmonary rehabilitation.

To a physiotherapist.

To social services and occupational therapy.

Treatment

Offer the person inhaled treatment — strategies for stepping up inhaled treatments differ according to the reduction in FEV1. See Inhaled treatments (FEV1 50% predicted or greater) and Inhaled treatments (FEV1 less than 50% predicted).

Consider treatment with a mucolytic or theophylline (methylxanthine).

Advise an annual influenza vaccination and a once-only pneumococcal vaccination.

Agree a self-management plan.

Manage nutritional needs.

Advice

Advise the person about medications, exercise, and flying.

Information and support can be obtained from the British Lung Foundation.

Managing cor pulmonale

Manage cor pulmonale , usually by referring the person to a respiratory specialist.

Follow up

Follow up all people with COPD; the frequency of follow up depends on the severity of disease.

Discussing end-of-life issues

Consider when to discuss end-of-life issues. See Discussing end-of-life issues in Scenario: End-stage COPD.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

In a review of the evidence on influenza and pneumococcal vaccinations, NICE cited two retrospective cohort studies (involving three analyses), which found that influenza and pneumococcal vaccinations were associated with reductions in both hospitalization and death rates in elderly people with chronic lung disease.

Assessment

How should I assess a person with COPD?

Assessment of severity

How should I assess the severity of COPD?

Assess the degree of airflow obstruction according to the reduction in post-bronchodilator forced expiratory volume in 1 second (FEV1) on spirometry and classify as follows:

Stage 1 — mild: FEV1 80% of predicted value or higher (symptoms must be present).

Stage 2 — moderate: FEV1 50–79% of predicted value.

Stage 3 — severe: FEV1 30–49% of predicted value.

Stage 4 — very severe: FEV1 less than 30% of predicted value.

Assess the degree of breathlessness according to the Medical Research Council dyspnoea scale.

Calculate the person's body mass index (weight in kg/height in m2). See Nutrition.

Assess for the presence of cor pulmonale — features include:

Peripheral oedema.

Raised jugular venous pressure.

Systolic parasternal heave.

A loud pulmonary second heart sound (over the second left intercostal space).

Widening of the descending pulmonary artery on chest X-ray.

Right ventricular hypertrophy on electrocardiography.

Medical Research Council dyspnoea scale

Medical Research Council dyspnoea scale

Table 1 . Medical Research Council (MRC) dyspnoea scale.
Grade Level of activity
1 Not troubled by breathlessness except during strenuous exercise
2 Short of breath when hurrying or walking up a slight hill
3 Walks slower than contemporaries on the level because of breathlessness, or has to stop for breath when walking at own pace
4 Stops for breath after walking about 100 m or after a few minutes on the level
5 Too breathless to leave the house, or breathless when dressing or undressing
Data from: [National Clinical Guideline Centre, 2010]

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE states that severity assessment is important because it has implications for treatment and relates to prognosis, but no single measure can adequately assess the true severity of COPD in an individual. Although spirometry alone may underestimate the impact of the disease in some people and overestimate it in others, spirometry can be used to assess the severity of airflow obstruction and to guide treatment and predict prognosis.

Different definitions of severity of airflow obstruction are recommended in the updated 2010 NICE guideline compared with the previous 2004 NICE guideline. Definitions of severity are now in line with other national and international guidelines.

Body mass index (BMI) reflects the impact of the disease in an individual and predicts prognosis. Evidence from cohort studies reviewed by NICE found that being underweight (BMI less than 20 kg/m2) was associated with increased mortality.

Features of cor pulmonale are based on observational studies and the opinion of the NICE guideline development group.

Several additional investigations recommended by NICE to assess severity are not feasible in primary care, and so are not recommended by CKS. These include transfer factor for carbon monoxide (TLCO), partial pressure of oxygen in arterial blood (PaO2), BODE index (a multidimensional index incorporating BMI, airflow obstruction, dyspnoea, and exercise capacity), and exercise capacity.

Specialist equipment is required to measure TLCO and PaO2.

A calculator or score sheet for the BODE index does not seem to be available online without subscription.

Substantial resources, including resuscitation equipment, are required to undertake a formal assessment of exercise capacity (that is, the 6-minute walk test) [American Thoracic Society Committee, 2002].

The DOSE index was recommended by two CKS reviewers. It is a composite index of severity of COPD for use in primary care that has four components: dyspnoea (D), measured using the MRC dyspnoea scale; airflow obstruction (O) according to FEV1; smoking status (S); and exacerbation frequency (E). Although the DOSE index is valid and feasible for use in primary care, it has not been included in CKS recommendations because it is unclear how it should be used to guide management. NICE recommends that a multidimensional assessment should be developed for use in primary care settings, but also states that 'any multidimensional assessment index would need to be subjected to health economic evaluation'.

NICE also recommends an assessment of health status; however, CKS could find no specific details of what measures this should include or how they would affect management.

Other assessments

What other assessments should I do in a person with COPD?

Document whether the person smokes or is an ex-smoker, and the number of pack-years smoked (number of cigarettes smoked per day, divided by 20, multiplied by the number of years smoked).

Assess for the presence of anxiety or depression in people who are hypoxic or have severe dyspnoea. See the CKS topic on Depression.

Be alert for the presence of depression in all people with chronic obstructive pulmonary disease.

Do the following investigations:

Pulse oximetry to assess the need for oxygen therapy if cyanosis or cor pulmonale is present, or if FEV1 (forced expiratory volume in 1 second) is less than 50% predicted normal.

Full blood count to identify anaemia or secondary polycythaemia (erythrocytosis).

Electrocardiography to assess cardiac status if the person has features of cor pulmonale.

Sputum culture to identify organisms if sputum is persistently present and purulent.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Referral

When should I refer a person with COPD?

Referral to a respiratory specialist

When should I refer a person with COPD to a respiratory specialist?

If lung cancer is suspected, refer the person urgently to a respiratory specialist to be seen within 2 weeks — see the CKS topic on Lung cancer - suspected.

If the person with chronic obstructive pulmonary disease (COPD) reports haemoptysis, suspect lung cancer and refer urgently.

Other reasons for referral to a respiratory specialist include:

Diagnostic uncertainty.

Referral may be needed for this reason for black and Asian people, for whom normal ranges for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) are not known.

COPD that is very severe (for example FEV1 less than 30% predicted) or worsening (rapid decline in FEV1).

Continued smoking, if the primary healthcare professional considers that referral would increase the likelihood of smoking cessation.

The person with COPD requests a second opinion.

Cor pulmonale.

Dysfunctional breathing (abnormal breathing patterns associated with anxiety).

Onset of symptoms at an age younger than 40 years, or a family history of alpha1-antitrypsin deficiency.

Frequent infections.

Symptoms disproportionate to lung function.

For pulmonary rehabilitation (for a person who considers themselves functionally disabled by COPD), if direct referral is not possible.

For assessment of the need for:

Long-term oxygen therapy , ambulatory oxygen therapy, or short-burst oxygen therapy.

Nebulizer therapy or long-term oral corticosteroids.

Lung surgery (for example, for a person with bullous lung disease who is still symptomatic on maximal therapy).

Basis for recommendation

Basis for recommendation

These recommendations are based on two National Institute for Health and Care Excellence (NICE) guidelines: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010] and Referral guidelines for suspected cancer [NICE, 2005].

The NICE guidelines on referral for suspected cancer and the NICE chronic obstructive pulmonary disease (COPD) guideline differ slightly in their guidance on the management of a person with haemoptysis.

The NICE guidelines on referral for suspected cancer indicate that a single episode of haemoptysis necessitates an urgent chest X-ray and non-urgent referral if the chest X-ray shows no signs of lung cancer, whilst only persistent haemoptysis or chest X-ray signs of possible lung cancer require urgent referral [NICE, 2005].

The NICE COPD guideline recommends referral for specialist advice if a person with COPD develops haemoptysis to exclude lung cancer [NICE, 2010].

Given that urgent referral is required if lung cancer is suspected, CKS recommends urgent referral if a person with COPD reports haemoptysis. This recommendation is supported by several CKS reviewers.

The other indications for referral were originally developed by the British Thoracic Society [British Thoracic Society, 1997] and were augmented by the NICE COPD guideline development group [National Clinical Guideline Centre, 2010].

Precise definitions of 'dysfunctional breathing' are scarce in the published literature; the definition here is based on a study of the prevalence of this problem in people with asthma [Thomas et al, 2001].

Referral for pulmonary rehabilitation

When should I refer a person with COPD for pulmonary rehabilitation?

Refer for pulmonary rehabilitation if the person considers themselves functionally disabled by chronic obstructive pulmonary disease (usually Medical Research Council dyspnoea scale grade 3 or above), or has had a recent hospitalization for an acute exacerbation.

Availability and content vary. Most programmes are hospital based, and referral to a specialist respiratory unit may be needed to access services. However, direct access from primary care is possible in some areas.

Inform the person that pulmonary rehabilitation improves quality of life and exercise capacity, and reduces breathlessness. However, commitment is required to gain these benefits.

Programmes usually involve 2–3 sessions/week and last for 6–12 weeks.

It is recommended that the rehabilitation process should involve physical training; disease education; and nutritional, psychological, and behavioural interventions tailored to the individual's needs. The aim is to optimize the person's physical and social performance, and to try to break the cycle of worsening breathlessness, reduced physical activity, and reduced fitness.

Do not refer for pulmonary rehabilitation people who cannot walk, have unstable angina, or have had a recent myocardial infarction.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Evidence reviewed by NICE from a Cochrane systematic review suggests that pulmonary rehabilitation improves health-related quality of life and exercise capacity. NICE also found evidence that pulmonary rehabilitation is cost effective in the outpatient setting compared with usual care.

The recommendations to refer people who consider themselves functionally disabled by chronic obstructive pulmonary disease (COPD), and that this is equivalent to Medical Research Council breathlessness scale grade 3, are based on the expert opinion of the NICE guideline development group, augmenting a British Thoracic Society statement [British Thoracic Society, 2001].

Evidence reviewed by NICE from one systematic review and one subsequent randomized controlled trial found that, compared with usual care, people with an exacerbation of COPD who received pulmonary rehabilitation within 1 month of hospitalization had a significantly decreased risk of readmission to hospital and significantly improved exercise capacity and health-related quality of life.

The information that direct access from primary care is possible in some areas is derived from Consultation on a strategy for services for chronic obstructive pulmonary disease (COPD) in England [DH, 2010].

Referral for LTOT assessment

When should I refer a person with COPD for assessment for long-term oxygen therapy?

Inappropriate oxygen therapy in people with chronic obstructive pulmonary disease (COPD) may cause respiratory depression. Do not start long-term oxygen therapy (LTOT) without a specialist assessment.

Refer the person with COPD to a respiratory specialist for assessment for LTOT if they have any of the following:

Oxygen saturation less than or equal to 92% breathing air.

Ensure that pulse oximetry is available.

Very severe airflow obstruction (forced expiratory volume in 1 second [FEV1] less than 30% predicted).

Cyanosis.

Secondary polycythaemia (erythrocytosis).

Peripheral oedema.

Raised jugular venous pressure.

Consider referring people with severe airflow obstruction (FEV1 30–49% predicted) for assessment for the need for LTOT.

Optimize medical treatment before referral.

Warn people using oxygen not to smoke because of the risk of fire or explosion.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE based its recommendations on long-term oxygen therapy on evidence from a Royal College of Physicians report.

NICE based the indications for referral for assessment on expert opinion.

Referral for ambulatory oxygen assessment

When should I refer a person with COPD for assessment for ambulatory oxygen?

Inappropriate oxygen therapy in people with chronic obstructive pulmonary disease may cause respiratory depression.

Refer to a respiratory specialist for assessment for ambulatory oxygen therapy (portable oxygen) people on long-term oxygen therapy who wish to continue oxygen therapy outside the home.

Warn people using oxygen not to smoke because of the risk of fire or explosion.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE states that ambulatory oxygen therapy can be used to ensure that people who require long-term oxygen therapy (LTOT) and leave their home on a regular basis receive oxygen for sufficient hours to gain the benefits of LTOT.

NICE did not identify any evidence on the effectiveness of ambulatory oxygen for people with exercise desaturation; this recommendation is based on the opinion of the guideline development group.

Referral for short-burst oxygen assessment

When should I refer a person with COPD for assessment for short-burst oxygen?

Inappropriate oxygen therapy in people with chronic obstructive pulmonary disease may cause respiratory depression.

Refer to a respiratory specialist for assessment for short-burst oxygen therapy (as-required intermittent use of supplemental oxygen for periods of 10–20 minutes to relieve breathlessness):

People not eligible for LTOT who have episodes of severe breathlessness not relieved by other treatments.

Referral for assessment may not be necessary or appropriate when short-burst oxygen is being used for terminal care (in the last days of life).

Warn people using oxygen not to smoke because of the risk of fire or explosion.

Basis for recommendation

Basis for recommendation

These recommendations are mainly based on expert opinion and evidence from quasi-experimental studies reviewed in the National Institute for Health and Clinical Excellence (NICE) guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

In addition, the statement that referral for assessment may not be necessary or appropriate when short-burst oxygen is being used for terminal care (in the last days of life) is based on what CKS considers to be good clinical practice.

Referral to multidisciplinary team

When should I refer a person with COPD to other professionals in the multidisciplinary team?

Consider referring people with excessive sputum to a physiotherapist to learn the use of positive expiratory pressure masks and the active cycle of breathing technique.

Consider referring people to social services and occupational therapy if they have difficulties with activities of daily living or disability.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Referral to a physiotherapist

The recommendations on the indications and reasons for referral to a physiotherapist are based on evidence from one small randomized controlled trial and one small quasi-experimental study reviewed by NICE.

Referral to social services and occupational therapy

This recommendation is based on the opinion of the NICE guideline development group.

Smoking cessation

How can I support a person with COPD to stop smoking?

Encourage smokers with chronic obstructive pulmonary disease (COPD) to stop smoking.

If the person is not willing to stop smoking, advise them to cut down, as this may still have some symptomatic benefit.

Document an up-to-date smoking history for people with COPD.

This should include pack-years smoked, which is the number of cigarettes smoked per day, divided by 20, multiplied by the number of years smoked.

Unless contraindicated, offer nicotine replacement therapy, varenicline, or bupropion, as appropriate, to people who are planning to stop smoking.

Drug treatments should be combined with an appropriate support programme to optimize smoking quit rates for people with COPD.

For more information, see the CKS topic on Smoking cessation.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

The evidence suggests that smoking cessation (at any age) reduces the rate of decline of forced expiratory volume in 1 second (FEV1), improves symptoms (cough, wheeze, and sputum production), and increases survival in people with chronic obstructive pulmonary disease (COPD).

Getting people with COPD to stop smoking is one of the most important interventions [National Clinical Guideline Centre, 2010].

Drug treatment

What drug treatment should I offer a person with COPD?

Inhaled treatments (FEV1 50% predicted or greater)

What inhaled treatments should I offer a person with COPD whose FEV1 is 50% predicted or greater?

If the person is breathless and has exercise limitation:

Prescribe a short-acting beta-2 agonist (SABA — salbutamol or terbutaline) or a short-acting muscarinic antagonist (SAMA — ipratropium bromide) as required to relieve symptoms.

If the person prescribed a SABA or SAMA remains breathless or has exacerbations, offer either of the following:

A long-acting beta-2 agonist (LABA — salmeterol or formoterol).

A long-acting muscarinic antagonist (LAMA — tiotropium).

Discontinue treatment with a SAMA if prescribing a LAMA.

A regular LAMA should be offered in preference to a regular SAMA four times daily.

A SABA (as required) may be continued at all stages.

If a person taking a LABA remains breathless or has exacerbations:

Consider changing to a LABA plus an inhaled corticosteroid (ICS) in a combination inhaler. If an ICS is declined or not tolerated, consider a LAMA plus a LABA.

An ICS should not be used as monotherapy in COPD.

If a person taking a LABA plus an ICS remains breathless or has exacerbations:

Add a LAMA.

If a person taking a LAMA remains breathless or has exacerbations:

Consider adding a LABA plus an ICS (in a combination inhaler).

For an algorithm on the use of inhaled treatments, see the NICE quick reference guide.

Consider using a mucolytic or theophylline (methylxanthine).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Short-acting bronchodilators compared with placebo

The evidence for short-acting bronchodilators compared with placebo in chronic obstructive pulmonary disease (COPD) is mainly from small, short-term randomized controlled trials. However, results show a short-term improvement in breathlessness, quality of life, and lung function.

Long-acting beta-2 agonists (LABAs) compared with placebo

The evidence suggests a general improvement in lung function, quality of life, and symptoms, and a reduction of exacerbation rates, when LABAs are compared with placebo.

Long-acting muscarinic antagonists (LAMAs) compared with placebo

The evidence suggests that LAMAs are superior to placebo in reduction of exacerbation rates. There was also a general improvement in lung function, quality of life, and symptoms in people with COPD treated with LAMAs compared with placebo.

LAMAs compared with a short-acting muscarinic antagonists (SAMA)

The evidence suggests an improvement in quality of life and symptoms, and reduction of exacerbation rates, when long-acting bronchodilators are compared with a SAMA (ipratropium bromide). Cost-utility studies (with limitations) comparing treatment with tiotropium and ipratropium in people with stable COPD show that once-daily tiotropium is more cost effective and may improve adherence.

LABAs compared with LAMAs

The evidence shows that LABAs and LAMAs are similar in improving quality of life and symptoms. Nevertheless, a LAMA (tiotropium) seems to be slightly better at reducing exacerbation rates and improving lung function compared with LABAs (salmeterol and formoterol). NICE suggests that both classes are equally effective for initial maintenance bronchodilator therapy in people with COPD whose forced expiratory volume in 1 second (FEV1) is 50% or greater.

Inhaled corticosteroids (ICS) as monotherapy

In the updated COPD guideline, NICE no longer makes any specific recommendations on the use of ICS as monotherapy in people with COPD.

The recommendation to avoid the use of ICS as monotherapy in COPD is based on evidence from a systematic review that ICS alone has no effect on exacerbation rates in people with mild COPD (defined as FEV1 greater than 50%), and that there is no significant difference in mortality between ICS (when used as monotherapy) and placebo.

Furthermore, there are no preparations containing only ICS that are licensed for use in COPD in the UK. The Medicines and Healthcare products Regulatory Agency recommends that ICS should not be used alone in COPD [MHRA, 2009]. They undertook a literature review of published and unpublished trials which found LABA plus ICS combinations to have greater efficacy than either LABAs or ICS alone in every study.

LABA plus ICS compared with LABAs alone

There is evidence to suggest that overall, compared with LABAs alone, people with COPD taking LABAs plus ICS have a significant increase in post-dose FEV1, and improvement in health-related quality of life. They also have fewer exacerbations. Economic studies found that LABA plus ICS is more cost effective than LABA alone in people with COPD with FEV1 less than 50% predicted.

LABA plus ICS plus LAMA (triple therapy) compared with LABA plus LAMA

The evidence shows that there is no significant difference between triple therapy (tiotropium plus fluticasone plus salmeterol) and tiotropium plus salmeterol in clinical outcome (breathlessness, exacerbation, mortality, pneumonia, myocardial infarction, or acute arrhythmia) in people with moderate to severe COPD. A cost-effectiveness study found triple therapy not to be more cost effective than LAMA plus LABA.

Inhaled treatments (FEV1 less than 50% predicted)

What inhaled treatments should I offer a person with COPD whose FEV1 is less than 50% predicted?

If the person is breathless and has exercise limitation:

Prescribe a short-acting beta-2 agonist (SABA — salbutamol or terbutaline) or a short-acting muscarinic antagonist (SAMA — ipratropium bromide) as required to relieve symptoms.

If the person prescribed a SABA or SAMA remains breathless or has exacerbations, offer either of the following:

A long-acting beta-2 agonist (LABA) plus an inhaled corticosteroid (ICS) in a combination inhaler. If an ICS is declined or not tolerated, consider a long-acting muscarinic antagonist (LAMA) as well as a LABA.

An ICS should not be used alone in COPD.

A long-acting muscarinic antagonist (LAMA — tiotropium).

Discontinue treatment with SAMA if prescribing a LAMA.

A regular LAMA should be offered in preference to regular SAMA four times daily.

A SABA (as required) may be continued at all stages.

If the person remains breathless or has exacerbations despite treatment with a LABA plus an ICS or a LAMA alone:

Treat with triple therapy: a LABA plus an ICS (in a combination inhaler) and a LAMA.

For an algorithm on the use of inhaled treatments, see the NICE quick reference guide.

Consider using a mucolytic or theophylline (methylxanthine).

Basis for recommendation

Basis for recommendation

These recommendations are mainly based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Short-acting bronchodilators compared with placebo

The evidence for short-acting bronchodilators compared with placebo in people with chronic obstructive pulmonary disease (COPD) is mainly from small, short-term randomized controlled trials. However, results show a short-term improvement in breathlessness, quality of life, and lung function compared with placebo.

Long-acting beta-2-agonists (LABAs) compared with placebo

The evidence suggests a general improvement in lung function, quality of life, and symptoms, and a reduction of exacerbation rates, when LABAs are compared with placebo.

Long-acting muscarinic antagonists (LAMAs) compared with placebo

The evidence suggests that LAMAs are superior to placebo in reduction of exacerbation rates. There was also a general improvement in lung function, quality of life, and symptoms in people with COPD treated with LAMAs compared with placebo.

LAMAs compared with short-acting muscarinic antagonists (SAMAs)

The evidence suggests an improvement in quality of life and symptoms, and reduction of exacerbation rates when LAMAs are compared with SAMA (ipratropium bromide). Cost-utility studies (with limitations), comparing treatment with tiotropium and ipratropium in people with stable COPD, show that once-daily tiotropium is more cost effective and may improve adherence.

Inhaled corticosteroids (ICS) as monotherapy

In the updated COPD guideline, NICE no longer makes any specific recommendations on the use of ICS as monotherapy in people with COPD.

Although there is evidence from a systematic review that ICS reduce the exacerbation rate by 25% compared with placebo in people with more severe COPD (mean forced expiratory volume in 1 second [FEV1] less than 50% predicted), there was no significant difference in mortality. More important, the Medicines and Healthcare products Regulatory Agency undertook a literature review of published and unpublished trials which found LABA plus ICS combinations to have greater efficacy than either LABA or ICS alone in every study, and they recommend that ICS should not be used alone in COPD [MHRA, 2009].

There are no preparations containing only ICS that are licensed for use in COPD in the UK.

LABA plus ICS compared with LABA alone

There is evidence to suggest that overall, compared with LABAs alone, people with COPD taking LABA plus ICS have a significant increase in post-dose FEV1, and improvement in health-related quality of life. They also have fewer exacerbations. Economic studies show that LABA plus ICS is more cost-effective than LABA alone in people with COPD whose FEV1 is less than 50% predicted.

LABA plus ICS compared with LAMA alone

The evidence suggests a small and clinically insignificant improvement in quality of life in people with COPD (FEV1 less than 50%) on LABA plus ICS, compared with LAMA alone. Exacerbation rates were similar between the two groups and were not clinically significant.

There is no evidence to favour LAMA plus ICS over LAMA alone or vice versa. Either regimen can be used for initial maintenance treatment in people with COPD whose FEV1 is less than 50% [National Clinical Guideline Centre, 2010].

LABA plus ICS plus LAMA (triple therapy) compared with LABA plus ICS and LAMA alone

Evidence suggests that LABA plus ICS or LAMA alone is more cost effective than triple therapy. However, triple therapy is more effective (highest quality-adjusted life-years). Owing to the limitations of the studies, NICE concluded that LABA plus ICS or LAMA alone should be offered as initial maintenance treatment to people with COPD whose FEV1 is less than 50%.

Triple therapy is recommended if symptoms or exacerbations persist because it is more effective in terms of exacerbation reduction and symptom relief [National Clinical Guideline Centre, 2010].

Mucolytics

When should I treat someone with COPD with a mucolytic?

If a person with stable chronic obstructive pulmonary disease (COPD) develops a chronic cough productive of sputum:

Consider prescribing a mucolytic.

Continue a mucolytic if there is symptomatic improvement (for example reduction in frequency of cough and sputum production).

Mucolytics should not be used routinely to prevent exacerbations in people with stable COPD.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE found evidence from a systematic review and three additional randomized controlled trials that mucolytics reduce exacerbation frequency and duration of disability in people with chronic bronchitis or chronic obstructive pulmonary disease (COPD). However, the quality of the evidence was low or very low, and benefits may occur only in people who are not receiving other maintenance treatments (for example inhaled corticosteroids). In view of this, the NICE guideline development group was concerned that a positive recommendation for the use of mucolytics purely to prevent exacerbations may preclude the use of other therapies which have a stronger evidence base, and incorrectly imply that mucolytics should be the first-line treatment for exacerbation prevention.

The recommendation by NICE to only treat people with stable COPD who have a chronic cough productive of sputum seems to be based on evidence from a cost-effectiveness analysis that mucolytics are cost-effective in people with chronic bronchitis (regular cough with sputum production).

Theophylline

When should I treat someone with COPD with a theophylline (methylxanthine)?

If a person with stable chronic obstructive pulmonary disease (COPD) is still symptomatic after a trial of short-acting and long-acting bronchodilators (with or without inhaled corticosteroids), or cannot use inhaler devices successfully:

Consider prescribing oral theophylline.

Theophylline has a narrow therapeutic window, and plasma levels should be monitored closely.

Particular caution needs to be taken when prescribing theophylline to elderly people because of differences in pharmacokinetics, increased likelihood of comorbidities, and the use of other medications.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

There is evidence that theophylline improves lung function, but it does not result in a statistically significant difference in symptoms (wheeze, dyspnoea, or walking distance), use of rescue medication, or exacerbation frequency compared with placebo.

The higher rate of adverse effects with theophylline needs to be balanced against any benefits.

Oral corticosteroids

When should I treat someone with COPD with oral corticosteroids?

Do not start oral corticosteroids for maintenance treatment of chronic obstructive pulmonary disease (COPD) in primary care.

Maintenance use of oral corticosteroids in COPD is not normally recommended.

Refer to a respiratory specialist if long-term treatment is being considered.

If a person is already taking oral corticosteroids for maintenance treatment which were not started by a specialist, refer to a respiratory specialist to assess the need for continuing treatment.

If a person is started on long-term oral corticosteroids in secondary care, ensure that they are monitored for the development of osteoporosis and/or given appropriate prophylaxis.

People 65 years of age or older, and people younger than 65 years of age with a previous fragility fracture, should be started on prophylactic treatment without the need for prior dual energy X-ray absorptiometry.

See the CKS topic on Osteoporosis - prevention of fragility fractures.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease (COPD) in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE identified a meta-analysis of 10 randomized controlled trials that compared oral corticosteroids with placebo. However, NICE concluded that owing to methodological limitations, this study did not establish the effects of sustained oral corticosteroid treatment on either forced expiratory volume in 1 second (FEV1) or more patient-oriented clinical outcomes. The study also did not establish the potential long-term adverse effects of sustained treatment.

On the basis of the opinion of the guideline development group, NICE concluded that:

No published studies were found that establish which people with COPD, if any, benefit from long-term oral steroid therapy.

There is a small group of people who experience frequent exacerbations or severe breathlessness for whom long-term oral steroid treatment is the only pragmatic management.

Some people with advanced COPD may require maintenance oral corticosteroids when these cannot be withdrawn following an exacerbation.

NICE did not update the evidence on oral corticosteroids for stable COPD; CKS identified a subsequent Cochrane systematic review of 24 randomized controlled trials [Walters et al, 2005]. Although FEV1 increased significantly in people taking high-dose oral corticosteroids compared with those taking placebo, there were no clinically important differences in health-related quality of life. The authors concluded that no evidence supports the long-term use of oral corticosteroids at doses of 15 mg or lower, and that potentially harmful adverse effects of higher doses prevent recommending their use.

The recommendation to refer the person to a respiratory specialist to assess the need for continuing treatment if the person is already taking oral corticosteroids for maintenance treatment that was not started by a specialist is based on what CKS considers to be good clinical practice.

Recommendations on osteoporosis monitoring and prophylaxis by NICE were based on guidelines from the Royal College of Physicians (RCP) on the prevention and treatment of osteoporosis [RCP, 1999]. The RCP has also published specific guidelines on the prevention and treatment of glucocorticoid-induced osteoporosis [RCP, 2002], which form the basis for the CKS topic on Osteoporosis - prevention of fragility fractures.

Self-management plan

What information should self-management plans offer for people with COPD?

People with chronic obstructive pulmonary disease (COPD) should have a verbal and/or written self-management plan that provides personalized advice on:

How to recognize the early signs of an exacerbation and respond appropriately.

Lifestyle and medication issues to prevent exacerbations.

Discuss and provide written information to all people with COPD on diet and exercise, and smoking cessation (if necessary).

For people who have frequent exacerbations, provide a structured, written action plan on:

How to recognize when COPD is getting worse (increased breathlessness, more sputum, coloured sputum, and/or fever).

How to initially increase the use of short-acting bronchodilators, and if there is no response, when to contact a primary healthcare professional.

If a person has a supply of medication at home, provide written information advising them:

To start oral corticosteroid therapy if their increased breathlessness interferes with activities of daily living.

To start antibiotics if sputum becomes discoloured or increases in volume.

To contact a primary healthcare professional if they start treatment or are uncertain about whether to start treatment.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion and evidence reviewed in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010].

NICE identified a Cochrane systematic review (three RCTs, 367 participants) which showed that people with self-management plans had better recognition of an exacerbation and reacted appropriately. Unfortunately, this behaviour did not result in any benefit in healthcare utilization, symptoms, quality of life, functional capacity, mental health, or mortality. The studies included were small and of poor quality.

Two subsequent randomized controlled trials identified by CKS (298 participants) also confirmed these findings, and added that there was no difference in exacerbation rates [McGeoch et al, 2006; Wood-Baker et al, 2006].

Despite the lack of evidence, experts believe that self-management plans are useful in the management of chronic obstructive pulmonary disease.

The recommendation that a person with a supply of medications at home should contact a primary healthcare professional if they start treatment is based on feedback from CKS expert reviewers. They suggest that a review should be done in any case:

To ensure that the patient understood what they are doing.

To ensure that medications are taken appropriately.

To record the exacerbation.

To review the time antecedent to the exacerbation to see if any other preventative factor might have been helpful.

To re plenish home stocks of oral steroids/antibiotics.

Nutrition

How should I manage nutritional needs in a person with COPD?

Calculate the person's body mass index (BMI).

BMI is calculated as weight in kg/height in m2.

The normal range of BMI is 20–25 kg/m2.

If the person's BMI is less than 20 kg/m2 or more than 25 kg/m2 or is changing over time, or there is a weight change of 3 kg or more (loss or gain) in an elderly person, refer for dietetic advice (if available).

People with a low BMI should be given nutritional supplements (after specialist advice) and encouraged to take regular exercise to augment the effects of nutritional supplementation.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE found evidence from nine cohort studies that in people with COPD, low body mass index (BMI) is associated with worse outcomes (including mortality) compared with those with normal BMI. Weight loss in people with a low BMI is associated with poorer survival, weight gain in people with a low or normal BMI is associated with increased survival, and weight loss or no weight change is associated with increased survival in people with high BMI.

NICE also cited evidence from a Cochrane systematic review that nutritional supplements have no significant benefit; it is unclear on what the NICE guideline development group has based the recommendation that people with COPD whose BMI is low should be given nutritional supplements to increase their total calorific intake.

The recommendation to encourage people taking nutritional supplements to take exercise to augment the effects of the supplements is based on the opinion of the NICE guideline development group.

Advice

What advice should I give to someone with COPD?

Advice about medications

What should I advise a person with COPD about their medications?

Explain that the purpose of most treatments for chronic obstructive pulmonary disease (COPD) is to control symptoms or to reduce the rate of exacerbations, but that only smoking cessation has been shown to slow the decline in lung function.

Explain that the effectiveness of treatments to control symptoms will vary among individuals.

Discuss the person's perceived clinical improvements and let the person's preference guide treatment decisions.

Always consider stopping a treatment if no benefits are seen after an adequate trial period.

Stress the importance of correct use of maintenance medication.

Explain when and how to use inhalers, and demonstrate the correct technique for using them. For more information, see Delivery systems.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Poor adherence to medication is common in people with COPD, with about half underusing their maintenance medication and a similar proportion overusing their medication during exacerbations (which may be particularly dangerous if the person is taking aminophylline or theophylline) [Canadian Thoracic Society Workshop Group, 1992].

Advice about exercise

What should I advise a person with COPD about exercise?

Encourage the person to exercise at their own level — to become a little short of breath, but not to overstrain themselves.

If they are mobile, they should aim to walk for 20–30 minutes, 3–4 times per week.

If they are immobile, encourage them to do upper-limb activities, such as twisting and arm stretches.

Seek advice from a rehabilitation professional (physiotherapist) on exercise programmes for people who are very symptomatic.

Provide written instructions if necessary.

For more information, see the literature provided by the British Lung Foundation.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010] and advice from the British Lung Foundation about living with chronic obstructive pulmonary disease (COPD).

Advice about flying

What should I advise a person with COPD about air travel?

Advise the person with chronic obstructive pulmonary disease (COPD) who is considering air travel that they will need a fitness-to-fly assessment.

If the person has known bullous disease, warn them that they are at theoretical increased risk of pneumothorax during air travel.

Refer people on long-term oxygen therapy or who have a forced expiratory volume in 1 second (FEV1) less than 50% to a specialist. A hypoxic challenge test may be appropriate.

Advise people with COPD to:

Carry inhalers in hand luggage.

Inform the airline if they require wheelchairs for transport to and from the aeroplane.

Keep mobile during the flight if possible. Leg exercises should be done as often as possible during the flight.

Avoid smoking and alcohol before and during air travel.

Inform the airline (when booking the holiday) if they require oxygen.

People who have ambulatory oxygen may be able to use their own oxygen, but they must inform the airline before flying, and a fee may be charged.

People requiring oxygen should request a seat near the toilets to avoid long walks.

Provide written information.

For further information, see www.brit-thoracic.org.uk, www.lunguk.org, and www.european-lung-foundation.org.

Fitness-to-fly assessment

Fitness-to-fly assessment

If a person has respiratory disease, the only absolute contraindications to air travel are:

Pneumothorax — airline companies suggest waiting 6 weeks after recovering from a pneumothorax before flying.

Bronchogenic cyst.

Severe pulmonary hypertension.

Clinically unstable respiratory disease.

The aim of pre-flight assessment is to identify people who are likely to develop respiratory symptoms (such as hypoxia) during air travel. The two main methods of pre-flight assessment are:

The walking test — this is a good measure of cardiopulmonary reserve to exercise (although it is not always feasible to do this at the GP's surgery).

The 50-metre walking test was put forward by the airline industry and involves asking the person whether they can walk for 50 metres on the flat. The 50-metre walking test has not yet been standardized and can be inaccurate, as many people cannot accurately assess distance.

The 6-minute walking test (which involves asking the person to walk for 6 minutes) is a standardized and validated test recommended by the British Thoracic Society to evaluate the fitness to fly in people with COPD.

If the person can perform the walking test, they are probably fit to travel. However, if the person cannot complete the test or develops severe breathlessness, further tests are needed, as they may require oxygen supplementation during the flight.

Pulse oximetry — saturation measured by pulse oximetry can be used to identify people who will definitely require oxygen supplementation during the flight.

If the person's oxygen saturation is 95% or greater, they do not need oxygen for flying, and there is no need for a referral to a respiratory specialist.

If the person's oxygen saturation is 92% or less and they have no other contraindications, they must travel with supplemental oxygen. Refer to a respiratory specialist for assessment for supplemental oxygen.

If the person's oxygen saturation is greater than 92% but less than 95%, they should be referred to a respiratory specialist for further evaluation. This may include a hypoxic challenge test, after which a decision will be made on whether oxygen is required while flying.

A fitness-to-fly assessment should also include taking a history focusing on previous flying experience — this will help identify ways to make the flight as comfortable as possible for the person.

Hypoxic challenge test

Hypoxic challenge test

The hypoxic challenge test is the gold standard for pre-flight assessments, and is performed in secondary care.

It involves measuring the person's response to a simulated aircraft cabin environment.

In this investigation, the person is exposed to an inspired oxygen tension of 15 kPa, which is the expected worst-case scenario for the aircraft passenger. This can be achieved by two methods:

Administering 15% oxygen in nitrogen using a face mask and non-rebreathing circuit.

Filling a body plethysmograph with 15% oxygen — a modification of this technique involves placing a hood over the person's head and shoulders which is ventilated with a constant supply of 15% oxygen. Alternatively, 15% oxygen can be administered by using a 40% Venturi mask with nitrogen as the driving gas (the Venturi mask dilutes the nitrogen with air, producing 15% oxygen).

During the hypoxic challenge test, the person is monitored continuously with pulse oximetry to prevent severe hypoxaemia. Blood gas tensions are measured before and after the hypoxic exposure.

Some experts recommend electrocardiographic monitoring to detect asymptomatic arrhythmias.

A predicted PaO2 of 6.6 kPa is used as the cut-off value below which supplemental oxygen is recommended for air travel.

Basis for recommendation

Basis for recommendation

Advice about flying

These recommendations are based on the British Thoracic Society (BTS) guidelines on managing people with respiratory disease who are planning air travel [British Thoracic Society, 2004] and on expert opinion from review articles [Johnson, 2003; Tzani et al, 2010].

Arterial oxygen levels fall in healthy air travel passengers, and altitude will exacerbate hypoxaemia in people with chronic obstructive pulmonary disease (COPD), especially if they are hypoxic at sea level.

People with large bullae may be at risk of pneumothorax, but there is no evidence to indicate at what volume (size of bullae) it is considered unacceptable to travel [British Thoracic Society, 2004].

For more information, see www.brit-thoracic.org.uk.

Fitness to fly assessment

This information is based on the BTS guidelines on managing passengers with respiratory disease planning air travel [British Thoracic Society, 2004] and on expert opinion from review articles [Johnson, 2003; Tzani et al, 2010].

Hypoxic challenge test

This information is based on expert opinion from review articles [Johnson, 2003; Tzani et al, 2010].

Advice about driving

What should I advise a person with COPD about driving?

For both group 1 (car or motorcycle) or group 2 (lorry or bus) entitlement:

The Driver and Vehicle Licensing Agency (DVLA) need not been informed unless attacks are associated with disabling giddiness, fainting, or loss of consciousness.

If the DVLA need to be notified, advise the person that it is their responsibility to do so.

The latest information from the DVLA regarding medical fitness to drive can be obtained at www.gov.uk/government/publications/at-a-glance.

Basis for recommendation

Basis for recommendation

This information on medical rules is from the Driver and Vehicle Licensing Agency's guidance for medical practitioners, At a glance guide to the current medical standards of fitness to drive [DVLA, 2010].

Management of cor pulmonale

How should I manage a person with cor pulmonale?

Consider the possibility of other causes of peripheral oedema, including congestive heart failure and chronic thromboembolic disease.

If cor pulmonale is the most likely diagnosis, refer the person to a respiratory specialist for assessment for the need for long-term oxygen therapy (if not recently assessed, or already receiving it), confirmation of the diagnosis, and optimization of medical therapy.

If necessary, treat oedema symptomatically with a diuretic, for example furosemide 20 mg once daily, increasing if necessary to 40 mg once daily.

Check serum electrolytes soon after starting or increasing the dose.

The following should not be used to treat cor pulmonale, but may be used for other indications.

Angiotensin-converting enzyme inhibitors.

Calcium-channel blockers.

Alpha-blockers.

Digoxin (unless there is atrial fibrillation).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE reviewed evidence from one randomized controlled trial and two controlled studies without randomization, which found benefits from long-term oxygen therapy for people with cor pulmonale.

NICE found insufficient evidence to recommend changing the current clinical practice of using diuretics to control peripheral oedema in people with cor pulmonale.

CKS found no published evidence to indicate appropriate starting or maximum dosages of diuretics. The recommended starting dosage, titration, and monitoring are based on expert opinion from CKS reviewers.

NICE reviewed the evidence for other treatments (angiotensin-converting enzyme inhibitors, calcium-channel blockers, alpha-blockers, and digoxin); studies either had methodological limitations or found no benefit in symptoms of COPD or cor pulmonale from active treatment.

Follow up

How should I follow up a person with COPD?

Frequency of follow up

Follow up people with very severe (stage 4) chronic obstructive pulmonary disease (COPD) at least twice per year.

Follow up people with mild, moderate, or severe (stages 1–3) COPD at least once a year.

In all people with COPD, assess or measure (and record) the following at follow up:

Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). See Spirometry and Assessment of severity.

Body mass index .

Medical Research Council dyspnoea score .

Smoking status and desire to quit — offer smoking cessation advice and treatment.

Adequacy of symptom control (breathlessness, exercise tolerance, exacerbation frequency).

Effects of each drug treatment.

Presence of complications (for example, cor pulmonale).

Inhaler technique.

Need for referral to a respiratory specialist.

Need for pulmonary rehabilitation.

Need for social services and occupational therapy input.

In addition to the above, in people with very severe (stage 4) COPD, assess or measure and record the following at follow up:

Oxygen saturation.

Ensure that pulse oximetry is available.

Need for referral for assessment for long-term oxygen therapy.

Presence of depression. See the CKS topic on Depression.

People receiving long-term oxygen therapy should have a review at least once per year which includes pulse oximetry.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], and the NICE Quality Standards Programme for chronic obstructive pulmonary disease [NICE, 2011].

NICE found no data to guide decisions on how frequently people with chronic obstructive pulmonary disease (COPD) should be reviewed. NICE indicates that this will vary according to individual circumstances and the severity of the person's disease.

A subsequent cluster randomized controlled trial found no difference in quality of life or other health outcomes for people with asthma or COPD managed in primary care who had more 3-monthly spirometry and regular medical reviews compared with those who had annual spirometry or usual care [Abramson et al, 2010]. Around a quarter of the people had COPD; the trial may have been underpowered to detect a significant difference in this subgroup.

Many of the recommendations are derived from statements made in the British Thoracic Society COPD guidelines [British Thoracic Society, 1997].

Scenario: Acute exacerbation

Scenario: Acute exacerbation of chronic obstructive pulmonary disease

192months3060monthsBoth

Assessment

How should I assess a person with an acute exacerbation of COPD?

Assess the severity of the exacerbation. The following physical signs are features of a severe exacerbation:

Marked dyspnoea and tachypnoea.

Pursed-lip breathing.

Use of accessory muscles at rest.

Acute confusion.

New-onset cyanosis or peripheral oedema.

Marked reduction in activities of daily living.

Consider the need for hospital admission.

Do not send sputum samples for culture routinely.

Assess oxygen saturation using pulse oximetry.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

When to admit

When should I arrange hospital admission for a person with an acute exacerbation of COPD?

Most people with an exacerbation can be managed at home. However, some people need hospital admission for interventions that are not available at home such as oxygen, nebulizers, intravenous antibiotics, or ventilation.

Consider hospital admission if any of the following are present:

Severe breathlessness, rapid onset, confusion, cyanosis, worsening peripheral oedema, or impaired consciousness.

The person is unable to cope or lives alone.

Their general condition is poor or deteriorating (poor activity, confined to bed, or on long-term oxygen therapy).

Significant comorbidity (particularly cardiac disease or type 1 diabetes mellitus).

A low oxygen saturation (less than 90%).

Ensure that pulse oximetry is available.

New acute changes on chest x-ray, if requested and available locally and urgently. X-ray is mainly requested mainly to exclude alternative or concomitant diagnoses, for example bronchopneumonia.

Hospital-at-home schemes, provided by community respiratory teams, may be available in some areas and are an alternative to hospital admission.

Follow locally agreed care pathways.

Data are insufficient to make firm recommendations about which patients with an exacerbation are most suitable for hospital-at-home.

Hospital-at-home schemes may be suitable for people with few of the above indications for hospital admission who prefer treatment at home.

Whilst awaiting transfer to hospital, check oxygen saturation on air in people with a severe acute exacerbation and give oxygen (if available) if less than 90%. If available, refer to local protocols. If local protocols are unavailable:

Follow instructions on an oxygen alert card (if the person has been given one because of a previous episode of hypercapnic respiratory failure).

If the person does not have an oxygen alert card, use a 28% Venturi mask at a flow rate of 4 L/min, and aim for an oxygen saturation of 88–92%.

If the oxygen saturation remains below 88% despite a 28% Venturi mask, change to nasal cannulae at 2–6 L/min or a simple mask at 5 L/min with target saturation of 88–92%. In this situation, request an emergency ambulance and alert the accident and emergency department or medical admissions unit that the patient requires immediate senior assessment on arrival.

If the oxygen saturation decreases after commencing oxygen, change to a 24% Venturi mask at a flow rate of 2 L/min.

Basis for recommendation

Basis for recommendation

When to admit

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Hospital-at-home

These recommendations are based on the NICE chronic obstructive pulmonary disease (COPD) guideline [National Clinical Guideline Centre, 2010; NICE, 2010].

Evidence from four randomized controlled trials identified by NICE suggests that hospital-at-home schemes are safe and effective alternatives to inpatient care for people with acute exacerbations of COPD. However, NICE found insufficient data to make firm recommendations about which patients with an exacerbation are most suitable for hospital-at-home. The recommendation that hospital-at-home schemes may be suitable for people with few indications for hospital admission who prefer treatment at home is based on the expert opinion of the guideline development group.

Oxygen

These recommendations are mainly based on evidence from audits of emergency admissions and on expert opinion in the Guideline for emergency oxygen use in adult patients from the British Thoracic Society [British Thoracic Society, 2008]. NICE did not include recommendations made in 2004 in their updated 2010 guideline because of concerns that they were out of date; they now refer readers to local protocols.

The recommendation to change to a 24% Venturi mask at a flow rate of 2 L/min if the oxygen saturation decreases after commencing oxygen is based on expert opinion from CKS reviewers.

Treatment

How should I treat a person with an acute exacerbation of COPD who is not being admitted?

Advise the person to take increased doses or increase the frequency of use of short-acting bronchodilators, for example by doubling the dose or frequency of use.

Advise the person to keep to the same delivery system (inhaler with spacer or nebulizer) during an exacerbation as is used on a day-to-day basis, if possible. Explain that both delivery systems (inhaler and spacer or nebulizer) are equally effective, and hospitals use nebulizers mainly for convenience.

If a person does not usually use a spacer device, recommend using one, as they may find it easier to use and it will help to deliver a maximum dose.

If the person is likely to become fatigued, a nebulizer may be more appropriate.

Prescribe systemic corticosteroids for people with a significant increase in breathlessness that interferes with daily activities.

Prescribe prednisolone 30 mg orally once daily for 7–14 days.

Consider osteoporosis prophylaxis for people requiring frequent courses of oral corticosteroids. See the CKS topic on Osteoporosis - prevention of fragility fractures.

See the sections on Contraindications and cautions, Adverse effects, Drug interactions, and Monitoring in the CKS topic on Corticosteroids - oral.

Prescribe oral antibiotics for people with a history of more purulent sputum or clinical signs of pneumonia. Consult local antibiotic prescribing guidelines.

Initial empirical treatment should usually be:

Amoxicillin 500 mg three times daily for 5 days or a tetracycline (for example doxycycline 200 mg on the first day then 100 mg once daily, for a total of 5 days).

If the person is allergic to penicillin and doxycycline is contraindicated, prescribe a macrolide (for example erythromycin 500 mg four times daily or clarithromycin 500 mg twice daily for 5 days).

If the person has antibiotic resistance risk factors (comorbid disease, severe COPD, frequent exacerbations, or antibiotic use in the past 3 months), prescribe co-amoxiclav 625 mg three times daily for 5 days.

Basis for recommendation

Basis for recommendation

Short-acting bronchodilators

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE did not review the evidence of bronchodilators specifically in the acute setting. However, NICE did review evidence on delivery systems for bronchodilators during exacerbations. A meta-analysis of randomized controlled trials found hand-held inhalers with a spacer and nebulizers to be equally effective at alleviating symptoms. NICE acknowledged that in very breathless people, a nebulizer may be more appropriate.

The example of doubling the dose or frequency is based on what CKS considers to be good clinical practice.

Systemic corticosteroids

These recommendations are based on the NICE guideline on chronic obstructive pulmonary disease (COPD) [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE identified three systematic reviews and one subsequent randomized controlled trial of oral/systemic corticosteroids for COPD exacerbations, although they noted limitations to the validity and generalizability of several of the included studies. A significant effect was demonstrated in favour of oral/systemic corticosteroids over placebo for FEV1 for at least 3 days, with some of the studies findings benefits for up to 5 days. Individual studies also found benefits in arterial PaO2. Findings on the effect on duration of hospitalization were inconsistent, and no difference in mortality was demonstrated. People taking corticosteroids were more likely to have adverse effects (for example hyperglycaemia).

Recommendations on the dose and duration of oral prednisolone are based on the expert opinion of the guideline development group, or on extrapolations from higher levels of evidence.

Antibiotics

The recommendation on when to prescribe an antibiotic is based on the NICE COPD guideline [National Clinical Guideline Centre, 2010; NICE, 2010].

NICE cited a meta-analysis of nine trials, which found a small but statistically significant effect favouring antibiotics over placebo in patients with exacerbations of COPD. Three studies found that the benefit from antibiotics was associated with the severity of the exacerbation; NICE based their recommendations on when to prescribe on their analyses of these studies.

Recommendations on the appropriate regimens are based on the NICE COPD guideline [National Clinical Guideline Centre, 2010; NICE, 2010] and Management of infection guidance for primary care for consultation and local adaptation, developed by the Health Protection Agency and the Association of Medical Microbiologists [HPA and Association of Medical Microbiologists, 2010].

NICE recommends that initial empirical treatment should be an aminopenicillin, a macrolide, or a tetracycline, and that guidance from local microbiologists should be taken into account [National Clinical Guideline Centre, 2010; NICE, 2010].

The preference for amoxicillin or a tetracycline first-line, the choice of antibiotics, the dosages, and the recommendations on the use of co-amoxiclav are based on the Management of infection guidance for primary care [HPA and Association of Medical Microbiologists, 2010].

Follow up

How should I follow up a person who has had an exacerbation of COPD?

Follow up all people who have had an exacerbation of COPD when they are clinically stable (for example, 6 weeks after the onset of symptoms of the exacerbation).

At follow up:

Manage any residual or changed symptoms.

Optimize medical treatment to reduce the risk of further exacerbations. See Drug treatment and Referral in Scenario: Stable COPD.

Consider referral or re-referral to pulmonary rehabilitation. See Referral for pulmonary rehabilitation in Scenario: Stable COPD.

Review the self-management plan. See Self-management plan in Scenario: Stable COPD.

Check for any problems arising with medications. See Advice about medications in Scenario: Stable COPD.

Basis for recommendation

Basis for recommendation

These recommendations are based on Consultation on a strategy for services for chronic obstructive pulmonary disease (COPD) in England [DH, 2010].

Scenario: End-stage COPD

Scenario: End-stage chronic obstructive pulmonary disease

192months3060monthsBoth

Defining end-stage COPD

How do I know a person has end-stage COPD?

There is no established definition of end-stage chronic obstructive pulmonary disease (COPD). Clinical judgement is needed.

End-stage COPD may be defined as COPD which is very severe (forced expiratory volume in 1 second [FEV1] less than 30% predicted), unresponsive to usual medical treatment for COPD, and associated with a probable life expectancy of less than 6–12 months. Assessing life expectancy is not straightforward — see Discussing end-of-life issues for details on factors that may be associated with survival of 6 months or less.

For people with end-stage COPD, the focus is on palliative care to relieve distressing symptoms. This is distinct from but similar to terminal care, which is care given during the last days of life.

A trigger for palliative care may be if the answer to the 'surprise' question is 'no': 'Would you be surprised if this person were to die in the next 6–12 months?'

Basis for recommendation

Basis for recommendation

In its clinical guideline on the management of chronic obstructive pulmonary disease (COPD), the National Institute for Health and Clinical Excellence (NICE) does not give an explicit definition of end-stage COPD [National Clinical Guideline Centre, 2010; NICE, 2010]. The definition of end-stage COPD given here is based on:

Expert opinion from review articles in relation to severity of airflow obstruction and probable life expectancy of less than 6–12 months [Barnett, 2008; Halpin et al, 2008]

NICE recommendations that palliative drug treatments should be offered when the person is unresponsive to usual medical treatments.

The 'surprise' question is recommended in Prognostic Indicator Guidance from the Gold Standards Framework and the Royal College of General Practitioners [RCGP, 2008].

General principles

What are the general principles of managing people with end-stage COPD?

Optimize medical treatment of chronic obstructive pulmonary disease (COPD) — see Scenario: Stable COPD.

Establish a clear management plan based on the wishes of the person with COPD (and if appropriate their family or carers).

Determine whether hospital admission for severe exacerbations is appropriate.

Start to coordinate care with a respiratory nurse specialist, district nurse, palliative care specialist nurse, and social services.

Consider admission to a hospice (for example if symptoms are not controlled or if this is the preferred place of death).

Discuss any advance decisions.

Consider using a management pathway for the terminal phase, such as the Liverpool Care Pathway (which offers a framework for caring for people at the end of life). For further information, see www.liv.ac.uk/mcpcil/liverpool-care-pathway.

Advise simple measures and offer drug treatments (including oxygen) for breathlessness. See the CKS topic on Palliative cancer care - dyspnoea.

Manage cough, secretions, pain, fatigue, insomnia, depression, and anxiety — see the CKS topics on:

Palliative cancer care - cough .

Palliative cancer care - secretions .

Palliative cancer care - pain .

Insomnia .

Depression .

For more information, see the CKS topics on Palliative cancer care - general issues.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], a review article [Rocker et al, 2009], and specialist textbooks [Hanks et al, 2010; Regnard and Dean, 2010].

Discussing end-of-life issues

When and how should I discuss end-of-life issues for people with end-stage COPD?

Deciding when and how to initiate discussions about end-of-life issues is difficult. Evidence is insufficient to make firm recommendations, but the following may be helpful:

Most people with chronic obstructive pulmonary disease (COPD) would find such discussions acceptable; if initiated by the clinician, ideally the discussions should occur when the person is stable rather than deteriorating or being hospitalized.

No criteria have been shown to effectively predict survival of 6 months or less. However, several features may indicate the need to discuss end-of-life issues:

Forced expiratory volume in 1 second (FEV1) less than 30% predicted.

Frequent exacerbations and hospital admissions.

Low body mass index or weight loss.

Comorbidities (especially left heart failure).

Some evidence indicates that people with advanced COPD may wish to discuss:

Diagnosis and the disease process (including what COPD is and what causes it) — see Background information.

Treatments (including explanations of both long-term treatments, such as inhalers and oxygen, and short-term crisis treatments, such as intubation and mechanical ventilation).

Prognosis .

What dying might be like and how distressing symptoms might be alleviated.

Advance decisions (for example whether or not to treat or hospitalize for an exacerbation, or whether to have life-support measures).

Discuss with the person whether to complete a DS1500 form so they can receive a disability living allowance. For more information, see www.dwp.gov.uk.

Basis for recommendation

Basis for recommendation

Difficulty deciding when and how to initiate discussions

In the National Institute for Health and Care Excellence (NICE) guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010] and review articles [Seamark et al, 2007; Curtis, 2008; Halpin et al, 2008; Spathis and Booth, 2008], there is agreement that deciding when and how to initiate discussions about end-of-life issues is difficult.

Acceptability and when to initiate

In one qualitative study identified in the NICE guideline [National Clinical Guideline Centre, 2010], a descriptive questionnaire was used to assess the attitudes of 105 people on a pulmonary rehabilitation programme to end-of-life decision making. Most people wanted to learn more about advance directives, mechanical ventilation, and intubation. They said they would find discussions with physicians about these issues acceptable, but such discussions should take place when the person was in a stable condition. Although only half thought physicians should initiate such discussions, only 20 people had had such discussions, almost all of which had been initiated by the patient and not the physician.

Criteria indicating the need to discuss end-of-life issues

In a systematic review of tools and predictor variables to help clinicians estimate survival and appropriate timing of palliative care for older adults with non-malignant life-threatening disease, low forced expiratory volume in 1 second (FEV1) was the only variable that can be measured in primary care that was found to be effective in estimating survival [Coventry et al, 2005]. A review article also considered the evidence for commonly used prognostic criteria, finding them to be unreliable [Spathis and Booth, 2008]. However, given that decisions about the timing of end-of-life discussions still need to be made, the criteria presented are based on prognostic factors each recommended in more than one review article [Seamark et al, 2007; Barnett, 2008; Curtis, 2008; Halpin et al, 2008; Spathis and Booth, 2008].

The Prognostic Indicators Guidance paper from the Gold Standards Framework and the Royal College of General Practitioners suggests indicators for survival of 12 months or less in people with COPD [RCGP, 2008]. The paper references the full 2004 NICE guideline [National Collaborating Centre for Chronic Conditions, 2004]; however, CKS could not locate in the NICE guideline the source of these proposed indicators.

What end-of-life issues to discuss

These issues are based on the findings of a focus group qualitative study of perspectives of people with COPD [Curtis et al, 2002], a qualitative study involving semi-structured interviews with people with moderate or severe COPD [Barnett, 2008], and qualitative studies reviewed in the NICE full guideline [National Clinical Guideline Centre, 2010].

DS1500 form for disability living allowance

This recommendation is based on what CKS considers to be good clinical practice.

Advance decisions

What do I need to know about advance decisions for people with end-stage COPD?

The usefulness of advance decisions in chronic obstructive pulmonary disease may be limited because:

It is rarely feasible to give precise instructions for all potential eventualities.

The person's views and values may change over time in response to the increasing severity of disease or during an exacerbation.

Advance decisions (also called advance directives or living wills):

Allow the person to specify (before they have lost the capacity to decide) what treatments they would not want and would not consent to (for example mechanical ventilation or cardiopulmonary resuscitation).

Cannot demand treatments.

Must be respected by clinicians.

Can be withdrawn if the person retains (or regains) capacity.

Can be made verbally, except for decisions that refuse life-sustaining treatment (such as artificial ventilation), which must be written, signed, and witnessed.

Cannot refuse basic care, such as the provision of warmth, shelter, hygiene, food for eating, and water for drinking. However, clinically assisted nutrition and hydration (that is given intravenously, subcutaneously, or via a gastrostomy), which are considered in law to be medical treatments, can be refused.

Clinicians are responsible for finding out if a valid advance decision exists.

An advance refusal of treatment is binding if:

The person making the advance decision was at least 18 years of age, and had the necessary mental capacity.

It specifies treatment to be refused, and the applicable circumstances.

It has not been withdrawn.

Nobody has subsequently been given power of attorney to make treatment decisions on the person's behalf.

The person making the advance decision has not subsequently given reason to believe that they have changed their mind.

The legal framework for advance decisions is provided by the Mental Capacity Act 2005, which also provides for resolution of disputes and disagreements about advance decisions. For further information, see the section on The Mental Capacity Act 2005 in the CKS topic on Dementia.

See the section on Important communication issues in the CKS topic on Palliative cancer care - general issues for further information on advance care planning.

Basis for recommendation

Basis for recommendation

This information is based on guidance from the General Medical Council, Treatment and care towards the end of life: good practice in decision making [GMC, 2010]; guidance on the Mental Capacity Act from government departments and the British Medical Association [Office of the Public Guardian, 2005; BMA, 2007; Department for Constitutional Affairs, 2007; BMA, 2008; BMA, 2009]; and review articles [Curtis, 2008; Halpin et al, 2008; Nicholson et al, 2008; Spathis and Booth, 2008].

The statements in relation to the usefulness of advance decisions in chronic obstructive pulmonary disease may be limited are based on expert opinion in review articles [Halpin et al, 2008; Spathis and Booth, 2008] and from CKS reviewers.

Simple measures for breathlessness

What simple measures can I advise to manage breathlessness for people with end-stage COPD?

Advise the person on the following simple measures to manage breathlessness.

Sitting in front of a fan or open window (or using a hand-held fan).

Positioning

For example, advise the person to sit or stand leaning forward (for example onto a table or the back of a chair) and supporting their weight with their arms and upper body.

Pursed-lip breathing

Advise the person to inhale through the nose and then exhale slowly, for 4–6 seconds, through pursed lips.

Other simple measures, not specific to chronic obstructive pulmonary disease (COPD) but recommended in the section on Simple measures to help dyspnoea in the CKS topic on Palliative cancer care - dyspnoea, may be useful for people with COPD.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in review articles [Seamark et al, 2007; Barnett, 2008; Spathis and Booth, 2008; Abernethy et al, 2009] and a specialist textbook [Hanks et al, 2010].

Bending forward is thought to improve diaphragmatic function [Hanks et al, 2010].

Pursed-lip breathing is thought to decrease air trapping by stenting the airways and preventing airway collapse [Abernethy et al, 2009].

Drug treatments for breathlessness

What drug treatments (including oxygen) can I use in people with end-stage COPD?

O ffer an opioid as first-line treatment to palliate breathlessness in people with end-stage chronic obstructive pulmonary disease (COPD) that is unresponsive to other medical treatment.

There is wide variation in the regimens used in trials and recommended in the literature. Seek specialist advice, or follow recommendations in the section on Opioids in the CKS topic on Palliative cancer care - dyspnoea.

If an opioid (in addition to other medical treatment) is insufficient to palliate breathlessness, offer a trial of either or both of the following:

Benzodiazepines (particularly if there is a significant anxiety component).

There is wide variation in the regimens recommended in the literature. Seek specialist advice, or follow recommendations in the section on Benzodiazepines in the CKS topic on Palliative cancer care - dyspnoea.

Oxygen (if the person is not already on long-term oxygen).

Short-burst oxygen therapy (intermittent use of supplemental oxygen for periods of 10–20 minutes) may be helpful.

Use a 24% or 28% Venturi mask at a flow rate of 2–4 L/min.

Seek specialist advice if these measures fail to palliate breathlessness sufficiently, or if considering a trial of tricyclic antidepressants or antipsychotics.

Basis for recommendation

Basis for recommendation

When to treat

The recommendation to offer opioids, benzodiazepines, and oxygen to people with end-stage chronic obstructive pulmonary disease (COPD) that is unresponsive to other medical therapy is based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Opioids

NICE [National Clinical Guideline Centre, 2010] identified one systematic review and meta-analysis of opioids for the palliation of breathlessness in terminal illness [Jennings et al, 2002]. Not all studies were of people with COPD, and most had methodological limitations, including small sample size and the potential for carry-over effects (in crossover trials). A statistically significant effect of opioids was demonstrated for breathlessness using non-nebulized opioids; however, when a subgroup analysis of nine COPD studies was done, no statistically significant difference between the treatment and control groups was found for breathlessness. In spite of this, the NICE guideline development group concluded that opioids are useful for palliating breathlessness in people in the end stages of COPD.

Most review articles and textbooks recommend the use of morphine, but there was considerable variation in the starting dosage between trials and that recommended in review articles and textbooks (from 1 mg daily to 30 mg daily) [Jennings et al, 2002; Seamark et al, 2007; Abernethy et al, 2009; Rocker et al, 2009; Regnard and Dean, 2010]. Consequently, firm recommendations cannot be made; CKS recommends that specialist advice be sought or that regimens recommended in the CKS topic on Palliative cancer care - dyspnoea be used.

Benzodiazepines

A recent Cochrane systematic review included three randomized controlled trials with 47 people with COPD in its meta-analysis [Simon et al, 2010]. No statistically significant effect was observed for benzodiazepines compared with control. The authors recommend a trial of benzodiazepines only in people who have not responded to opioids and non-pharmacological measures.

Benzodiazepines were recommended by NICE on the basis of the expert opinion of the guideline development group [National Clinical Guideline Centre, 2010].

Because few review articles or textbooks make suggestions on the choice and dosage of benzodiazepine specifically for people with end-stage COPD, CKS recommends that specialist advice should be sought or that regimens recommended in the CKS topic on Palliative cancer care - dyspnoea are used.

Oxygen

Oxygen is recommended by NICE for the palliation of breathlessness not relieved by other therapies; this recommendation is based on the expert opinion of the guideline development group [National Clinical Guideline Centre, 2010].

The recommendation to use short-burst oxygen is based on a report of the expert working group of the Scientific Committee of the Association of Palliative Medicine [Booth et al, 2004].

The recommendation on the dose of oxygen is based on recommendations by the British Thoracic Society [British Thoracic Society, 2006] and a report of the expert working group of the Scientific Committee of the Association of Palliative Medicine [Booth et al, 2004].

Tricyclic antidepressants and major tranquilizers

Although NICE also recommends (on the basis of the expert opinion of the guideline development group) the use of tricyclic antidepressants and major tranquilizers (antipsychotics), CKS could find no other expert opinion in favour of these drugs, or on recommended regimens. Consequently, CKS recommends that specialist advice should be sought if these drugs are being considered.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Inhaled bronchodilators

Inhaled bronchodilators

Inhaled bronchodilators are the first-line drugs for the treatment of chronic obstructive pulmonary disease (COPD). They reduce breathlessness and improve exercise tolerance without producing large improvements in forced expiratory volume in 1 second (FEV1).

Two types of inhaled bronchodilators are available:

Beta-2 agonists — these act directly on beta2 receptors, causing smooth-muscle relaxation and dilation of the airways.

Short-acting beta-2 agonists (SABAs), such as salbutamol and terbutaline, have a rapid onset of action (15 minutes) and their effects last for up to 4 hours.

Long-acting beta-2 agonists (LABAs) have prolonged receptor occupancy. Salmeterol and formoterol are relatively lipophilic and have a duration of action of 12 hours. Indacaterol (a new LABA) has a duration of action of 24 hours.

Muscarinic antagonists (also called antimuscarinics) — these cause bronchodilation by blocking the cholinergic nerves in the airways.

Ipratropium is a short-acting muscarinic antagonist. It has a slower onset of action than SABAs. Its maximal effect occurs 30–60 minutes after use and lasts for 3–6 hours.

Tiotropium is a long-acting muscarinic antagonist. It has a duration of action of at least 24 hours, making it suitable for once-daily use.

Basis for recommendation

This information is based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010] and the British National Formulary [BNF 59, 2010].

Beta-2 agonists

Beta-2 agonists

Choice of beta-2 agonist

Which beta-2 agonists are available for COPD?

Short-acting

Salbutamol and terbutaline are not licensed for the treatment of chronic obstructive pulmonary disease (COPD). However, they are recommended by the National Institute for Health and Care Excellence (NICE).

Salbutamol is available as a pressurized metered-dose inhaler, a dry powder inhaler, and a nebulizer solution.

Salbutamol is also available as a combination product containing a short-acting muscarinic antagonist, ipratropium bromide (Combivent® UDVs®).

Combivent® UDVs® are single dose units licensed for bronchospasm in COPD.

Long-acting

Salmeterol, formoterol, and indacaterol are licensed for COPD.

Salmeterol is available as a pressurized metered-dose inhaler and dry powder inhaler. It is also available as a combination product containing fluticasone propionate (Seretide Accuhaler® and Seretide Evohaler®).

Seretide Accuhaler® is available in three strengths. However, only Seretide 500 Accuhaler® (50 micrograms salmeterol and 500 micrograms fluticasone propionate) is licensed for the treatment of COPD in people who require regular treatment with both ipratropium and salbutamol.

Seretide Evohaler® is not licensed for COPD.

Formoterol is available as a pressurized metered-dose inhaler and dry powder inhaler. It is also available as combination preparation containing budesonide (Symbicort Turbohaler®).

Symbicort Turbohaler® is available in three strengths. However, only Symbicort® 200/6 and Symbicort® 400/12 are licensed for symptomatic treatment of people with severe COPD (forced expiratory volume in 1 second [FEV] less than 50% predicted normal) and a history of repeated exacerbations who have significant symptoms despite regular treatment with long-acting bronchodilators.

Indacaterol (Onbrez Breezhaler®) is not currently recommended because although it is licensed for the treatment of COPD, it is a 'black triangle' drug. Further post-marketing data are needed to establish its safety, and it is currently subject to intensive surveillance by the Medicines and Healthcare products Regulatory Agency (MHRA).

Basis for recommendation

This information is based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2010f; ABPI Medicines Compendium, 2010g; ABPI Medicines Compendium, 2010h; ABPI Medicines Compendium, 2010k], and the British National Formulary [BNF 59, 2010].

Dose of short-acting

What doses of short-acting beta-2 agonists should I prescribe for COPD?

Salbutamol

Aerosol inhalation — 100 micrograms to 200 micrograms (one or two puffs) up to four times daily.

Dry powder inhalation — 200 micrograms to 400 micrograms up to four times daily.

Nebulized solution — 2.5 mg to 5 mg, repeated up to four times daily, or more frequently in severe cases to a maximum of 40 mg daily.

If dilution is necessary, sterile sodium chloride 0.9% should be used.

The recommended doses may vary slightly for the different brands available. Doses for specific brands can be found in the manufacturers' Summaries of Product Characteristics.

Combivent ® UDVs® (salbutamol plus ipratropium)

Nebulized solution — 2.5 mL (one vial) three or four times daily.

Terbutaline sulphate

Dry powder inhalations — 500 micrograms (one inhalation) up to four times daily.

Nebulized solution — 5 mg to 10 mg two to four times daily.

Basis for recommendation

This information is from the manufacturers' Summaries of Product Characteristics (SPCs) [ABPI Medicines Compendium, 2007b; ABPI Medicines Compendium, 2009c; ABPI Medicines Compendium, 2010j] and the British National Formulary [BNF 59, 2010].

Dose of long-acting

What doses of long-acting beta-2 agonists should I prescribe for COPD?

Formoterol

Aerosol inhalation — 12 micrograms twice daily for symptom relief. Additional doses may be taken to a total maximum of 48 micrograms daily (maximum single dose is 24 micrograms).

Dry powder inhalation — 12 micrograms twice daily.

Symbicort Turbohaler® 200/6 (formoterol plus budesonide) — two inhalations twice daily.

Symbicort Turbohaler® 400/12 (formoterol plus budesonide) — one inhalation twice daily.

Salmeterol

Aerosol inhalation — 50 micrograms (two puffs) twice daily.

Dry powder inhalation — 50 micrograms (one blister) twice daily.

The recommended doses may vary slightly for the different brands available. Doses for specific brands can be found in the manufacturers' Summaries of Product Characteristics.

Seretide 500 Accuhaler® (salmeterol plus fluticasone propionate) — one inhalation twice daily.

Indacaterol (Onbrez Breezhaker®) is not currently recommended because although it is licensed for the treatment of COPD, it is a 'black triangle' drug. Further post-marketing data are needed to establish its safety, and it is currently subject to intensive surveillance by the Medicines and Healthcare products Regulatory Agency (MHRA).

Basis for recommendation

This information is from the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2010g; ABPI Medicines Compendium, 2010h] and the British National Formulary [BNF 59, 2010].

Cautions

When should beta-2 agonists be used with caution?

Beta-2 agonists should be used with caution in people with:

Hyperthyroidism — beta-2 agonists may stimulate thyroid activity.

Diabetes mellitus — there is a rare risk of ketoacidosis (especially after intravenous beta-2 agonist administration). Additional blood glucose measurements are recommended when treatment with a beta-2 agonist is commenced.

Cardiovascular disease (including hypertension) — beta-2 agonists may cause an increased risk of arrhythmias and significant changes to blood pressure and heart rate.

Hypokalemia — plasma potassium concentration can be reduced by beta-2 agonists (particularly high doses).

Convulsive disorders.

Basis for recommendation

This information is from the British National Formulary [BNF 59, 2010] and a drug reference database [Micromedex, 2010].

Adverse effects

What are the adverse effects of beta-2 agonists?

Adverse effects of short-acting and long-acting beta-2 agonists are similar. They are usually dose related and include:

Fine tremor — occurs particularly in the hands and is usually worse in the first few days of treatment.

Palpitations.

Headache.

Seizure.

Nervousness.

Hypokalaemia.

Monitor potassium levels in people on high doses of beta-2 agonists (for example people receiving parenteral and nebulized beta-2 agonists).

Acute angle-closure glaucoma has been reported in people on nebulized short-acting beta-2 agonists.

Use a mouthpiece rather than a mask to minimize exposure of the eyes to the drug.

Cardiac dysrhythmia and paradoxical bronchospasm are serious, but rare adverse effects.

The risk of adverse events may be higher in people with a predisposition to arrhythmias and in people with pre-existing cardiovascular disease, including hypertension.

To minimize adverse effects, advise people who are inhaling terbutaline via a turbohaler to rinse their mouth with water after each use.

Basis for recommendation

This information is from the British National Formulary [BNF 59, 2010] and a drug reference database [Micromedex, 2010]. In addition, the information on hypokalaemia is from the Commission on Human Medicines [CSM, 1990] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009d].

The Commission on Human Medicines (formerly the Committee on Safety of Medicines) has advised that plasma potassium concentration can be reduced (which may be potentially serious) [CSM, 1990]. However, monitoring is more important in people on high doses (for example via parenteral and nebulized administration) [ABPI Medicines Compendium, 2009d].

The recommendation to advise people using a terbutaline turbohaler to rinse their mouth after each use is based on the SPC for Bricanyl Turbohaler®. A fraction of the dose will always be deposited in the mouth and rinsing the mouth after use will minimize the amount of terbutaline absorbed systemically [ABPI Medicines Compendium, 2011].

Drug interactions

What drug interactions are important with beta-2 agonists?

Corticosteroids, diuretics, and theophylline — monitor potassium levels.

Beta-2 agonists can cause hypokalaemia (particularly at high doses), and this can be increased by other potassium-depleting drugs, such as corticosteroids, loop diuretics, and theophylline.

Digoxin — monitor potassium levels and be alert to signs of digoxin toxicity, such as loss of appetite, nausea, vomiting, bradycardia, visual disturbance, and drowsiness.

Basis for recommendation

These recommendations are based on the textbook Stockley's drug interactions [Baxter, 2010] and the British National Formulary [BNF 59, 2010].

Muscarinic antagonists

Muscarinic antagonists

Choice of muscarinic antagonist

Which muscarinic antagonists are available for COPD?

Short-acting

Ipratropium is licensed for chronic obstructive pulmonary disease (COPD) and is available as a pressurized metered-dose inhaler, a dry powder inhaler and a nebulizer solution.

Ipratropium is also available as a combination product with a short-acting beta-2 agonist.

Combivent® nebulizer solution (ipratropium bromide and salbutamol) is licensed for bronchospasm in COPD.

Long-acting

Tiotropium licensed for COPD and is available as a dry powder inhaler and a soft mist inhaler.

Basis for recommendation

This information is from the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010i; ABPI Medicines Compendium, 2010j] and the British National Formulary [BNF 59, 2010].

Dose of short-acting

What doses of short-acting muscarinic antagonists should I prescribe for COPD?

Ipratropium

Aerosol inhalation — usually 20 micrograms to 40 micrograms, three or four times daily, although some people may need up to four puffs at a time to obtain maximum benefit during early treatment.

Dry powder inhalation — 40 micrograms three to four times daily (may be doubled in people who are less responsive).

One Atrovent Aerocap® is equivalent to two puffs of Atrovent® metered aerosol inhalation.

Nebulized solution — 250 micrograms to 500 micrograms (one vial of 250 micrograms of ipratropium Bromide per mL or one vial of 500 micrograms of ipratropium Bromide in 2 mL) three to four times daily.

If dilution is necessary, use sterile sodium chloride 0.9%.

The recommended doses may vary slightly for the different brands available. Doses for specific brands can be found in the manufacturers' Summaries of Product Characteristics.

Combivent ® (salbutamol plus ipratropium)

Nebulizer solution — 2.5 mL (one vial) three or four times daily.

Basis for recommendation

This information is from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010j] and the British National Formulary [BNF 59, 2010].

Dose of long-acting

What doses of long-acting muscarinic antagonists should I prescribe for COPD?

Tiotropium

Inhalation powder, hard capsule (18 micrograms tiotropium bromide monohydrate) for use with Handihaler® device — 18 micrograms once daily (at the same time of the day).

Nebulized solution (Spiriva Respimat®) — 5 micrograms (two puffs) once daily (at the same time of the day).

Spiriva Respimat® should be reserved for use in people with chronic obstructive pulmonary disease who have difficulties using the Handihaler® device.

Basis for recommendation

This information is from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010i].

Cautions

When should antimuscarinics be used with caution?

Antimuscarinics should be used with caution in:

Men with prostatic hyperplasia and bladder-outflow obstruction — worsened urinary retention has been reported in elderly men.

People with moderate to severe renal failure (creatinine clearance of 50 mL per minute or less) — because of the risk of drug toxicity.

People with angle-closure glaucoma — nebulized mist of anticholinergic drugs can precipitate or worsen acute closed-angle glaucoma. This may also occur with aerosols or dry powders if these agents accidentally get into the eyes.

Advise people to use a mouthpiece rather than a mask with a nebulizer, if possible, to minimize exposure of the eyes to the drug.

Advise people on correct administration of dry powder and aerosol inhalers to avoid accidental release of the contents into the eye.

Advise people with angle-closure glaucoma who are using muscarinic antagonists to stop and consult a specialist immediately if they experience eye pain or discomfort, visual halos or coloured images, or temporary blurring of vision.

People with cardiac rhythm disorders — the Spiriva Respimat® formulation should be used with caution.

Basis for recommendation

This recommendation is based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010i], the British National Formulary [BNF 59, 2010], and a drug reference database [Micromedex, 2010], except for the recommendation regarding cardiac rhythm disorders.

Cardiac rhythm disorders

The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that a recent safety study found a non statistically significant increase in all cause mortality with the Spiriva Respimat® formulation. Conversely, a double-blind randomized controlled trial showed a non-statistically significant decrease in all-cause mortality with the Spiriva Handihaler®. There were differences in the baseline characteristics of these study populations. While further studies are ongoing to investigate these differences and whether there is a causal link, the Spiriva Respimat® should be used with caution in people with known cardiac disorders [MHRA, 2010].

A recent systematic review and meta-analysis of randomized controlled trials found that compared with placebo, Spiriva Respimat® 5 micrograms/day was associated with a statistically significant increased risk of mortality [Singh et al, 2011]. A two–year head to head study between Spiriva Respimat® and Spiriva Handihaler® is ongoing to help clarify the situation.

Adverse effects

What are the adverse effects of antimuscarinics?

Antimuscarinics are poorly absorbed systemically and are well tolerated. Their adverse effects include:

Dry mouth.

Abnormal taste in the mouth.

Nasal congestion.

Dryness of nasal mucosa.

Acute angle-closure glaucoma has been reported in people on nebulized ipratropium.

Use a mouthpiece rather than a mask with a nebulizer, if possible, to minimize exposure of the eyes to the drug.

Advise people on correct administration of dry powder and aerosol inhalers to avoid accidental release of the contents into the eye.

Advise people with angle-closure glaucoma who are using muscarinic antagonists to stop and consult a specialist immediately if they experience eye pain or discomfort, visual halos or coloured images, or temporary blurring of vision.

Basis for recommendation

This information is from a drug reference database [Micromedex, 2010] and the British National Formulary [BNF 59, 2010].

Drug interactions

What drug interactions are important with tiotropium?

There are no important drug interactions with muscarinic antagonists.

Concurrent use of tiotropium bromide with other anticholinergic-containing drugs is not recommended because it has not been studied.

Basis for recommendation

This recommendation is based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010a].

Inhaled corticosteroids

Inhaled corticosteroids

Choice of inhaled corticosteroid

What inhaled corticosteroids are available?

Inhaled corticosteroids should not be prescribed alone in people with chronic obstructive pulmonary disease (COPD) — they should always be prescribed in combination with a long-acting bronchodilator.

Inhaled corticosteroid preparations licensed for the management of COPD include:

Symbicort Turbohaler ® (budesonide plus formoterol)

Symbicort Turbohaler® is available in three strengths. However, only Symbicort® 200/6 and Symbicort® 400/12 are licensed for symptomatic treatment of people with severe COPD (forced expiratory volume in 1 second [FEV1] less than 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular treatment with long-acting bronchodilators.

Seretide Accuhaler® (fluticasone propionate and salmeterol)

Seretide Accuhaler® is available in three different strengths. However, only Seretide 500 Accuhaler® (50 micrograms salmeterol and 500 micrograms fluticasone propionate) is licensed for the treatment of COPD in people with FEV1 less than 60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy.

Consider issuing a steroid treatment card to:

People using prolonged high doses of inhaled corticosteroids (including off-label high doses, and maximum inhaled doses in conjunction with oral corticosteroids).

People taking inhaled corticosteroids plus drugs that inhibit their metabolism (for example cytochrome P450 inhibitors, such as HIV protease inhibitors).

Basis for recommendation

This information is from the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], a drug reference database [Micromedex, 2010], and information produced by the Commission on Human Medicines [CHM, 2006].

Steroid cards should be routinely given to people who require long-term treatment with high doses of inhaled corticosteroids. This includes [CHM, 2006]:

People using prolonged high doses of inhaled corticosteroids (off-label high doses, or maximum doses in conjunction with oral corticosteroids).

People taking inhaled corticosteroids plus drugs that inhibit their metabolism (for example cytochrome P450 inhibitors, such as HIV protease inhibitors).

The information on Symbicort Turbohaler® and Seretide Accuhaler® are from the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2010g; ABPI Medicines Compendium, 2010h; ABPI Medicines Compendium, 2010f].

Cautions, adverse effects, interactions

What are the contraindications, cautions, adverse effects, drug interactions, and recommended monitoring for inhaled corticosteroids?

See the sections on Contraindications and cautions, Adverse effects, and Drug interactions in the CKS topic on Corticosteroids - inhaled.

There is a small (but real) risk of non-fatal pneumonia in people with chronic obstructive pulmonary disease treated with inhaled corticosteroids.

Basis for recommendation

The information on non-fatal pneumonia is based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010].

Oral corticosteroids

Oral corticosteroids

Prescribing issues

What issues need to be considered when prescribing oral corticosteroids?

Short courses of systemic corticosteroids are commonly used for acute exacerbations of chronic obstructive pulmonary disease (COPD).

Maintenance use of oral corticosteroid therapy in COPD is not normally recommended. However, some people with advanced COPD may require maintenance oral corticosteroids when these cannot be withdrawn after an exacerbation. In these cases, the dose of oral corticosteroids should be kept as low as possible.

People on long-term treatment with oral corticosteroids should be given a steroid card, which gives guidance on minimizing risk and provides details of prescriber, drug, dosage, and duration of treatment.

See the sections on Contraindications and cautions, Adverse effects, Drug interactions, and Monitoring in the CKS topic on Corticosteroids - oral.

Basis for recommendation

This recommendation is based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], and a drug reference database [Micromedex, 2010].

Short courses of systemic corticosteroids are commonly used for acute exacerbations of COPD, despite limited evidence of clinical benefit. However, a systematic review concluded that the benefit from corticosteroid therapy is evident within the first day and lasts for at least 5 days of therapy, although there is no evidence suggesting an advantage to courses for longer than 2 weeks [Micromedex, 2010].

The recommendation on a steroid card is based on information produced by the Commission on Human Medicines [CHM, 2006] and from the British National Formulary [BNF 59, 2010].

Delivery systems

Delivery systems

Choosing delivery systems

What issues do I need to consider when choosing delivery systems?

When choosing a delivery system for inhaled medications, consider:

The ability of the person to develop and maintain an effective technique with the specific device — this may depend on such factors as age, dexterity, coordination, and inspiratory flow.

When used alone, a standard pressurized metered-dose inhaler is rarely appropriate for elderly people, as many have poor inhaler technique. The addition of a large-volume spacer improves both acquisition and retention of drug and allows carers to assist those people with cognitive impairment or physical disabilities affecting hand function.

The suitability of the device to the person's (and carer's) lifestyle, considering such factors as portability and convenience.

The person's preference for, and willingness to use, a particular device.

The medication (and dose) being prescribed.

A spacer should be used by people on high-dose inhaled corticosteroids.

A mouthpiece, rather than a mask, should be used with a nebulizer if possible.

Cost — choose the device with the lowest overall cost (taking into account the daily required dose and product price per dose).

Good technique is essential in ensuring optimum use of inhaler devices. Only prescribe the inhaler after the person (or their carer) has received training in its use and has demonstrated an acceptable technique.

Repeated checks are essential, as poor technique, even after training, is common.

Some frail people cannot consistently achieve the minimum inspiratory flow rate required for use of dry-powder devices or breath-actuated metered-dose inhalers.

Basis for recommendation

Factors guiding the choice of a delivery system are based on published expert opinion [MeReC, 2002; Dolovich et al, 2005] and a guideline produced by the Scottish Intercollegiate Guidelines Network and British Thoracic Society [SIGN and BTS, 2008].

Spacer devices

What do I need to know about spacer devices?

A standard metered-dose inhaler (MDI) is rarely appropriate for elderly people when used without a large-volume spacer. The spacer improves acquisition and retention of technique; it also allows carers to help people with cognitive impairment or with functional problems.

Spacers are plastic devices with a mouthpiece at one end and a hole for a pressurized metered-dose inhaler (pMDI) to be inserted at the other.

They are not interchangeable and must be compatible with the pMDI used.

The drug is administered by single-dose actuations from the pMDI into the spacer, with each actuation followed by inhalation.

There should be minimal delay between inhaler actuation and inhalation, as the drug aerosol is very short-lived.

Tidal breathing can be used, as it is as effective as single breaths.

Advantages of spacers include:

They require less coordination than use of a pMDI alone.

They slow down the particles of the drug and allow more time for evaporation of the propellant, so that more of the drug can be inhaled.

They increase the proportion of the drug delivered to the airways and reduce the amount of drug deposited in the oropharynx (thereby reducing local adverse effects and reducing the amount of systemic absorption).

They are useful in people needing high doses of inhaled steroids and people with poor inhalation technique.

Spacers should be cleaned monthly by washing in mild detergent and allowing to air dry (without rinsing). The mouthpiece should be wiped clean of detergent before use. They should be replaced every 6–12 months.

Basis for recommendation

This information is from a guideline produced by the Scottish Intercollegiate Guidelines Network and British Thoracic Society [SIGN and BTS, 2008]. The recommendation on cleaning the spacer device is from the British National Formulary [BNF 59, 2010].

Nebulizers and nebulizer solutions

What do I need to know about nebulizers and nebulizer solutions?

The main advantages of a nebulizer is that no coordination is required by the user, and high doses of drug can be delivered to the airways.

Nebulizers are not suitable for people who cannot develop or maintain satisfactory inhaler technique, as loading and operating the nebulizer requires physical and cognitive skills.

People with distressing or disabling breathlessness despite maximal inhaled drug treatment and people requiring large doses of inhaled bronchodilators may benefit from a nebulizer for home use.

Refer for assessment by a respiratory specialist before prescribing a nebulizer.

Only continue with a nebulizer if the person experiences at least one of the following:

A reduction in symptoms.

An increase in the ability to undertake activities of daily living.

An increase in exercise capacity.

An improvement in lung function.

Warn people using nebulized bronchodilators that it is dangerous to exceed the prescribed dose, and that they should seek medical advice if they do not respond to the usual dose. The dose of a bronchodilator given by nebulization is usually much higher than from an aerosol inhaler.

For people with hypercapnia, the nebulizer should be driven by air. If oxygen is required, it should be given simultaneously by nasal cannula.

The performance of nebulizers and compressors varies considerably. It is important to ensure that the nebulizer used complies with European standard EN 13544–1:2001. Complementary equipment, including tubing and connectors, also needs to comply with European standards.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010] and the British National Formulary [BNF 59, 2010].

Mucolytics

Mucolytics

Doses

What doses of mucolytics are commonly prescribed?

Two oral mucolytics are available and are licensed for use in people with chronic obstructive pulmonary disease.

Carbocisteine

The manufacturers recommend a starting dose of 2250 mg in divided doses, reducing to 1500 mg daily in divided doses when a satisfactory response is obtained (for example two 375 mg capsules three times a day reducing to one 375 mg capsule four times a day).

Mecysteine hydrochloride

The starting dose is 200 mg four times a day for 2 days; then 200 mg three times a day for 6 weeks.

Once a satisfactory improvement in sputum viscosity and expectoration has been achieved, the dose should be reduced to 200 mg twice a day.

Basis for recommendation

This information is from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010l] and the British National Formulary [BNF 59, 2010].

Contraindications and cautions

What contraindications and cautions are important with mucolytics?

Contraindications

Carbocisteine — avoid in people with active peptic ulceration, and in the first trimester of pregnancy.

Mecysteine hydrochloride — avoid in pregnancy and breastfeeding.

Cautions

Mucolytics should be used with caution in people with a history of peptic ulceration.

Carbocisteine — use with caution in pregnancy.

Basis for recommendation

This information is from the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2010l] and the British National Formulary [BNF 59, 2010].

Theophylline and aminophylline

Theophylline and aminophylline

Brand names

How should theophylline and aminophylline be prescribed?

Prescribe theophylline and aminophylline by brand name.

A person discharged from hospital should be maintained on the brand of aminophylline or theophylline on which they were stabilized as an inpatient.

Basis for recommendation

This recommendation is based on the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], and the textbook Stockley's drug interactions [Baxter, 2010].

Because of bioavailability differences between brands, people should be maintained on the same brand of aminophylline or theophylline. To assist this, the brand should be specified on the prescription [Baxter, 2010].

Dose

What dose of theophylline and aminophylline should I prescribe for COPD?

Theophylline

Nuelin SA®

SA 175 tablet (modified-release theophylline 175 mg) — 175 mg twice daily, increasing to 350 mg if necessary.

SA 250 tablets (modified-release, scored theophylline 250 mg) — 250 mg twice daily, increasing to 500 mg if necessary.

Slo-Phyllin® modified-release capsules — 250 mg to 500 mg every 12 hours.

Uniphyllin Continus® modified-release tablets — 200 mg every 12 hours. This may be titrated to either 300 mg or 400 mg dependent on the therapeutic response.

Consider prescribing a larger evening or morning dose to achieve optimum therapeutic effect when symptoms are most severe.

In people not currently receiving theophylline whose night-time or daytime symptoms persist despite other treatment, the total daily requirement may be given as a single evening or morning dose.

Aminophylline

Phyllocontin Continus® (modified release aminophylline hydrate 225 mg) — one tablet twice daily, increased after 1 week to two tablets twice daily according to plasma-theophylline concentration.

Other brands of modified-release aminophylline 225 mg include Norphyllin® SR.

Phyllocontin Forte® (modified-release aminophylline hydrate 350 mg) — one tablet twice daily, increased after 1 week to two tablets twice daily if necessary.

Phyllocontin Continus® Forte tablets are suitable for smokers and other people in whom theophylline will have a shorter half-life.

Basis for recommendation

This information is from the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2010b; ABPI Medicines Compendium, 2010c; ABPI Medicines Compendium, 2010d] and the British National Formulary [BNF 59, 2010].

Monitoring

How should theophylline and aminophylline be monitored?

Before starting aminophylline or theophylline, check:

Urea and electrolyte levels (paying particular attention to potassium levels).

Liver function tests.

Once the person is maintained on theophylline or aminophylline, check drug plasma levels:

Routinely every 6–12 months.

Check more regularly in elderly people or those with heart failure or liver impairment.

At least 3 days after any dose adjustments.

If an enzyme-inhibiting drug is prescribed (raises plasma levels) or if an enzyme-inducing is prescribed (lowers plasma levels).

If the person stops smoking (as a dose reduction may be necessary).

Check potassium levels regularly in:

People with severe asthma.

People taking beta2-agonists, corticosteroids, or diuretics — theophylline and aminophylline can potentiate hypokalaemia resulting from these drugs.

People who are hypoxic — theophylline and aminophylline can potentiate hypokalaemia resulting from hypoxia.

Basis for recommendation

These recommendations are based on monitoring guidance published by the London and South East Medicines Information Service [London and South East Medicines Information Service et al, 2008], the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2010b], and the British National Formulary [BNF 59, 2010].

Aminophylline and theophylline plasma levels may be increased in elderly people or those with heart failure or liver impairment. Plasma levels may also be increased in people on enzyme-inhibiting drugs.

Aminophylline and theophylline plasma levels may be decreased in people who smoke, and in people who consume a lot of alcohol. Plasma levels may also be decreased in people on enzyme-inducing drugs.

The recommendation to check potassium levels in people with severe asthma is based on monitoring guidance published by the London and South East Medicines Information Service [London and South East Medicines Information Service et al, 2008].

The Commission on Human Medicines (formerly the Commission on Safety of Medicines) has advised that potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is required in severe asthma, because this effect may be potentiated by concomitant treatment with theophylline and its derivatives, corticosteroids, and diuretics, and by hypoxia. Plasma potassium concentration should therefore be monitored in severe asthma.

Cautions

When should aminophylline and theophylline be used with caution?

Aminophylline and theophylline should be used with caution in people with:

Cardiovascular disease (cardiac arrhythmias and severe hypertension).

Hepatic impairment.

Hypertension.

Hyperthyroidism.

Peptic ulcers.

Epilepsy.

Basis for recommendation

This information is from the National Institute for Health and Care Excellence (NICE) clinical guideline Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010; NICE, 2010], and the British National Formulary [BNF 59, 2010].

Particular caution needs to be observed with the use of aminophylline or theophylline in elderly people because of differences in pharmacokinetics, increased likelihood of comorbidities, and the use of other medications [NICE, 2010].

Adverse effects

What important adverse effects are associated with aminophylline and theophylline?

The adverse effects of aminophylline and theophylline include nausea (most common), vomiting, tremor, headache, central nervous system stimulation, insomnia, palpitations, arrhythmias, and rarely convulsion.

Adverse effects can occur within a plasma aminophylline or theophylline concentration of 10 mg/L to 20 mg/L. However, a plasma concentration in this range is required in most people to achieve a satisfactory clinical effect.

Both the frequency and severity of adverse effects increase when plasma concentrations of aminophylline or theophylline are above 20 mg/L.

Basis for recommendation

This information is from a drug reference database [Micromedex, 2010] and from the British National Formulary [BNF 59, 2010].

Drug interactions

What drug interactions are important with theophylline and aminophylline?

The following drug interactions are important with theophylline and aminophylline.

Over-the-counter preparations — cough and decongestant preparations containing theophylline, such as Do-Do Chesteze®, Franol®, and Franol Plus®, will increase plasma levels of theophylline.

Beta2-agonists — hypokalaemia may be potentiated by concomitant treatment with beta2-agonists.

Benzodiazepines — effect of benzodiazepines may be reduced by concomitant treatment with theophylline.

Corticosteroids — hypokalaemia may be potentiated by concomitant treatment with corticosteroids.

Diuretics — hypokalaemia may be potentiated by concomitant treatment with acetazolamide or loop or thiazide diuretics.

Doxapram — increased central nervous system stimulation may occur with concomitant treatment.

Lithium — excretion of lithium may be potentiated by concomitant treatment with theophylline.

Quinolones — increased risk of convulsions with concomitant treatment with theophylline.

Plasma levels of theophylline and aminophylline can also be altered by concomitant use with liver enzyme-inhibiting drugs or liver enzyme-inducing drugs.

For more information on drug interactions with theophylline and aminophylline, see the British National Formulary.

Basis for recommendation

These recommendations are based on the textbook Stockley's drug interactions [Baxter, 2010] and the British National Formulary [BNF 59, 2010].

Drugs that raise plasma levels

Liver enzyme-inhibiting drugs

If people who are stabilized on aminophylline or theophylline begin to take a liver enzyme-inhibiting drugs, the aminophylline or theophylline dose may need to be reduced.

The following liver enzyme inhibiting drugs can raise the plasma levels of theophylline:

Allopurinol.

Azithromycin.

Clarithromycin.

Ciprofloxacin.

Cimetidine.

Diltiazem.

Disulfiram.

Erythromycin.

Estrogen.

Fluvoxamine — avoid concomitant use, but if not possible, halve the theophylline dose and monitor plasma theophylline levels.

Fluconazole.

Isoniazid.

Interferon alfa.

Influenza vaccine.

Ketoconazole.

Methotrexate.

Norfloxacin.

Pentoxifylline (oxpentifylline).

Sucralfate — absorption of theophylline is reduced. Both drugs should be taken at least 2 hours apart.

Verapamil.

Zafirlukast (plasma concentration of zafirlukast is also reduced).

Basis for recommendation

This information is from the British National Formulary [BNF 59, 2010].

Drugs that lower plasma levels

Liver enzyme-inducing drugs

If people who are stabilized on aminophylline or theophylline begin to take a liver enzyme-inducing drug, the aminophylline or theophylline dose may need to be increased.

The following liver enzyme-inducing drugs can lower the plasma levels of theophylline:

Barbiturates.

Carbamazepine.

Phenytoin — plasma concentrations of both theophylline and phenytoin are reduced.

Primidone.

Ritonavir.

Rifampicin.

St John's wort — avoid concomitant use.

Sulfinpyrazone.

Tobacco.

If people who are stabilized on aminophylline or theophylline stop smoking, a dose reduction may be necessary.

Basis for recommendation

This information is from the British National Formulary [BNF 59, 2010].

Antibiotics

Antibiotics

Amoxicillin and co-amoxiclav

Amoxicillin and co-amoxiclav

Contraindications and cautions

What contraindications and cautions are associated with amoxicillin and co-amoxiclav?

Contraindications

Amoxicillin and co-amoxiclav should not be taken by people who have an allergy to penicillin.

Gastrointestinal adverse effects alone (nausea, vomiting, or diarrhoea) do not constitute an allergy to penicillin.

Caution

Co-amoxiclav should be used with caution in people with:

Liver impairment.

Hypersensitivity to cephalosporins.

Basis for recommendation

This information is from a drug reference database [Micromedex, 2010] and the British National Formulary [BNF 59, 2010].

Co-amoxiclav should be used with caution in people with hypersensitivity to cephalosporins, as there is a risk of cross-sensitivity reactions [Micromedex, 2010].

Adverse effects

What are the adverse effects of amoxicillin and co-amoxiclav?

Amoxicillin

Adverse effects are mainly gastrointestinal and include nausea, vomiting, and diarrhoea. These are usually mild, but if they are severe, consider trying an alternative antibiotic, such as a macrolide or doxycycline.

Co-amoxiclav

Co-amoxiclav may rarely cause cholestatic jaundice during, or shortly after, its use. This is more common in men, in people older than 65 years of age, and with long courses of treatment (over 14 days).

Basis for recommendation

This information is from the Committee on Safety of Medicines [CSM, 1997] and the British National Formulary [BNF 59, 2010].

Drug interactions

What drug interactions are important with amoxicillin and co-amoxiclav?

Allopurinol — be aware of the increased risk of rash when allopurinol given with amoxicillin. It is not necessary to stop either drug if this occurs.

Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of amoxicillin or co–amoxiclav.

However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on Antibiotics in the CKS topic on Contraception - assessment.

Warfarin — monitor the international normalized ratio closely during concomitant use. Any significant changes seem to occur after 4 days of concurrent use.

Methotrexate — consider measuring platelet and white cell counts twice weekly for 2 weeks initially, and measure methotrexate levels if toxicity is suspected.

For more information on drug interactions with amoxicillin and co-amoxiclav, see the British National Formulary.

Basis for recommendation

These recommendations are based on the textbook Stockley's drug interactions [Baxter, 2010] and the British National Formulary [BNF 59, 2010]. The recommendation on contraceptives is from guidelines published by the Faculty of Sexual and Reproductive Health Care [FSRH, 2011].

Doxycyline

Doxycyline

Contraindications and cautions

What contraindications and cautions are important with doxycycline?

Contraindications

Doxycycline should be avoided by pregnant or breastfeeding women, and by people with:

Liver problems.

Systemic lupus erythematosus.

Myasthenia gravis.

Porphyria.

Caution

Sunlight or ultraviolet light exposure should be avoided while taking doxycycline.

Basis for recommendation

This information is from a drug reference database [Micromedex, 2010] and the British National Formulary [BNF 59, 2010].

Exposure to sunlight or ultraviolet light whilst on doxycycline can lead to photosensitivity [Micromedex, 2010].

Adverse effects

What are the adverse effects of doxycycline?

The adverse effects of doxycycline include:

Gastrointestinal adverse effects, such as nausea, vomiting, and diarrhoea. If these are severe, consider trying an alternative antibiotic, such as a macrolide.

Less frequently, doxycycline may cause photosensitivity.

Advise the person to minimize exposure to direct sunlight and to avoid sunlamps during the course of treatment.

Severe adverse effects are unusual with a short course. However, benign intracranial hypertension is a rare but important adverse effect of tetracyclines.

If a person taking doxycyline develops headache and visual disturbances, the drug should be stopped immediately.

Basis for recommendation

This information is from a drug reference database [Micromedex, 2010] and from the British National Formulary [BNF 59, 2010].

Drug interactions

What drug interactions are important with doxycycline?

Phenobarbital, carbamazepine, phenytoin, and primidone — monitor the therapeutic effect of doxycyline, as a dose increase may be necessary.

Metabolism of doxycycline may be accelerated, leading to a reduced plasma concentration.

Rifampicin — monitor the effects of concurrent use and increase the doxycycline dosage as necessary.

Rifampicin may cause a reduction in doxycycline levels, leading to undertreatment.

Sucralfate and antacids — advise the person taking tetracycline to wait at least 2 hours before taking sucralfate or antacids, as these agents can reduce the absorption of tetracyclines.

Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of doxycycline.

However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on Antibiotics in the CKS topic on Contraception - assessment.

For more information on drug interactions with doxycycline, see the British National Formulary.

Basis for recommendation

These recommendations are based on the textbook Stockley's drug interactions [Baxter, 2010] and the British National Formulary [BNF 59, 2010]. The recommendation on contraceptives is from guidelines published by the Faculty of Sexual and Reproductive Health Care [FSRH, 2011].

Erythromycin and clarithromycin

Erythromycin and clarithromycin

Contraindications and cautions

What contraindications and cautions are important with erythromycin and clarithromycin?

Erythromycin should be used with caution in:

People with hepatic and renal impairment — increased risk of erythromycin-associated hearing loss (especially in elderly people).

Elderly people — increased susceptibility to torsades de pointes arrhythmias.

People with myasthenia gravis — erythromycin may aggravate weakness in people with myasthenia gravis.

Clarithromycin should be used with caution in people with:

Hepatic impairment.

Severe renal impairment (creatinine clearance less than 30 mL/min) — reduce the total daily dosage by half to 250 mg once daily or 250 mg twice daily in more severe infections.

Basis for recommendation

The information on cautions is based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2010e] The recommendation to reduce the dose of clarithromycin in severe renal impairment is from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010e].

Adverse effects

What are the adverse effects of macrolides?

Erythromycin commonly causes gastrointestinal adverse effects, especially at higher doses.

If gastrointestinal adverse effects are known to occur, consider prescribing clarithromycin instead, as it usually has milder gastrointestinal adverse effects.

If gastrointestinal adverse effects occur with both erythromycin and clarithromycin and are severe, consider trying an alternative antibiotic, such as doxycyline.

Cardiac arrhythmias have been very rarely reported in people taking erythromycin or clarithromycin.

Basis for recommendation

This information is from a drug reference database [Micromedex, 2010] and from the British National Formulary [BNF 59, 2010].

Drug interactions

What drug interactions are important with erythromycin and clarithromycin?

Terfenadine or astemizole — concomitant use of erythromycin with either astemizole or terfenadine is contraindicated.

Concomitant use of erythromycin with terfenadine or astemizole is likely to result in an enhanced risk of cardiotoxicity with these drugs, as their metabolism is significantly altered.

Drugs metabolized by cytochrome P450 isoenzymes (for example theophylline, carbamazepine, digoxin, warfarin, quinidine, sildenafil, phenytoin, and valproate) — monitor concurrent use and adjust the dose as necessary.

The effects of these drugs may be increased because erythromycin and clarithromycin inhibit cytochrome P450 isoenzymes.

An additional concern is that broad-spectrum antibiotics can reduce the number of bacteria in the gut that produce vitamin K, and thus potentiate the effects of warfarin.

Drugs that can prolong the QT interval (such as antiarrhythmics, antipsychotics, and tricyclic antidepressants) — avoid concomitant use.

Macrolides also prolong the QT interval.

Statins — avoid concomitant use.

The risk of myopathy and rhabdomyolysis is increased, as macrolides can inhibit the metabolism of statins.

Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of erythromycin and clarithromycin.

However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on Antibiotics in the CKS topic on Contraception - assessment.

For more information on drug interactions with macrolides, see the British National Formulary.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2010e] and the British National Formulary [BNF 59, 2010]. In addition:

The recommendation on contraceptives is from guidelines published by the Faculty of Sexual and Reproductive Health Care [FSRH, 2011].

The recommendation on statins is from the British National Formulary [BNF 59, 2010] and a review article [Aronson, 2006].

Evidence

Evidence

Supporting evidence

This section summarizes evidence identified by the full National Institute for Health and Care Excellence (NICE) clinical guideline Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) [National Clinical Guideline Centre, 2010] that supports recommendations about the primary healthcare treatment of people with chronic obstructive pulmonary disease (COPD).

The original NICE guideline on COPD was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010].

CKS has not summarized evidence published subsequently to the search date of the NICE partial update, or new evidence not considered by NICE in its partial update.

Smoking cessation

Evidence on smoking cessation in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on smoking cessation was not reviewed in the updated 2010 guideline, although the NICE clinical guideline on smoking cessation and technology appraisals on varenicline, bupropion, and nicotine replacement therapy were incorporated.

NICE identified one systematic review and three additional randomized controlled trials (RCTs) comparing the effects of smoking cessation in people with COPD with those in people who did not quit smoking. They looked at effects on forced expiratory volume in 1 second (FEV1) and symptoms and concluded that in people who stopped smoking, there was a significant reduction in FEV1 decline and significantly lower prevalence of such symptoms as chronic cough, sputum production, wheezing, and shortness of breath compared with people who continued to smoke (p < 0.0001). In addition, smokers with early COPD who stopped smoking had fewer respiratory symptoms after 5 years of follow up.

The systematic review was specific to COPD and contained five RCTs (6491 participants). Only two of the five RCTs were of high quality, so NICE reviewed them individually.

One of the two studies investigated the effect of sustained-release bupropion compared with placebo in promoting abstinence from smoking in people with mild to moderate COPD.

The other was part of the Lung Health Study [Anthonisen et al, 2005].

The additional RCTs were also part of the Lung Health Study, with the exception of one study that was a NICE Technology Appraisal on smoking cessation treatments and nicotine replacement therapy and was not specific to COPD.

The Lung Health Study was a multicentre RCT of smoking cessation. It was carried out in 10 clinical centres in the United States and Canada, involved 5887 participants, and aimed to assess the effects of smoking cessation on long-term mortality. The participants were followed for 14.5 years.

The intervention group received a 10-week smoking cessation program that included a strong message from a doctor and 12 group sessions using behaviour modification, and nicotine gum, plus either ipratropium or a placebo inhaler. The intervention was compared with usual GP care.

Participants in the intervention groups had a significantly smaller decline in FEV1 compared with the control group. The average decreases from baseline to 5 years were 267 mL for the control group, 209 mL for the smoking intervention group without ipratropium, and 184 mL with ipratropium (p < 0.002).

One of the RCTs (also included in the Lung Health Study) looked at the effects of smoking cessation on chronic cough, chronic phlegm production, wheezing, and shortness of breath. The prevalence of the four symptoms was significantly lower in the two intervention groups than in the usual care group (p < 0.0001).

Short acting bronchodilators

Evidence on short-acting bronchodilators for COPD

Short-acting beta-2 agonists compared with placebo

Evidence on short-acting beta2-agonists compared with placebo in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on short-acting beta2-agonists (SABAs) compared with placebo was not reviewed in the updated 2010 guideline.

NICE identified one systematic review of the regular use (longer than 7 days) of SABAs in people with stable COPD. The review concluded that SABAs improved lung function, reduced breathlessness, and reduced treatment failure compared with placebo.

The systematic review comprised 13 randomized controlled trials (RCTs) (four from the same cohort of patients) and looked at the efficacy of SABAs compared with placebo in people with stable COPD.

Results showed an improvement in forced expiratory volume in 1 second (FEV1) (196 participants; weighted mean difference [WMD] 0.14, 95% CI 0.04 to 0.25; p = 0.008) and breathlessness (94 participants; standardized mean difference [SMD] 1.33, 95% CI 1.01 to 1.65; p < 0.0001) with regular use of SABAs compared with placebo.

No studies reported serious adverse effects during treatment with inhaled beta2-agonists. However, none of the studies were of sufficient length or size to provide meaningful information on long-term occurrence of adverse effects. Large-scale, longer-term studies would be needed to investigate the effect of treatment with regular inhaled beta2-agonists on mortality, disease progression, and adverse effects.

One very small study with 32 participants (included in the systematic review, but not the meta-analysis), showed significant improvements in health-related quality of life, with improvements in breathlessness and fatigue with SABAs.

The majority of evidence for SABAs comes from older (date range 1975–1991), short-term (1–8 weeks' duration), small studies (sample size of 5–48 participants), some of which used older SABAs, such as isoproterenol and metaproterenol.

Short-acting muscarinic antagonists compared with placebo

Evidence on short-acting muscarinic antagonists compared with placebo in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on short-acting muscarinic antagonists compared with placebo was not reviewed in the updated 2010 guideline.

NICE identified three randomized controlled trials (RCTs) comparing short-acting muscarinic antagonists (SAMAs) with placebo in people with COPD. Results showed a significant increase in forced expiratory volume in 1 second (FEV1) with the use of SAMAs compared with placebo. However, the effects of SAMA on breathlessness, health-related quality of life, and the need for rescue medications varied among the trials.

The three trials demonstrated significant increases in FEV1 with the use of SAMAs compared with placebo: p < 0.001, p < 0.026, and p < 0.001.

One trial found that breathlessness was significantly improved with SAMAs compared with placebo. However, two trials found no significant differences for breathlessness or walking distance.

One trial found that health related quality of life was significantly higher for SAMAs compared with placebo (p = 0.007). However, two studies found no significant differences between both groups for quality of life.

The three trials looked at the need for rescue medication, and two found a decrease in use of rescue medication in the SAMA group compared with the placebo group: p < 0.047. One study found no significant difference between the two groups in use of rescue medication.

Long acting bronchodilators

Evidence on long-acting bronchodilators for COPD

Long-acting beta-2 agonist compared with placebo

Evidence on long-acting beta-2 agonists compared with placebo in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on long-acting beta-2 agonists (LABAs) compared with placebo was not reviewed in the updated 2010 guideline.

NICE found a systematic review and seven additional trials comparing LABAs with placebo in people with stable COPD. There was a general improvement in lung function, symptoms, and quality of life with LABAs compared with placebo.

The systematic review included eight randomized controlled trials (RCTs) (two crossover studies and six parallel-group design trials) comparing LABAs with placebo in people with COPD. Studies were predominantly done with salmeterol. The methodological quality of the included studies varied greatly, and only a few of the results could be combined in meta analyses owing to differences in methods of reporting outcomes.

The results of the studies (systematic review and additional trials) are summarized below.

Symptom scores

Within the systematic review, results for symptom scores across four studies varied. However, the largest of the trials demonstrated that LABAs reduced symptom scores: daytime, p = 0.01; night-time, p = 0.001. One of the additional trials also found that symptom scores were reduced (p < 0.001).

Reduction of breathlessness

Five trials in the systematic review found no significant differences between LABAs and placebo. One trial with the largest sample size (674 participants) demonstrated that LABAs reduced the degree of breathlessness produced by exercise.

Two of the additional trials with large sample sizes that demonstrated a statistically significant difference with the use of LABAs in reducing breathlessness (p = 0.002 and p < 0.05).

Use of supplemental short-acting bronchodilators

One study showed a significant reduction in overall use of supplemental salbuterol after treatment with salmeterol compared with placebo (p = 0.045).

The five trials within the systematic review found no significant differences between LABAs and placebo. In one trial with the largest sample size (674 participants), LABAs reduced the need for supplemental short-acting beta-2 agonists in 154 people.

Exacerbations

The systematic review found that LABAs did not significantly affect the incidence of COPD exacerbations compared with placebo; however, this meta-analysis was based on only two RCTs. Another crossover study also included in the systematic review also found no significant difference in exacerbation between the two groups.

Of the additional studies identified by NICE, two found no significant difference in exacerbation. However, two found significant differences favouring LABAs compared with placebo for exacerbations.

A large multicentre trial done over 1 year found that formoterol was significantly superior to placebo for the mean percentage of bad days, which were defined as mild COPD exacerbation (p = 0.008).

Another large multicentre RCT with 1465 participants showed that compared with placebo, salmeterol significantly reduced the number of exacerbations per patient per year and the number of exacerbations that needed treatment with oral corticosteroids. The rate of exacerbations decreased by 20% (p = 0.0027) in the salmeterol group compared with placebo.

Acute episodes of symptom exacerbation that required oral corticosteroids were reduced by 29% in the salmeterol group (p = 0.0003) compared with placebo.

Health-related quality of life

Three studies showed that LABA significantly improved health-related quality of life according to the St George's Respiratory Questionnaire (p < 0.01, p = 0.030, and p = 0.01).

Four other studies also looked at health-related quality of life, and two did not find a statistically significant difference between LABAs and placebo.

Long-acting muscarinic antagonists compared with placebo

Evidence on long-acting muscarinic antagonists compared with placebo in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on long-acting muscarinic antagonists (LAMA) compared with placebo was not reviewed in the updated 2010 guideline.

NICE identified five randomized controlled trials (RCTs) comparing LAMAs with placebo in people with stable COPD. Results showed a significant increase in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in favour of LAMAs compared with placebo.

A 1-year-long RCT with 921 participants found that tiotropium significantly improved morning and evening peak expiratory flow rate (p < 0.005), as well as wheezing and breathlessness (p < 0.05), compared with placebo. The study also found that the proportion of people with COPD experiencing exacerbation was lower in the tiotropium group (36%) than the placebo group (42%), with a reduction of 14% (p < 0.05). The reduction in breathlessness and wheezing was also confirmed by two other studies.

In addition, two of the studies measured breathlessness and both found that LAMAs were superior to placebo (p < 0.001). The studies also found that tiotropium was superior to placebo in improving health-related quality of life (p < 0.05 and p < 0.01), and the use of rescue medication was less in the tiotropium group than the placebo group (p < 0.001 and p < 0.0001).

One study found that people with COPD treated with long-acting anticholinergics had significantly fewer exacerbations per patient-year than the placebo group (p < 0.05). There was no significant difference between the groups in the proportion of patients having at least one exacerbation, but long-acting anticholinergics delayed the time to the first exacerbation (p = 0.001) compared with placebo.

Long-acting muscarinic antagonists compared with short-acting muscarinic antagonists

Evidence on long-acting muscarinic antagonists compared with short-acting muscarinic antagonists in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on long-acting muscarinic antagonists (LAMAs) compared with short-acting muscarinic antagonists (SAMAs) was reviewed in the updated 2010 guideline.

NICE found a 1-year-long randomized controlled trial (RCT) comparing LAMAs with SAMAs in people with stable COPD. The study showed LAMA to be more effective than SAMAs in improving lung function, symptoms and quality of life, and in reducing exacerbations. NICE also reviewed two cost-utility analyses comparing LAMAs with SAMAs. Results showed LAMAs to be more cost effective than SAMAs.

The RCT was done in 535 participants and compared tiotropium with ipratropium in people with stable COPD.

The results showed that LAMAs were superior to SAMAs at:

Improving morning and evening peak expiratory flow rate: p < 0.01.

Improving forced expiratory volume in 1 second (FEV1) and forced vital capacity: p < 0.05.

Reducing breathlessness: p < 0.05.

Improving health-related quality of life, measured using the St George's Respiratory Questionnaire (SGRQ). There were significant improvements in the SGRQ total and impact scores with LAMA compared with SAMA. The mean difference in SGRQ impact score was –4.28 +/– 1.32, 95% CI –6.87 to –1.68; p = 0.001, and the mean difference in total SGRQ score was –3.30 +/– 1.13; 95% CI –5.51 to –1.09; p = 0.004.

The study also found that rescue medications were used less often in the LAMA group than the SAMA group, and the proportion of people who experienced exacerbations was significantly lower in the LAMA group (35%) than the SAMA group (46%): p = 0.014.

The cost-utility analyses found tiotropium to be cost-effective compared with ipratropium in people with COPD. Both studies had several limitations and were judged partially applicable owing to their non-UK perspectives.

On the basis of the evidence, NICE concluded that the clinical use of a once-daily LAMA is preferred to regular use of a SAMA, as it is more cost effective and may improve adherence [National Clinical Guideline Centre, 2010].

Long-acting muscarinic antagonists compared with long-acting beta-2 agonists

Evidence on long-acting muscarinic antagonists compared with long-acting beta2-agonists in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on long-acting muscarinic antagonists (LAMAs) compared with long-acting beta2-agonists (LABAs) was reviewed in the updated 2010 guideline.

NICE identified three randomized controlled trials (RCTs) comparing LAMAs with LABAs in people with COPD. Results showed a statistically significant increase in forced expiratory volume in 1 second (FEV1) with LAMAs compared with LABAs. However, there was no significant difference between the groups in breathlessness or improvement in quality of life. LAMAs or LABAs did not significantly differ for the proportion of people who had exacerbations requiring additional treatment (this included people who were hospitalized for an exacerbation of COPD) or hospitalizations. NICE also reviewed two cost-utility studies (using QALY as the health outcome measure) comparing LAMAs with LABAs in people with stable COPD. This results showed that LAMAs were more cost effective than LABAs in people with COPD.

The RCTs identified were from two articles. One article [Vogelmeier et al, 2008] described an RCT that compared tiotropium (18 micrograms once daily) with formoterol (10 micrograms twice daily). The other article [Brusasco et al, 2003] presented the combined the results of two 6-month RCTs comparing tiotropium (18 micrograms once daily) with salmeterol (50 micrograms twice daily) in people with COPD.

Data from the RCTs were pooled for two outcomes: exacerbations and exacerbations requiring hospitalization.

NICE appraised some of the evidence as very low quality because of the limitations of the trials. All three trials had unclear allocation concealment, and the formoterol trial [Vogelmeier et al, 2008] was open label.

The cost-effectiveness studies, presenting three analyses, found tiotropium to be cost effective compared with salmeterol in people with stable COPD.

One of the analyses found the use of tiotropium to be cost saving and to improve outcomes, with any increase in drug costs completely offset by reduced healthcare resource use.

The other two analyses found that increased drug costs were partially offset by reduced healthcare resource use.

However, all analyses were judged partially applicable owing to their non-UK perspectives and potentially serious limitations.

On the basis of the evidence, NICE concluded that tiotropium and salmeterol are both clinically effective, and there is no strong evidence to make a recommendation in favour of one class of long-acting bronchodilator over another where their use as monotherapy is indicated.

Inhaled corticosteroids as monotherapy

Evidence on inhaled corticosteroids as monotherapy in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on the use of inhaled corticosteroids (ICS) as monotherapy was not reviewed in the updated 2010 guideline.

NICE found one systematic review of ICS monotherapy in people with stable COPD compared with placebo. The only significant benefit was a reduction of around 25% in exacerbation rates in people with more severe COPD (mean forced expiratory volume in 1 second [FEV1] 50% predicted). ICS as monotherapy did not reduce exacerbation rates in people with milder COPD (FEV1 greater than 50%) and had no effect on mortality. ICS were associated with increased adverse effects, such as bruising and oropharyngeal candidiasis. The result of bone mineral density varied among the studies.

The systematic review included nine randomized trials (including four with a systemic corticosteroid run-in phase) and a total of 3976 participants. One of the trials was part of the Lung Health Study [Lung Health Study Research Group, 2000].

Benefits

No significant differences were found between ICS and placebo in terms of mortality rates.

One of the included RCTs found that ICS monotherapy in people with mild COPD (defined as FEV1 greater than 50% and FEV1/FVC [forced vital capacity] ratio less than 70%) had no effect on exacerbation rates.

One of the included RCTs in people with more severe COPD (mean FEV1 of 50% predicted) showed a 25% reduction in median exacerbation rates (1.32 per year on placebo compared with 0.99 per year on fluticasone; p = 0.026) [Burge et al, 2000].

Four RCTs found no significant differences in the annual rate of FEV1 decline.

One RCT comparing inhaled corticosteroid with placebo in people with moderate to severe COPD over 36 months found no significant difference in health status (St George's Respiratory Questionnaire [SGRQ] score) over the first 6 months of the trial. However, SGRQ score deteriorated at a faster rate with placebo, by 3.2 units per year compared with 2.0 units per year with ICS (p = 0.0043).

Harms

ICS compared with placebo was associated with increased rates of oropharyngeal candidiasis (Relative risk [RR] 2.1; 95% CI 1.5 to 3.1) and skin bruising (RR 2.1; 95% CI 1.6 to 2.8). However, definitions of adverse events were different in the individual trials. The systematic review showed no significant differences for cataract or fracture rates. However, follow up was generally of short duration.

One RCT with 328 participants found significantly lower bone density values in the lumbar spine and femur (p < 0.01) in people treated with ICS.

One additional study (which was not included in the systematic review, but was an analysis of a trial that was included) explored bone mineral density in 192 participants with mild COPD (defined as FEV1 greater than 50% and FEV1/FVC [forced vital capacity] ratio less than 70%). It found no significant changes in bone mineral density at any site or fracture rates in the ICS group compared with the placebo group over 3 years.

The Lung Health Study found that the incidence of respiratory symptoms over the preceding 12 months (measured at the 36-month visit) did not significantly differ between the groups, with the exception of breathlessness, which was more frequent in the placebo group (p = 0.02).

Mucolytics

Evidence on mucolytics in stable COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. New evidence on mucolytics was reviewed in the updated 2010 guideline.

NICE updated one systematic review with three additional randomized controlled trials (RCTs) comparing oral mucolytics (carbocisteine, erdosteine, or N-acetylcysteine) with placebo in people with COPD. Although meta-analysis found mucolytics to be associated with a small reduction in frequency of acute exacerbations and a reduction in total number of days of disability in people with chronic bronchitis or COPD, the quality of evidence was low or very low, and benefits may only occur in people who are not receiving other maintenance treatments (for example inhaled corticosteroids). NICE also identified a cost-effectiveness analysis which suggested that mucolytic therapy is cost effective compared with placebo. However, the studies were not of a mucolytic available in the UK, and were in people with chronic bronchitis rather than COPD.

The NICE meta-analysis included up to 7042 people from a systematic review of twenty-eight RCTs, and up to 999 people from the three additional RCTs. NICE excluded studies with less than 6 months of follow up, and not all of the individual studies were included in all of the analyses for each outcome measure (for example the meta-analysis for frequency of exacerbations included 4065 people).

Compared with placebo, mucolytics significantly reduced the frequency of exacerbations (expressed as number of exacerbations per patient per month). Mucolytics also increased the number of people who remained exacerbation free, and increased forced expiratory volume in 1 second (FEV1). There was no significant difference between mucolytics and placebo in terms of hospitalization, change from baseline in health-related quality of life, adverse effects, and death.

The quality of evidence was appraised as low or very low, no beneficial effect was found on quality of life, and there was a high degree of heterogeneity. The reason for the heterogeneity was thought to be that a greater positive effect seemed to be linked to having less treatment with other COPD maintenance therapy. Others limitations were that several studies used N-acetylcysteine (a drug currently without a UK marketing authorization for use as a mucolytic) and that comparisons were with placebo (and not other known effective therapies).

The cost-effectiveness analysis used data from published placebo-controlled trials of N-acetylcysteine as preventive treatment in people with chronic bronchitis.

The analysis found mucolytics (N-acetylcysteine) to be cost effective compared with placebo because they reduce the rate of exacerbations, leading to a reduction in hospitalization and resource use. They are also associated with a reduction in days off sick, leading to a decrease in indirect costs.

The generalizability of the analysis is limited because N-acetylcysteine is unavailable in the UK, and the included studies were in people with chronic bronchitis (that is, they had regular cough with sputum production) rather than COPD.

Combination therapy

Evidence on combination therapy for COPD

LABA plus ICS compared with LABA alone

Evidence on long-acting beta2-agonists plus inhaled corticosteroids compared with long-acting beta2-agonists alone in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on long-acting beta2-agonists (LABAs) plus inhaled corticosteroids (ICS) compared with LABAs alone was reviewed in the updated 2010 guideline.

NICE found one systematic review and one additional randomized controlled trial (RCT) comparing LABA plus ICS with LABAs alone in people with COPD. Outcomes of interest included all-cause mortality, exacerbations, hospitalizations, decline in forced expiratory volume in 1 second (FEV1), and adverse events (pneumonia, fractures, myocardial infarction, arrhythmia, congestive heart failure).

Results showed that overall, compared with LABA alone, people in the LABA plus ICS group had a significant increase in post-dose FEV1) and improvement in health-related quality of life. The LABA plus ICS group also showed a decrease in the proportion of people experiencing one or more exacerbation, a decrease in the rate ratio of exacerbations, and a decrease in the mean rate of exacerbations per patient per year. The people in the LABA plus ICS group had an increase in the risk of pneumonia compared with people in the LABA group. There was no significant difference between LABA plus ICS and LABA alone for exacerbations that require hospitalization, breathlessness, mortality, and the development of cataracts and fractures. NICE also reviewed three economic studies which found LABA plus ICS to be more cost-effective than LABAs alone in people with COPD with FEV1 less than 50% predicted. The studies were judged partially applicable due to their non-UK setting.

The systematic review included 10 RCTs of good methodological quality (7598 participants with severe COPD). Eight studies assessed fluticasone/salmeterol, and two studies budesonide/formoterol. RCTs were included if there was a minimum 6-month follow-up period and the population consisted of adults with stable COPD characterized by no recent infections, no exacerbations, or hospitalizations in the previous month, and a minimum of 10 pack-years of smoking.

Owing to the limitations of the studies, NICE appraised the quality of most of the evidence as low or very low. The evidence for an increase from baseline in post-dose FEV1 (litres) was appraised as moderate quality.

The additional RCT, a post hoc subgroup analysis of the TOwards a Revolution in COPD Health (TORCH) study, compared salmeterol plus fluticasone with salmeterol or placebo or fluticasone in people with COPD, stratified by Global initiative for chronic Lung Disease (GOLD) severity (stage II, III, or IV).

This study focused on the comparison of salmeterol plus fluticasone with placebo, as there was little statistical analysis for the relevant comparison of salmeterol plus fluticasone versus salmeterol. Nevertheless, mortality data were available for the comparison of salmeterol plus fluticasone versus salmeterol in people with GOLD stage II disease (baseline post-bronchodilator FEV1 50% or greater; 1084 participants), GOLD stage III disease (baseline post-bronchodilator FEV1 30% to less than 50%; 1467 participants), and GOLD stage IV disease (baseline post-bronchodilator FEV1 less than 30%; 503 participants).

There was no significant difference between salmeterol plus fluticasone compared with salmeterol for death in people with:

Baseline post-bronchodilator FEV1 less than 30% (very low-quality evidence).

Baseline post-bronchodilator FEV1 30% to less than 50% (very low-quality evidence).

Baseline post-bronchodilator FEV1 50% or greater (very low-quality evidence).

This study had several limitations, including the fact that it was not designed to test for differences between GOLD stages or differences between treatment arms within GOLD stages. The number of people in each GOLD stage was different; and the study was probably underpowered for most comparisons.

The economic studies found LABAs plus ICS to be more cost effective than LABAs alone in people with COPD with FEV1 less than 50% predicted.

One of the three studies found that the use of LABAs plus ICS was cost saving and improved health outcomes, with the additional cost of treatment offset by saving in healthcare resource use.

One study examined the cost-effectiveness of different strategies for using LABAs plus ICS and found that it was cost-effective only when given to people with COPD with an FEV1 less than 50% predicted.

NICE judged the studies partially applicable owing to their non-UK setting.

LABA plus ICS compared with LAMA alone

Evidence on long-acting beta-2 agonists plus inhaled corticosteroids compared with long-acting muscarinic antagonists alone in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on long-acting beta-2 agonists (LABAs) plus inhaled corticosteroids (ICS) compared with long-acting muscarinic antagonists (LAMAs) was reviewed in the updated 2010 guideline.

NICE found one double-blind randomized controlled trial (RCT) comparing LABA plus ICS with LAMAs alone in adults with stable COPD. The primary outcome was mean exacerbations requiring oral corticosteroids, antibiotics, or hospitalization. Results showed that LABAs plus ICS did not significantly differ from LAMAs alone for the primary outcome. Compared with LAMAs alone, LABAs plus ICS significantly increased mean exacerbations requiring antibiotics, decreased mean exacerbations requiring oral corticosteroids, and decreased risk of all-cause mortality. The LABA plus ICS group also showed improved health-related quality of life and increased risk of pneumonia. There was no significant difference between LABAs plus ICS and LAMAs alone for exacerbations requiring hospitalization, change from baseline in post-bronchodilator forced expiratory volume in 1 second (FEV1), and bone disorders.

The RCT compared salmeterol plus fluticasone propionate (50 micrograms/500 micrograms) with tiotropium bromide (18 micrograms) in 1323 participants for 2 years.

The dropout rates for the study were lower in the LABA plus ICS group than the LAMA alone group (35% compared with 42%; p < 0.005). The guideline development group thought the dropout rate was not unexpected in a 2-year study of people with decreased lung function, and that the difference could have been a treatment effect.

NICE appraised most of the evidence as low quality, apart from the evidence on change in primary outcomes and change in post-bronchodilator FEV1, which was thought to be of moderate quality. The evidence on bone disorders was thought to be of very low quality.

LAMA plus LABA compared with LABA alone

Evidence on long-acting muscarinic antagonists plus long-acting beta2-agonists compared with long-acting beta2-agonists alone in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on long-acting muscarinic antagonists (LAMAs) plus long-acting beta2-agonists (LABAs) compared with LABAs alone was reviewed in the updated 2010 guideline.

NICE identified one randomized controlled trial (RCT) comparing LAMAs plus LABAs with LABAs alone in people with COPD. The results of the study showed no strong evidence favouring LAMAs plus LABAs over LABAs alone. NICE identified an additional study that compared people with COPD who were randomized to placebo or tiotropium (18 micrograms once daily) in which both arms had LABAs at baseline. NICE concluded that there might be a benefit in adding LAMAs to LABAs where the person remained symptomatic on LABAs alone.

The RCT was an open-label trial which compared treatment with formoterol (10 micrograms twice daily) plus tiotropium (18 micrograms once daily) with formoterol (10 micrograms twice daily) in 417 adults with stable COPD (6-month follow up).

The results showed that after 6 months, post-bronchodilator forced expiratory volume in 1 second (FEV1) was significantly better in the formoterol plus tiotropium group than the formoterol group. However, there was no significant difference between people receiving tiotropium plus formoterol and those receiving formoterol alone for number of people having exacerbations requiring hospitalization, as well as number of people having exacerbations requiring additional therapy (includes people who had been hospitalized).

The additional study was an unpublished post hoc subgroup analysis of the Understanding the Potential Long Term Impacts on Function with Tiotropium (UPLIFT) trial, which was done in 678 participants. The participants had predominantly moderate to severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] stage II [43%] and GOLD stage III [46%]). There was a higher percentage of men in the tiotropium plus LABA at baseline group than the placebo plus LABA at baseline group (80% compared with 73%, respectively). The tiotropium plus LABA at baseline group also had a longer smoking history than the placebo plus LABA at baseline group (50.2 compared with 47.0 pack-years, respectively).

The results showed that compared with people in the placebo plus baseline LABA group, people in the tiotropium plus baseline LABA group experienced a significantly increased mean post-bronchodilator FEV1 at 1 year (primary outcome), decreased risk of COPD exacerbations (includes hospitalizations), and fewer mean COPD exacerbations per patient-year (includes hospitalizations; expressed as a rate ratio). However, there was no significant difference between people on LABAs at baseline who were randomized to placebo or tiotropium for:

Mean post-bronchodilator FEV1 at 4 years (primary outcome).

Health-related quality of life (measured with the St George's Respiratory Questionnaire [SGRQ]) at 1 year.

Health-related quality of life (measured with the SGRQ) at 4 years.

Mean hospitalizations for COPD exacerbations (expressed as a rate ratio).

Mortality.

In this subgroup analysis, only placebo and tiotropium were randomized; the background LABA was not randomized. It was also unclear whether the subgroup analysis had sufficient statistical power to detect a difference between the two groups.

LAMA plus LABA plus ICS compared with LABA plus ICS

Evidence on triple therapy compared with long-acting beta2-agonists plus inhaled corticosteroids in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on triple therapy compared with long-acting beta2-agonists (LABAs) plus inhaled corticosteroids (ICS) was reviewed in the updated 2010 guideline.

NICE found no published randomized controlled trials (RCTs) for this treatment strategy. However, they identified a suitable, unpublished, post hoc subgroup analysis of the UPLIFT trial that compared people with predominantly moderate to severe COPD randomized to placebo or long-acting muscarinic agents (LAMAs) in which both arms had LABA plus ICS at baseline. The results of the subgroup analysis showed that compared with people in the placebo plus LABA plus ICS group, the triple therapy (LAMA plus LABA plus ICS) group experienced a significantly higher mean post-bronchodilator forced expiratory volume in 1 second (FEV1) at 1 or 4 years, better health-related quality of life at 1 or 4 years, decreased risk of exacerbations, lower rate of COPD exacerbations, and decreased risk of hospitalisation for COPD exacerbations. The groups did not significantly differ for rate of exacerbations requiring hospitalizations and all-cause mortality.

The UPLIFT trial compared people with COPD randomized to placebo or tiotropium (18 micrograms once daily) in which both arms had LABA plus ICS at baseline. The trial recruited 2926 participants with predominantly moderate to severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] stage II [42%] and GOLD stage III [46%]).

Although the two arms were similar at baseline, only placebo and tiotropium were randomized (the background LABA plus ICS arm was not randomized).

NICE appraised most of the evidence as low quality or very low quality.

LAMA plus LABA plus ICS compared with LAMA alone

Evidence on triple therapy compared with long-acting muscarinic antagonists alone in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on triple therapy compared with long-acting muscarinic antagonists (LAMAs) was reviewed in the updated 2010 guideline.

NICE identified one trial done in people with moderate to severe COPD. The participants were randomized to one of three arms: LAMAs plus placebo or LAMAs plus LABAs or triple therapy (LAMAs plus LABAs plus ICS). The results after 1 year showed that triple therapy was significantly better than LAMAs plus placebo at improving health-related quality of life. Triple therapy also significantly reduced hospitalizations for acute exacerbations, compared with LAMAs plus placebo. However, the groups did not differ in terms of the proportion of people with one or more acute exacerbations (including people who were hospitalized) and mean exacerbations per patient year (expressed as a rate ratio). There was also no significant difference between triple therapy compared with LAMAs plus placebo for change from baseline in mean pre-bronchodilator forced expiratory volume in 1 second (FEV1), breathlessness, all-cause mortality, and adverse events (pneumonia leading to mechanical ventilation or death, myocardial infarction, or acute arrhythmia). NICE identified one additional study which found triple therapy not to be cost-effective compared with LAMAs alone.

The Canadian Optimal Therapy of COPD (OPTIMAL) trial, identified by NICE, was a double-blind randomized controlled trial (RCT) that recruited 449 participants and randomized them to tiotropium (18 micrograms once daily) plus placebo inhaler (two puffs twice daily), or tiotropium (18 micrograms once daily) plus salmeterol (25 micrograms per puff, two puffs twice daily), or tiotropium (18 micrograms once daily) plus fluticasone/salmeterol (250/50 micrograms per puff, two puffs twice daily).

The additional study identified by NICE was a prospective, economic analysis which was aimed at determining the cost effectiveness of adding salmeterol or fluticasone plus salmeterol to tiotropium for COPD. It was based on costs and health outcomes from the OPTIMAL trial, and the incremental cost-effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided and per additional quality-adjusted life-year (QALY) between treatments.

The study showed that although participants in the triple therapy group had significantly better quality of life and fewer hospitalizations than people in the tiotropium plus placebo group, these improvements in health outcomes were associated with increased costs. The study found triple therapy not to be cost effective compared with LAMA alone.

The study had potentially serious limitations, including the fact that the drug costs for LABAs plus ICS were based on 250/50 microgram per puff inhaler (two puffs, twice daily). In the UK, this would cost £260 more than using the 500/50 microgram per puff inhaler (one puff, twice daily). A minor limitation was the time frame of 1 year. NICE thought that a longer study would have given more accurate results. However, the authors consider this unlikely to affect results greatly.

LAMA plus LABA plus ICS compared with LABA plus LAMA

Evidence on triple therapy compared with long-acting beta2-agonists plus long-acting muscarinic antagonists in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on triple therapy compared with long-acting beta2-agonists (LABAs) plus long-acting muscarinic antagonists (LABAs) was reviewed in the updated 2010 guideline.

NICE identified one trial (the OPTIMAL trial) comparing triple therapy (LAMAs plus LABAs plus ICS) with LABAs plus LAMAs in people with moderate to severe COPD. At 1 year, there was no significant difference between triple therapy and LAMAs plus LABAs for people with one or more acute exacerbations (primary outcome; includes people who were hospitalized), breathlessness, all-cause mortality, pneumonia leading to mechanical ventilation or death, and myocardial infarction or acute arrhythmia. NICE also identified a cost-effectiveness study which found triple therapy not to be cost effective compared with LAMAs plus LABAs.

The OPTIMAL trial was a double-blind randomized controlled trial (RCT) that recruited 449 participants and randomized them to tiotropium (18 micrograms once daily) plus placebo inhaler (two puffs twice daily), or tiotropium (18 micrograms once daily) plus salmeterol (25 micrograms per puff, two puffs twice daily), or tiotropium (18 micrograms once daily) plus fluticasone/salmeterol (250/50 micrograms per puff, two puffs twice daily).

A limitation of the OPTIMAL trial is that it was not designed or powered to compare tiotropium plus fluticasone plus salmeterol with tiotropium plus salmeterol.

The additional study identified by NICE was a prospective, economic analysis which was aimed at determining the cost effectiveness of adding salmeterol or fluticasone plus salmeterol to tiotropium for COPD. It was based on costs and health outcomes from the OPTIMAL trial and the incremental cost-effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided, and per additional quality-adjusted life-year (QALY) between treatments.

The study showed that although participants in the triple therapy group had significantly better quality of life and fewer hospitalizations than people in the tiotropium plus placebo group, these improvements in health outcomes were associated with increased costs. The study found triple therapy not to be cost-effective compared to LAMA plus LABA.

The study had some limitations.

A potentially serious limitation was that the drug costs of LABAs plus ICS were based on 250/50 micrograms per puff inhaler (two puffs, twice daily). In the UK, this would cost £260 more than using the 500/50 micrograms per puff inhaler (one puff, twice daily).

A minor limitation was the time frame of 1 year. NICE thought that a longer study would have given more accurate results. However, the authors consider this unlikely to affect results greatly.

NICE appraised the study to be partially applicable due to its non-UK setting.

Theophylline

Evidence on theophylline for COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. The new evidence on theophylline was not reviewed in the updated 2010 NICE COPD guideline.

NICE found one systematic review comparing theophylline with placebo in people with stable COPD. NICE also identified a randomized controlled trial (RCT) which compared formoterol, theophylline, and placebo within the same study. In conclusion, NICE suggested that theophylline improves lung function, but there is no statistically significant difference in symptoms (wheeze, dyspnoea, walking distance), use of rescue medication, or exacerbation frequency compared with placebo. Nausea was experienced more often with theophylline (relative risk [RR] 7.67, 95% CI 1.5 to 39.9). However, people preferred theophylline over placebo (RR 2.27, 95% CI 1.47 to 39.94). The RCT had a dropout rate of 39%.

The systematic review included 20 worldwide RCTs of a crossover design with a total sample size of 480 participants and the duration of the studies ranged from 7 to 90 days. The participant's ages ranged from 59 to 69 years, and their concomitant therapy varied from none to any other bronchodilator plus corticosteroid.

The evidence from the systematic review showed a statistically significant improvement in forced expiratory volume in 1 second (FEV1) (weighted mean difference [WMD] 100 mL, 95% CI 40 to 160 mL) and forced vital capacity (FVC) (WMD 210 mL, 95% CI 100 to 320 mL) in favour of theophylline compared with placebo. The treatment group also had a statistically significant improvement in oxygen uptake (VO2 max) (WMD 195 mL/min, 95% CI 113 to 278 mL/min) and improvement in partial pressure of oxygen in arterial blood (PaO2) (WMD 3.18 mmHg, 95% CI 1.23 to 5.13 mmHg), and a statistically significant decrease in partial pressure of carbon dioxide in arterial blood (PaCO2) (WMD –2.36 mmHg, 95% CI –3.52 to –1.21 mmHg) compared with placebo.

The systematic review had several limitations, which may have resulted in an overestimation of the effects of theophylline compared with placebo.

The studies were small in size and lasted for a maximum of only 90 days.

All but two of the studies were double blind, and none were open-label studies.

Eleven studies did not describe the washout periods, so the chances of contamination cannot be excluded.

The RCT was a 12-month open-label study with 854 participants (122 were randomized to placebo and 209 to theophylline).

Results showed that theophylline was significantly more effective at increasing FEV1 than placebo at every time point (p < 0.005), and the difference was clinically relevant at 5, 7, 8, 10, 11, and 12 hours. There were fewer moderate and severe exacerbations over 12 months in the theophylline group compared with placebo (5% versus 8%; p = 0.019), and statistically significant improvements from baseline in the total St George's Respiratory Questionnaire (SGRQ) score over 12 months were seen for theophylline compared with placebo.

The study was limited by the fact that it was short (12 months) and the theophylline arm was open label, and hence both the physicians and participants were aware of the drug intervention. The authors acknowledged this limitation and suspected that it may have contributed to the very high dropout rate associated with the treatment (39%, 25%, and 19% in the theophylline, formoterol, and placebo groups, respectively).

No data were available for health status and mortality with theophylline compared with placebo in people with COPD.

Pulmonary rehabilitation

Evidence on pulmonary rehabilitation for COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. New evidence on the effectiveness and cost-effectiveness of pulmonary rehabilitation was not reviewed in the updated 2010 guideline. However, NICE did review new evidence on the timing of pulmonary rehabilitation.

Benefits and cost-effectiveness

Evidence reviewed by NICE from one Cochrane systematic review and one economic evaluation suggests that pulmonary rehabilitation improves health-related quality of life and exercise capacity. The quality of evidence was considered high.

The Cochrane systematic review compared pulmonary rehabilitation (defined as exercise training for at least 4 weeks with or without education and/or with psychological support) with conventional community care (control), and showed a significant improvement in health-related quality of life [Lacasse et al, 2006]. There was also a small but statistically significant benefit in functional and maximum exercise capacity; however, this result fell slightly below the clinically beneficial threshold for the 6-minute-walk test. These findings were short-term (after rehabilitation had finished), and the longer-term benefits remain uncertain.

No randomized trials were found that examined whether predetermined factors influence a person's response to pulmonary rehabilitation.

One economic evaluation alongside a clinical trial found that pulmonary rehabilitation is cost effective in the outpatient setting compared with usual care.

Timing

NICE re-analyzed the evidence from a systematic review of six randomized controlled trials (RCTs) [Puhan et al, 2005] and one subsequent RCT. They excluded data from one of the RCTs in the systematic review because of its inclusion criteria. NICE found that compared with usual care, people with an exacerbation of COPD who received pulmonary rehabilitation within 1 month of hospitalization had a significantly decreased risk of readmission to hospital, and significantly improved exercise capacity and health-related quality of life. However, the quality of evidence was considered low or very low. NICE identified no relevant health economic studies on the timing of pulmonary rehabilitation.

Compared with people receiving usual care, people with an exacerbation of COPD who received pulmonary rehabilitation within 1 month of hospitalization had:

Significantly decreased risk of readmission to hospital (relative risk 0.43, 95% CI 0.27 to 0.70).

Significantly improved 6-minute walking distance and shuttle walking distance.

Significantly improved health-related quality of life (mean difference 11.14, 95% CI 5.17 to 17.11).

Mortality or exacerbations did not significantly differ between the intervention and control groups.

Oxygen therapy

Evidence on oxygen therapy for COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. New evidence on oxygen therapy was not reviewed in the updated 2010 guideline.

Long-term oxygen therapy (LTOT)

NICE based their recommendations on LTOT on a Royal College of Physicians report, from which they found that two randomized controlled trials showed a survival benefit of LTOT in people with COPD when used for at least 15 hours daily. These RCTs showed conflicting results on whether only certain groups of people with COPD benefit (for example those who hypercapnic or who had had a previous documented episode of oedema indicating cor pulmonale).

Ambulatory oxygen therapy for exercise desaturation

NICE did not identify any evidence on the effectiveness of ambulatory oxygen for people with exercise desaturation.

Short-burst oxygen therapy

Quasi-experimental studies reviewed by NICE found some improvement in exercise capacity and dyspnoea when short-burst oxygen was used before exercise and in people with chronic hypoxaemia due to COPD or interstitial lung disease.

NICE states that the use of short-burst oxygen therapy for people with suspected exercise desaturation has not been specifically studied.

Nutritional factors

Evidence on nutritional factors for COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. New evidence on nutritional factors was not reviewed in the updated 2010 guideline.

NICE included in their review of nutritional factors in people with COPD evidence from one Cochrane systematic review, one additional randomized controlled trial (RCT), and nine cohort studies. Low body mass index (BMI) is associated with worse outcomes (including mortality) compared with normal BMI. Weight loss in people with a low BMI is associated with poorer survival, and weight gain in people with a low or normal BMI results is associated with increased survival. Weight loss or no weight change is associated with increased survival in people with high BMI. There was no evidence that nutritional supplements have any significant benefit.

Evidence from cohort studies found that:

People with COPD and a low BMI have higher mortality (COPD-related and all-cause), poorer lung function (as measured by forced expiratory volume in 1 second [FEV1], FEV1/FVC [forced vital capacity] ratio, and transfer factor [DLCO]), poorer peak exercise performance, and reduced muscular ventilatory strength compared with people with a normal BMI.

Weight loss in people with a low BMI is associated with poorer survival, and weight gain in people with a low or normal BMI is associated with increased survival.

People with a high BMI had better survival if their weight remained stable or decreased.

One Cochrane systematic review of 14 RCTs (including 487 people) [Ferreira et al, 2005] in people with stable COPD found that there was no evidence that simple nutritional support (supplements given for at least 2 weeks) had any significant benefit on the primary outcomes of anthropometric measures (BMI, lean body mass, and body weight) and functional exercise capacity (timed walk test and submaximal or graded exercise) compared with people receiving a normal diet or placebo. There was no significant benefit in secondary outcomes of respiratory mechanics (lung volume and lung function), peripheral muscle function, and quality of life. The evidence on these secondary outcomes was limited to a few studies, and further research is needed to assess the impact of nutritional supplements on quality of life in people with COPD.

One additional small RCT of 28 people found that nutritional supplementation produced weight gain (1.5 kg compared with 0.16 kg in the control group; p < 0.01) in malnourished people with emphysema, but it did not change other indices of wellbeing.

Vaccination

Evidence for vaccination in COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. New evidence on vaccinations was not reviewed in the updated 2010 guideline.

NICE included in their review two retrospective cohort studies (involving three analyses), which found that influenza and pneumococcal vaccinations were associated with reductions in both hospitalization and death rates in elderly people with chronic lung disease.

One cohort study of 1898 elderly people with chronic lung disease compared outcomes for those who were vaccinated with annual influenza with those who were unvaccinated, over three influenza seasons.

The study reported a 52% reduction in hospitalizations for pneumonia and influenza (adjusted risk ratio [RR] 0.48; p = 0.0008) in the vaccinated group compared with the unvaccinated group. There was also a 70% reduction in the risk of death (adjusted RR 0.30; p < 0.001).

For the same cohort, the addition of pneumococcal vaccine compared with no vaccination was associated with an added benefit: 63% (95% CI 29 to 80) reduction in hospitalizations and 81% (95% CI 68 to 88) reduction in risk of death.

In another cohort study of 1989 elderly people with chronic lung disease, pneumococcal vaccine was associated with a 43% reduction in the number of hospitalizations for pneumonia and influenza (adjusted RR 0.57; p = 0.005) and a 29% reduction in the risk for death from all causes (adjusted RR 0.71; p = 0.008) over two influenza seasons [National Collaborating Centre for Chronic Conditions, 2004].

Oral corticosteroids for exacerbations

Evidence on oral corticosteroids for exacerbations of COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. New evidence on the management of exacerbation was not reviewed in the updated 2010 guideline.

NICE identified three systematic reviews and one subsequent randomized controlled trial, which found only limited evidence of benefit from oral corticosteroids for exacerbations of COPD.

NICE noted limitations to the validity and generalizability of several of the included studies.

A significant effect was demonstrated in favour of oral/systemic corticosteroids over placebo for forced expiratory volume in 1 second (FEV1) for at least 3 days, with some of the studies findings benefits for up to 5 days.

Individual studies also found benefits in positive pressure of oxygen in arterial blood (PaO2).

There were conflicting findings on the effect on duration of hospitalization, and no difference in mortality was demonstrated.

People taking corticosteroids were more likely to have adverse effects (for example hyperglycaemia).

Antibiotics for exacerbations

Evidence on antibiotics for exacerbations of COPD

The original National Institute for Health and Care Excellence (NICE) guideline on chronic obstructive pulmonary disease (COPD) was published in 2004 [National Collaborating Centre for Chronic Conditions, 2004]. In 2010, NICE published an updated version of this guideline, in which they considered new evidence on specific clinical questions only [National Clinical Guideline Centre, 2010; NICE, 2010]. New evidence on the management of exacerbation was not reviewed in the updated 2010 guideline.

NICE identified one meta-analysis, one subsequent small RCT, and one large cohort study on the effects of antibiotics in exacerbations of COPD. NICE also identified a pharmacoeconomic review. Overall, antibiotics seem to be beneficial, although benefits may only occur in people with more severe exacerbations.

In the meta-analysis of nine trials identified by NICE, a small but statistically significant effect was found favouring antibiotics over placebo in people with exacerbations of COPD (effect size 0.22, 95% CI 0.1 to 0.34).

Three studies found that the benefit from antibiotics was associated with the severity of the exacerbation. One study demonstrated that people with increased amount and purulence of sputum and dyspnoea benefited most from antibiotics, whereas people meeting none of these criteria did not show any benefit.

The subsequent small RCT was in people who were ventilated, and so is not generalizable to primary care populations.

The cohort study of 26,301 people who had been hospitalized in the previous 30 days found a lower odds for all-cause mortality in people who had used antibiotics within 30 days of hospitalizations compared with those who had not.

The pharmacoeconomic review found too few appropriately designed economic evaluations to make any conclusions about cost-effectiveness of antibiotics for COPD exacerbations.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on the primary care management of chronic obstructive pulmonary disease, with additional searches in the following areas:

Lifestyle advice

Advice on Flying

Cor pulmonale

Palliative care at end of life stage

Search dates

Medline and Embase

January 2007 – July 2010

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Pulmonary Disease, Chronic Obstructive/, exp Bronchitis, Chronic/, chronic bronchitis.tw., exp Pulmonary Emphysema/, copd.tw., Chronic Obstructive pulmonary Disease.tw., exp Lung Diseases, Obstructive/, chronic obstructive airways disease.tw., chronic obstructive airway disease.tw.,

Cor pulmonale.tw, exp Hypertension, Pulmonary/, exp Pulmonary Heart Disease/,

exp Furosemide/

exp Adrenergic beta-Agonists/

exp Muscarinic Antagonists/

exp Cholinergic Antagonists/

inhaled corticosteroid$.tw

exp Anti-Bacterial Agents/

exp Life Style/, exp Diet/, exp Exercise/

exp Aerospace Medicine/

exp Terminal Care/, exp Withholding Treatment/, exp Palliative Care/, exp Terminally Ill/

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

NICE Evidence

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Royal Australian College of General Practitioners

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

BMJ Clinical Evidence

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

References

Abernethy, A.P., Uronis, H.E., Wheeler, J.L. and Currow, D.C. (2009) Management of dyspnea in patients with chronic obstructive pulmonary disease. Wiener Medizinische Wochenschrift 159(23-24), 583-590. [Abstract]

ABPI Medicines Compendium (2007a) Summary of product characteristics for Erythrocin 250 tablets. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2007b) Summary of product characteristics for Atrovent aerocaps. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk

ABPI Medicines Compendium (2009a) Summary of product characteristics for Phyllocontin Continus tablets 225mg, Phyllocontin Forte Continus tablets 350mg. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2009b) Summary of product characteristics for Combivent metered aerosol. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk

ABPI Medicines Compendium (2009c) Summary of product characteristics for Atrovent UDVs. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2009d) Summary of product characteristics for Ventolin evohaler. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010a) Summary of product characteristics for Spiriva 18 microgram inhalation powder, hard capsule. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010b) Summary of product characteristics for Nuelin SA 175 mg tablets. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010c) Summary of product characteristics for Slo-Phyllin 60mg, 125mg, 250mg, capsules. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010d) Summary of product characteristics for Uniphyllin Continus tablets. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010e) Summary of product characteristics for Klaricid 250mg tablets. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010f) Summary of product characteristics for Seretide 100, 250, 500 Accuhaler. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010g) Summary of product characteristics for Symbicort Turbohaler 200/6 inhalation powder. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010h) Summary of product characteristics for Symbicort Turbohaler 400/12, inhalation powder. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010i) Summary of product characteristics for Spiriva Respimat 2.5 micrograms solution for inhalation. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010j) Summary of product characteristics for Combivent UDVs. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010k) Summary of product characteristics for Onbrez Breezhaler 150 and 300 microgram inhalation powder, hard capsules. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2010l) Summary of product characteristics for Mucodyne capsules, syrup and paediatric syrup. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2011) Summary of product characteristics for Bricanyl Turbohaler, 0.5mg/dose, inhalation powder. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

Abramson, M.J., Schattner, R.L., Sulaiman, N.D. et al. (2010) Do spirometry and regular follow-up improve health outcomes in general practice patients with asthma or COPD? A cluster randomised controlled trial. Medical Journal of Australia 193(2), 104-109. [Abstract]

American Thoracic Society (1995) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 152(5 Pt 2), S77-S121. [Free Full-text]

American Thoracic Society Committee (2002) ATS statement: guidelines for the six-minute walk test. American Journal of Respiratory and Critical Care Medicine 166(1), 111-117. [Free Full-text]

Anthonisen, N.R., Skeans, M.A., Wise, R.A. et al. (2005) The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Annals of Internal Medicine 142(4), 233-239. [Abstract] [Free Full-text]

Aronson, J.K. (Ed.) (2006) Meyler's side effects of drugs. The international encyclopedia of adverse drug reactions and interactions. Volume 4: J-O. 15th edn. Amsterdam: Elsevier.

Bach, P.B., Brown, C., Gelfand, S.E. and McCrory, D.C. (2001) Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Annals of Internal Medicine 134(7), 600-620. [Abstract]

Barnett, M. (2008) Management of end-stage chronic obstructive pulmonary disease. British Journal of Nursing 17(22), 1390-1394. [Abstract]

Baxter, K. (Ed.) (2010) Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management. 9th edn. London: Pharmaceutical Press.

BMA (2007) Mental Capacity Act: guidance for GPs. British Medical Association. www.gp-training.net [Free Full-text]

BMA (2008) Mental Capacity Act tool kit: guidance from the British Medical Association. British Medical Association. www.bma.org.uk

BMA (2009) The Mental Capacity Act 2005: guidance for health professionals. British Medical Association. www.bma.org.uk

BMA and NHS Employers (2011) Summary of 2011/12 QOF indicator changes, points and thresholds. BMA and NHS Employers. www.nhsemployers.org [Free Full-text]

BMA and NHS Employers (2012) Quality and outcomes framework for 2012/13. Guidance for PCOs and practices. BMA and NHS Employers. www.bma.org.uk [Free Full-text]

BMA and NHS Employers (2013) Summary of QOF changes for 2013/14 in England. British Medical Association and NHS Employers. www.nhsemployers.org [Free Full-text]

BNF 59 (2010) British National Formulary. 59th edn. London: British Medical Association and Royal Pharmaceutical Society of Great Britain.

Booth, S., Wade, R., Johnson, M. et al. (2004) The use of oxygen in the palliation of breathlessness. A report of the expert working group of the Scientific Committee of the Association of Palliative Medicine. Respiratory Medicine 98(1), 66-77. [Abstract]

Bradley, B., Branley, H.M., Egan, J.J. et al. (2008) Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 63(Suppl 5), 1-58.

British Thoracic Society (1997) BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 52(Suppl 5), S1-S28. [Free Full-text]

British Thoracic Society (2001) Pulmonary rehabilitation. British Thoracic Society. www.brit-thoracic.org.uk [Free Full-text]

British Thoracic Society (2004) Managing passengers with respiratory disease planning air travel: British Thoracic Society recommendations. British Thoracic Society. www.brit-thoracic.org.uk [Free Full-text]

British Thoracic Society (2006) Clinical component for the home oxygen service in England and Wales. British Thoracic Society. www.brit-thoracic.org.uk [Free Full-text]

British Thoracic Society (2008) Guideline for emergency oxygen use in adult patients. British Thoracic Society. www.brit-thoracic.org.uk [Free Full-text]

Brusasco, V., Hodder, R., Miravitlles, M. et al. (2003) Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 58(5), 399-404. [Abstract] [Free Full-text]

Burge, P.S., Calverley, P.M.A., Jones, P.W. et al. (2000) Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 320(7245), 1297-1303. [Abstract] [Free Full-text]

Canadian Thoracic Society Workshop Group (1992) Guidelines for the assessment and management of chronic obstructive pulmonary disease. Canadian Medical Association Journal 147(4), 420-428. [Abstract] [Free Full-text]

CHM (2006) High dose inhaled steroids: new advice on supply of steroid treatment cards. Current Problems in Pharmacovigilence 31(May), 5. [Free Full-text]

Coventry, P.A., Grande, G.E., Richards, D.A. and Todd, C.J. (2005) Prediction of appropriate timing of palliative care for older adults with non-malignant life-threatening disease: a systematic review. Age and Ageing 34(3), 218-227. [Abstract] [Free Full-text]

CSM (1990) Beta-agonists, xanthines and hypokalaemia. Current Problems in Pharmacovigilance 28(May), 3. [Free Full-text]

CSM (1997) Revised indications for co-amoxiclav (Augmentin). Current Problems in Pharmacovigilance 23(May), 8. [Free Full-text]

Currie, G.P. (Ed.) (2007) ABC of COPD. Oxford: Blackwell Publishing.

Curtis, J.R. (2008) Palliative and end-of-life care for patients with severe COPD. European Respiratory Journal 32(3), 796-803. [Abstract] [Free Full-text]

Curtis, J.R., Wenrich, M.D., Carline, J.D. et al. (2002) Patients' perspectives on physician skill in end-of-life care: differences between patients with COPD, cancer and AIDS. Chest 124(2), 771-772. [Abstract] [Free Full-text]

Department for Constitutional Affairs (2007) Mental capacity act 2005: code of practice. The Stationary Office. www.dca.gov.uk [Free Full-text]

DH (2010) Consultation on a strategy for services for chronic obstructive pulmonary disease (COPD) in England. Department of Health. www.lunguk.org

Dolovich, M.B., Ahrens, R.C., Hess, D.R. et al. (2005) Device selection and outcomes of aerosol therapy: evidence-based guidelines. Chest 127(1), 335-371. [Abstract] [Free Full-text]

DVLA (2010) At a glance guide to the current medical standards of fitness to drive (August update). Driver and Vehicle Licensing Agency. www.gov.uk [Free Full-text]

Efraimsson, E.O., Hillervik, C. and Ehrenberg, A. (2008) Effects of COPD self-care management education at a nurse-led primary health care clinic. Scandinavian Journal of Caring Sciences 22(2), 178-85. [Abstract]

Eva, O.E., Birgitta, K., Kjell, L. et al. (2009) Communication and self-management education at nurse-led COPD clinics in primary health care. Patient Education and Counseling 77(2), 209-17. [Abstract]

Ferreira, I.M., Brooks, D., Lacasse, Y. et al. (2005) Nutritional supplementation for stable chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 2. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

FSRH (2011) Drug interactions with hormonal contraception. Faculty of Sexual and Reproductive Healthcare. www.fsrh.org [Free Full-text]

GMC (2010) Treatment and care towards the end of life: good practice in decision making. General Medical Council. www.gmc-uk.org [Free Full-text]

GOLD (2009) Global strategy for diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD). www.goldcopd.com

Halpin, D.M., Seamark, C.J. and Seamark, D.A. (2008) End-of-life care for patients with COPD in the community setting. British Journal of General Practice 58(551), 390-392. [Free Full-text]

Hanks, G., Cherny, N.I., Christakis, N.A. et al. (Eds.) (2010) Oxford textbook of palliative medicine. 4th edn. Oxford: Oxford University Press.

HPA and Association of Medical Microbiologists (2010) Management of infection guidance for primary care for consultation and local adaptation. Health Protection Agency. www.hpa.org.uk [Free Full-text]

Jennings, A.L., Davies, A.N., Higgins, J.P. et al. (2002) A systematic review of the use of opioids in the management of dyspnoea. Thorax 57(11), 939-944. [Abstract] [Free Full-text]

Johnson, A.O. (2003) Chronic obstructive pulmonary disease * 11: fitness to fly with COPD. Thorax 58(8), 729-732. [Free Full-text]

Lacasse, Y., Goldstein, R.S., Lasserson, T.J. and Martin, S. (2006) Pulmonary rehabilitation for chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 4. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Levy, M.L., Quanjer, P.H., Booker, R. et al. (2009) Diagnostic spirometry in primary care: proposed standards for general practice compliant with American Thoracic Society and European Respiratory Society recommendations. Primary Care Respiratory Journal 18(3), 130-147. [Abstract]

London and South East Medicines Information Service, South West Medicines Information Service and Croydon Primary Care Trust (2008) Suggestions for drug monitoring in adults in primary care. National Electronic Library for Medicines. www.evidence.nhs.uk

Lung Health Study Research Group (2000) Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. New England Journal of Medicine 343(26), 1902-1909. [Abstract] [Free Full-text]

Maurer, J., Rebbepragada, V., Borson, S. et al. (2008) Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest 134(4 Suppl), 43S-56S. [Abstract] [Free Full-text]

McGeoch, G.R., Willsman, K.J., Dowson, C.A. et al. (2006) Self-management plans in the primary care of patients with chronic obstructive pulmonary disease. Respirology 11(5), 611-618. [Abstract]

MeReC (2002) Chronic asthma. MeReC Briefing 18(Jun), 1-5. [Free Full-text]

MHRA (2009) Use of long-acting B-agonists in chronic obstructive pulmonary disease. Drug Safety Update 2(12), 7-8. [Free Full-text]

MHRA (2010) Tiotropium: safety studies of Spiriva Respimat. Drug Safety Update 4(4), H2. [Free Full-text]

Micromedex (2010) MICROMEDEX [CD-ROM]Thomson Healthcare.

National Clinical Guideline Centre (2010) Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update of CG12) (full NICE guideline). . Clinical guideline 101. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

National Collaborating Centre for Chronic Conditions (2004) Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 59(Suppl 1), 1-232. [Free Full-text]

NICE (2005) Referral guidelines for suspected cancer (NICE guideline). . Clinical guideline 27. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2010) Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care (Partial update of CG12) (NICE guideline). . Clinical guideline 101. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2011) Quality standards programme - chronic obstructive pulmonary disease. Quality Standard advice to the Secretary of State for Health. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

Nicholson, T.R., Cutter, W. and Hotopf, M (2008) Assessing mental capacity: the Mental Capacity Act. BMJ 336(7639), 322-325.

Office of the Public Guardian (2005) The Mental Capacity Act: making decisions. A guide for people who work in health and social care. Office of the Public Guardian. [Free Full-text]

Puhan, M.A., Scharplatz, M., Troosters, T. and Steurer, J. (2005) Respiratory rehabilitation after acute exacerbation of COPD may reduce risk for readmission and mortality – a systematic review. Respiratory Research 6(1), 54. [Abstract] [Free Full-text]

Qaseem, A., Snow, V., Shekelle, P. et al. (2007) Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians. Annals of Internal Medicine 147(9), 633-638. [Abstract] [Free Full-text]

RCGP (2008) Prognostic indicator guidance. The Gold Standard FrameworkNational Gold Standards Framework Centre.

RCP (1999) Osteoporosis. Clinical guidelines for prevention and treatment. Royal College of Physicians. www.rcplondon.ac.uk

RCP (2002) Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment. Royal College of Physicians. www.rcplondon.ac.uk [Free Full-text]

Regnard, C. and Dean, M. (2010) A guide to symptom relief in palliative care. 6th edn. Oxford: Radcliffe Publishing.

Rocker, G., Horton, R., Currow, D. et al. (2009) Palliation of dyspnoea in advanced COPD: revisiting a role for opioids. Thorax 64(10), 910-915. [Abstract]

Seamark, D.A., Seamark, C.J. and Halpin, D.M. (2007) Palliative care in chronic obstructive pulmonary disease: a review for clinicians. Journal of The Royal Society of Medicine 100(5), 225-233. [Abstract] [Free Full-text]

Sichletidis, L., Chloros, D., Spyratos, D. et al. (2007) The validity of the diagnosis of chronic obstructive pulmonary disease in general practice. Primary Care Respiratory Journal 16(2), 82-88. [Abstract]

SIGN and BTS (2008) British guideline on the management of asthma: a national clinical guideline (revised 2009). Scottish Intercollegiate Guidelines Network and The British Thoracic Society. www.sign.ac.uk [Free Full-text]

Silverman, E.K. and Speizer, F.E. (1996) Risk factors for the development of chronic obstructive pulmonary disease. Medical Clinics of North America 80(3), 501-522. [Abstract]

Simon, S.T., Higginson, I.J., Booth, S. et al. (2010) Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults (Cochrane Review). The Cochrane Library. Issue 1. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Singh, S., Loke, Y.K., Enright, P.L. and Furgberg, C.D. (2011) Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ 342(), d3215. [Abstract] [Free Full-text]

Spathis, A. and Booth, S. (2008) End of life care in chronic obstructive pulmonary disease: in search of a good death. International Journal of Chronic Obstructive Pulmonary Disease 3(1), 11-29. [Abstract] [Free Full-text]

Thomas, M., McKinley, R.K., Freeman, E. and Foy, C. (2001) Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey. BMJ 322(7294), 1098-1100. [Abstract] [Free Full-text]

Tzani, P., Pisi, G., Aiello, M. et al. (2010) Flying with respiratory disease. Respiration 80(2), 161-170. [Abstract] [Free Full-text]

Vogelmeier, C., Kardos, P., Harari, S. et al. (2008) Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Respiratory Medicine 102(11), 1511-1520. [Abstract]

Walters, J.A.E., Walters, E.H. and Wood-Baker, R. (2005) Oral corticosteroids for stable chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library. Issue 3. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Wood-Baker, R., McGlone, S., Venn, A. and Walters, E.H. (2006) Written action plans in chronic obstructive pulmonary disease increase appropriate treatment for acute exacerbations. Respirology 11(5), 619-626. [Abstract]