Asthma
"Management - Management of catastrophic sudden severe (brittle) asthma - Prognosis"
Management
The aims of treatment are to:
■ abolish symptoms
■ restore normal or best possible lung function
■ reduce the risk of severe attacks
■ enable normal growth to occur in children
■ minimize absence from school or employment.
This involves:
■ patient and family education about asthma
■ patient and family participation in treatment
■ avoidance of identified causes where possible
■ use of the lowest effective doses of convenient medications to minimize short-term and long-term side-effects.
Many asthmatics belong to self-help groups whose aim is to further their understanding of the disease and to foster self-confidence and fitness.
Control of extrinsic factors
Measures must be taken to avoid causative allergens such as pets, moulds and certain foodstuffs (see allergic rhinitis), particularly in childhood. Avoidance of the house-dust mite is very difficult. A recent Cochrane review confirms earlier data that there is no evidence for the effectiveness of physical or chemical measures to control house-dust mite levels. The use of covers for bedding and changes to living accommodation has no beneficial effect on outcomes Active and passive smoking should be avoided, as should betablockers in either tablet or eye drop form. Individuals intolerant to aspirin should avoid all NSAIDs. Other agents (e.g. preservatives and colouring materials such as tartrazine) should be avoided if shown to be a causative factor. Fifty per cent of individuals sensitized to occupational agents may be cured if they are kept permanently away from exposure. The remaining 50% continue to have symptoms that may be as severe as when exposed to materials at work, especially if they were symptomatic for a long time before the diagnosis was made.
This emphasizes that:
■ The rapid identification of extrinsic causes of asthma and their removal is necessary wherever possible (e.g. occupational agents, family pets).
■ Once extrinsic asthma is initiated, it may become selfperpetuating, possibly by non-immune mechanisms.
Drug treatment
The mainstay of asthma therapy is the use of therapeutic agents delivered as aerosols or powders directly into the lungs (Practical box). The advantages of this method of administration are that drugs are delivered direct to the airways and first-pass metabolism in the liver is avoided; thus lower doses are necessary and systemic unwanted effects are minimized.
The aims of treatment are to:
■ abolish symptoms
■ restore normal or best possible lung function
■ reduce the risk of severe attacks
■ enable normal growth to occur in children
■ minimize absence from school or employment.
This involves:
■ patient and family education about asthma
■ patient and family participation in treatment
■ avoidance of identified causes where possible
■ use of the lowest effective doses of convenient medications to minimize short-term and long-term side-effects.
Many asthmatics belong to self-help groups whose aim is to further their understanding of the disease and to foster self-confidence and fitness.
Control of extrinsic factors
Measures must be taken to avoid causative allergens such as pets, moulds and certain foodstuffs (see allergic rhinitis), particularly in childhood. Avoidance of the house-dust mite is very difficult. A recent Cochrane review confirms earlier data that there is no evidence for the effectiveness of physical or chemical measures to control house-dust mite levels. The use of covers for bedding and changes to living accommodation has no beneficial effect on outcomes Active and passive smoking should be avoided, as should betablockers in either tablet or eye drop form. Individuals intolerant to aspirin should avoid all NSAIDs. Other agents (e.g. preservatives and colouring materials such as tartrazine) should be avoided if shown to be a causative factor. Fifty per cent of individuals sensitized to occupational agents may be cured if they are kept permanently away from exposure. The remaining 50% continue to have symptoms that may be as severe as when exposed to materials at work, especially if they were symptomatic for a long time before the diagnosis was made.
This emphasizes that:
■ The rapid identification of extrinsic causes of asthma and their removal is necessary wherever possible (e.g. occupational agents, family pets).
■ Once extrinsic asthma is initiated, it may become selfperpetuating, possibly by non-immune mechanisms.
Drug treatment
The mainstay of asthma therapy is the use of therapeutic agents delivered as aerosols or powders directly into the lungs (Practical box). The advantages of this method of administration are that drugs are delivered direct to the airways and first-pass metabolism in the liver is avoided; thus lower doses are necessary and systemic unwanted effects are minimized.
| Practical Box | Inhaled therapy |
| Patients should be taught how to use inhalers and their technique checked regularly. Use of a metered-dose inhaler 1. The canister is shaken. 2. The patient exhales to functional residual capacity (not residual volume), i.e. normal expiration. 3. The aerosol nozzle is placed to the open mouth. 4. The patient simultaneously inhales rapidly and activates the aerosol. 5. Inhalation is completed. 6. The breath is held for 10 seconds if possible. Even with good technique only 15% of the contents is inhaled and 85% is deposited on the wall of the pharynx and ultimately swallowed. NB Chlorofluorocarbon (CFC) propellants have been/are being replaced by hydrofluoralkane (HFA) propellants. The new aerosols may feel and taste different and patients need reassurance of their efficacy. Spacers These are plastic conical spheres inserted between the patient’s mouth and the inhaler. They are designed to reduce particle velocity so that less drug is deposited in the mouth. Spacers also diminish the need for coordination between aerosol activation and inhalation. They are useful in children and in the elderly and they reduce the risk of candidiasis. | |
Both national and international guidelines have been published on the stepwise treatment of asthma (previous Box) based on three principles:
■ Asthma self-management with regular asthma monitoring using PEF meters and individual treatment plans discussed with each patient and written down.
■ The appreciation that asthma is an inflammatory disease and that anti-inflammatory (controller) therapy should be started even in mild cases.
■ Use of short-acting inhaled bronchodilators (e.g. salbutamol and terbutaline) only to relieve breakthrough symptoms. Increased use of bronchodilator treatment to relieve increasing symptoms is an indication of deteriorating disease.
A list of drugs used in asthma is shown in next Box. These are given in a stepwise fashion (1 to 6) as indicated in previous Box.
Once the asthma is under control, for at least 2–3 months, the drug therapy should be re-assessed in order to use the minimal dosage of inhaled steroids, combined with an oral long-acting β2 agonist (stepdown). These agents should not be stopped for at least 6 months, if at all.
β2-adrenoceptor agonists
The most widely used bronchodilator preparations contain β2-adrenoceptor agonists that are selective for the respiratory tract and do not stimulate the β1 adrenoceptors of the myocardium. These drugs are potent bronchodilators because they relax the bronchial smooth muscle. Such treatment is very effective in relieving symptoms but does little for the underlying inflammatory nature of the disease.
- Uses
■ Mildest asthmatics with intermittent attacks. Only these people should rely on bronchodilator treatment alone.
■ Asthma self-management with regular asthma monitoring using PEF meters and individual treatment plans discussed with each patient and written down.
■ The appreciation that asthma is an inflammatory disease and that anti-inflammatory (controller) therapy should be started even in mild cases.
■ Use of short-acting inhaled bronchodilators (e.g. salbutamol and terbutaline) only to relieve breakthrough symptoms. Increased use of bronchodilator treatment to relieve increasing symptoms is an indication of deteriorating disease.
A list of drugs used in asthma is shown in next Box. These are given in a stepwise fashion (1 to 6) as indicated in previous Box.
Once the asthma is under control, for at least 2–3 months, the drug therapy should be re-assessed in order to use the minimal dosage of inhaled steroids, combined with an oral long-acting β2 agonist (stepdown). These agents should not be stopped for at least 6 months, if at all.
β2-adrenoceptor agonists
The most widely used bronchodilator preparations contain β2-adrenoceptor agonists that are selective for the respiratory tract and do not stimulate the β1 adrenoceptors of the myocardium. These drugs are potent bronchodilators because they relax the bronchial smooth muscle. Such treatment is very effective in relieving symptoms but does little for the underlying inflammatory nature of the disease.
- Uses
■ Mildest asthmatics with intermittent attacks. Only these people should rely on bronchodilator treatment alone.
| ||||
| Step | PEFR | Treatment | ||
| 1 Occasional symptoms, less frequent than daily | 100% predicted | As-required short-acting b2 agonists If used more than once daily, move to step 2 | ||
| 2 Daily symptoms | ≤ 80% predicted | Regular inhaled preventer therapy: Anti-inflammatory drugs: inhaled low-dose corticosteroids up to 800 μg daily. Leukotriene receptor agonists (LTRA), theophylline and sodium cromoglicate are less effective If not controlled, move to step 3 | ||
| 3 Severe symptoms | 50–80% predicted | Inhaled corticosteroids and long-acting inhaled b2 agonist Continue inhaled corticosteroid Add – regular inhaled long-acting β2 agonist (LABA) Still not controlled, add either LTRA, modified release oral theophylline or β2 agonist If not controlled, move to Step 4 | ||
| 4 Severe symptoms uncontrolled with highdose inhaled corticosteroids | 50–80% predicted | High-dose inhaled corticosteroid and regular bronchodilators Increase high-dose inhaled corticosteroids up to 2000 μg daily Plus regular long-acting β2 agonists Plus either LTRA or modified release theophylline or β2 agonist | ||
| 5 Severe symptoms deteriorating | ≤ 50% predicted | Regular oral corticosteroids Add prednisolone 40 mg daily to step 4 | ||
| 6 Severe symptoms deteriorating in spite of prednisolone | ≤ 30% predicted | Hospital admission | ||
| Short-acting bronchodilator treatment taken at any step on an as required basis. | ||||
Short-acting β agonists (SABAs) such as salbutamol (100 μg), known as albuterol in the USA, or terbutaline (250 μg) should be prescribed as ‘two puffs as required’. Some patients use nebulizers at home for self-administration of salbutamol or terbutaline. Such treatment is effective, but patients must not rely on repeated home administration of nebulized β2- adrenoceptor agonists for worsening asthma, and must be encouraged to seek medical advice urgently if their condition does not improve. The excessive use of β2 agonists has been linked to the two epidemics of asthma mortality in the 1960s and 1980s.
| Practical Box | Drugs used in asthma |
| Short-acting relievers Inhaled β2 agonists (e.g. salbutamol (albuterol in USA), terbutaline) Long-acting relief/disease controllers Inhaled long-acting β2 agonists (e.g. salmeterol, formoterol) Inhaled corticosteroids (e.g. beclometasone, budesonide, fluticasone) Compound inhaled salmeterol and fluticasone Sodium cromoglicate Leukotriene modifiers (e.g. montelukast, zafirlukast, zileuton) Other agents with bronchodilator activity Inhaled antimuscarinic agents (e.g. ipratropium, oxitropium) Theophylline preparations Oral corticosteroids (e.g. prednisolone 40 mg daily) Steroid-sparing agents Methotrexate Ciclosporin Intravenous immunoglobulin Anti-IgE monoclonal antibody – omalizumab Etanercept | |
■ SABAs can be taken at any step, as and when required from step 1 to step 6.
■ Poorly controlled asthmatics on standard doses of inhaled steroids. These patients require salmeterol or formoterol, which are highly selective and potent longacting β2-adrenoceptor agonists (LABA) effective by inhalation for up to 12 hours, thereby reducing the need for administration to once or twice daily. Long-acting β2- adrenoceptor agonists improve symptoms and lung function and reduce exacerbations in patients. They should never be used alone but always in combination with an inhaled corticosteroid. Increasingly these drugs are administered as fixed-dose combinations with corticosteroids (salmeterol/fluticasone and formoterol/ budesonide) in the same inhaler (step 3).
β2-adrenoceptor agonists are less effective when given by mouth than when the drug is inhaled, and to help those who cannot coordinate activation of the aerosol and inhalation, several breath-activated or dry powder devices have been developed.
Antimuscarinic bronchodilators
Muscarinic receptors are found in the respiratory tract; large airways contain mainly M3 receptors whereas the peripheral lung tissue contains M3 and M1 receptors. Nonselective muscarinic antagonists – ipratropium bromide (20– 40 μg three or four times daily) or oxitropium bromide (200 μg twice daily) – by aerosol inhalation can be useful during asthma exacerbations, but their overall role in asthma is limited.
Anti-inflammatory drugs
Sodium cromoglicate and nedocromil sodium prevent activation of many inflammatory cells, particularly mast cells, eosinophils and epithelial cells, but not lymphocytes, by blocking a specific chloride channel which in turn prevents calcium influx. These drugs are effective in patients with milder asthma (step 2). Sodium cromoglicate is taken regularly either in the form of a Spincap containing 20 mg or in aerosol form from a metered-dose inhaler delivering 5 mg per puff. The dose should be two puffs four times daily from an inhaler, or one Spincap three or four times daily. Nedocromil sodium is taken as an aerosol at a dose of 4 mg (two puffs) two to four times daily.
Asthma guidelines advise that inhaled corticosteroids are more efficacious than the chromones, but the latter are free of side-effects and, therefore, may offer some advantages in children, especially when there is strong evidence for an allergic component.
Inhaled corticosteroids
All patients who have regular persistent symptoms (even mild symptoms) need regular treatment with inhaled corticosteroids delivered in a stepwise fashion (from step 2 upwards) or as a high dose followed by a reduction to maintenance levels. Beclometasone dipropionate (BDP) is the most widely used inhaled steroid and is available in doses of 50, 100, 200 and 250 μg per puff. Other inhaled steroids include budesonide, fluticasone, mometasone and triamcinolone.
Much of the inhaled dose does not reach the lung but is either swallowed or exhaled. Deposition in the lung varies between 10% and 25% depending on inhaler technique and the technical characteristics of the aerosol device. Drug which is deposited in the airways reaches the systemic circulation directly, through the bronchial circulation, while any drug that is swallowed has to pass through the liver before it can reach the systemic circulation. Gram for gram, fluticasone and mometasone are more potent than beclometasone with considerably less systemic bioavailability, owing to their greater sensitivity to hepatic metabolism. The newer hydrofluoroalkane (HFA) aerosols of beclometasone deliver a higher proportion of useable drug than the old CFC-based aerosols, and the effective dosage of HFA-beclometasone is equivalent to the same dose of HFA-fluticasone, whereas previously the effective dose ratio was 2 : 1. Absorption of beclometasone and budesonide does not seem to present a risk at doses up to 800 μg/day, but when using high-dose inhaled steroids in patients who have not responded to standard doses, fluticasone or mometasone may be preferred because of their lower bioavailability. The dose–response curve for inhaled corticosteroids is flat beyond 800 μg beclometasone or equivalent, and in patients with moderate asthma who are taking this daily, addition of salmeterol or formoterol is more effective than doubling the dose of inhaled corticosteroid.
The unwanted effects of inhaled corticosteroids are oral candidiasis (5% of patients), and hoarseness due to the effect of corticosteroids on the laryngeal muscles. Subcapsular cataract formation is rare but can occur in the elderly. Osteoporosis is a complication when inhaled corticosteroids are taken in high doses (beclometasone or budesonide > 800 μg daily). In children, inhaled corticosteroids at doses greater than 400 μg daily have been shown to retard short-term growth. Inhaled corticosteroid use should be stepped down once asthma comes under control. Candidiasis and GI absorption can be reduced by using spacers, mouthwashing and teeth cleaning after use. More recently inhaled corticosteroids, e.g. ciclesonide 80 μg daily, that are esterified in the lung thereby reducing systemic effects, have become available with a higher therapeutic index.
Asthmatic patients who smoke are less responsive to inhaled corticosteroids, and additional therapy, e.g. with leukotriene receptor antagonists, is required.
Many patients with anything more than mild/moderate asthma benefit from combination LABA/corticosteroid therapy and there is some evidence that the two drugs interact therapeutically. Adding a LABA once the dose of inhaled corticosteroid has reached 800–1000 μg is of proven greater benefit than further increasing the steroid dose.
Oral corticosteroids and steroid-sparing agents
Oral corticosteroids may be necessary for those individuals not controlled on inhaled corticosteroids (step 5). The dose should be kept as low as possible to minimize side-effects. The effect of short-term treatment with prednisolone 30 mg daily. Some patients require continuing treatment with oral corticosteroids. Several studies suggest that treatment with low doses of methotrexate (15 mg weekly) can significantly reduce the dose of prednisolone needed to control the disease in some patients, and ciclosporin also improves lung function in some steroiddependent asthmatics. Several other steroid-sparing strategies including ciclosporin and immunoglobulin have also been tried, but with varying success.
Cysteinyl leukotriene receptor
antagonists (LTRAs)
This class of anti-asthma therapy targets one of the principal asthma mediators by inhibiting the cysteinyl LT1 receptor. A second receptor (cyst LT2) has been identified on inflammatory cells. Montelukast, pranlukast (only available in South East Asia) and zafirlukast are given orally and are effective in a subpopulation of patients. However, it is not possible to predict which individuals will benefit: a 4-week trial of LTRA therapy is recommended before a decision is made to continue or stop. LTRAs should be considered in any patient who is not controlled on low to medium doses of inhaled steroids (step 2). Their action is additive to that of long-acting β2 agonists. LTRAs are particularly useful in patients with aspirin-intolerant asthma, in those patients requiring highdose inhaled or oral corticosteroids and in asthmatic smokers. Because these drugs are orally active they are helpful in asthma combined with rhinitis and in young children with asthma and/or virus associated wheezing.
Monoclonal antibodies
Newer agents that modulate IgE-associated inflammation are being developed. The most promising of these is a recombinant humanized monoclonal antibody that complexes with free IgE – omalizumab – blocking its interaction with mast cells and basophils. Clinical trials in children and adults with severe asthma despite corticosteroids show good efficacy when omalizumab is given subcutaneously once or twice each month depending on total serum IgE level and body weight. Recent proof-of-concept trials have also suggested a place for anti-TNF therapy (blocking monoclonal antibody or soluble receptor fusion protein, etanercept) in corticosteroid refractory severe asthma. There is a need to examine other biologicals as potential new controller therapies for the 5–10% of patients with severe disease, which accounts for a high proportion of the health costs of asthma.
Antibiotics
Although wheezing frequently occurs in infective exacerbations of COPD, there is limited evidence that antibiotics are helpful in the management of patients with asthma. Yellow or green sputum containing eosinophils and bronchial epithelial cells may be coughed up in acute exacerbations of asthma. This is normally due to viral, not bacterial, infection and antibiotics are not required. Occasionally, mycoplasma and Chlamydia infections can cause chronic relapsing asthma and in such cases the use of appropriate antimicrobials is worthwhile if a bacterial diagnosis has been established by culture or serology.
Asthma attack
Although these may occur spontaneously, asthma exacerbations are most commonly caused by lack of treatment adherence, respiratory virus infections associated with the common cold, and exposure to allergen or triggering drug, e.g. an NSAID. Whenever possible patients should have a written personalized plan that they can implement in anticipation of or at the start of an exacerbation that includes the early use of a short course of oral corticosteroids. If the PEFR is greater than 150 L/min, patients may improve dramatically on nebulized therapy and may not require hospital admission. Their regular treatment should be increased, to include treatment for 2 weeks with 30–60 mg of prednisolone followed by substitution by an inhaled corticosteroid preparation. Short courses of oral prednisolone can be stopped abruptly without tailing down the dose.
Acute severe asthma
The term ‘status asthmaticus’ was defined as asthma that had failed to resolve with therapy in 24 hours. Although this term is still used occasionally, it has been mainly discarded and replaced by ‘acute severe asthma’, i.e. severe asthma that has not been controlled by the patient’s use of medication.
Patients with acute severe asthma typically have:
■ inability to complete a sentence in one breath
■ respiratory rate ≥ 25 breaths per minute
■ tachycardia ≥ 110 beats/min (pulsus paradoxus, is not useful as it is only present in 45% of cases)
■ PEFR < 50% of predicted normal or best. Features of life-threatening attacks are:
■ a silent chest, cyanosis or feeble respiratory effort
■ exhaustion, confusion or coma
■ bradycardia or hypotension
■ PEFR < 30% of predicted normal or best (approximately 150 L/min in adults).
Arterial blood gases should always be measured in asthmatic patients requiring admission to hospital. Pulse oximetry is useful in monitoring oxygen saturation during the admission and reduces the need for repeated arterial puncture. Features suggesting very severe life-threatening attacks are:
■ a high Paco2 > 6 kPa
■ severe hypoxaemia Pao2 < 8 kPa despite treatment with oxygen
■ a low and falling arterial pH.
- Treatment (Emergency box) is commenced with 5 mg of nebulized salbutamol or 10 mg terbutaline with oxygen as the driving gas. Nebulized antimuscarinics (e.g. ipratropium bromide) are also helpful. A chest X-ray is taken to exclude a pneumothorax. If no improvement occurs with nebulized therapy, intravenous infusions of β2-adrenoceptor agonist (salbutamol or terbutaline 250 μg over 10 min) and/or magnesium sulphate (1.2–2 g over 20 min, which also relaxes airways smooth muscle) should be used. Intravenous aminophylline is not given as trials show marginal benefit and side-effects such as nausea and vomiting, cardiac arrhythmia and CNS side-effects are problematic. Hydrocortisone 200 mg i.v. should be administered 4-hourly for 24 hours, and 60 mg of prednisolone should be given orally daily. In patients who do not respond to this regimen, ventilation is often required.
Ideally, patients should be kept in hospital for at least 5 days, since the majority of sudden deaths occur 2–5 days after admission. During this time oxygen saturation should be monitored by oximetry. Oral prednisolone can be reduced from 60 mg to 30 mg once improvement occurs. Further reduction should be gradual on an outpatient basis until an appropriate maintenance dose or substitution by inhaled corticosteroid aerosols can be achieved.
A recent approach for moderate to severe persistent asthma is bronchial thermoplasty. This bronchoscopic procedure reduces the mass of airway smooth muscle, reducing bronchoconstriction, and is being evaluated.
■ Poorly controlled asthmatics on standard doses of inhaled steroids. These patients require salmeterol or formoterol, which are highly selective and potent longacting β2-adrenoceptor agonists (LABA) effective by inhalation for up to 12 hours, thereby reducing the need for administration to once or twice daily. Long-acting β2- adrenoceptor agonists improve symptoms and lung function and reduce exacerbations in patients. They should never be used alone but always in combination with an inhaled corticosteroid. Increasingly these drugs are administered as fixed-dose combinations with corticosteroids (salmeterol/fluticasone and formoterol/ budesonide) in the same inhaler (step 3).
β2-adrenoceptor agonists are less effective when given by mouth than when the drug is inhaled, and to help those who cannot coordinate activation of the aerosol and inhalation, several breath-activated or dry powder devices have been developed.
Antimuscarinic bronchodilators
Muscarinic receptors are found in the respiratory tract; large airways contain mainly M3 receptors whereas the peripheral lung tissue contains M3 and M1 receptors. Nonselective muscarinic antagonists – ipratropium bromide (20– 40 μg three or four times daily) or oxitropium bromide (200 μg twice daily) – by aerosol inhalation can be useful during asthma exacerbations, but their overall role in asthma is limited.
Anti-inflammatory drugs
Sodium cromoglicate and nedocromil sodium prevent activation of many inflammatory cells, particularly mast cells, eosinophils and epithelial cells, but not lymphocytes, by blocking a specific chloride channel which in turn prevents calcium influx. These drugs are effective in patients with milder asthma (step 2). Sodium cromoglicate is taken regularly either in the form of a Spincap containing 20 mg or in aerosol form from a metered-dose inhaler delivering 5 mg per puff. The dose should be two puffs four times daily from an inhaler, or one Spincap three or four times daily. Nedocromil sodium is taken as an aerosol at a dose of 4 mg (two puffs) two to four times daily.
Asthma guidelines advise that inhaled corticosteroids are more efficacious than the chromones, but the latter are free of side-effects and, therefore, may offer some advantages in children, especially when there is strong evidence for an allergic component.
Inhaled corticosteroids
All patients who have regular persistent symptoms (even mild symptoms) need regular treatment with inhaled corticosteroids delivered in a stepwise fashion (from step 2 upwards) or as a high dose followed by a reduction to maintenance levels. Beclometasone dipropionate (BDP) is the most widely used inhaled steroid and is available in doses of 50, 100, 200 and 250 μg per puff. Other inhaled steroids include budesonide, fluticasone, mometasone and triamcinolone.
Much of the inhaled dose does not reach the lung but is either swallowed or exhaled. Deposition in the lung varies between 10% and 25% depending on inhaler technique and the technical characteristics of the aerosol device. Drug which is deposited in the airways reaches the systemic circulation directly, through the bronchial circulation, while any drug that is swallowed has to pass through the liver before it can reach the systemic circulation. Gram for gram, fluticasone and mometasone are more potent than beclometasone with considerably less systemic bioavailability, owing to their greater sensitivity to hepatic metabolism. The newer hydrofluoroalkane (HFA) aerosols of beclometasone deliver a higher proportion of useable drug than the old CFC-based aerosols, and the effective dosage of HFA-beclometasone is equivalent to the same dose of HFA-fluticasone, whereas previously the effective dose ratio was 2 : 1. Absorption of beclometasone and budesonide does not seem to present a risk at doses up to 800 μg/day, but when using high-dose inhaled steroids in patients who have not responded to standard doses, fluticasone or mometasone may be preferred because of their lower bioavailability. The dose–response curve for inhaled corticosteroids is flat beyond 800 μg beclometasone or equivalent, and in patients with moderate asthma who are taking this daily, addition of salmeterol or formoterol is more effective than doubling the dose of inhaled corticosteroid.
The unwanted effects of inhaled corticosteroids are oral candidiasis (5% of patients), and hoarseness due to the effect of corticosteroids on the laryngeal muscles. Subcapsular cataract formation is rare but can occur in the elderly. Osteoporosis is a complication when inhaled corticosteroids are taken in high doses (beclometasone or budesonide > 800 μg daily). In children, inhaled corticosteroids at doses greater than 400 μg daily have been shown to retard short-term growth. Inhaled corticosteroid use should be stepped down once asthma comes under control. Candidiasis and GI absorption can be reduced by using spacers, mouthwashing and teeth cleaning after use. More recently inhaled corticosteroids, e.g. ciclesonide 80 μg daily, that are esterified in the lung thereby reducing systemic effects, have become available with a higher therapeutic index.
Asthmatic patients who smoke are less responsive to inhaled corticosteroids, and additional therapy, e.g. with leukotriene receptor antagonists, is required.
Many patients with anything more than mild/moderate asthma benefit from combination LABA/corticosteroid therapy and there is some evidence that the two drugs interact therapeutically. Adding a LABA once the dose of inhaled corticosteroid has reached 800–1000 μg is of proven greater benefit than further increasing the steroid dose.
Oral corticosteroids and steroid-sparing agents
Oral corticosteroids may be necessary for those individuals not controlled on inhaled corticosteroids (step 5). The dose should be kept as low as possible to minimize side-effects. The effect of short-term treatment with prednisolone 30 mg daily. Some patients require continuing treatment with oral corticosteroids. Several studies suggest that treatment with low doses of methotrexate (15 mg weekly) can significantly reduce the dose of prednisolone needed to control the disease in some patients, and ciclosporin also improves lung function in some steroiddependent asthmatics. Several other steroid-sparing strategies including ciclosporin and immunoglobulin have also been tried, but with varying success.
Cysteinyl leukotriene receptor
antagonists (LTRAs)
This class of anti-asthma therapy targets one of the principal asthma mediators by inhibiting the cysteinyl LT1 receptor. A second receptor (cyst LT2) has been identified on inflammatory cells. Montelukast, pranlukast (only available in South East Asia) and zafirlukast are given orally and are effective in a subpopulation of patients. However, it is not possible to predict which individuals will benefit: a 4-week trial of LTRA therapy is recommended before a decision is made to continue or stop. LTRAs should be considered in any patient who is not controlled on low to medium doses of inhaled steroids (step 2). Their action is additive to that of long-acting β2 agonists. LTRAs are particularly useful in patients with aspirin-intolerant asthma, in those patients requiring highdose inhaled or oral corticosteroids and in asthmatic smokers. Because these drugs are orally active they are helpful in asthma combined with rhinitis and in young children with asthma and/or virus associated wheezing.
Monoclonal antibodies
Newer agents that modulate IgE-associated inflammation are being developed. The most promising of these is a recombinant humanized monoclonal antibody that complexes with free IgE – omalizumab – blocking its interaction with mast cells and basophils. Clinical trials in children and adults with severe asthma despite corticosteroids show good efficacy when omalizumab is given subcutaneously once or twice each month depending on total serum IgE level and body weight. Recent proof-of-concept trials have also suggested a place for anti-TNF therapy (blocking monoclonal antibody or soluble receptor fusion protein, etanercept) in corticosteroid refractory severe asthma. There is a need to examine other biologicals as potential new controller therapies for the 5–10% of patients with severe disease, which accounts for a high proportion of the health costs of asthma.
Antibiotics
Although wheezing frequently occurs in infective exacerbations of COPD, there is limited evidence that antibiotics are helpful in the management of patients with asthma. Yellow or green sputum containing eosinophils and bronchial epithelial cells may be coughed up in acute exacerbations of asthma. This is normally due to viral, not bacterial, infection and antibiotics are not required. Occasionally, mycoplasma and Chlamydia infections can cause chronic relapsing asthma and in such cases the use of appropriate antimicrobials is worthwhile if a bacterial diagnosis has been established by culture or serology.
Asthma attack
Although these may occur spontaneously, asthma exacerbations are most commonly caused by lack of treatment adherence, respiratory virus infections associated with the common cold, and exposure to allergen or triggering drug, e.g. an NSAID. Whenever possible patients should have a written personalized plan that they can implement in anticipation of or at the start of an exacerbation that includes the early use of a short course of oral corticosteroids. If the PEFR is greater than 150 L/min, patients may improve dramatically on nebulized therapy and may not require hospital admission. Their regular treatment should be increased, to include treatment for 2 weeks with 30–60 mg of prednisolone followed by substitution by an inhaled corticosteroid preparation. Short courses of oral prednisolone can be stopped abruptly without tailing down the dose.
Acute severe asthma
The term ‘status asthmaticus’ was defined as asthma that had failed to resolve with therapy in 24 hours. Although this term is still used occasionally, it has been mainly discarded and replaced by ‘acute severe asthma’, i.e. severe asthma that has not been controlled by the patient’s use of medication.
Patients with acute severe asthma typically have:
■ inability to complete a sentence in one breath
■ respiratory rate ≥ 25 breaths per minute
■ tachycardia ≥ 110 beats/min (pulsus paradoxus, is not useful as it is only present in 45% of cases)
■ PEFR < 50% of predicted normal or best. Features of life-threatening attacks are:
■ a silent chest, cyanosis or feeble respiratory effort
■ exhaustion, confusion or coma
■ bradycardia or hypotension
■ PEFR < 30% of predicted normal or best (approximately 150 L/min in adults).
Arterial blood gases should always be measured in asthmatic patients requiring admission to hospital. Pulse oximetry is useful in monitoring oxygen saturation during the admission and reduces the need for repeated arterial puncture. Features suggesting very severe life-threatening attacks are:
■ a high Paco2 > 6 kPa
■ severe hypoxaemia Pao2 < 8 kPa despite treatment with oxygen
■ a low and falling arterial pH.
- Treatment (Emergency box) is commenced with 5 mg of nebulized salbutamol or 10 mg terbutaline with oxygen as the driving gas. Nebulized antimuscarinics (e.g. ipratropium bromide) are also helpful. A chest X-ray is taken to exclude a pneumothorax. If no improvement occurs with nebulized therapy, intravenous infusions of β2-adrenoceptor agonist (salbutamol or terbutaline 250 μg over 10 min) and/or magnesium sulphate (1.2–2 g over 20 min, which also relaxes airways smooth muscle) should be used. Intravenous aminophylline is not given as trials show marginal benefit and side-effects such as nausea and vomiting, cardiac arrhythmia and CNS side-effects are problematic. Hydrocortisone 200 mg i.v. should be administered 4-hourly for 24 hours, and 60 mg of prednisolone should be given orally daily. In patients who do not respond to this regimen, ventilation is often required.
Ideally, patients should be kept in hospital for at least 5 days, since the majority of sudden deaths occur 2–5 days after admission. During this time oxygen saturation should be monitored by oximetry. Oral prednisolone can be reduced from 60 mg to 30 mg once improvement occurs. Further reduction should be gradual on an outpatient basis until an appropriate maintenance dose or substitution by inhaled corticosteroid aerosols can be achieved.
A recent approach for moderate to severe persistent asthma is bronchial thermoplasty. This bronchoscopic procedure reduces the mass of airway smooth muscle, reducing bronchoconstriction, and is being evaluated.
| Emergency Box | Treatment of severe asthma |
At home 1. The patient is assessed. Tachycardia, a high respiratory rate and inability to speak in sentences indicate a severe attack. 2. If the PEFR is less than 150 L/min (in adults), an ambulance should be called. (All doctors should carry peak flow meters.) 3. Nebulized salbutamol 5 mg or terbutaline 10 mg is administered. 4. Hydrocortisone sodium succinate 200 mg i.v. is given. 5. Oxygen 40–60% is given if available. 6. Prednisolone 60 mg is given orally. At hospital 1. The patient is reassessed. 2. Oxygen 40–60% is given. 3. The PEFR is measured using a low-reading peak flow meter, as an ordinary meter measures only from 60 L/min upwards. Measure O2 saturation with a pulse oximeter. 4. Nebulized salbutamol 5 mg or terbutaline 10 mg is repeated and administered 4-hourly. 5. Add nebulized ipratropium bromide 0.5 mg to nebulized salbutamol/terbutaline. 6. Hydrocortisone 200 mg i.v. is given 4-hourly for 24 hours. 7. Prednisolone is continued at 60 mg orally daily for 2 weeks. 8. Arterial blood gases are measured; if the Paco2 is greater than 7 kPa, ventilation should be considered. 9. A chest X-ray is performed to exclude pneumothorax. 10. One of the following intravenous infusions is given if no improvement is seen: salbutamol 3–20 μg/min, or terbutaline 1.5–5.0 μg/min, or magnesium sulphate 1.2–2 g over 20 min. | |
Management of catastrophic sudden
severe (brittle) asthma
This is an unusual variant of asthma in which patients are at risk from sudden death in spite of the fact that their asthma may be well controlled between attacks. Severe life-threatening attacks may occur within hours or even minutes. Such patients require a carefully worked out management plan agreed by respiratory physician, primary care physician and patient, and require:
■ emergency supplies of medications at home, in the car and at work
■ oxygen and resuscitation equipment at home and at work
■ nebulized β2-adrenoceptor agonists at home and at work; inhaled long-acting β2-agonists with a corticosteroid can be very effective
■ self-injectable epinephrine (adrenaline): two Epipens of 0.3 mg epinephrine at home, at work and to be carried by the patient at all times
■ prednisolone 60 mg
■ Medic Alert bracelet.
On developing wheeze, the patient should attend the nearest hospital immediately. Direct admission to intensive care may be required.
severe (brittle) asthma
This is an unusual variant of asthma in which patients are at risk from sudden death in spite of the fact that their asthma may be well controlled between attacks. Severe life-threatening attacks may occur within hours or even minutes. Such patients require a carefully worked out management plan agreed by respiratory physician, primary care physician and patient, and require:
■ emergency supplies of medications at home, in the car and at work
■ oxygen and resuscitation equipment at home and at work
■ nebulized β2-adrenoceptor agonists at home and at work; inhaled long-acting β2-agonists with a corticosteroid can be very effective
■ self-injectable epinephrine (adrenaline): two Epipens of 0.3 mg epinephrine at home, at work and to be carried by the patient at all times
■ prednisolone 60 mg
■ Medic Alert bracelet.
On developing wheeze, the patient should attend the nearest hospital immediately. Direct admission to intensive care may be required.
Prognosis of asthma
Although asthma often improves in children as they reach their teens, the disease frequently returns in the second, third and fourth decades. In the past the data indicating a natural decrease in asthma through teenage years have led to childhood asthma being treated as an episodic disorder. However, airway inflammation is present continuously from an early age and usually persists even if the symptoms resolve. Moreover, airways remodelling accelerates the process of decline in lung function over time. This has led to a reappraisal of the treatment strategy for asthma, mandating the early use of controller drugs and environmental measures from the time asthma is first diagnosed.
Although asthma often improves in children as they reach their teens, the disease frequently returns in the second, third and fourth decades. In the past the data indicating a natural decrease in asthma through teenage years have led to childhood asthma being treated as an episodic disorder. However, airway inflammation is present continuously from an early age and usually persists even if the symptoms resolve. Moreover, airways remodelling accelerates the process of decline in lung function over time. This has led to a reappraisal of the treatment strategy for asthma, mandating the early use of controller drugs and environmental measures from the time asthma is first diagnosed.
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