Risk factor	Comment
Smoking	Risk increases with increasing consumption but there is also large interindividual variation in susceptibility
Age	Increasing age results in ventilatory impairment; most frequently related to cumulative smoking
Gender	Male gender was previously thought to be a risk factor but this may be due to a higher incidence of tobacco smoking in men. Women have greater airway reactivity and experience faster declines in FEV₁, so may be at more risk than men
Occupation	The development of COPD has been implicated with occupations such as coal and gold mining, farming, grain handling and the cement and cotton industries
Genetic factors	α₁-Antitrypsin deficiency is the strongest single genetic risk factor, accounting for 1–2% of COPD. Other genetic disorders involving tissue necrosis factor and epoxide hydrolase may also be risk factors
Air pollution	Death rates are higher in urban areas than in rural areas. Indoor air pollution from burning biomass fuel is also implicated as a risk factor, particularly in underdeveloped areas of the world
Socio-economic status	More common in individuals of low socio-economic status
Airway hyper-responsiveness and allergy	Smokers show increased levels of IgE, eosinophils and airway hyper-responsiveness but how these influence the development of COPD is unknown

Inflammation

COPD is characterised by chronic inflammation throughout the airways, parenchyma and pulmonary vasculature. This is a different pattern of inflammation from that of asthma, with an increase in neutrophils, macrophages and T-lymphocytes (particularly CD8⁺); increased eosinophils occur in some patients during exacerbations. These inflammatory cells cause the release of inflammatory mediators and cytokines such as leukotriene B4, interleukin-8 and tumour necrosis factor-α (TNF-α). Over time the actions of these mediators damages the lungs and leads to the characteristic pathological changes observed.

Proteinase and antiproteinase imbalance

The observation that α₁-antitrypsin-deficient individuals are at increased risk of developing emphysema has led to the theory that an imbalance between proteinases and antiproteinases leads to lung destruction. In COPD, there is either an increased production/activity of proteinases or a decreased production/activity of antiproteinases. The main proteinases, proteolytic enzymes such as neutrophil elastin are released by macrophages or neutrophils. The antiproteinases inhibit the damage caused by the proteolytic enzymes. The main antiproteinase is α₁-antitrypsin, also known as α₁-proteinase inhibitor. Cigarette smoke has been shown to inactivate this protein. Oxidative stress also decreases the activity of antiproteinases.

Oxidative stress

An imbalance of oxidants and antioxidants exists in COPD with the balance in favour of the oxidants. This state of oxidative stress contributes to the development of the disease by damaging the intracellular matrix, oxidising biological molecules which cause cell destruction and promoting histone acetylation. There also seems to be a link between oxidative stress and the poor response to corticosteroids seen in COPD. To work, corticosteroids must recruit histone deacetylase to switch off the transcription of inflammatory genes. In COPD, the activity of histone deacetylase is impaired by the oxidative stress, thereby reducing the responsiveness to corticosteroids. Cigarette smoke also impairs the function of histone deacetylase.

Pathophysiology

The pathogenic mechanisms and pathological changes described above lead to the physiological abnormalities of COPD: mucus hypersecretion, ciliary dysfunction, airflow limitation and hyperinflation, gas exchange abnormalities, pulmonary hypertension and systemic effects (American Thoracic Society/European Respiratory Society Task Force, 2004).

Mucus hypersecretion, ciliary dysfunction and complications

Enlarged mucus glands cause hypersecretion of mucus and the squamous metaplasia of epithelial cells results in ciliary dysfunction. These are typically the first physiological abnormalities in COPD.

Normally, cilia and mucus in the bronchi protect against inhaled irritants, which are trapped and expectorated. The persistent irritation caused by cigarette and other smoke causes an exaggeration in the response of these protective mechanisms and leads to inflammation of the small bronchioles (bronchiolitis) and alveoli (alveolitis). Cigarette smoke also inhibits mucociliary clearance, which causes a further build-up of mucus in the lungs. As a result, macrophages and neutrophils infiltrate the epithelium and trigger a degree of epithelial destruction. This, together with a proliferation of mucus-producing cells, leads to plugging of smaller bronchioles and alveoli with mucus and particulate matter.

This excessive mucus production causes distension of the alveoli and loss of their gas exchange function. Pus and infected mucus accumulate, leading to recurrent or chronic viral and bacterial infections. The primary pathogen is usually viral but bacterial infection often follows. Common bacterial pathogens include Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae.

Bronchiectasis is a pathological change in the lungs where the bronchi become permanently dilated. It is common after early attacks of acute bronchitis during which mucus both plugs and stretches the bronchial walls. In severe infections, the bronchioles and alveoli can become permanently damaged and do not return to their normal size and shape. The loss of muscle tone and loss of cilia can contribute to COPD because mucus has a tendency to accumulate in the dilated bronchi.

Airflow limitation and hyperinflation

Fibrosis and narrowing (airway remodelling) of the smaller conducting airways (<2 mm diameter) is the main site of expiratory airflow limitation in COPD. This is compounded by the loss of elastic recoil (destruction of alveolar walls), destruction of alveolar support/attachments and the accumulation of inflammatory cells mucus and plasma exudates during exercise. The degree of airflow limitation is measured by spirometry.

This progressive destructive enlargement of the respiratory bronchioles, alveolar ducts and alveolar sacs is referred to as emphysema. Adjacent alveoli can become indistinguishable from each other, with two main consequences. The first is loss of available gas exchange surfaces, which leads to an increase in dead space and impaired gas exchange. The second consequence is the loss of elastic recoil in the small airways, vital for maintaining the force of expiration, which leads to a tendency for them to collapse, particularly during expiration. Increased thoracic gas volume and hyperinflation of the lungs result. The causes of airflow limitation in COPD are summarised in Box 26.1.

Gas exchange abnormalities

This occurs in advanced disease and is characterised by arterial hypoxaemia with or without hypercarbia. The anatomical changes during COPD result in an abnormal distribution of ventilation and perfusion within the lungs and create the abnormal gaseous exchange.

Pulmonary hypertension and cor pulmonale

Pulmonary hypertension develops late in COPD after gas exchange abnormalities have developed. The thickening of the bronchiole and alveolar walls resulting from chronic inflammation and oedema leads to blockage and obstruction of the airways. Alveolar distension and destruction result in distortion of the blood vessels that are closely associated with the alveoli. This causes a rise in the blood pressure in the pulmonary circulation. Reduction in gas diffusion across the alveolar epithelium leads to a low partial pressure of oxygen in the blood vessels (hypoxaemia) due to an imbalance between ventilation and perfusion. By a mechanism that is not clearly established, chronic vasoconstriction results and causes a further increase in blood pressure and further compromises gas diffusion from air spaces into the bloodstream. The chronic low oxygen levels lead to polycythaemia, thereby increasing blood viscosity. In advanced disease, persistent hypoxaemia develops along with pathological changes in the pulmonary circulation. Sustained pulmonary hypertension results in a thickening of the walls of the pulmonary arterioles, with associated pulmonary remodelling and an increase in right ventricular pressure within the heart.

The consequence of continued high right ventricular pressure is eventual right ventricular hypertrophy, dilation and progressive right ventricular failure (cor pulmonale). Pulmonary oedema develops as a result of physiological changes subsequent to the hypoxaemia and hypercapnia, such as activation of the renin–angiotensin system, salt and water retention and a reduction in renal blood flow.

Systemic effects

Systemic inflammation and skeletal muscle wasting can occur in COPD which limit exercise capacity and worsen prognosis. Osteoporosis, depression, normocytic normochromic anaemia are potential sequelae, as well as increased risk of cardiovascular disease associated with elevated levels of C-reactive protein.

Clinical manifestations

Diagnosis

A diagnosis of COPD should be considered in any patient who has symptoms of cough, wheeze, regular sputum production or exertional dyspnoea and/or a history of exposure to COPD risk factors (see Table 26.2). Spirometry is then used to confirm the diagnosis. There is no single diagnostic test for COPD.

Clinical features

COPD is a progressive disorder, which passes through a potentially asymptomatic mild phase, before the moderate phase and then severe disease. The traditional description of COPD symptoms, particularly in severe disease, depends on whether bronchitis or emphysema predominate. Chronic bronchitic patients exhibit excess mucus production and a degree of bronchospasm, resulting in wheeze and dyspnoea. Hypoxia and hypercapnia (high levels of carbon dioxide in the tissues) are common. This type of patient has a productive cough, is often overweight and finds physical exertion difficult due to dyspnoea. The bronchitic patient is sometimes referred to as a ‘blue bloater’. This term is used because of the tendency of the patient to retain carbon dioxide caused by a decreased responsiveness of the respiratory centre to prolonged hypoxaemia that leads to cyanosis, and also the tendency for peripheral oedema to occur. Bronchitic patients lose the ability to increase the rate and depth of ventilation in response to persistent hypoxaemia. The reason for this is not clear, but decreased ventilatory drive may result from abnormal peripheral or central respiratory receptors. As the disease progresses, patients will experience an increasing frequency of exacerbations of acute dyspnoea triggered by excess mucus production and obstruction. In severe disease, the chest diameter is often increased, giving the classic barrel chest. As obstruction worsens, hypoxaemia increases, leading to pulmonary hypertension. Right ventricular strain leads to right ventricular failure, which is characterised by jugular venous distension, hepatomegaly and peripheral oedema, all of which are consequences of an increase in systemic venous blood pressure. Recurrent lower respiratory tract infections can be severe and debilitating. Signs of infection include an increase in the volume of thick and viscous sputum, which is yellow or green in colour and may contain bacterial pathogens, squamous epithelial cells, alveolar macrophages and saliva, but pyrexia may not be present. Eventually, cardiorespiratory failure with hypercapnia will occur, which may be severe, unresponsive to treatment and result in death.

The clinical features of emphysema are different from those of bronchitis. A patient with emphysema will experience increasing dyspnoea even at rest, but often there is minimal cough and the sputum produced is scanty and mucoid. Generally, bronchial infections tend to be less common in emphysema. The patient with emphysema is sometimes referred to as a ‘pink puffer’ because he or she hyperventilates to compensate for hypoxia by breathing in short puffs. As a result, the patient appears pink with little carbon dioxide retention and little evidence of oedema. The patient will breathe rapidly (tachypnoea), because the respiratory centres are responsive to mild hypoxaemia, and will have a flushed appearance. Typically, a patient with emphysema will be thin and have pursed lips in an effort to compensate for a lack of elastic recoil and exhale a larger volume of air. Such a patient will tend to use the accessory muscles of the chest and neck to assist in the work of breathing. Hypoxaemia is not a problem until the disease has progressed. Emphysema patients will become progressively dyspnoeic, without exacerbations triggered by increased sputum production. Eventually, cor pulmonale will develop very rapidly, usually in the late stages of the disease, leading to intractable hypercapnia and respiratory arrest. The bronchitic ‘blue bloater’ and emphysemic ‘pink puffer’ represent two ends of the COPD spectrum. In reality, the underlying pathophysiology may well be a mixture, and the resulting signs and symptoms somewhere between the two extremes described.

The clinical progress of COPD depends on whether bronchitis or emphysema predominates.

Additional specific problems are also common in patients with COPD:

• Obstructive sleep apnoea hypopnoea syndrome (OSAHS)

• Acute respiratory failure

The sleep apnoea syndrome is a respiratory disorder characterised by frequent or prolonged pauses in breathing during sleep. It leads to a deterioration in arterial blood gases and a decrease in the saturation of haemoglobin with oxygen. Hypoxaemia is often accompanied by pulmonary hypertension and cardiac arrhythmias, which may lead to premature cardiac failure.

Acute respiratory failure is said to have occurred if the PaO₂ suddenly drops and there is an increase in PaCO₂ that decreases the pH to 7.3 or less. The most common cause is an acute exacerbation of chronic bronchitis with an increase in volume and viscosity of sputum. This further impairs ventilation and causes more severe hypoxaemia and hypercapnia. The clinical signs and symptoms of acute respiratory failure include restlessness, confusion, tachycardia, cyanosis, sweating, hypotension and eventual unconsciousness.

Investigations

Lung function tests are used to assist in diagnosis. A spirometer is used to measure lung volumes and flow rates. The main measurement made is the forced expiratory volume in the first second of exhalation (FEV₁). Other tests can be performed, such as:

• Vital capacity (VC): the volume of air inhaled and exhaled during maximal ventilation;

• Forced vital capacity (FVC): the volume of air inhaled and exhaled during a forced maximal expiration after full inspiration;

• Residual volume (RV): the volume of air left in the lungs after maximal exhalation.

Airflow obstruction is defined as:

• FEV₁ less than 80% of that predicted for the patient and

• FEV₁/FVC less than 0.7.

VC decreases in bronchitis and emphysema. RV increases in both cases but tends to be higher in patients with emphysema due to air being trapped distal to the terminal bronchioles. Total lung capacity is often normal in patients with bronchitis but is usually increased in emphysema, again due to air being trapped. Smoking increases the normal deterioration in FEV₁ over time, from about 30 mL/year to about 45 mL/year. The major criticism of measuring FEV₁ and FVC is that they detect changes only in airways greater than 2 mm in diameter. As airways less than 2 mm in diameter contribute only 10–20% of normal resistance to airflow, there is usually severe obstruction and extensive damage to the lungs by the time the lung function tests (FEV₁ and FVC) detect abnormalities. Additionally, lung function tends to deteriorate with age even in the absence of COPD, and so use of FEV₁/FVC can lead to overdiagnosis in the elderly. Underdiagnosis may also be a problem in patients under 45 years of age.

Both UK and international COPD guidelines use spirometry to categorise the severity of COPD. These are summarised in Table 26.3. Testing should be carried out after a dose of inhaled bronchodilator to prevent overdiagnosis or overestimation of severity.

Table 26.3 Assessment of severity of airflow obstruction

FEV₁	Severity (NICE)	Severity (GOLD)
Greater than 80% predicted		Stage I: Mild
50–80% predicted	Mild	Stage II: Moderate
30–49% predicted	Moderate	Stage III: Severe
Less than 30% predicted	Severe	Stage IV: Very severe

(adapted from National Institute for Health and Clinical Excellence, 2010; GOLD, 2009)

At diagnosis and evaluation, patients may receive other investigations as outlined in Table 26.4.

Table 26.4 Additional investigations at the diagnosis of COPD

Investigation	Note
Chest X-ray	To exclude other pathologies
Full blood count	To identify anaemia or polycythaemia
Serial domiciliary peak flow measurements	To exclude asthma if there is a doubt about diagnosis
α₁-Antitrypsin	Particularly with early-onset disease or a minimal smoking/family history
Transfer factor for carbon monoxide	To investigate symptoms that seem disproportionate to the spirometric impairment
CT scan of the thorax	To investigate symptoms that seem disproportionate to the spirometric impairment
	To investigate abnormalities seen on the chest X-ray
	To assess suitability for surgery
ECG	To assess cardiac status if features of cor pulmonale
Echocardiogram	To assess cardiac status if features of cor pulmonale
Pulse oximetry	To assess need for oxygen therapy
Pulse oximetry	If cyanosis or cor pulmonale is present or if FEV₁ <50% of predicted value
Sputum culture	To identify organisms if sputum is persistently present and purulent

Chest radiographs reveal differences between the two disease states. A patient with emphysema will have a flattened diaphragm with loss of peripheral vascular markings and the appearance of bullae. These are indicative of extensive trapping of air. A patient with bronchitis will have increased bronchovascular markings and may also have cardiomegaly (increased cardiac size due to right ventricular failure) with prominent pulmonary arteries.

Treatment

Stable COPD

Drug treatments, together with other measures such as physiotherapy and artificial ventilation, have not been shown to improve the natural progression of COPD. Quality of life and symptoms will, however, improve with suitable treatment and it is likely that the correct management of the patient will lead to a reduction in hospital admissions and prevent premature death. In patients with severe COPD and hypoxaemia, long-term oxygen therapy (LTOT) is the only treatment known to improve the prognosis.

The aims of treatment for patients with COPD are shown in Box 26.2 and the common therapeutic problems associated with COPD in Box 26.3. Drug treatment itself can only relieve symptoms; it does not modify the underlying pathology. Most patients with COPD are considered to have irreversible obstruction, in contrast to patients with asthma, but a significant number do seem to respond to bronchodilators.

Box 26.2 Treatment aims for patients with COPD

• Prevent disease progression

• Relieve symptoms

• Improve exercise tolerance

• Improve health status

• Prevent and treat complications such as hypoxaemia and infections

• Prevent and treat exacerbations

• Reduce mortality

Box 26.3 Common therapeutic problems associated with COPD

• Failure of patient to stop smoking

• Inadequate inhaler technique leading to subtherapeutic dosing

• Poor adherence with treatment regimen

• Inappropriate prescribing of antibiotics in an acute exacerbation of COPD

• Failure to properly assess a patient for home nebuliser therapy

• Failure to ensure adherence to 15 h a day of home oxygen therapy

Smoking cessation

Smoking is the most important factor in the development of obstructive airways disease. All COPD patients who are still smoking, regardless of age, should be encouraged to stop and be offered help to do so, at every opportunity. Unless contraindicated, all patients who are planning to stop smoking should be offered nicotine replacement therapy (NRT), varenicline or bupropion, as appropriate along with a support programme (NRT) (National Institute for Health and Clinical Excellence, 2010). Individually targeted advice may prove to be more successful in persuading individuals to give up, especially in those who are well.

Bronchodilators

Bronchodilators in COPD are used to reverse airflow limitation. As the degree of limitation varies widely, their effectiveness should be assessed in each patient using respiratory function tests and by assessing any subjective improvement reported by the patient. Patients may experience improvements in exercise tolerance or relief of symptoms such as wheeze and cough. Treatment options for the use of bronchodilators and inhaled corticosteroids (ICSs) are outlined in Fig. 26.1.

Fig. 26.1 Stepwise approach to the pharmacological management of chronic COPD (National Institute for Health and Clinical Excellence, 2010; with kind permission from National Institute for Health and Clinical Excellence).

Initial empiric therapy with short-acting bronchodilators, prescribed ‘when required’, for the relief of breathlessness and exercise limitation are recommended for initial use (National Institute for Health and Clinical Excellence, 2010). If patients remain breathless or have exacerbations despite short-acting bronchodilators then maintenance therapy is recommended, with:

• FEV₁ ≥50% predicted: long-acting β₂-adrenoceptor agonist (LABA) or long-acting antimuscarinic (LAMA)

• FEV₁ <50% predicted: a combination of either LABA and ICSs or LABA and LAMA

If the patient remains breathless, or has exacerbations, then triple therapy should be considered (i.e. ICS and LABA in a combination inhaler together with a LAMA).

Short-acting bronchodilators (short-acting β₂-adrenoceptor agonist or short-acting antimuscarinic)

Selective β₂-agonists provide rapid relief and have a low incidence of side effects. Inhaled treatment is as efficacious as oral agents and is, therefore, preferred because of fewer side effects. The dose–response curve for β₂-agonists in COPD is almost flat and there is little benefit in giving more than 1 mg. The effects of short-acting β₂-agonists last for 4 h and they should be used ‘as required’ for symptom relief. Used before exercise, they can improve exercise tolerance. Poor patient response to bronchodilators may be due to poor inhalation technique, so this should be checked as often as possible and the inhaler device changed if necessary.

In patients with COPD, parasympathetic (vagal) airway muscle tone is the major reversible component. Inhaled anticholinergic drugs reverse this vagal tone and have a significant bronchodilator effect, especially in the elderly.

Corticosteroids

Patients with COPD show a poor response to corticosteroids and have a largely steroid-resistant pattern of inflammation (Barnes, 2004). It is postulated that the oxidative stress of COPD inhibits the mechanism by which corticosteroids, acting through histone deacetylase, switch off activated inflammatory genes.

The long-term benefits of ICSs in COPD have only been shown in patients with moderate-to-severe disease, with an FEV₁ less than 50% of predicted value and who are having exacerbations requiring treatment with antibiotics and oral corticosteroids (National Institute for Health and Clinical Excellence, 2010). A reduction in the number of exacerbations and a slowing of the decline in health status have been shown, but these have no effect on improving lung function and result in an increased risk of pneumonia.

ICSs should be used, although there is no consensus over the minimum effective dose. In the UK, no inhaled steroid is licensed for use in COPD except when used with LABA in combination devices.

There is little place for oral steroids in stable COPD. Some patients with advanced disease may require maintenance oral therapy if this cannot be withdrawn after a short course prescribed to treat an exacerbation. In this instance, the lowest dose possible should be used. The patient should be regularly assessed for osteoporosis and the need for osteoporosis prevention. Patients over 65 years receiving maintenance therapy should automatically receive prophylactic treatment for osteoporosis.

Mucolytics

Mucolytics may be of benefit in stable COPD if there is a chronic cough productive of sputum. Benefit must be assessed, for example, with a reduction in the frequency of cough and/or sputum production. If there is no benefit, then mucolytics should be stopped.

Antibiotics and immunisation

Prophylactic antibiotics have no place in the management of COPD. Antibiotic therapy is, however, vital if a patient develops purulent sputum. If a patient frequently develops acute infective exacerbations of bronchitis then they should be given a supply of antibiotics to keep at home to start at the first sign of an exacerbation.

Initial routine sputum cultures are unhelpful in these patients as they are unreliable in identifying the pathogenic organisms.

The normal pathogens involved are S. pneumoniae, H. influenzae or M. catarrhalis. The usual antibiotics of choice are co-amoxiclav, amoxicillin, erythromycin or doxycycline. If the infection follows influenza, Staphylococcus aureus may be present and an anti-staphylococcal agent such as flucloxacillin should be added to the regimen. If the infection is considered atypical in presentation or if the purulent sputum is still present after 1 week of treatment, then sputum cultures should be taken to try to identify the pathogenic organisms. A single dose of pneumococcal vaccine and annual influenza vaccinations have been shown to reduce hospitalisations and the risk of death in the elderly with chronic lung disease, and should be offered to those with chronic airflow obstruction. The prevalent strains of influenza change, so the vaccine composition is, correspondingly, altered annually.

Acute exacerbations of COPD

Patients with COPD suffer acute worsenings of the disease, referred to as acute exacerbations. These exacerbations can be spontaneous but are often precipitated by infection and lead to respiratory failure with hypoxaemia and retention of carbon dioxide. Many patients can be managed at home (see National Institute for Health and Clinical Excellence, 2010) but some will require admission to hospital.

Bronchodilators

Bronchodilators are used to treat the increased breathlessness that is associated with exacerbations. These can be given by metered-dose inhaler (MDI) or nebuliser, although practically breathless patients are often unable to use MDIs effectively. A β₂-agonist can be given with or without an anticholinergic agent, depending on the benefits obtained.

Antibiotics

Bacteria can be isolated from the sputum of patients with stable COPD but antibiotics can be used to treat exacerbations of COPD associated with a history of more purulent sputum. The choice of antibiotic should be dependent on local policy, sensitivity patterns and any previous treatments. An aminopenicillin or a macrolide with increased activity against H. influenzae or oxytetracycline is generally suitable as a first-line agent. Sputum should be sent for culture in order to check the appropriateness of initial therapy, and the antibiotic changed if necessary.

Corticosteroids

A short course of oral steroids has been shown to benefit FEV₁ and reduce the duration of hospitalisation. Patients managed at home who have increased breathlessness which interferes with daily activities and all those admitted to hospital should be treated. A suitable course is prednisolone 30 mg every morning, given for 7–14 days.

Other treatment

Intravenous aminophylline can be considered, if there is an inadequate response to bronchodilators. The loading dose and maintenance dose required should be carefully chosen as these depend on various factors (see Chapter 25).

Oxygen therapy is necessary to improve hypoxia. In about a quarter of patients with COPD, a predisposition to carbon dioxide retention will be present. Administration of high concentrations of oxygen to these individuals can lead to an increase in retention of carbon dioxide and, thus, to respiratory acidosis. The widely held view that this effect is due to loss of hypoxic ventilatory drive has been questioned; a more complex process involving a mismatch between ventilation and perfusion is now thought to play a significant role. The goal is an initial oxygen saturation of between 88% and 92% to avoid respiratory acidosis but to allow enough oxygen to be administered to overcome potentially life-threatening hypoxia (O’Driscoll et al., 2008). The initial concentration used should be 24–28% and then titrated to oxygen saturation. Arterial blood gases should be monitored regularly.

During an acute attack, pyrexia, hyperventilation and the excessive work of breathing can result in an inability to eat or drink. This can lead to dehydration which requires treatment with intravenous hydration.

Chest physiotherapy is employed to mobilise secretions, promote expectoration and expand collapsed lung segments. Nebulised 0.9% sodium chloride has also been used to help.

Although largely superseded by non-invasive ventilatory support, doxapram (as a continuous infusion at a rate of 1–4 mg/min) can be tried in patients with acute respiratory failure, carbon dioxide retention and depressed ventilation. Doxapram stimulates the respiratory and vasomotor centres in the medulla, increases the depth of breathing and may slightly increase the rate of breathing. Arterial oxygenation is usually not improved because of the increased work of breathing induced by doxapram. This agent has a narrow therapeutic index with side effects such as arrhythmias, vasoconstriction, dizziness and convulsions and may be harmful if used when the PaCO₂ is normal or low.

Treatment of hypoxaemia and cor pulmonale

COPD is responsible for over 90% of cases of cor pulmonale. Although patients often tolerate mild hypoxaemia, once the resting PaO₂ drops below 8 kPa signs of cor pulmonale develop. Treatment is symptomatic and involves managing the underlying airways obstruction, hypoxaemia and any pulmonary oedema that develops. Peripheral oedema is managed using thiazide or loop diuretics, although there are concerns over their metabolic effects reducing respiratory drive. Oxygen is used to treat hypoxaemia, and this should also promote a diuresis. All patients should be assessed for the need for LTOT.

Domiciliary oxygen therapy

The aim of therapy is to improve oxygen delivery to the cells, increase alveolar oxygen tension and decrease the work of breathing to maintain a given PaO₂. Domiciliary oxygen therapy can be given in two ways.

Intermittent (short burst) administration

Intermittent administration is used to increase mobility and capacity for exercise and to ease discomfort. Intermittent administration is of most benefit in patients with emphysema.

Continuous LTOT.

LTOT for at least 15 h/day has been shown to improve survival in patients with severe, irreversible airflow obstruction, hypoxaemia and peripheral oedema (MRC Working Party, 1981). LTOT can only be prescribed if specific conditions are met, as described in Box 26.5. The main aim of treatment is to achieve a PaO₂ of at least 8 kPa without causing a rise in PaCO₂ of more than 1 kPa, achieved by adjusting the oxygen flow rate. Before LTOT can be prescribed each individual must be assessed accordingly (see Box 26.5).

Box 26.5 Guidelines for prescribing long-term oxygen therapy in COPD (National Institute for Health and Clinical Excellence, 2010)

A. PaO₂ is consistently below 7.3 kPa whilst the patient is clinically stable

B. PaO₂ between 7.3 and 8 kPa if secondary polycythaemia, pulmonary hypertension, nocturnal hypoxaemia or peripheral oedema is present

Oxygen can be prescribed as oxygen cylinders but 15 h/day at 2 L/min requires ten 1340-L cylinders a week. A more convenient system is to use a concentrator, which converts ambient air to 90% oxygen using a molecular sieve. The concentrator is sited in a well-ventilated area in the home with plastic tubing to terminals in rooms such as the living room and bedroom. Tubing from the terminals delivers oxygen to the patient, who wears a mask or uses the more convenient nasal prongs. This tubing should be long enough to allow some mobility.

Patient care

Pulmonary rehabilitation

Early pulmonary rehabilitation should be considered for patients at all stages of disease progression when symptoms and disability are present. Patients should participate in a co-coordinated programme of non-pharmacological treatment including:

• advice and support to stop smoking

• nutritional assessment

• aerobic exercise training to increase capacity and endurance for exercise

• strength training for upper and lower limbs

• relaxation techniques

• breathing retraining, for example, diaphragmatic and pursed lips breathing to improve the ventilatory pattern and improve gas exchange

• education about their medicines, nutrition, self-management of their disease and lifestyle issues

• psychological support because COPD patients often have decreased capacity to participate in social and recreational activities and can become anxious, depressed or fatigued.

A multidisciplinary team should deliver these programmes and should include a minimum of 6 and a maximum of 12 weeks of physical exercise, disease education, psychological and social interventions (National Institute for Health and Clinical Excellence, 2010).

Pulmonary rehabilitation programmes that include at least 4 weeks exercise training have been shown to improve dyspnoea and exercise capacity. The long-term effects, however, of these programmes has yet to be established, although personalised education to COPD patients about their condition has been shown to reduce their need for health services.

Stopping smoking

The health hazards associated with smoking are well known and publicised. To give up smoking, which has been described as a form of drug addiction, requires self-motivation. Stopping smoking does not, however, have an immediate effect. A reduction in COPD mortality is not seen until about 10 years or more after cessation of smoking.

Members of the healthcare team can educate smokers about the dangers and actively encourage and motivate those who want to give up. Brief conversations between individuals and health professionals about stopping smoking are both effective and cost-effective in encouraging individuals to quit (National Institute for Health and Clinical Excellence, 2006).

Once a decision to quit has been made, it is the degree of dependence rather than the level of motivation that will influence the success rate. Smokers need both initial advice from all healthcare professionals and follow-up support. For example, especially in the early stages, symptoms such as coughing increase after the cigarettes are stopped. The patient must be closely supported to avoid a return to the habit. Strategies such as individual behavioural counselling, group behaviour therapy and use of self-help materials and telephone counselling and ‘quit lines’ have been advocated as effective interventions.

There are a number of therapeutic options to help an individual to stop smoking and these include NRT, bupropion and varenicline.

Nicotine replacement

The major mode of action of NRT is thought to involve stimulation of nicotine receptors in the brain and the subsequent release of dopamine. This, together with the peripheral effects of nicotine, leads to a reduction in nicotine withdrawal symptoms. NRT may also act as a coping mechanism, making cigarette smoking less rewarding. NRT does not, however, completely eliminate the effects of withdrawal as none of the available products reproduces the rapid and high levels of nicotine obtained from cigarettes.

There is little research comparing the relative effectiveness of NRT products, but all seem to have similar success rates. Choice of product should be made on the number of cigarettes smoked (irrespective of the nicotine content), the smoker’s personal preference and tolerance to side effects. An individual is more likely to adhere to the cessation programme if using a product which suits him or her. The types of NRT available are summarised in Table 26.5.

Table 26.5 Comparison of selected nicotine replacement products

Formulation	Use and comments	Specific side effects
Patch: 24 h: 7, 14 and 21 mg; 16 h: 5, 10, 15 and 25 mg	One daily on clean, non-hairy, unbroken skin. Remove before morning (16 h) or next morning (24 h). Apply to fresh site or non-hairy skin, usually at the hip, trunk or upper arm. Should not be applied to broken skin	Local skin irritation and rashes, insomnia. Do not use with generalised skin disease
Gum: 2 and 4 mg	Chew until taste is strong then rest gum between gum and cheek; chew again when taste has faded. Repeat this for 30 min or until taste dissipates. Avoid acidic drinks for 15 min before and during chewing the gum	Jaw ache, headache and dyspnoea. Mild burning sensation in the mouth and throat
Sublingual tablet: 2 or 4 mg each	Rest under tongue until dissolved
Lozenge: 1, 2 or 4 mg each	Place between gum and cheek and allow to dissolve. Delivers slightly more nicotine than the equivalent gum	Nasal irritation, rhinorrhoea, sneezing, throat irritation and cough. This usually dissipates with continued use
Inhalator : 10 mg per cartridge	Inhale as required. Helps to satisfy the hand-to-mouth ritual of using a cigarette which may help some people. The nicotine is absorbed through the mouth rather than the lungs. Use with caution in people with asthma	Nasal irritation, rhinorrhoea, sneezing, throat irritation and cough. This usually dissipates with continued use
Nasal spray: 500 μcg per spray	One spray into each nostril as needed. More rapidly absorbed than other forms of NRT so often used for acute relief of cravings. Not recommended for people with nasal or sinus conditions, allergies or asthma

NRT approximately doubles smoking cessation rates compared with controls (either placebo or no NRT), irrespective of the intensity of adjunctive therapy. The strongest evidence is for use of patches and gum. The choice of product and initial dose is also influenced by the degree of tobacco dependence; heavy smokers (15 to 20+ cigarettes a day and/or smoking within 30 min of waking) will require higher NRT doses. The available types of NRT product are set out below:

Long acting

Long-acting transdermal patches are considered to be most suitable for people who smoke regularly through the day. The 24-h patch, worn overnight, is better for people who crave nicotine first thing in the morning. Use of the patch can cause insomnia or vivid dreams and so can either be removed before bedtime or a 16-h patch used instead. Heavy smokers should be started on the high-dose patches.

Short acting

There are several short-acting products available:

Gum

It is important to chew nicotine gum correctly. The gum should be chewed slowly until the taste becomes strong and then allowed to rest between the cheek and teeth to allow absorption. When the taste has faded the gum should be chewed again. Nicotine gum is not a good choice for people with dentures or other vulnerable dental work. Most gum users do not consume enough in a day to match the nicotine levels from smoking. Patients should be encouraged to use 10–15 pieces of gum a day, for example, as one piece an hour.

Lozenge

These are allowed to dissolve in the mouth and periodically moved around, until completely gone. One lozenge per hour is recommended during the initial period of use to provide adequate nicotine absorption.

Inhalator

Inhalators may be particularly useful for people who miss the physical act of smoking. Nicotine is absorbed via the buccal mucosa, peaking in 20–30 min. To achieve sufficient blood levels, the user should puff on the inhalator for 2 min each hour, changing the cartridge after three 20-min sessions.

Nasal spray

A nasal spray is most useful for people who smoke 20 or more cigarettes per day. The side effects of sneezing and a burning sensation in the nose usually wear off after a day or two, so patients should be encouraged to persevere.

Sublingual tablets

These tablets dissolve under the tongue and may be useful for people with dentures who have difficulty using nicotine gum. Hourly use should be recommended.

Bupropion (amfebutamone)

Originally used as an antidepressant, bupropion has been licensed for use in smoking cessation. It inhibits neuronal noradrenaline and dopamine uptake, reducing tobacco withdrawal symptoms by increasing CNS dopamine levels. Treatment should be started while the patient is still smoking with a target date to stop smoking set during the second week of use. The total treatment period should be for 7–9 weeks. The initial dose should be 150 mg daily for 6 days, increasing to 150 mg twice a day thereafter (with at least 8 h between doses). Bupropion is as effective as NRT and intensive behavioural support. There is no clear evidence of benefit over NRT but there is some evidence of better results if used in combination with NRT.

Bupropion should not be used in patients with a current or previous seizure disorder or in patients with bulimia, anorexia nervosa, bipolar disorder, severe hepatic cirrhosis or those taking monoamine oxidase inhibitors; nor is it appropriate for use in smokers under the age of 18. Bupropion inhibits cytochrome P450 enzymes and so may inhibit the metabolism of other drugs. The main side effects experienced include dry mouth, insomnia (avoid bedtime dosing), headache, dizziness, allergic reactions, taste disorder and seizures.

Varenicline

Varenicline is an oral selective partial α₄β₂ agonist at the neuronal nicotinic acetylcholine receptor. Varenicline alleviates the symptoms of craving and withdrawal, whilst reducing the rewarding and reinforcing effects of smoking by preventing nicotine binding to α₄β₂ receptors. Trial evidence suggests use may result in a higher abstinence rate than either bupropion or NRT, although this may not be sustained after 12 months. Use is recommended as an option for smokers aged 18 or over wishing to quit, ideally in the context of a behavioural support programme (National Institute for Health and Clinical Excellence, 2007). Varenicline should be started 1–2 weeks before stopping smoking. The main side effects are nausea, vomiting, abnormal dreams and insomnia. Fears over a possible increased risk of depression and suicide have been allayed (Gunnell et al., 2009), although individuals who develop agitation, depressed mood or suicidal thoughts are required to seek prompt medical advice.

Combination therapy involving varenicline and bupropion (either with each other or in conjunction with NRT) is not recommended.

Use of inhaled therapy

For individuals suffering from obstructive airways disease with a degree of reversibility, the correct use of inhaled therapy is a vital part of overall management.

Medication counselling needs to highlight the modes of action of the bronchodilators, particularly the more rapid onset of the β₂-agonists to relieve breathlessness rather than the slower-acting anticholinergics. If inhaled steroids are prescribed, the importance of regular administration must be stressed. The incorrect use of any inhaler will lead to subtherapeutic dosing. The correct use of inhalers is, therefore, as vital in the management of COPD patients as it is for patients with asthma (see Chapter 25). The advantages and disadvantages of each type of inhaler device are summarised in Table 26.6.

Table 26.6 Comparison of inhaler devices

Domiciliary oxygen therapy

Studies have shown that only about 50% of patients on LTOT comply with the requirement for 15 h of treatment a day. Counselling will be required to persuade the patient to comply with this minimum figure. Emphasis must be given to the improvement in quality of life gained from treatment rather than the idea of being continually ‘tied’ to the oxygen supply. If an oxygen concentrator is used, limited mobility can be gained by installing at least two terminals for the unit (usually in the living room and bedroom) with long tubing between the terminal and nasal prongs.

Patients should be actively encouraged to stop smoking if they still do; because of the fire risk if they use LTOT. Moreover, the carbon monoxide present in tobacco smoke binds to haemoglobin and forms carboxy-haemoglobin, which decreases the amount of oxygen that can be transported by the blood and will partially or completely negate the beneficial effects of LTOT.

The long-term, chronic nature of COPD may leave a patient with a fear of exercise as this will cause dyspnoea (breathlessness). Thus, the patient with COPD may decide not to undertake any exercise. Ambulatory oxygen cylinders can be used to encourage mobility and increase exercise tolerance during travel outside the home.

Patients using domiciliary oxygen are followed up to provide education and support, to assess the oxygen saturation of the patient and to assess the suitability of the delivery device for ambulatory oxygen if provided. Suitable devices have been suggested (National Institute for Health and Clinical Excellence, 2010) depending on the amount of time required for use (Table 26.7).

Table 26.7 Oxygen delivery for ambulatory oxygen therapy (National Institute for Health and Clinical Excellence, 2010)

How long is the oxygen used by the patient?	Best type of delivery device
Less than 90 min	Small cylinder
90 min to 4 h	Small cylinder with oxygen-conserving device
More than 4 h	Liquid oxygen
More than 30 min, with flow rates greater than 2 L/min	Liquid oxygen

Case studies

Case 26.1

Mr JF, a 74-year-old man, has a long-standing history of COPD. He has a 70-pack-year history of smoking, but finally managed to give up 4 years ago, after numerous admissions to hospital for infective exacerbations. He is recovering on the respiratory ward from his first admission for 6 months. His consultant believes he may be a candidate for long-term oxygen therapy.

Questions

1. What criteria should Mr JF fill in order to be eligible for long-term oxygen therapy?

2. How is long-term oxygen therapy delivered?

3. Why might Mr JF be anxious about starting long-term oxygen therapy?

4. How would you allay these concerns?

5. What is the intended outcome of using long-term oxygen therapy?

Answers

1. In order to be eligible for long-term oxygen therapy, patients should have, when stable and on two separate occasions at least 3 weeks apart:

pO₂ <7.3 kPa

pO₂ >7.3 kPa and <8.0 kPa as well as at least one of the following:

• secondary polycythaemia

• nocturnal hypoxaemia (O₂ saturations <90% for >30% of the time)

• peripheral oedema

• pulmonary hypertension

2. It is impractical to deliver long-term oxygen therapy using cylinders. Instead, an oxygen concentrator, a device which increases the relative concentration of oxygen in environmental air via a molecular ‘sieving’ process, is used. In most cases, a flow rate of 2 L/min is delivered via nasal cannulae. Patients must use the concentrator for at least 15 h, and preferably over 20 h a day to achieve intended therapeutic outcomes (see below).

3. Mr JF may be concerned for several reasons listed:

• the length of time he will be tied to the machine each day

• restrictions on leaving the house once he starts his 15 h a day

• the cost of the electricity required to drive the concentrator

• loss of supply if there is a power cut

4. Mr JF’s concerns are logical but he can be reassured. The concentrator can be used while he is asleep (generally two outlets are installed, one in the living room and the other in the bedroom) and so this leaves him up to 9 h a day where he does not need to be using oxygen. The 15-h minimum does not have to be continuous, and so he can leave the house or interrupt the oxygen delivery as necessary to carry out activities of daily living. The cost of the electricity is covered by the oxygen contractor, who will monitor usage using a meter. Contractors are required to install a backup power supply which will continue to drive the concentrator for a minimum of 8 h should the mains supply fail.

5. Provided patients receive the required duration of therapy each day, beneficial effects on life expectancy, exercise tolerance and mental capacity can be anticipated.

Case 26.2

Mrs VL, a 58-year-old lady, has been brought into hospital by ambulance having been struggling with dyspnoea and significantly reduced exercise tolerance for several days. You review her chart and medical notes on the hospital admissions ward. The working diagnosis is an infective exacerbation of COPD. The patient presents with:

Thick green sputum which the patient reports is usually clear/white.

O₂ saturation of 82% on 28% oxygen delivered via a Venturi mask

Arterial blood gases (ABG):

pH 7.33 (7.35–7.45)

pO₂ 7.24 kPa (10.7 kPa)

pCO₂ 7.1 kPa (4.7–6.0 kPa)

Bicarbonate 46 mmol/L (22–26 mmol/L)

D-dimer negative

Drug history:

Salbutamol 2.5 mg via a nebuliser four times a day

Symbicort® 200/6 2 puffs twice a day

Tiotropium 18 µcg daily

Furosemide 40 mg twice a day

Ramipril 5 mg daily

Alendronate 70 mg weekly on Saturdays

Adcal D3 2 tablets daily

Mrs VL is commenced on:

Salbutamol 5 mg via a nebuliser 4 hourly

Ipratropium bromide 500 µcg via a nebuliser 6 hourly

Prednisolone 30 mg daily

Co-amoxiclav 1.2 g i.v. three times a day

Doxycycline 200 mg stat then 100 mg od thereafter.

Questions

1. Explain the arterial blood gas profile.

2. What is the significance of the negative D-dimer result?

3. If she does not respond to initial therapy, what might it be appropriate to change or introduce?

Answers

1. The low pO₂ indicates significant hypoxia. A slightly low pH and slightly elevated pCO₂ suggest a respiratory acidosis. The high bicarbonate level indicates that this acid/base disturbance is compensated at this level. The bicarbonate is likely to have accumulated over a relatively prolonged period.

2. A negative D-dimer is a strong indicator that Mrs VL’s dyspnoea is not as a result of a pulmonary embolism. Although a raised D-dimer is not a reliable means of confirming thromboembolic disease (low specificity – frequent false positives), it is far more reliable in excluding such conditions where the result falls within the normal range (high sensitivity – rare false negatives). It is important to exclude conditions such as pulmonary embolism or acute left ventricular failure when patients with COPD present with increased shortness of breath to avoid missed diagnoses.

3. The concentration of oxygen could be increased to 35%. Mrs VL may be at risk of developing hypercapnia as a result of her COPD, and so her arterial blood gases should be rechecked 30–60 min after the change in her oxygen therapy. Particular attention should be made to any increase in the carbon dioxide concentration. If Mrs VL’s respiratory rate exceeds 30 breaths/min while using a Venturi mask, the oxygen flow rate should be increased by 50%. The target for oxygen therapy is to achieve a saturation of 88–92%.

Inadequate response to nebulised bronchodilators is an indication where intravenous aminophylline should be considered. A loading dose of 5 mg/kg over at least 20 min followed by a continuous infusion of 500 μcg/kg/h can be administered. Levels should be checked within the first 24 h of therapy.

There is no evidence that use of mucolytics at this acute stage will be of benefit.

Case 26.3

Mrs SS is a 61-year-old retired factory worker who has been recently diagnosed with COPD after admission to hospital. She was discharged a few days ago having been started on a nicotine patch, 14 mg every 24 h. She asks you for advice on the best way to give up smoking as she has tried several times in the past and failed to quit. She smokes around 25 cigarettes a day and has been smoking since she was 17. She has a history of oesophageal reflux and also has epilepsy.

Questions

1. Why is it important for Mrs SS to give up smoking?

2. How many pack-years has she smoked?

3. What aspects should be discussed when helping someone to stop smoking?

When you question Mrs SS about her previous attempts to stop smoking, she confides that her husband smokes in the house and she finds it difficult not to smoke when he does. She has tried nicotine gum but finds it difficult to use with her dentures. Her current patch does not seem to be helping, it has reduced her craving but not eliminated it, especially when she wakes up in the morning.

4. Is the current management of Mrs SS appropriate?

5. What non-pharmacological support should be offered to Mrs SS?

Answers

1. Stopping smoking is the single most important way of affecting a patient’s outcome at all stages of COPD. Giving up smoking will slow down the gradual decline in FEV₁ that is seen in smokers.

Mrs SS has smoked approximately 55 pack-years.

3. There are five key steps in helping a smoker to stop smoking, the ‘five As’:

• Ask about tobacco use. This should include an assessment of the degree of addiction

• Advise to quit

• Assess willingness to make an attempt

• Assist in quit attempt

• Arrange follow-up.

Motivation from the patient is the key to giving up smoking but is related to the degree of dependence on tobacco. Heavy smokers may exhibit low motivation to quit as they lack confidence in their ability to do so.

4. Nicotine replacement patches are considered to be most suitable for people who smoke regularly through the day but a 21- to 25-mg patch would have been a more appropriate starting dose for someone smoking 20 or more cigarettes a day. Two of the most common side effects are insomnia or vivid dreams, if these occur the patch can either be removed before bedtime or a 16-h patch used. A suitable alternative would be the short-acting gum, lozenge or nasal spray. Mrs SS would require the 4-mg gum and should be encouraged to use the 8- to 12-pieces of gum a day to provide approximately 20 mg of absorbed nicotine per day. As the nasal spray is most useful for people who smoke 20 or more cigarettes per day, this may be the preferred formulation.

Mrs SS may benefit from a combination of products. Although this practice is not specifically recommended by product manufacturers, it is considered suitable in highly dependent patients, or in those who have had unsuccessful quit attempts using a single nicotine replacement therapy preparation. If breakthrough cravings are felt despite a background patch then the addition of short-acting dosage forms may be used as ‘rescue’ medication.

A date on which to quit smoking should be set. Nicotine replacement therapy should be prescribed in blocks of 2 weeks. Mrs SS should be seen and helped regularly throughout this process, before and after her quit date. The duration of nicotine replacement therapy in people who maintain an abstinence is usually 8–12 weeks, depending on the product, followed by a dose reduction.

Another option would be to try varenicline. This may be more effective in achieving continuous abstinence (National Institute for Health and Clinical Excellence, 2007) than either nicotine replacement therapy or bupropion. Varenicline should be started 1–2 weeks before Mrs SS’s quit date and is continued for a total of 12 weeks, although an additional 12 weeks’ therapy may be required. Bupropion is contraindicated as this may increase Mrs SS’s risk of seizures.

5. It is thought that around 3% of smokers quit every year on their own but that percentage increases when they are given simple advice whilst encouraging the quit attempt. Several non-pharmacological strategies exist to help:

• Written self-help material.

• Counselling and behavioural therapy. These aim to motivate the smoker and help with the skills and strategies required to cope with nicotine withdrawal, psychological pressures to smoke and situations of temptation to smoke.

In all cases, pharmacological therapy should also be offered as appropriate.

Several NHS, patient and charitable organisations can provide help and support to people wishing to stop smoking. Information can be obtained from the followed web sites:

http://smokefree.nhs.uk/

http://www.quit.org.uk/

http://www.patient.co.uk/health/Smoking-Tips-to-Help-you-Stop.htm

References

American Thoracic Society/European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients with COPD Version 1.2. New York: American Thoracic Society, 2004. [updated 8 September 2005]. Available at: http://www.thoracic.org/go/copd

Barnes P.J. Corticosteroid resistance in airway disease. Proc. Am. Thorac. Soc.. 2004;1:264-268.

Boe J., Dennis J.H., O’Driscoll B.R., for the European Respiratory Society Task Force. European Respiratory Society guidelines on the use of nebulizers. Eur. Respir. J.. 2001;18:228-242. Available at http://erj.ersjournals.com/cgi/content/full/18/1/228