Outpatient Evaluation and Management of Asthma

Symposium on The Chest

Outpatient Evaluation and Management of Asthma Louis 1. Landau, M.D., F.RA.C.P. *

One in every five children will wheeze at sometime during early childhood and one in 20 will have recurrent wheezing recognized as asthma. 35 Asthma remains one of the major reasons for school absenteeism and an important cause of emotional and financial strain on families, and is still an occasional cause of death in childhood when family or physician fails to recognize the child at risk. Over the past decade advances have been made in understanding the pathogenesis and pharmacologic management of asthma. With appropriate care the child should lead a relatively normal life with minimal disturbance of physical activities as well as intellectual and emotional development.

PRESENTATION A wheeze is a prolonged sound heard at the mouth during expiration and is produced by dynamic compression of the larger airways secondary to widespread bronchial narrowing. An episodic wheeze, precipitated by factors such as viral infection, changes in the weather, exertion, exposure to an allergen, or anxiety, which resolves either spontaneously or as a result of treatment can readily be recognized as asthma. However, the family or the physician is often reluctant to make this diagnosis in young children. Although other diagnoses such as infective bronchitis, cystic fibrosis, milk inhalation, and foreign body aspiration should be considered, asthma is by far the most common cause of recurrent wheeze. Somewhat more difficult to diagnose is asthma in the child with intermittent cough. Intermittent cough may be a manifestation of repeated viral bronchitis, but in many children it is a manifestation of asthma. The asthmatic cough is most commonly associated with exercise and tends to be worse in the late afternoon and early hours of the *Deputy Director, Department of Thoracic Medicine, Royal Children's Hospital, Melbourne, Australia

Pediatric Clinics of North America - Vol. 26, No.3, August 1979

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morning. Other evidence of atopic disease may be present, such as hay fever and eczema, or there may be a family history of asthma. A physical examination should include a request for the child to cough in order to elicit the typical asthmatic cough, and should encompass listening to the chest after a period of exertion or cough to identify rhonchi which indicate persistent asthma. Attempts should be made to expectorate sputum if it is present. A clear mucoid sputum or pale yellow sputum is compatible with asthma. Yellow sputum should be smeared for eosinophils. Yellow or green sputum should always be cultured to exclude underlying suppurative lung disease. Further investigation is rarely necessary in the majority of children with asthma. Chest Radiograph A chest radiograph is warranted in those with a chronic cough or focal signs on physical examination. In persistent asthma, hyperinflation with some peribronchial thickening may be seen in an interval phase. Occasionally in those with hypersecretory asthma, areas of collapse which will vary from time to time will appear in the lung. Extensive areas of collapse or consolidation should alert one to the possibility of an alternative diagnosis. Allergy Tests The role of allergy tests in childhood asthma is not clearly defined. Most children do not require skin tests to identify sensitivity to specific allergens, since the place of hyposensitization in childhood asthma is fairly limited. The presence of type 1 skin reactions to common allergens may help to confirm an atopic diathesis in the child with persistent cough. Differential white cell counts and IgE levels are rarely useful diagnostic procedures in individual children. These measurements differ in populations of normal children and those with asthma, but the overlap between the two groups precludes their clinical usefulness. Similarly, there is a very limited place for RAST (radioallergosorbent, allergen specific IgE) measurements in most children with asthma. These give no more useful information than can be obtained by a careful history and skin testing. Pulmonary Function Tests Pulmonary function testing is usually not necessary in the majority of children with mild episodic asthma. These tests are most useful in the management of the patient with moderate to severe asthma and are valuable in the assessment of the child in whom the history does not appear to correlate with the physical eXaInination. They also provide important objective criteria for the evaluation of response to drugs. The most useful measurements include peak expiratory flow rate, vital capacity, forced expiratory volume in 1 second, forced expiratory flow rate between 25 per cent and 75 per cent of vital capacity, all measured from a spirometric tracing. If the equipment is available,

OUTPATIENT EVALUATION AND MANAGEMENT OF ASTHMA

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measurement of lung volumes and a maximum expiratory flowvolume curve will provide added sensitivity. The presence of reduced flow rates with an increased residual volume during an interval phase will indicate the presence of chronic asthma and provide an accurate reflection of severity.9 In some children extraneous factors influence the perception of the severity of asthma. Pulmonary function measurements will help in the evaluation of the child with mild asthma whose activities are markedly restricted owing to parental anxiety as well as in the child who describes minimal symptoms but has severe asthma. The latter often have minimal symptoms because they severely limit activities that induce wheeze. Periodic measurements of pulmonary function are much more valuable than a single measurement because of the variable nature of asthma. If necessary, a diary card recording twice daily peak flow rates measured at home can be most helpful. Tests for responsiveness to bronchodilators may be diagnostically useful. Obstruction of the airways is probably a result of asthma if there is improvement after inhalation of a sympathomimetic agent. Similarly, lack of responsiveness when asthma is suspected may indicate the need for steroid therapy. The return of responsiveness to bronchodilators after commencement of steroids is characteristic of severe asthma. It may occasionally take up to 14 days of high dose steroids to regain responsiveness to bronchodilators in severe chronic asthma. Bronchial provocation with exercise, histamine, metacholine, or allergens is usually only necessary in the few children in whom a diagnosis of asthma has not been possible on clinical grounds or with simple laboratory investigations. Most children will show a fall in flow rates following inhalation of histamine or methacholine and about two out of three will demonstrate a fall in flow rates following a standardized exercise test. 20 A major deficiency of pulmonary function testing in the management of children with asthma is the inability to study children under six or seven years of age.

MANAGEMENT The most important aspect of management, and one that is frequently neglected, is to provide appropriate time to give advice to the parents and the child when he is old enough. Many children express resentment that the physician has not discussed their asthma with them. It is vitally important that the family establish good rapport with the doctor. Family members must clearly understand when attention from the physician is needed. A detailed explanation of all the drugs used and their mechanism of action, as well as the appropriate times to introduce them, is vitally important and will improve compliance. Information regarding the reasonably optimistic natural history of childhood asthma and lack of irreversible damage to heart and lungs

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is important to allay anxiety. Parents often fear that they must change the location of their homes, pull up carpets, and dispose of pets. Sensible discussion about simple measures of allergen control and the lack of benefit from extreme measures is important. Parents sometimes develop fears and prejudices before a diagnosis of asthma has been made, which they are often unable to discuss. It is reasonable to avoid the term "asthma" for one or two episodes of mild wheeze, but once the wheeze becomes recurrent it is better that the parents appreciate the diagnosis and the availability of appropriate measures which will allow the child to lead a normal life. They must be told that there is no cure for asthma or they may seek cures that are not available. They must appreciate that the aim of therapy is to keep the asthma under control until improvement occurs, as it will in most children. With therapy, little restriction of the child's activities should be necessary, and absence from school, impairment of sleep, and avoidance of sport indicate inadequate control of the disease. As an aid to communication with the family of a child with asthma, one of the publications outlining the management of asthma may be helpful.*

ENVIRONMENTAL CONTROL

Simple measures of environmental control can be useful as long as their application does not enslave the family. Measures that may reduce house dust might include regular airing of bedding and regular cleaning of the child's bedroom, but parents should be aware that results may be disappointing. There is no evidence that electrostatic filters have a beneficial effect. Some feel it is unwise for asthmatic children to have pets and occasionally children do develop asthma after contact with cats or dogs. In general, however, allergy to pets appears to be a relatively unimportant cause of asthma in children and the child's cat or dog should not be removed unless there is good evidence that it is a major aggravating factor. It is reasonable for the cat or dog not to sleep in the child's bedroom. Unless it has been observed that asthma occurs after eating a particular food, there is usually no reason to restrict the child's diet. Children are more likely to have skin reactions than an asthmatic response to food allergens. The role of cow's milk in producing asthma is unclear. Some are of the opinion that feeding breast milk rather than cow's milk in the first year of life may prevent the development of an atopic state. Although breast feeding should certainly be encouraged for many reasons, there is still doubt that this will affect the natural history of childhood asthma. At present there is no evidence that removing cow's milk products from an infant's diet will affect the course of asthma in most children. Those who are truly allergic to cow's milk will usually have a clear-cut response to the ingestion of milk. 'Children with Asthma: Understanding Your Wheezing Child," published by the Royal Children's Hospital, Melbourne in conjunction with the Asthma Foundation of Victoria.

OUTPATIENT EVALUATION AND MANAGEMENT OF ASTHMA

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Sensitivity to aspirin and tartrazine has been reported. It is extremely difficult to define those children in whom these sensitivities play a part and there is as yet little evidence to recommend widespread prohibition of these substances in the majority of children with asthma. Parents should be advised not to smoke, as this will add another nonspecific environmental challenge. Children with asthma must also be discouraged from smoking. H YPOSENSITIZATION

Hyposensitization to allergens possibly helps some who are very sensitive to one or two specific allergens. Childhood asthma is rarely characterized by this pattern and further studies will be necessary to define whether hyposensitization therapy has a role in the long-term management of the child with asthma. Although hyposensitization is widely practiced, existing controlled studies are inadequate to show that it is superior to management with long-term bronchodilator or cromolyn therapy. Hyposensitization therapy is also associated with significant morbidity to the child and cost to the family. Complications include anaphylaxis and exacerbation of symptoms. Hyposensitization may work in allergic rhinitis and it may perhaps be appropriate in selected individuals with asthma. However, at present there is no means of defining which group will obtain a beneficial response and it cannot be recommended as routine therapyY

PHYSIOTHERAPY

Relaxation and breathing exercises may help children who are not physically fit and allow them to breathe more easily and reduce anxiety during an acute attack of asthma. Faulty posture should be improved. However, a child often becomes bored with regular sessions of breathing exercises and it is better to replace breathing exercises with games, sports, and swimming. Swimming and interval phase games are particularly useful, as they appear to be sports which children with asthma can perform with less wheezing. They improve fitness, instill confidence, and promote socialization, although the effect on pulmonary function and exercise provocation appears to be variable. It is most important that children with asthma be as physically active as possible. Wheezing on exertion should be prevented with the use of cromolyn or a bronchodilator.

PSYCHOTHERAPY

Family therapy, psychotherapy, residential therapy, and other types of behavioral therapy have been used in the management of asthma. In the majority of children with asthma, the physician plays a

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A diary card may be used for day to day assessment of persistent asthma.

major role in the psychotherapeutic relationship by allaying anxiety within the family, since most of the emotional problems are a result of the asthma rather than a cause of it. There is a very small group of children with severe social and emotional upheaval in whom psychiatric and institutional care may be necessary. It is important to recognize these children, who often have severe chronic asthma with severe abnormalities of pulmonary function. They are frequently absent from school and may have been hospitalized repeatedly.

DIARY CARD

In the presence of an inadequate history or of difficulty in controlling symptoms it may be particularly useful for the patient to maintain a diary card for twice daily recording of symptoms of cough and wheeze, drugs needed, limitation of exercise, and flow rates measured with a simple home flow meter (Fig. 1). Assessment of drug compliance is vital, since it is likely that at least 80 per cent of children will not take the drugs prescribed by the physician. There is very high noncompliance rate with drugs such as cromolyn, which requires the spinhaler for administration, theophylline syrups, which are unpalatable, and occasionally sympathomimetic agents, which may produce muscle tremor.

OUTPATIENT EVALUATION AND MANAGEMENT OF ASTHMA

587

DRUGS

The major groups of drugs in the management of asthma are bronchodilators (xanthines and sympathomimetic agents), cromolyn, and corticosteroids. Drugs such as antihistamines and antibiotics are commonly used in the management of asthma but have little value in specific management of obstruction of airways. Antihistamines Antihistamines have no prophylactic or curative effect on the obstruction of airways. They may provide some symptomatic relief in children with nocturnal cough and may help in the treatment of associated allergic rhinitis. Recent evidence suggests that mouth breathing can lead to narrowing of the airways particularly during exercise and any means of encouraging nasal breathing may therefore be useful. Superiority of anyone of the current antihistamines available has not been demonstrated. Antibiotics Antibiotics are rarely necessary in the management of asthma. Bacterial infections do not precipitate attacks of asthma. It has been suggested that Hemophilus influenzae infection may induce wheezing, but this observation has not been confirmed. Yellow sputum in asthma need not indicate infection, since it may be yellow as a result of the presence of eosinophils. In a few children with asthma the primary disease is hypersecretion of mucus; these children may suffer areas of collapse and secondary infection in the lungs. Intermittent or longterm courses of antibiotics may be beneficial, but there have been no controlled trials to confirm this observation. Cough Suppressants There is little place for cough suppressants, expectorants, and mucolytic agents in the management of asthma in childhood. Expectorants with potassium iodide have been very popular; however, no data exist to prove that they have a significant beneficial effect. Sedatives should not be used because they involve significant morbidity, may mask the irritability and lethargy which are early signs of hypoxia, and, in the case of barbiturates, may alter the metabolism of theophylline. Sympathomimetic Agents Ephedrine sulphate was the first sympathomimetic agent used in the treatment of asthma. However, it is not very potent, and it affects the heart and central nervous system. It appears to work by stimulating release of sympathetic amines from the adrenal gland. Patients may show tolerance to ephedrine after a period of continued usage possibly as a result of depletion of the amine pool. Epinephrine (adrenaline) has been used in the management of asthma for many years. It is nonspecific and acts on both alpha and beta receptors so that it affects the cardiac and central nervous sys-

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tems and other smooth muscle. Used by subcutaneous injection it can be very effective in the management of acute asthma and it is still the drug of choice for acute anaphylaxis. However, with the introduction of more specific beta 2 agonists its use in asthma is now very limited. When used subcutaneously it is usually given in a dose of 0.01 mg per kg and only rarely is more than 0.3 ml of 1: 1000 solution (1 mg per ml) required. Isoprenaline causes beta sympathetic stimulation with minimal alpha stimulation. It produces a quick response but its action lasts only about 20 Ininutes. It is therefore ideal for use in the laboratory for testing responsiveness to bronchodilators, but has a limited role in clinical practice. It has been given intravenously for the management of status asthmaticus but has now been replaced by the more specific beta 2 agonists. The beta sympathetic agonists act by stimulation of the enzyme adenyl cyclase leading to higher levels of cyclic AMP, which is thought to be important in producing bronchodilatation as well as in preventing release of bronchoreactive aInines from mast cells. An initial drop in response may occur with prolonged use of the beta agonists but this is not maintained and there is no evidence of significant tolerance with chronic use. 23 Alterations in the chain of the sympathetic agonist result in more specific beta 2 stimulation and longer duration of action.14 Specific beta 2 agonists produce relaxation of smooth muscle in the lungs, gastrointestinal tract, blood vessels, and uterus, without beta 1 cardiac effects.I3 Beta 2 sympathetic agonists currently widely used include metaproterenol or orciprenaline, terbutaline, salbutamol, and fenoterol (Table 1). These drugs are proving to be extremely useful in the management of acute asthma as well as for maintenance therapy in chronic asthma. They produce rapid relief of acute symptoms and their effects last from four to six hours. They appear to be extremely safe, although side effects of tremor and excitation may be noticed in some children. The tremor, which appears to be a direct action of the drug on skeletal muscle, appears to be dose related and is less commonly seen with inhalation than with oral therapy. Palpitations occasionally occur, but are rarely seen with the customary doses. The presence of side effects may be seen with one drug but not with others. Preference for beta 2 agonists varies among individuals, but it is rarely possible to show objective reasons for the preference of one agent over another. It is not clear at what age children become responsive to beta agonists. It is unlikely that children with bronchiolitis in the first six months of life will respond to adequate doses of beta agonists,26 and there are data to suggest that they will not become responsive until 18 months of age. I5 Between six and 18 months of age, however, some children with asthma respond dramatically to sympathomimetic medication. There appears to be no way of predicting which children will respond and a therapeutic trial may be necessary in this age group. Fortunately, distressing episodes of wheeze are uncommon at this age. Should they occur, the infant usually requires hospitalization for oxygen and intravenous therapy.

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Table 1. Specific Beta 2 Sympathetic Agonists Currently Used in Clinical Practice

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. PROPRIETARY DRUG

Metaproterenol or Orciprenaline

Terbutaline

Salbutamol

Fenoterol

NAME

Alupent

Brethine Bricanyl

Proventil Ventolin

Berotec

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PREPARATIONS

DOSE

Oral: 20 mg tablets 10 mg per 5 ml syrup Metered aerosol: 650 JL g per puff Respirator solution: 2 per cent

0.3 to 0.5 mg per kg per dose

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0.075 mg per kg per dose 1 to 2 puffs 0.03 ml per kg to a maximum of 1 ml, diluted to 2 ml 0.005 mg per kg per dose

Oral: 4 mg tablets 2 mg per 5 ml syrup Metered aerosol: 100 JL g per puff Respirator solution: 0.5 per cent

0.10 to 0.15 mg per kg per dose

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During the 1960s the death rate from asthma increased in England and Australia, a fact which was attributed to the use of high doses of aerosol isoprenaline. Suggested explanations included suspicion that children with unrecognized severe asthma were being treated at home with repeated doses of aerosol medication instead of receiving more aggressive management in the hospital or physician's office, that tachyphylaxis or resistance to epinephrine were developing as a result of repeated use of aerosols, and that some children might have experienced toxic myocardial reactions to the carrier agent. The specific beta 2 agonists currently used in aerosol form have not been associated with mortality. Beta 2 sympathetic agonists are most effective when administered by aerosol. Anderson and colleagues 1 demonstrated that sympathomimetic agents more effectively prevent exercise-induced asthma when administered by aerosol than when given orally. The effect of the inhaled drug is almost immediate and is thought to be a result of local action, since bronchodilatation begins before the drug is detectable in the plasma. Peak effect occurs at about 10 minutes, at which time the drug is present in the plasma. It is probably absorbed from the mucosa of the respiratory tract. Equivalent bronchodilatation is obtained with a much lower plasma level when the drug is administered by inhalation than when given orally. Administration of sympathomimetic medications by metered aerosol is appropriate for older children. However, they are less satisfactory for children under eight to 10 years of age, particularly when distressed. Nebulized sympathomimetic medication using a compressed air pump and nebulizer have proved to be effective in the management of acute asthma and in the home management of chronic asthma in young children. 2. 12. 36 Compressed air pumps deliver an air flow rate of approximately 6 liters per minute, and may be used with nebulizers which nebulize at 0.2 to 0.3 ml per minute, resulting in a five to 10 minute inhalation for a 2 ml mixture. Drugs available for nebulization include 2 per cent metaproterenol, 1 per cent terbutaline, and 0.5 per cent salbutamol in a dose of 0.01 to 0.03 ml per kg to a maximum of 1 ml. This is then diluted to 2 ml with saline or propylene glycol spray diluent (propylene glycol 10 per cent, glycerol 2 per cent, normal saline). For delivery in young children a mask is usually necessary (Fig. 2). In older children it is probably better to use a mouthpiece which minimizes nasal deposition and depresses the tongue, allowing more of the mist to deposit distally within the lung (Fig. 3). It is still likely that only 10 to 20 per cent of the aerosol is deposited within the lungs. 3s The possibility exists that the equipment itself may be a reservoir for infection and that it may cause reflex bronchoconstriction,31 but this has not occurred in 20 years of experience. The main disadvantage of nebulization is the expense of the equipment and drugs. However, in children with chronic asthma requiring intensive therapy and frequent admissions to hospital, it is valuable therapy. Buccal administration of fenoterol has been described as effective

OUTPATIENT EVALUATION AND MANAGEMENT OF ASTHMA

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in the management of acute asthma but this has not been confinned and cannot be recommended at this time. 30 Xanthines The xanthine group of drugs were first used in the management of asthma in 1936. Although they have been through periods of favor and disrepute, improved knowledge of their pharmacokinetics is leading to better use and they are proving to be valuable in the management of asthma. The xanthines are phosphodiesterase competitive inhibitors which result in a reduced degradation of cyclic AMP, thus resulting in relaxation of smooth muscle and inhibition of mediator release. They also stimulate the central nervous system and cardiac muscle. It has been shown that they probably act synergistically with the beta sympathetic agonists when used in combination. 25, 37 Cohen and Elizabeth found that the combination of xanthine and sympathomimetic medication produced the same effect as a high dose of each alone without the side effects of such high dosage. 4 Side effects of xanthines include nausea, vomiting, hematemesis, hypertension, arrhythmias, insomnia, restlessness, and convulsions, which are centrally mediated and cannot be avoided by intravenous or rectal administration. A major disadvantage of xanthines is that all preparations have an unpleasant and bitter taste, and many young children do not take them readily. The effect of xanthines is related to dose and plasma concentration; side effects may be avoided with careful use. Most will have no effect with serum levels below 5 p,g per ml. There will be an adequate therapeutic response with a serum level between 5 and 20 p,g per ml (50 to 110 p,mole per liter). Side effects will occur with serum levels greater than 20 p,g per ml. However, about 5 to 15 per cent of people are sensitive to xanthines and will suffer gastrointestinal symptoms with lower serum levels. These symptoms are probably caused by local gastric irritation; changing the preparation often helps.21, 33 Theophylline preparations for oral administration are many and varied (Table 2). Since theophylline is almost completely absorbed when given orally, it is important to calculate the appropriate dosage of the theophylline base, which is the active component of the drug. Preparations with pure theophylline should be given in a dosage of 5 mg per kg per dose in children under 45 kg in weight, repeated every six hours if needed. Salts, such as choline theophyllinate (oxtryphylline), contain only 64 per cent effective theophylline base and the dosage of preparations must be adjusted upward (7 to 8 mg per kg of the salt). It has been claimed that absorption of an alcoholic preparation is advantageous but this has not been supported. Alcohol may make younger children vomit. Controversy exists as to the efficacy of combinations containing theophylline, ephredine, and phenobarbital. Phenobarbital may in fact reduce the half-life of theophylline. 34 Theophyllines are metabolized more rapidly in children than in adults so that larger doses are needed. However, wide variability

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Table 2.

Xanthines: Theophylline Preparations

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DRUG

PROPRIETARY NAME

PREPARATIONS

DOSE

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Aerolate

Capsules 260, 130,65 mg Syrup 160 mg per 15 ml

4 to 5 mg per kg every 8 to 12 hrs.

Elixophyllin

Capsules 200 mg Syrup 80 mg per 15 ml

4 to 5 mg per kg every 6 hrs.

Quibron

Capsules 150, 100 mg Syrup 10 mg per ml

4 to 5 mg per kg every 6 hrs.

Tablets 200, 100 mg Syrup 80 mg per 15 ml Gyrocaps 250, 125, 60

4 to 5 mg per kg every 6 hrs. 4 to 5 mg per kg every 8 to 12 hrs.

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Theophyl

Tablets 225, 100 mg

4 to 5 mg per kg every 6 hrs.

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Theophyl SR

Capsules 250, 125 mg

4 to 5 mg per kg every 8 to 12 hrs.

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Tablets 250, 125 mg

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Aminophylline

Tablets 200, 100 mg

5 to 6 mg per kg every 6 hrs.

Aminodur duratabs

Tablets 300 per mg

5 to 6 mg per kg every 8 to 12 hrs.

Somophyllin

Capsules 250, 200, 100 Syrup 105 mg per 5 ml

5 to 6 mg per kg every 6 hrs.

Choledyl

Tablets 200, 100 mg Syrup 100 mg per 5 ml

7 to 8 mg per kg every 6 hrs.

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exists between individuals, with half-life varying from 1%· hours to over 8 hours.5 Elimination of theophylline may be slowed by troleandomycin, erythromycin, liver disease, heart failure, and fever. Smoking may increase the rate of elimination. 34 The long-term ingestion of theophylline does not appear to alter its metabolism and tolerance does not develop.3 Round-the-clock dosage is often needed to maintain adequate serum concentrations; consequently, the drug is often necessary four times a day but some patients may require up to 5 doses per day. Serum levels of theophylline should be used to determine the appropriate dosage when a child fails to respond to the usual starting dose of 4 to 5 mg per kg per dose every six hours. Measurements of salivary levels of theophylline are satisfactory, but because tests for serum levels can now be performed on micro specimens of blood, they are no longer necessary. If serum levels are not available it is reasonable to start with the standard dosage and increase this by 25 per cent every three days until a response is obtained or side effects are observed. However, this procedure is less satisfactory and has the potential for causing significant side effects. Serum levels may need to be checked every 6 to 12 months. It is usual to take blood one to two hours after the drug is ingested (four hours after administration of a sustained release preparation). Sustained release preparations are proving useful in the management of nocturnal wheeze since they can be given at a 12 hourly interval. Aminophylline remains a particularly useful drug in the management of severe acute asthma when it is given intravenously over 10 to 20 minutes. The use of rectal preparations of aminophylline has led to a number of complications, including deaths, from this drug in children. 27. 24 Higher doses are given unwittingly, absorption is erratic, and cumulative effects occur.32 Suppositories should be used cautiously, if at all, and should never be prescribed for very small infants.

Cromolyn Cromolyn sodium or disodium cromoglycate (Intal, Aarane) has recently been introduced in the management of asthma. It is not a bronchodilator or anti-inflammatory agent but appears to act primarily as a mast cell stabilizer preventing the release of bronchoactive amines after specific or nonspecific stimulation. Its action is therefore purely prophylactic. Between 25 per cent and 65 per cent of children will obtain some relief with cromolyn.6 Its main side effect is coughing and wheezing owing to local irritation, which is rarely bad enough to stop its use. There is no information about the effect of prolonged use on the developing lung but as yet there are no obvious ill effects. Major adverse effects reported include urticaria, polymyositis, anaphylaxis, rashes, and pulmonary infiltrates, which seem to be allergic in nature. Fortunately they are extremely rare. Cromolyn should be tried for four to six weeks with detailed instructions on the correct technique of using the spinhaler. Intal cannot be given orally since less than 0.5 per cent is absorbed. It is taken with a spinhaler containing the base drug on a lactose powder carrier. The capsule is pierced and the spinhaler inserted well into the mouth

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to avoid deposition of the powder on the tongue and the capsule emptied by deep inspiration. The breath should be held for a few seconds at the end of the inspiration. If there is no improvement over the trial period with this drug it should be withdrawn. It should always be commenced when the child is well, as otherwise the powder will tend to cause severe coughing. If there is a good response it is reasonable to continue long-term therapy and attempt to wean the child from cromolyn after the child is free of wheeze for six months. If the child is particularly young and is unable to use a spinhaler, cromolyn may be nebulized in 2 ml of saline. 10 Young children, however, rarely respond well to cromolyn so that the use for this type of administration is fairly limited. Cromolyn is an adjunct to the therapy of asthma and is not a panacea. Late failures of treatment may occur. An additional major disadvantage to its widespread use is that it is very expensive. Corticosteroids Corticosteroids should be added to, and not substituted for, bronchodilator therapy. They should be used when all other modes of therapy have failed to enable the child to participate in reasonably normal activity. Corticosteroids are anti-inflammatory agents but also appear to stimulate adenyl cyclase and so increase levels of cyclic AMP. They inhibit the release of histamine, but their most profound effect is probably to reinforce the activity of other bronchodilators. Steroids inhibit catechol-o-methyl transferase and therefore potentiate catecholamines. 29 Side effects include cushingoid appearance, growth retardation, cataracts, osteoporosis and aseptic necrosis, benign intracranial hypertension, and many others. Side effects are rare in children when the drug is used judiciously. All children should be given a skin test for tuberculosis and a radiologic examination of the chest before longterm steroids are begun. Live virus immunization must be up-to-date prior to commencement of treatment. Beclomethasone dipropionate (Becotide, Vanceril, Viarex, Aldecin), triamcinolone acetonide (Aristocort, Kenacort), and betamethasone valerate (Bextasol) are inhaled steroids which appear to be of considerable value in the management of moderate to severe chronic asthma. l l They are of little use in acute severe asthma as the inspiratory flow rate is usually too low for adequate inhalation of the drug. They can only be used in children old enough to use a metered aerosol effectively. Demonstration of the technique is vitally important. Beclomethasone aerosols contain 50 JLg per puff and triamcinolone aerosols, 100 JLg per puff. Administration of eight puffs per day of the metered aerosol appears to produce an effect equivalent to that seen with 7.5 mg of prednisolone without the systemic side effects. Even 16 puffs a day is unlikely to cause side effects, which may include oral candidiasis and hoarseness. However, these are rarely severe enough to warrant withdrawal of the drug and are seen less frequently in children than adults. 22 The effect on mucosal defense and on growing lungs is uncertain but there is no evidence to date of any increased tendency to infection or alteration in growth pattern. Children weaned from oral

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steroid preparations and given aerosol steroids are at risk for persisting adrenal suppression and the parents must be instructed that the child will require prednisolone by mouth at any time that he fails to respond readily to a bronchodilator.19 This risk may persist for up to two years after withdrawal of prednisolone. Resurgence of rhinitis and eczema is also seen with this change in therapy. Prednisolone is the drug of choice for oral administration because of its short half-life. It is usually effective when given for short courses starting at 1 to 2 mg per kg per day, with weaning off over 5 to 10 days. On a long-term basis children can be controlled on doses of 3 to 4 mg per day, although occasionally a much higher dose is needed. If the dose can be kept below 6 mg per m 2 per day, side effects are Ininimal. It is preferable to give prednisolone as a single early morning dose which coincides with peak secretion of cortisone. Longer acting steroids, such as betamethasone, triamcinolone, and beclomethasone, which suppress adrenal glands for up to three days, are more likely to cause side effects. Alternate day dosages have been used. These usually start on a regimen in which the daily dose is tripled and slowly decreased until the Ininimum dose which controls symptoms is obtained. However, the alternate day dosage regimen is usually effective only in those children in whom adequate bronchodilators or aerosol beclomethasone would be effective. Synthetic ACTH or tetracosactrin has been used in the management of unresponsive asthma because it was thought to be less growth suppressing. However, this is unproven and as these drugs must be given by injection, there is very little indication for their use. Viral infections do not appear to be the scourge that they are in children with neoplastic disease but it is still reasonable to use hyperimmunoglobulins if exposure to serious viral infections occurs. Some assess the efficacy of steroid effects by the eosinophil counts. However, eosinopoenia will not occur in steroid resistant patients with chronic asthma, possibly as a result of an abnormal metabolic turnover of cortisone. 28 Some asthmatic children have a hypersecretory pattern with a moist cough and the production of excessive sputum, with frequent changes of collapse-consolidation seen on radiologic exaInination. These children do not respond adequately to bronchodilators, physiotherapy, or antibiotics but may show a dramatic response to steroids. The introduction of steroids is particularly useful once infection has been excluded.

Newer Drugs Anti-cholinergic agents have recently been considered in the management of asthma. Atropine causes bronchodilatation but also produces a dry mouth; its place in the management of asthma is not yet clear. It may be used in doses of approximately 0.6 mg orally three times daily or as an aerosol. SCH1000 (Atrovent) has a bronchodilating effect with fewer side effects and is administered from a metered aerosol which produces 40 JLg per puff. It seems to act on larger airways and may be the treatment of preference in some, but there is no

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way as yet of predicting which children will respond. 7 Alpha blockers such as phentolamine have also been used experimentally but as yet have no place in the standard management of childhood asthma.

PATTERNS OF MANAGEMENT It is useful to consider the management of children with asthma in four separate groups (Table 3).

Mild, Acute Episodes of Asthma This group includes 75 per cent of children with asthma. 18 A previously healthy child with mild to moderate acute episodes of asthma will usually respond to administration of an oral beta sympathomimetic agent or xanthine or a combination of both. For more distressing episodes, an initial inhalation or subcutaneous injection of sympathomimetic agent may be helpful. The drug should be continued for at least 48 hours after overt wheezing has ceased, as airway obstruction persists for a considerable period after symptoms have subsided. The parents should have the appropriate drugs at home to commence early administration with the onset of the asthmatic cough or wheeze. Frequent Episodic Asthma This group includes the 20 per cent of children with asthma who have acute episodes of wheeze more frequently than every four to six weeks, but in whom there are symptom-free intervals in between. Parents should understand simple measures of allergen control and the need for normal activity. Two possible regimens may be used in this group and the choice requires pharmacologic, medical and sociopsychologic considerations. Oral xanthine and beta sympathetic agonists may be used. If the child is old enough and if oral medication is ineffective, a combination of oral xanthine and metered aerosol for administration of a beta sympathomimetic agent is particularly useful. Alternatively, cromolyn may be commenced. Some children will respond to cromolyn, and bronchodilators may then be used intermittently with wheezing attacks. Others will require bronchodilators as well as cromolyn to be maintained on a long-term basis. If this regimen remains inadequate then a combination of oral xanthine, cromolyn, and aerosol sympathomimetic agents using a compressed air pump and nebulizer will be necessary. The parents must be aware that a lack of response to bronchodilators at home indicates the need for more intensive therapy which must be sought at either the physician's office or the hospital emergency room. Chronic Asthma About 4 per cent of children with asthma have low grade wheeze present on most days. They wheeze with exertion, have nocturnal cough, and usually have some limitation of physical activity. Testing of pulmonary function will show persisting obstruction of airways dur-

'"

~

00

Table 3. Flow Chart of Drug Treatment in Various Patterns of Asthma EPISODIC

FREQUENT EPISODIC

CHRONIC

SEVERE CHRONIC

Intermittent oral theophylline and/or oral sympathomimetic

I

Inadequate response

Intermittent oral theophylline Cromolyn prophylaxis with and/or aerosol sympathomimetic intermittent bronchodilator I

I

Inadequate response

Long-term theophylline and aerosol sympathomimetic (metered aerosol or nebulizer)

Long-term cromolyn and bronchodilators

I

Inadequate response

Beclomethasone aerosol. oral theophylline. and aerosol sympathomimetic (metered aerosol or nebulizer)

Oral corticosteroid intermittently with long-term aerosol beclomethasone and bronchodilators

1

Not controlled

Long-term oral steroid. aerosol beclomethasone. oral theophylline. and aerosol sympathomimetic

t'"'

o

S rJl

t'"'

~

t:I

>

C

OUTPATIENT EVALUATION AND MANAGEMENT OF ASTHMA

599

ing the interval phase. This group requires long-term therapy with xanthine, sympathomimetic agents, and cromolyn. Some will not be maintained on a regimen of oral therapy and a combination of oral xanthine, cromolyn, and aerosol sympathomimetic agent will be necessary. If they are still unable to lead a normal life, beclomethasone should be added and cromolyn ceased. If the lungs are significantly obstructed when this therapy is commenced, a short course of oral prednisolone is useful to obtain bronchodilator responsiveness and to enable them to adequately inhale the beclomethasone. Once the child begins taking beclomethasone the parents need to be aware that a course of oral prednisolone may be needed when obstruction occurs, since obstruction interferes with adequate inhalation of beclomethasone. Severe Chronic Asthma This group (about 1 in 2,000 children) has symptoms present every day. The most severely affected are stunted in growth and underweight for age, and have a barrel chest deformity with rhonchi heard in the chest during the interval phase. Pulmonary function tests show severe obstruction of airways and marked trapping of gas. This group of children requires at least a combination of oral xanthine, aerosol sympathomimetic agent, and cromolyn. Many will not respond to this regimen. In this case cromolyn may be substituted with beclomethasone. This will still be ineffective in a very small number of children and oral prednisolone will be essential. The oral prednisolone is started in a high dosage and then weaned down to the minimum necessary. If possible, full tests of pulmonary function should be performed to show recurrence of bronchodilator responsiveness after commencement of steroids. Regular flow measurements at home and keeping a diary card of symptoms will help to assess the efficacy of treatment. Evidence of social or emotional upheaval should be sought in this group.

CONCLUSION The management of asthma requires cooperation between patients, faInily, and all medical and paramedical personnel. With cooperation the child can lead a relatively normal life and his activities will not need to be significantly restricted. Parents should be aware of the situation requiring consultation by a physician, and the physician should be aware of the signs indicating the need for hospitalization. Appropriate recognition at each level of care will result in optimal therapy.

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1 :158, 1978.

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3. Bierman, C. W., Shapiro, G. G., Pierson, W. E., et al.: Acute and chronic theophylline therapy in exercise-induced bronchospasm. Pediatrics, 60:845, 1977. 4. Cohen, B. M., and Elizabeth, N. J.: Sympathomimetic/xanthine broncholysis in obstructive ventilatory disorders. Int. J. Clin. Pharmacol., 9:6, 1974. 5. Ellis, E. F., Koysooko, R., and Levy, G.: Pharmacokinetics of theophylline in children with asthma. Pediatrics, 58:542, 1976. 6. Godfrey, S., Balfour-Lynn, L., and Konig, P.: The place of cromolyn sodium in the long term management of childhood asthma based on a 3 to 5 year follow up. J. Pediat., 87:465, 1975. 7. Gross, N. J.: Sch 1000: A new anticholinergic bronchodilator. Am. Rev. Resp. Dis., 112:823, 1975. 8. Hambleton, C., Weinberger, M., Taylor, J., et al.: Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. A collaborative study. Lancet, 1 :381, 1977. 9. Hill, D. J., Landau, L. 1., and Phelan, P. D.: Asthma: The physiological and clinical spectrum in childhood. Respiratory function tests in its assessment. Arch. Dis. Child., 47:874, 1972. 10. Hiller, E. J., Milner, A. D., and Lenney, W.: Nebulized sodium cromoglycate in young asthmatic children. Arch. Dis. Child., 52 :875, 1977. 11. Kershnar, H., Klein, R., Waldman, D., et al.: Treatment of chronic childhood asthma with beclomethasone dipropionate aerosols. II. Effect on pituitary-adrenal function after substitution. Pediatrics, 62: 189, 1978. 12. Landau, L. 1.: Nebulized bronchodilator therapy in asthma. Aust. Paediat. J., 14:139, 1978. 13. Lands, A. M., Arnold, A., McAuliff, J. P., et al.: Differentiation of receptor systems activated by sympathomimetic amines. Nature, 214:597, 1967. 14. Leifer, K. N., and Wittig, H. J.: The beta 2 sympathomimetic aerosols in the treatment of asthma. Ann. Allergy, 35:69, 1975. 15. Lenney, W., and Milner, A. D.: At what age do bronchodilators work? Arch. Dis. Child., 53 :532, 1978. 16. Levy, G., Ellis, E. F., and Koysooko, R.: Indirect plasma theophylline monitoring in asthmatic children by determination of theophylline concentration in saliva. Pediatrics, 53 :873, 1974. 17. Lichtenstein, L. M.: Editorial: An evaluation of the role of immunotherapy in asthma. Am. Rev. Resp. Dis., 117:191,1978. 18. McNicol, K. N., and Williams, H. E.: Spectrum of asthma in children. 1. Clinical and physiological components. Br. Med. J., 4:7, 1973. 19. Mellis, C. M., and Phelan, P. D.: Asthma deaths in children - a continuing problem. Thorax, 32:29, 1977. 20. Mellis, C. M., Kattan, M., Keens, T. G., et al.: Comparative studies of histamine and exercise challenges in asthmatic children. Am. Rev. Resp. Dis., 117 :911, 1978. 21. Mitenko, P. A., and Ogilvie, R. 1.: Rational intravenous doses of theophylline. New Engl. J. Med., 289:600, 1973. 22. Morrow Brown, H., and Storey, G.: Beclomethasone dipropionate steroid aerosol in treatment of perennial allergic asthma in children. Br. Med. J., 3: 161, 1973. 23. Nelson, H. S., Raine, D. Jr., Doner, H. C., et al.: Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am. Rev. Resp. Dis., 116:871, 1977. 24. Nolke, A. C.: Severe toxic effects from aminophylline and theophylline suppositories in children. J.A.M.A., 161 :693,1956. 25. Orange, R. P., Austen, W. C., and Austen, K. F.: Immunological release of histamine and slow reacting substance of anaphylaxis from human lung. I. Modulation by agents influencing cellular levels of cyclic 3'5' adenosine monophosphate. J. Exp. Med., 134(Suppl.): 136, 1971. 26. Phelan, P. D., and Williams, H. E.: Sympathomimetic drugs in acute viral bronchiolitis. Their effect on pulmonary resistance. Pediatrics, 44:493, 1969. 27. Rounds, V. J.: Aminophylline poisoning. Pediatrics, 14:528, 1954. 28. Schwartz, H. J., Cowell, F. C., and Melby, J. C.: Steroid resistance in bronchial asthma. Ann. Intern. Med., 69:493, 1968. 29. Shenfield, G. M., Hudson, M. E., Clarke, S. W., et al.: Interaction of corticosteroids and catecholamines in the treatment of asthma. Thorax, 30:430, 1975. 30. Shore, S. G., Weinberg, E. G., and Durr, M. H.: Buccal administration of fenoterol aerosol in young children with asthma. S. Afr. Med. J., 50:1362,1976. 31. Taussig, L. M.: Mists and aerosols: New studies, new thoughts. J. Pediat., 84:619, 1974. 32. Waxler, S. H., and Schack, J. A.: Administration of aminophylline. J.A.M.A., 143:736, 1950.

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33. Weinberger, M. M., and Bronsky, E. A.: Evaluation of oral bronchodilator therapy in asthmatic children. J. Pediat., 84 :421, 1974. 34. Weinberger, M. M.: Theophylline for treatment of asthma. J. Pediat., 92:1,1978. 35. Williams, H. E., and McNicol, K. N.: Prevalence natural history and relationship of wheezy bronchitis and asthma in children. Br. Med. J., 4:321,1969. 36. Williams, H. E., and Phelan, P. D: Respiratory Illness in Children. Oxford, Blackwell, 1975. 37. Wolfe, J. D., Tashkin, D. P., Calvarese, B., et al.: Bronchodilator effects of terbutaline and aminophylline alone and in combination with asthmatic patients. New Eng. J. Med., 298:363, 1978. 38. Wolfsdorf, J., Swift, D. L., and Avery, M. E.: Mist therapy reconsidered; an evaluation of the respiratory deposition of labelled water aerosols produced by jet and ultrasonic nebulizers. Pediatrics, 43: 799, 1969. Department of Thoracic Medicine Royal Children's Hospital Parkville, Victoria 3052 Australia