Local side effects \200 Dysphonia \200 Oropharyngeal candidiasis \200 Cough Systemic side effects \200 Adrenal suppression \200 Growth suppression \200 Bruising \200 Osteoporosis \200 Cataracts \200 Glaucoma \200 Metabolic abnormalities (glucos e, insulin, triglycerides) \200 Psychiatric disturbances Side effects \200 Corticosteroids inhibit cortisol secretion by a negative feedback effect on the pituitary g land. Hypothalamo \200\223 pituitary \200\223adrenal axis suppression is dependent on dose, and usually occurs when a dose of prednisolone of >7.5 mg daily is used. Significant suppr ession after short courses of corticosteroid therapy is not usually a prob- lem, but prolon ged suppression may occur after several months or years; corticosteroid doses after prolong ed oral therapy must therefore be reduced slowly. Symptoms of \200\230corticosteroid withd rawal syndrome \200\231 include lassitude, musculoskeletal pains and occasionally fever. Si de-effects of long-term oral corticosteroid therapy include \202 uid retention, increased appetite, weight gain, osteoporosis, capillary fragility, hypertension, peptic ulceration, diabetes, cataracts and psychosis. The inci- dence increases with age. Systemic side-effec ts, such as cataract formation and osteoporosis are reported but often in patients who are also receiving oral corticosteroids. There has been par- ticular concern about growth suppr ession in children The fraction of corticosteroid inhaled into the lungs acts locally on the airway mucosa and may be absorbed from the airway and alveolar surface, thereby reaching the sys- temic circ ulation. The fraction of inhaled corticosteroid deposited in the oropharynx is swallowed an d absorbed from the gut (Fig. 4.3.4). The absorbed fraction may be metabolized in the liver before it reaches the systemic circulation. Budesonide and \202 uticasone have a greater \201 rst-pass metabolism than beclomethasone dipropion- ate and are therefore less likel y to produce systemic effects at high inhaled doses. The use of a spacer reduces oropharyng eal deposition, thereby reducing systemic absorption of corticosteroid Inhaled corticostero ids may have local side-effects caused by deposition of corticosteroid in the orophar- ynx, including dysphonia, oral candidiasis and dry cough. MDI 10-20% inhaled Mouth and pharynx Lungs Systemic circulation 80-90% swallowed ( \206\223 spacer/mouth-wash) Absorption from GI tract Liver GI tract Systemic side effects Inactivation in liver \200\234first pass \200\235 Fig. 4.3.4 Pharmacokinetics of inhaled glucocorticoids (GI = gastrointestinal). CHAPTER 4.3 Pharmacology 73 Cromones Cromones include sodium cromoglycate, and the structurally- related nedocromil sod ium. The dry-powder inhaler may cause throat irritation, coughing and, occasionally, wheezing, b ut this is usually prevented by prior administration of a B-agonist inhaler. Very rarely, a transient rash and urticaria or pulmonary eosinophilia are seen as a result of hypersensit ivity. Side effects are not usually a problem with nedocromil, though some patients have no ticed a sensation of \202 ush- ing after using the inhaler. Mode of action \200 Initial investigations suggested that cromoglycate acts as a mast-cell stabilizer, but this effect is weak in human mast cells. Cromoglycate blocks the early response to allergen, wh ich is mediated by mast cells, Cromones also inhibit bronchoconstriction induced by sulfur dioxide, metabisulphite and bradykinin, which are believed to act through activation of sen sory nerves in the airways. Cromones have variable inhibitory actions on other in \202 amm atory cells that may participate in allergic in \202 am- mation, including macrophages and eosinophils and inhibits the late response to allergen. The molecular mechanism of cromone action is not understood; recent evidence suggests they may block a type of chloride chann el that may be expressed in sensory nerves, mast cells and other in \202 ammatory cells. Anti-leukotrienes Anti-leukotrienes (leukotriene receptor antagonists), such as montelukast and za \201 rlukast, are much less effective than inhaled corticosteroids in the control of asthma. Mode of action Elevated levels of leukotrienes are detectable in broncho- alveolar lavage \202 uid, exhaled breath condensate, sputum and urine of asthmatic patients. Cysteinyl-leu kotrienes (cys-LTs) are generated from arachidonic acid by the rate- limiting enzyme 5-lipo xygenase (5 -LO)(Fig. 4.3.5). Cys-LTs are potent constrictors of human airways in vitro and in vivo, cause airway microvascular leakage in animals, and stimulate airway mucus secreti on. These effects are all mediated in human airways via cys-LT1-receptors. Montelukast and za \201 rlukast are potent cys-LT1-receptor antagonists that markedly inhibit the bronchoc onstrictor response to inhaled leukotrienes, reduce allergen-induced, exercise-induced and cold air-induced asthma by about 50 \200\22370%, and inhibit aspirin-induced responses in a spirin- sensitive asthmatics almost completely. 5 -LO inhibitors (e.g. zileuton) have a sim ilar inhibitory and clinical effect but are not currently available outside the USA. Clinical use Cromones are prophylactic treatments and must be given regularly. They protect against indirect bronchoconstrictor stimuli such as exercise, allergen and fog. Cromones a re poorly effective compared to low doses of inhaled corti- costeroids as they have a very short duration of action and systematic reviews show that they provide little bene \201 t in chronic asthma. Cromones are administered four times daily and may also be taken before exercise in children with exercise-induced asthma. There has been an increas- ing tendency to substitute low dose inhaled corticoster- oids for cromoglycate in adults and children so they are now rarely used. Clinical use Anti-leukotrienes may have a small and variable bronchodi- lator effect, indic ating that leukotrienes may contribute to baseline bronchoconstriction in asthma. Long-term admin- istration reduces asthma symptoms and the need for rescue B2-agonists, and improves lung function. However, their effects are signi \201 cantly less than with inhaled cortic osteroids Side effects Cromoglycate is one of the safest drugs available and side effects are extreme ly rare. Cold air Allergen Exercise PAF MC Eos Aspirin (ASA patients) SO2 Arachidonic acid 5 \200\231-lipoxygenase 5-LO inhibitors zileuton Cysteinyl-leukotrienes (LTC4, LTD4, LTE4) LT-antagonist montelukast pranlukast zafirlukast Plasma exudation Cys-LT1 receptors Bronchoconstriction Mucus secretion Eos recruitment Fig. 4.3.5 Effects of cysteinyl-leukotrienes on the airways and their inhibition by anti-le ukotrienes (LT = leukotriene; 5-LO = 5 -lipoxygenase; ASA = aspirin sensitive asthmatic). P BARNES 74 in terms of symptom control, improvement in lung function and reduction in exacerbations. A nti-leukotrienes are not as effective as inhaled corticosteroids in the management of mild asthma and are not the preferred therapy. They may be useful in some patients whose asthma is not con- trolled on inhaled corticosteroids as an add-on therapy to inhaled corticostero ids, but are less effective in this respect than a long-acting B2-agonist or low dose theop hylline. They are effective in some but not all patients with aspirin- sensitive asthma. Pa tients appear differ in their response to anti-leukotrienes, and it is impossible to predic t which patients will respond best. A major advantage of anti-leukotrienes is that they are orally active, and this is likely to improve compliance with long-term therapy. However, t hey are expensive, and a trial of therapy is indicated to determine which patients will ben e \201 t most. blocking of IgE reduces its synthesis from B-lymphocytes results in a sustained reduction i n IgE (Fig. 4.3.6). Clinical use Omalizumab reduces airway in \202 ammation in patients with mild to moderate asthma, and reduces the incidence of asthma exacerbations with improved control of asthma i n patients maintained on reduced doses of inhaled corticos- teroids. Omalizumab is most use ful in patients with severe asthma who are not controlled of maximal doses of inhaled thera py as it reduces exacerbations and improves asthma control. Only about 30% of patients show a good response and this is not predictable by any clinical features and therefore a trial of therapy over 4 months is indicated. Omalizumab should only given in patients with serum IgE levels of 20 \200\223700 IU/ml; above these levels it is not possible to give enough a ntibody to neutralize the IgE. The dose of omalizumab is determined by the serum IgE levels and is given either once or twice a month. Because of its high cost, only patients at step s 4 (severe) and 5 (very severe) of the BTS Guidelines who have frequent exacerbations (>5/ year) are suitable for this therapy. Side effects \200 \200 Montelukast is well tolerated. Za \201 rlukast may produce mild liver dysfunction, so live r function tests are needed. Several cases of Churg \200\223Strauss syndrome (systemic vas- culitis with eosinophilia and asthma) have been observed in patients on anti-leukotrienes, but this is likely to be because a concomitant reduction in oral corticosteroids (made pos sible by the anti-leukotriene) allows the vas- culitis to \202 are up. Side effects \200 Occasionally local reactions occur at the injection sites and very rarely anaphylactic reac tions have been seen. Immunosuppressive/corticosteroid-sparing therapy Immunosuppressive th erapy has been considered in asthma when other treatments have been unsuccessful or when a reduction in the dosage of oral corticoster- oids is required; it is therefore indicated in very few (<1%) asthmatic patients at present. \200 Anti-IgE therapy Mode of action Omalizumab is a humanized recombinant monoclonal anti- body that binds to circulating IgE and thus blocks it from activating high af \201 nity IgE re ceptors on mast cells and low af \201 nity IgE receptor on other in \202 ammatory cells. This results in reduced responses to allergens. Over time the Methotrexate Low-dose methotrexate, 15mg weekly, has a corticosteroid- sparing effect in so me patients with asthma, but side effects are relatively common and include nausea (reduced if FceRI Y Y IL-4, IL-13 Histamine Cys-LTs PGD2 Y Mast cell FceRII (CD23) Y Y Y Y IgEIgE Y Y e Y Y Y Y Y Macrophage Chronic inflammation Y Y B lymphocyte T lymphocyte Anti-IgE omalizumab Y Basophil Fig. 4.3.6 IgE play a central role in allergic diseases and blocking IgE using an monoclona l antibody omalizumab is bene \201 cial in some patients with severe asthma. IgE may activ ate high af \201 nity receptors (FcBRI) on mast cells as well as low af \201 nity recepto rs (FcBRII, CD23) on other in \202 ammatory cells so that anti-IgE therapy inhibits mast c ell mediated effects as well as reducing chronic in \202 ammation. (IL = interleukin, cys- LT = cysteinyl-leukotriene, PG = prostaglandin). CHAPTER 4.3 Pharmacology 75 Anti-tumor necrosis factor Anti-TNF-A therapy (antibody or soluble receptor) is reported to improve symptoms or reduce exacerbations in patients with severe asthma, but large control led studies have not so far shown ef \201 cacy, so that this treatment is not approved for asthma. Anti-TNF is ineffective in COPD patients. methotrexate is given as a weekly injection), blood dyscra- sia and hepatic damage. Careful monitoring (monthly blood counts and liver enzymes) is essential. Gold Gold has long been used in the treatment of chronic arthritis. A controlled trial of a n oral gold preparation (aurano \201 n) demonstrated some corticosteroid-sparing effect in chronic asthmatic patients maintained on oral cor- ticosteroids, but side effects (skin ra shes and nephropathy) are a limiting factor. Mucolytics Several drugs have been shown to reduce mucus viscosity in vitro by breaking dow n disuphide bonds between mucus glycoproteins, but these drugs have been disappointing in c linical practice. The most widely used drug N-acetyl- cysteine (NAC) appeared to reduce exa cerbations in meta- analyzes, but a large placebo-controlled study in COPD showed no overal l clinical bene \201 t, although patients not on inhaled corticosteroids a reduction in ex acerbations. Cyclosporin A Low-dose oral cyclosporin A in patients with corticoster- oid-dependent asthm a is reported to improve control of symptoms, but in clinical practice it is unimpressive a nd its use is limited by severe side effects (nephrotoxicity, hypertension). M PLUMMERIDGE 76 4.4 Asthma in pregnancy Epidemiology Asthma is the commonest respiratory disease occurring in pregnancy, affecting up to 12% of pregnant women. Approximately one fifth of pregnant asthmatics suffer exacerba tions during pregnancy. The major risk to mother and fetus is due to uncontrolled, sub-opti mally treated asthma. There is an associated mortality (Table 4.4.1). Pregnancy: effect on asthma (Table 4.4.4) Table 4.4.4 Effects of pregnancy on asthma Proposed mechanisms 33% No change 33% Improved Rise in serum free cortisol Progesterone mediated smooth muscle relaxation Table 4.4.1 Maternal deaths in the UK from asthma, other respiratory disease and, for compa rison, pulmonary embolism. 33% Worsened Cessation of maintenance therapy Reduced B2 adrenoreceptor response Changes in immunological response 1997 \200\22399 2000 \200\2232 2003 \200\2235 Oesophageal re \202 ux Asthma 5 5 5 Female fetus Other 4 5 1 Pulmonary embolism 31 25 33 Asthma: effect on pregnancy There is no effect for the majority; good medical manage- ment of asthma in pregnancy is important. Babies born to women with uncontrolled asthma with sev ere gestational exacerbation are at increased risk of low birth weight. Poorly controlled m aternal asthma may be associated with higher incidence of pre-term labor, pre-eclampsia and Cesarean section. Source \200\230Saving Mothers \200\231 Lives 2003-2005 \200\231 Con \201 dential Enquiry into Maternal and Child Health Physiological changes during pregnancy The major changes in respiratory physiology are outl ined in Table 4.4.2. So-called physiological breathlessness is common in pregnancy, happeni ng in up to three-quarters of pregnant women. Management of asthma in pregnancy The importance of smoking cessation in pregnancy should b e emphasized and support to stop offered. Effective communication prior to conception and d uring pregnancy is important to allay fears about medication use in pregnancy. Asthma thera py is safe in pregnancy; poorly controlled asthma is not. Close liaison between the physici an and obstetrician involved in management is important Table 4.4.2 Changes in respiratory physiology in pregnancy pH Mild alkalosis Increased PaO2 PaCO2 Minute ventilation Reduced Increased Total lung capacity Reduced/static Long-term management There is no evidence that standard asthma therapy, used appropriately, is unsafe in pregnancy. Management of chronic asthma in pregnancy should be aimed at maxim is- ing control and minimizing the risk of acute exacerbation. The use of leukotriene recep tor antagonists (LTRAs) in pregnancy should be limited to those women already on them prior to conception whose asthma was not ade- quately controlled without them. LTRAs should not be started in pregnancy. All other drugs for asthma are thought to be safe. Self-monitoring and regular review are important to detect any changes and intervene early. Functional residual capacity Reduced Tidal volume Increased DLCO supine Reduced Peak \202 ow No change No change FEV1 Differentiating this from pathological breathlessness is important, requiring careful clini cal assessment. Easily assessable features of potentially pathological breathless- ness are listed in Table 4.4.3. Table 4.4.3 Features of \200\230pathological breathlessness \200\231 in pregnancy Acute exacerbations Exacerbations affect some 20% of pregnant asthmatics. They are more com mon in mothers with severe, poorly controlled asthma and occur most commonly late into the second trimester. Acute severe asthma should be promptly managed in hospital as per standar d guidelines for adult treatment of adults. Systemic steroids should not be denied pregnant women. Fetal monitoring should be available and maternal oxygen saturations kept at >95%. Previous history of cardio-respiratory disease Sudden change in symptom of breathlessness Increased respiratory rate >20/minute Abnormal spirometry Abnormal total lung capacity Abnormal alveolar \200\223arterial oxygen gradient CHAPTER 4.4 Asthma in pregnancy 77 Asthma in labor Normal medication should be continued during labor where possible. The incr eased stress of labor theoretically increases the risk of hypoadrenalism in women taking re gu- lar corticosteroids. Hydrocortisone, 100mg IV 6-hourly, should be given to women in lab or who have taken 7.5mg prednisolone or more daily for the preceding 2 weeks. B-blockers, p rostaglandin F2, and (in aspirin/NSAID- sensitive subjects) NSAIDs can cause bronchospasm a nd should be avoided. Further reading BTS/SIGN British Guideline on the Management of Asthma 2005 Update. www.brit-thoracic.org.uk Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and asso ciation with adverse pregnancy outcomes. Thorax 2006; 61: 169 \200\223176 Schatz M. Asthma and rhinitis during pregnancy. In Busse WM, Holgate ST (eds) Asthma and Rh initis, 2nd edn. Oxford: Blackwells Scienti \201 c, 2000; pp. 1811 \200\2231826. Breastfeeding and asthma The benefits of breastfeeding to baby and mother are well establis hed. All drugs used to treat asthma appear safe. Asthma therapy need not be modi \201 ed d uring breastfeeding. B HIGGINS 78 4.5 Acute asthma There is no general agreement on the definition of an exacerbation of asthma, or on grading of severity. An increase in symptoms is an obvious component, but most definitions also in clude a measure of peak expiratory \202 ow (PEF) because some patients remain rela- tivel y uncomplaining despite signi \201 cant bronchoconstric- tion, and because this provides a n objective measurement of severity. \200 in the treatment of the various causes of acute wheeze, and it is almost always reasonable to treat suspected acute asthma as asthma and arrange con \201 rmatory investigations when the patient has recovered. AUTHOR \200\231S TIP Always question why an asthma attack has arisen, with particular atten tion to under-treatment and poor con- cordance. Some pharmacological studies have de \201 ned a severe exacerbation as a PEF level below 7 0% of that patient \200\231s best PEF, but most clinical guidelines require a lower value f or an attack to be regarded as severe. The GINA guideline (2006) classi \201 es a moderate exacer- bation on the basis of symptom increase plus a PEF persistently below 80% best (or predicted) and a severe episode as one with PEF below 60%. The BTS/SIGN guideline uses thr esholds of 75% for moderate and 50% for severe attacks; this guideline also incorporates th e term \200\230life-threatening \200\231 asthma where PEF is less than 33% The principle t hat treatment intensity should be tailored to disease severity is more important than quibb les about precise thresholds. In patients with known asthma, attempts should be made to understand why the attack has occ urred. \200 There is some evidence that viral (but not bacterial) infection is a common precipitant. It is important to explore whether regular control has been adequate (chronic under-treatment ). Consider concordance. Ask about any recent change in medication (including asthma medica tion, but also any treatment for other conditions, e.g. NSAIDs). \200 Examination Patients will exhibit some degree of tachypnoea and will usually have widesprea d wheeze. Features which should be particularly noted are: \200 Epidemiology There are no reliable data on the frequency of exacerba- tions of asthma in th e population, since there is no formal method of collecting information on minor or moderat ely severe episodes. We know that deaths from asthma in the UK have been falling since the late 1970s, as have hospital admissions, although the latter is more evident in children th an adults. These changes have occurred against a back- ground of high asthma prevalence, po ssibly increasing but certainly not falling, and imply that management of asthma has improv ed and that patients are less likely to have severe exacerbations. Nonetheless, most asthma tic patients will have exacerbations of some degree at some point in the course of their il lness. In a large community study in the UK 12.5% of patients with asthma had required a co urse of oral steroids in the previous year. A number of risk factors have been shown to inc rease the likelihood of a life-threatening episode of asthma, mostly of a behavioral or psy chological nature. These include: \200 Pulse rate. This will increase with severity (bradycardia may develop in extremis, but by t his stage the patient will be obviously critically unwell). Respiratory rate. Also increase s with severity, and serial measurement is a useful, objective measure of improve- ment wit h treatment. Inability to complete sentences is a sign of a severe exac- erbation. Ausculta tion will usually reveal widespread wheeze. A difference between the two sides of the chest should prompt consideration of additional pathology, particu- larly the possibility of pne umothorax. \200 Quiet breath sounds indicate life-threatening asthma. Factors such as cya nosis, exhaustion and confusion indi- cate life-threatening asthma but are fortunately rare . Hypotension is also associated with extreme severity, but attempts to measure pulsus para doxus are unnecessary. Investigations PEF An objective measurement of airway caliber is crucial to the assessment of severity of an attack, and in turn to deci- sions on management. In some regards, FEV1 i s a superior measurement, and its use is now becoming more frequent, but PEF retains the ad vantage of being more easily availa- ble, and of being measurable by the patient at home sh ould they be in any doubt about the severity of an attack. Ideally patients should possess an Action Plan instructing them to start oral corticosteroids if their PEF drops to a pre-a greed level (usually set at about 75% of best PEF). non-compliance with treatment, monitoring or appoint- ments; alcohol or other drug abuse; l earning dif \201 culties; employment or income problems; any severe domestic stress. \200 \200 \200 Clinical features History Most patients presenting with an acute asthma attack will already have a diagnosis of asthma, but in a few the acute attack will be the \201 rst presentat ion. In these patients it is usually possible to obtain a history suggesting the correct di agnosis (see Chapter 4.6), but in a few with severe dysp- noea the diagnosis will necessari ly be based mainly on examination \201 ndings. Although other conditions can be confused with acute asthma, there is considerable overlap AUTHOR \200\231S TIP Always obtain an objective measure of air \202 ow obstruc- tion at an early stage in an acute asthma attack. CHAPTER 4.5 Acute asthma 79 The aim should be to achieve an SaO2 of 94 \200\22398%. Failure to achieve a level of 92% i n any patient indicates either life-threatening asthma, or the presence of additional compl icating pathology. Pulse oximetry Signi \201 cant uncorrected hypoxia will contribute to end- organ damage an d to death from asthma. Monitoring of oxygenation using pulse oximetry is mandatory in seve re asthma attacks. The suggested target level is an oxygen saturation (SaO2) of 94 \200 \22398%. Blood gasses Elevation of PaCO2 does not occur in acute asthma until the attack is advanced; high PaCO2 is one of the de \201 ning features of a life-threatening attack. Ho wever, blood gas measurement is painful, and performing this unnecessarily might discourage patients from seeking medical help in future exacerbation. Blood gasses are not required i f SaO2 is 92% or better on room air and no other life threatening features are present. B-agonists \200 B-agonists will usually relieve bronchospasm quickly, although repeat doses are often neces sary for a variable period of time. In mild asthma, patients can treat them- selves at home Traditionally B-agonists have been given in Accident & Emergency Departments, or to inpati ents, using a neb- uliser. However, there is good evidence that in most cases repeated acti vation of a metered-dose inhaler (MDI) with a large volume spacer works just as well, with a lower incidence of side-effects. This is particularly so in children, but the evidence is also convincing in adults. However, it should be noted that many of these studies have exc luded those patients with the most severe attacks, and it is still preferable to use a nebu liser in these instances. Other blood tests Once through the hospital door, \200\230routine \200\231 blood tests ten d to be done irrespective of the illness causing admission. A full blood count can be justi \201 ed since signi \201 cant anemia will reduce oxygen carriage despite satisfactory Sa O2. Treatment of acute asthma can lower serum potassium; both B-agonists (especially nebuli sed or IV) and corticos- teroids can have this effect. It is therefore worth establish- ing whether the baseline is low. Corticosteroids and B-agonists can also elevate blood glucose levels. CXR A CXR is not necessary in all patients. One should de \201 nitely be performe d if: \200 AUTHOR \200\231S TIP B-agonists work better by the inhaled route than intravenously, and us ing an MDI via a spacer is preferable to a nebuliser (except in life-threatening asthma). If nebulised bronchodilators are judged necessary, consideration should be given to continu ous nebulisa- tion. This technique uses a nebuliser designed to deliver a steady, constant dose of B-agonist (5 \200\22310 mg/hour). Studies have shown some advantages over conven- t ional repeated bolus nebulisation. There are reports of \200\230continuous \200\231 nebuli sation being misinterpreted as administration of a consecutive series of bolus nebulisa- ti ons, one after the other without gaps; this is an abuse of the concept and increases the ri sk of signi \201 cant side effects. In theory, IV B-agonists might be expected to have adv antages where bronchospasm is so severe that air- ways are completely obstructed, preventin g access of nebulised or inhaled agents. In practice, the majority of studies have failed t o show any advantage of IV adminis- tration in severe asthma. there is any suspicion of additional pathology such as pneumothorax; there are any signs of life-threatening asthma; the patient fails to show an adequate response to treat- ment. \200 Treatment The intensity of treatment must re \202 ect the severity of the attack. Minor ex acerbations of asthma can be treated at home with a temporary increase in use of short-acti ng bronchodilators with or without a course of oral corticos- teroid. Asthma action plans f acilitate this, and management need not necessarily involve a health care professional. Con versely, life-threatening asthma represents a medical emergency requiring urgent high depen dency or ITU assessment. The following forms of treatment may be required. Ipratropium \200 The addition of ipratropium to a B-agonist via a nebuliser has been shown to produce signif icantly greater bronchodilation than the B-agonist alone, and to reduce the length of hospi tal admission. In milder attacks, B-agonists alone are likely to produce close to the maxim al possible bronchodilatation and the value of adding ipratropium is questionable. Even in the more severe attacks, it is not clear whether adding ipratropium is superior to simply i ncreasing the dose of B-agonist; this comparison has not been made. A sensible strategy bas ed on the available evidence is to add ipratropium during more severe attacks, or where the re is a poor response to initial B-agonist therapy. Adding ipratropium to a B-agonist using a MDI plus spacer has also been studied and shown to be of value, but again the comparison with a higher dose of the B-agonist has not been made. AUTHOR \200\231S TIP High \202 ow O2 should be given immediately to patients with: PEF <5 0% best; inability to speak full sentences; res- piratory rate >25/min; pulse >110/min. It can be adjusted later when O2 saturation results are available. Oxygen \200 Therapy can be guided by pulse oximetry, supplemented if necessary by blood gasses (see Blo od gasses). If the measurement is not available, and the patient has any signs of severe as thma, hypoxaemia is likely and oxygen should be administered without waiting for oximetry. Treatment should be started with a high concentration of oxygen. An MC mask can be used to give an inspired oxygen concentration of 40 \200\22360%; a reservoir bag can be added if ne cessary. B HIGGINS 80 its decreased gaseous viscosity (compared to air) reduces turbulent \202 ow. It may there fore help alleviate symptoms, although would not necessarily be expected to expedite recove ry from an asthma attack. There is insuf \201 cient evidence to recommend routine use of h eliox at this time. Leukotriene receptor antagonists are of proven bene \201 t in the trea tment of chronic asthma, and an IV prepara- tion has been shown to produce bronchodilatatio n in acute asthma. At the time of writing the product is not licensed for use, and there is insuf \201 cient evidence to recommend it. Corticosteroids \200 Corticosteroids reduce mortality from acute attacks, expedite recovery and reduce the risk of relapse. Although not needed for minor exacerbations, BTS/ SIGN guidelines recommend the ir use where PEF is below 75% predicted (or best recorded for that patient). In such circum stances they should be given as soon as possible during an attack. Corticosteroids take sev eral hours to produce their effect, and tablets are well absorbed. Accordingly, there is no advantage to IV administration, unless there are con- cerns that the patient is at risk of vomiting. There are speculative reasons for suggesting that an inhaled steroid might be of bene \201 t in addition to oral steroid, but no practical bene \201 t of the combination has yet been shown in terms of outcome of exacerbations. However, it is good practice to c ontinue the patient \200\231s regular inhaled steroid during an exacerbation in order to em phasize its importance in regular treatment. The practice of treating mild exacerbations of asthma with a temporary doubling of inhaled corticosteroid dose has not been shown to be e ffective. Differential diagnosis In an adult with acute dyspnoea and wheeze the common diagnostic que stion is whether the patient has asthma or COPD. The younger the patient, the more likely i s asthma. Absence of a significant smoking history also favors asthma. However, in neither case does the converse apply. AUTHOR \200\231S TIP Antibiotics should not be given in an acute asthma attack unless there is a good reason for suspecting bacterial infection. AUTHOR \200\231S TIP Don \200\231t stop inhaled corticosteroids when patients are taking a booster course of prednisolone. This could give the patient the wrong impression of the imp ortance of inhaled corticosteroids. A detailed history and supplementary tests can usually make the distinction between asthma and COPD, but may not be possible in the acute situation. Fortunately, the acute treatment of the two conditions does not differ hugely. Corticosteroids and bronchodilators will help both, as will oxygen (although thresholds for measuring blood gasses will differ between t he two). Use of antibiotics is more likely to be of bene \201 t in COPD. Vocal cord dysfun ction (VCD) can be dif \201 cult to distin- guish from asthma. The astute physician may ap preciate that wheezing is not generated from the lower airways in patients with VCD, and no te the absence of hyperin \202 ation on examination (or on the CXR if performed). However, distinction can be almost impossible without direct inspec- tion of the vocal cords, somet hing which should only be attempted by the experienced and which is rarely practical. It is safer to treat the patient as if dealing with asthma unless completely con \201 dent in t he alternative. Intravenous aminophylline or magnesium \200 Aminophylline offers acute bronchodilatation via a dif- ferent mechanism than either B-agon ist or ipratropium, and anecdotally, individual patients get clinically useful bene \201 t from aminophylline despite having responded poorly to inhaled agents. However, it is dif \201 cult to dem- onstrate bene \201 t from the addition of aminophylline in controlled st udies, so such patients appear to be rare. Side effects are not uncommon, and use of aminop hyl- line is therefore con \201 ned to those patients with life- threatening asthma who ha ve not responded to initial treatment. The potential indications for IV magnesium are simil ar to those of aminophylline. Unlike aminophylline, intrave- nous magnesium given as a sing le bolus dose has been shown to be of bene \201 t in acute severe asthma, and side effects appear less common. Bene \201 t from magnesium is less obvious in adults than in children . Moreover, some of the studies showing bene \201 t from magnesium are not of high standar d, and bene \201 t is not observed in all studies. Magnesium and aminophylline have not be en compared directly against one another. Critical care unit Any feature of life-threatening asthma should prompt immediate discussion with the critical care team, whether present on admission and failing to improve quickly, or if developing d espite treatment. Such features are: \200 \200 \200 \200 \200 \200 deteriorating PEF; hypoxia which fails to improve; elevated CO2; acidosis on blood gas anal ysis; exhaustion, drowsiness or confusion; respiratory arrest. Other agents \200 Antibiotics are often given to patients with an exacerba- tion of asthma who feel that the attack has been caused by an infection \200\230going to my chest \200\231. Whilst infectio ns are certainly implicated in acute asthma, these are almost always viral rather than bact erial. Routine prescription of antibiotics is therefore not indicated, and their use should be the exception rather than the rule. Heliox (helium/oxygen mixture containing 70 \200 \22380% helium) improves the \202 ow of an inspired breath because It is dif \201 cult to be dictatorial about the need for intubation since this depends to some degree on the time which ther- apy has had to work, and the rate of change of vital si gns. The decision should be made by the most experienced available medical staff. However, the clear indications for intubation are development of type-2 respiratory failure and decr eased consciousness. CHAPTER 4.5 Acute asthma 81 PEF 33 \200\22375% and no life- threatening features PEF <33% or any life- threatening features PEF >75% Take usual bronchodilator. Monitor symptoms and PEF High-dose bronchodilator \200 Prednisolone High flow O2 \200 Nebulised bronchodilator \200 Prednisolone If improved, continue treatment PEF 50 \200\22375% If symptoms fail to settle, consider need for short prednisolone course. If PEF falls to \211 75%, give short course of prednisolone If no improvement consider : \200 IV magnesium \200 continuous nebulisation PEF >75% PEF <50% Repeat high-dose bronchodilator Observe. Once PEF > 75% consider completing prednisolone course at home Fig. 4.5.1 Overview of the management of acute asthma attacks. Management is guided by symp toms and an objective measure of severity, usually PEF \200\223 decision to admit to hospi tal is in \202 uenced by a number of factors including symptom severity, PEF level, histor y of previous life-threatening attacks, and social ciircumstances. Further reading Anderson HR, Gupta R, Strachan DP, et al. Time trends in allergic Parameswaran K, Belda J, Rowe BH. Additions of intravenous aminophylline to beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev 2000; 4: CD002742. disorders in the UK. Thorax 2007; 62:85 \200\22390. Pauwels RA, Lofdahl C-G, Postma DS, et al. Effect of inhaled for- moterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337:140501411. British Guideline on the Management of Asthma. Thorax 2003; 58 (Suppl 1): i1 \200\223i84. Camargo CA, Spooner CH, Rowe BH. Continous versus intermit- tent beta-agonists in the treat ment of acute asthma. Cochrane Database Syst Rev 2003; 4:CD001115. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergies in the treatment of children and adults w ith acute asthma: a systematic review with meta-analysis. Thorax 2005; 60:640-646. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006; 2:CD000052. Rowe BH, Bretzlaff JA, Bourdon C, et al. Magnesium sulfate for treating exacerbations of ac ute asthma in the emergency department. Cochrane Database of Syst Rev 2000; 1: CD001490. Tr avers A, Jones AP, Kelly K, et al. Intravenous beta2-agonists for acute asthma in the emerg ency department. Cochrane Database of Syst Rev 2001; 1: CD002988. Global strategy for asthma management and prevention, Global Initiative for Asthma (GINA) 2006. http://www.ginasthma.org Harrison TW, Oborne J, Newton S, et al. Doubling the dose of inhaled corticosteroid to prev ent asthma exacerbations: ran- domised controlled trial. Lancet 2004; 363: 271 \200\223275. Walsh LJ, Wong CA, Cooper S, et al. Morbidity from asthama in relation to regular treatment : a community based study. Thorax 1999; 54:296 \200\223300. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacer- bations of asthma in adults. Br Med J 1993; 307:982 \200\223986. P HALDER & I PAVORD 82 4.6 Chronic asthma management Overview Between 10 \200\22315% of adults in Western societies have a diagnosis of asthma, and for the majority the disorder is chronic. This represents a signi \201 cant burden on economic and healthcare resources. In the UK, it is estimated that asthma-management costs exceed 850 million per year to the health service and result in the loss of 12.5 million working days. Despite therapeutic advances, asthma-related mortality has failed to decline signi \201 cantly and remains at approximately 1400 deaths per year. Con \201 dential enq uiries of asthma mortality suggest over 80% are preventable. Together, these statistics hig hlight both the impact of asthma as a chronic disease to society and the de \201 ciencies that remain in its management. to anxiety and depression that can lead to a vicious cycle of deteriorating control. Exacerbations Exacerbations are defined as periods of poor asthma control manifest by an in crease in symptoms and deterio- ration in lung function that are not adequately managed by the individual \200\231s usual therapeutic regimen. They are fre- quently precipitated by a llergen exposure or viral infec- tions. Severe exacerbations may lead to hospitalization an d are the major cause of asthma mortality. Although exacerbations may be precipitated by a number of different aetiologies, recent evidence suggests a close rela- tionship between th