Antiasthmatic Therapy in Children

Clinical Pharmacology

0031-3955/89 $0.00 + .20

Antiasthmatic Therapy in Children

Miles Weinberger, MD*

Currently, we are faced with the paradox of increased medication use for asthma in the presence of an increasing frequency of hospitalizations40 and continued fatalities. 114 It is therefore essential that we examine the components of care for asthma. A rational approach to the management of asthma requires an understanding of the pathophysiology of the disease, its variation in clinical patterns, and the therapeutic potential of alternative treatment modalities. Treatment requires consideration of the potential for environmental factors to contribute to the disease, the role of aeroallergens and "allergy shots," and an understanding of the clinical pharmacology of the various antiasthmatic drugs. Last but not least, careful consideration must be given to the delivery of medical care to the patient with asthma.

PHYSIOLOGIC ABNORMALITY

Asthma is a disease characterized by hyperresponsiveness of the trachea and bronchi to various stimuli, resulting in airway obstruction that is reversible either spontaneously or as a result of treatment. 7 This definition is based on the well-documented abnormal physiology of the airways of asthma and thus defines the disease in terms of an abnormal end-organ response without attributing an etiologic basis. The airway obstruction of asthma occurs from two major physiologic components. Bronchospasm, spasm of bronchial smooth muscle, is the component classically associated with asthma. Of equal importance, however, is the presence of inflammation that results in mucosal edema and mucous secretions. These two components of airway obstruction have important therapeutic implications. Bronchodilators relax bronchial smooth muscle but have no effect on the inflammatory component of airway obstruction. Anti-inflammatory corticosteroids decrease mucosal edema and *Professor of Pediatrics; Director, Pediatric Allergy and Pulmonary Division, University of Iowa Hospital, Iowa City, Iowa

Pediatric Clinics of North America-Vol. 36, No.5, October 1989

1251

1252

MILES WEINBERGER

mucous secretions but have no bronchodilator effect. There is an interaction between these two components of airway obstruction, however, in that inflammation of the airways increases acute responsiveness of the bronchial smooth muscle, perhaps by opening tight junctions between epithelial cells of the bronchial mucosa and exposing irritant receptors.

CLINICAL PATTERNS

Varying frequency and severity of symptoms, the role of various physical stimuli, and the potential, although variable, role for aeroallergens make it essential that appropriate assessment and characterization of the disease in each individual be conducted prior to considering the ultimate therapeutic plan. 24, 57, 134a The diagnosis itself needs to be confirmed by determining that symptoms consistent with asthma (i. e., wheezing, coughing, or shortness of breath) occur as a result of hyperresponsive airways resulting in reversible obstruction. A careful clinical database is needed to not only support the diagnosis, but also to identify those factors to which the airways are hyperreactive. It is especially important to identify those factors that may have therapeutic implications. This may include passive (or active) exposure to cigarette smoke or other irritants, the presence of clinically important aeroallergens in the home environment, or seasonal symptoms that correspond to identification of substantial specific IgE antibody to seasonally recurring aeroallergens outside. A careful history and allergy skin testing are essential aspects of the evaluation. Pharmacological treatment strategies relate to the pattern of disease, which can be usefully classified as intermittent, seasonal, or chronic (see Table 1 for definitions). Episodic treatment is satisfactory for intermittent symptoms, while maintenance prophylactic measures are needed for prolonged periods of symptoms associated with seasonal or chronic patterns of disease.24, 134a Table 1. Criteria for Classification of Asthma TIPE OF ASTHMA

Intermittent

Chronic (with or without seasonal allergic exacerbations) Seasonal allergic

Indeterminate (not clearly intermittent or chronic)*

CRITERIA

Symptoms of relatively brief duration (e.g" s; 5 days symptoms per month and extended symptom-free periods) Absence of extended symptom-free periods Symptoms reproducibly occur for prolonged periods only in response to exposure to seasonal inhalant allergens Symptoms recur at variable times for prolonged periods, but extended symptom-free periods also occur without identifiable pattern

*This classification is usually a result of inadequate history or short duration of illness and requires a period of observation before classification can be final, Datafrom Ekwo E, Weinberger M: J Allergy Clin ImmunoI61:240, 1978; with permission.

ANTIASTHMATIC THERAPY IN CHILDREN

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THERAPEUTIC ALTERNATIVES

The primary purpose of this review is to consider the clinical pharmacology and therapeutic applications of antiasthmatic drugs. Nonetheless, there is a potential for alterable environmental factors to play an important role in disease. To the extent that they can be identified, and the environment altered, there is the potential to minimize the need for medication. 83 Allergy shots are a hallowed therapeutic measure recommended almost universally by some physicians for the treatment of asthma. They are not indicated as routine treatment for asthma, however. Rather, their use should be reserved as an alternative for those patients where the following clinical criteria are met: 1. A clinical judgment can be made, based on available evidence that aeroallergens contribute substantially to the patient's symptomatology. This should not be presumed a priori nor can this judgment be based solely on skin testing results. This must be a reasoned and convincing judgment based on careful consideration of all. the evidence. 2. The antigens involved should be those for which there has been reasonable evidence suggesting clinical efficacy. This has been well established for some pollens, but there are concerns regarding the antigenic adequacy of commercially available mold spore preparations. This is of clinical relevance in parts of the country, such as the north-central United States where Alternaria and other seasonal mold spores are major contributors to seasonal asthma, and pollens, in contrast, are minor contributors to asthmatic (but not rhinitis) symptoms. 3. A personal judgment is made on the part of the physician with informed input from the patient that the risks, bother, and expense of allergy shots do not outweigh potential advantages over medical therapy. Severity of asthma, amount and type of medication needed for control of the disease, and access to a physician for the initial series of weekly injections all need to be considered.

An excellent example that frequently meets these criteria is grass pollen sensitivity in northern California and the Pacific Northwest. This is frequently associated with miserable symptoms of the eye, nose, and lungs, is likely to result in considerable medication needs, has a prolonged season, and injection therapy with allergenic extracts convincingly improves both the asthma and rhinitis. 104

CLINICAL PHARMACOLOGY OF ANTIASTHMATIC DRUGS SYMPATHOMIMETIC BRONCHODILATORS

Since 1906, when epinephrine was found to be a potent bronchodilator, adrenergic drugs have been studied extensively and a relationship identified between structure and function of sympathomimetic amines (Fig. 1). Epinephrine had multiple actions on both the bronchial smooth muscle and the cardiovascular system. The therapeutic goal for the newer drugs has been greater selectivity for beta2 (bronchial smooth muscle) adrenergic receptors for improved specificity of bronchodilator effect (Table 2) and

1254

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1255

ANTIASTHMATIC THERAPY IN CHILDREN

Table 2. Selected Pharnwcologic Effects of Sympathomimetics CLINICAL EFFECf

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RECEPTOR

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longer duration of action. Additionally, the newer agents can be used orally because of the resistance to degradation by intestinal and hepatic enzymes. Inhaled Sympathomimetic Bronchodilator Aerosols Sympathomimetic drugs with specific bet~ agonist effect delivered by inhalation can provide the most rapid and effective means of relief from acute asthmatic symptoms. Many are at least as effective as parenterally administered medications but have fewer side effects and are more suitable for self-administration. An exception is the nonprescription formulation of the older nonspecific sympathomimetic bronchodilator, epinephrine (available in metered-dose inhalers as Primatine or Medihaler-Epi), which has only a very modest degree of transient bronchodilator effect compared with other agents. 15 The weak potency of the preparation is further evidenced by the absence of cardiovascular effects. 107 For inhaled be~ agonists to exert their antiasthmatic effects, they must first reach the appropriate receptors. These are located in the lower airways. no The inhaled bet~ agonists appear to exert their effect topically rather than by way of the systemic circulation after absorption from the oral mucosa or GI tract.20· 88 The major effect is probably mediated by receptors throughout the conducting airways on the surface airway smooth muscle cells, but effects on neural structures, lOS mast cells,56. 73 or other structures also may playa clinical role. The degree and duration of therapeutic effect of the inhaled bronchodilators relates to the intrinsic potency of the pharmacologic agents, the dose given, the dose actually delivered to the receptors, and the subsequent rate of removal or degradation of the drug in the airways. Because these are not readily measured, it is the measure of effect (i. e., the pharmacodynamics) that is used to assess the pharmacokinetics (i.e., the time course) of effect. The catecholamine bronchodilators, isoproterenol and isoetharine, appear to exert their maximal effect within 5 minutes after aerosol administration. 5 , 123 The newer noncatecholamine bronchodilators are recognized as having peak effect somewhat later, but nonetheless produce about 80 per cent of their peak effect within the first 5 minutes. Thus, although the newer agents have a "later" peak effect, the difference in rate of onset of bronchodilator effect is generally of trivial clinical importance. Looking at effect by examining only the intensity and duration of bronchodilatation may be deceptive. Bronchodilatation has an obvious

1256

MILES WEINBERGER

limitation of measurable effect since intensity of action at the receptor site cannot be detected once near maximal airway smooth muscle relaxation has been attained (Fig. 2).2 Once maximal dilatation is reached, greater potency is not detectable by simply examining for bronchodilator effect, and, in fact, a rapidly declining effect at the receptor site will not be readily detectable when only bronchodilator effect is examined. In contrast, eXe amination of airway responsiveness permits the ability to see the rapid decline of the effect of the drug at the receptor, thereby potentially giving a more accurate picture of the pharmacokinetics of drug effect (Fig. 2, lower pane0. This methodology has been used to examine various of the currently marketed aerosol bronchodilator medications with differences in apparent duration by bronchodilatation having been found in some cases to be differences in intensity of effect (i.e., failure to use equipotent doses) whereas differences in rate of disappearance from the receptor site have also been seen as illustrated by the metaproterenol-isoetharine example in Figure 2.2, 3, 42, 43 Formoterol is a new beta2 agonist under investigation by Ciba-Geigy that has been reported to have considerably longer duration of bronchodilator effect than albuterol (salbutamol)8, 75 although other data suggest the prolongation of effect on airway reactivity is modest. 90 Salmeterol is another investigational beta2 agonist with similar evidence for prolonged bronchodilation, but duration of effect on airway responsiveness has not yet been examined. 128 Various strategies for delivery of inhaled sympathomimetic bronchodilators have been used. The pressurized metered-dose inhaler is the most convenient means of administration; however, the desired response may be difficult to obtain in a severely dyspneic patient or a younger child who is unable to coordinate inhalation with activation. Various strategies therefore have been developed (Fig. 3). These range from careful instruction of technique for timing inhalation from end-tidal volume to maximal inspiration with the burst of spray that is ejected by actuation of the metered-dose inhaler to the use of spacers and aerosol receiving chambers of various designs. Valved devices can minimize the problems of coordination. Spacers and aerosol receiving chambers may minimize the amount of high-velocity particles impacting on the posterior pharnyx and thereby improve delivery to the airways, The use of solutions of these drugs in compressed-airdriven nebulizers can permit administration even to totally uncooperative patients such as infants and toddlers.- However, delivery by intermittent positive-pressure equipment gives no additional benefit80 and may increase the risk of pneumothorax when used for acute exacerbations of asthma. 64 Concern has been repeatedly expressed regarding the potential for repeated use of sympathomimetic bronchodilators to be associated with tolerance or "subsensitivity, "60,87, 101 This phenomena involves decreases in apparent duration and intensity of effect with repeated use. Alarming observations of actual paradoxical bronchospasm were described with extensive overuse of isoproterenol and even from one case of intravenous albuterol. 96 Routine use of the newer inhaled sympathomimetic bronchodilators four times daily, while not showing progressive loss of effect, does readily demonstrate decrease in effect from initiation of therapy over the first month of treatme~t but not apparently beyond that. 129 However, we

1257

ANTIASTHMATIC THERAPY IN CHILDREN

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HOURS AF1rR DOSE Figure 2. The effects of aerosol metaproterenol, 1300 mcg (long dash line), isoetharine, 680 fLg (short dash line), and placebo (solid line) on FEVj (top panel) and nonspecific airway responsiveness as reflected by the activity ratio (bottom panel). Activity ratio is the provocative concentration that induces a 20 per cent fall in FEV j (PC 20 FEVj) after drug divided by PC w FEV j before drug. The effect on nonspecific airway responsiveness is more sensitive at distinguishing differences in potency and diminishes much more rapidly than apparent bronchodilator effect. Vertical bars indicate standard error of the mean. Tests of significance are against zero per cent increase in FEV!> and against 1 for activity ratio (* = p < 0.05, ** = p < 0.001). (From Ahrens RC, Bonham AC, Maxwell GA, et al: Am Rev Respir Dis 129:903-906, 1984; with permission.)

1258

MILES WEINBERGER

Figure 3, Various inhalation devices to bypass the inherent coordination difficulty with pressurized metered-dose inhalers (upper left), A compressed air-driven nebulizer with a face mask (upper right) enables delivery to even infants and toddlers; the mouthpiece with nasal prongs provides better assurance of delivery (lower left); an aerosol-receiving chamber adapts the portability of the pressurized metered-dose inhaler to a system that does not require coordination of activation with inspiration (lower right),

have observed a disturbing degree of flattening of the dose-response curve to suppression of histamine-induced bronchospasm has been observed among heavy users of inhaled beta2 agonists,4 When used in recommended dosage and under appropriate medical supervision, inhaled sympathomimetic bronchodilators have a very high margin of safety. However, epidemics of fatalities were reported during the mid-1960s in both England and Australia in association with apparent laxity in medical supervision and nonprescription availability of these agents. 13, 53, 59 Upon reviewing the experience of these epidemics, Inman 58 commented: It seems possible that we are dealing with an entirely new type of hazard, caused, paradoxically, by the provision of a highly effective rather than an intrinsically dangerous form of self-treatment.

It is thus important that these medications not be dispensed casually without adequate instruction for proper use, that contingency measures are available when response is inadequate, and that sufficient appropriate maintenance measures are prescribed as needed to prevent chronic or frequently recurring symptoms. 51 Parenteral Sympathomimetic Drugs In acute asthma, epinephrine and terbutaline may be administered by subcutaneous injection as an alternative to inhaled sympathomimetic drugs; this is the route of choice in an asthmatic who is so dyspneic that aerosolized

ANTIASTHMATIC THERAPY IN CHILDREN

1259

administration is ineffective. Of these, terbutaline has a higher therapeutic index because of its beta2 specificity and permits safe, progressive dosing to well above that conventionally used with less risk of toxicity. Terbutaline additionally has an inherently longer duration of action than epinephrine. Injected epinephrine, however, is the drug of choice for anaphylaxis because of its alpha-adrenergic activity, which acts as a physiologic antagonist against the anaphylactic-induced vascular collapse. Terbutaline (or other newer beta2 agonists when available as parenteral solutions) is the parenteral drug of choice when an injected sympathomimetic is needed for bronchospasm. Although isoproterenol has been administered intravenously with considerable success to avoid mechanical ventilation in children with respiratory failure,99 it requires special precautions to avoid serious complications, and intravenous terbutaline (or albuterol when available) is probably as effective with less associated cardiac risk. 63 Oral Sympathomimetic Bronchodilators The original oral sympathomimetic bronchodilator, ephedrine, has relatively weak bronchodilator effect and historically was used extensively in combination with theophylline. In these fixed-dose combinations of ephedrine and theophylline, it added only a small degree of bronchodilator effect, but was associated with synergism for toxicity. 135, 136 The newer agents appear to exceed the bronchodilator effects of ephedrine and avoid the central nervous system (CNS) effects because of their resistance to crossing the blood-brain barrier. They share with ephedrine, however, the presence of only modest and transient clinical effect and still possess the annoying systemic effect of tremor. Because of the frequency of annoying adverse effects and the considerably lesser potency as compared with the same agent given by inhalation,6 the best of the oral sympathomimetics still have limited clinical applicability. Moreover, they appear not to be free of at least a degree of tolerance (i. e., decreasing effect with continuous therapy). 87, !OI

THEOPHYLLINE

Theophylline is one of various xanthine bronchodilators (Fig. 4) and the only one so far with important clinical use for asthma, Enprophylline, a 3-propyl xanthine derivative, is of potential interest because of apparent greater specificity of action. Although five times more potent than theophylline, it does not share theophylline's adenosine receptor inhibition and has less potential for CNS toxicity, diuresis, and cardiac sphincter relaxation. Nausea and headache, however, appear to be common side effects,68, 69 a 2-hour half-life of elimination may complicate clinical use,67 and therapeutic advantage over theophylline has not been demonstrated. 70, 71 Pharmacodynamics Theophylline has been used in the past mainly for its acute bronchodilatory effect. Since the early 1970s, definition of its pharmacokinetics and pharmacodynamics has provided greater safety and efficacy. Most impor-

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1261

ANTIASTHMATIC THERAPY IN CHILDREN

tantly, studies of theophylline have demonstrated its efficacy as maintenance therapy in the prevention of asthmatic symptoms. 130. 135. 136 Although newer drug regimens for maintenance therapy have been demonstrated to be effective, comparative studies continue to demonstrate the high degree of efficacy of theophylline for this purpose. In a multicentered comparative study with cromolyn, theophylline was associated with a greater frequency of asymptomatic days among children chosen because of relatively severe chronic asthma,41 although subsequent studies of children with milder disease have shown little difference between these two regimens. lI6. 132 Comparison with an oral beta2 agonist has similarly shown therapeutic advantage for theophylline. 21 When compared with the more potent route of sympathomimetic administration, inhaled delivery, theophylline has still demonstrated therapeutic advantage. 61 The explanation for the difference in clinical effect was the rapid fall-off of effect on the airways that was associated with a progressive increase in symptoms at periods beyond 4 hours from the inhaled albuterol used in this study. Of particular note was the greater than twofold frequency of nocturnal symptoms in association with maintenance therapy during the inhaled albuterol as compared with the slow-release theophylline regimen. The degree of clinical effect from theophylline described in the above studies is most readily seen when serum concentrations are maintained between 10 and 20 j.Lg per ml. 86, 135, 136 Moreover, response of the airways can be demonstrated to parallel changes in serum concentration (Fig. 5). Similar to the relationship of serum concentration to bronchodilator activity, Serum Theophylline Concentration (fJ.9/ml)

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1262

MILES WEINBERGER

effect on stabilizing the responsiveness of the asthmatic airways to exercise also can be demonstrated to relate closely to serum concentration. lo2 Theophylline thus has a great potential for efficacy in suppressing the symptoms and signs of chronic asthma when used in appropriate doses. When doses are inappropriate, however, theophylline has the greatest potential for serious toxicity of any medication used for asthma. Toxicity relates closely to serum concentration and increases in likelihood and degree as serum concentrations exceed 20 Ilg per ml. 46 An extensive review of the world's English language literature of reported cases of theophylline toxicity is recorded elsewhere. 49 That review emphasizes that toxicity is not idiosyncratic. Except for ingestions, excessive serum concentrations can be attributed predominantly to therapeutic misadventure. Attention has recently focused on reports of school and behavior problems alleged to be caused by theophylline. 142 While theophylline is related to caffeine, and shares with caffeine the potential for central nervous system stimulation,62 the reports have had little substance. 142 The issue was reviewed by the Pulmonary/Allergy Advisory Committee to the U.S. Food and Drug Administration in an open meeting on October 17, 1987, and found to be without sufficient established merit to warrant any change in current labeling. 32 Whereas minor effects have been detectable, although inconsistently, on some neuropsychological tests and idiosyncratic behavioral responses can occur, impressions of a high frequency of intolerance to theophylline can be attributed primarily to failure to follow prudent dosage practices incorporated into the package inserts since 1979 that utilize slow clinical titration with guidance of final dosage by measurement of serum theophylline concentrations (see Dosage). Some small, although statistically significant, physiologic effects also have been described, including increased uric acid, decreased serum bicarbonate, and increased serum and urinary calcium. However, no clinical importance has yet been attributed to the very small effects observed on these measurements. Formulation Selection of formulation for treatment with theophylline has become an important issue. While theophylline is still used occasionally for acute therapy for which rapid onset of action from the intravenous route may be indicated, oral treatment has become largely targeted at maintenance prophylactic therapy, in which the sustained action of slow-release theophylline preparations has been desirable. During the 50 years of clinical usage of theophylline, many formulations have been marketed as companies vie for perceived commercial advantage. As such, many available preparations have lacked scientific justification. For example, the addition of ethylenediamine to theophylline to form so-called aminophylline, simply raises the pH of the solution which, by any means attained, increases the solubility of theophylline. A theophylline solution without ethylenediamine marketed by Travenol is becoming increasingly popular because of its rationality and absence of ethylenediamine, which has been associated with occasional allergic reactions. 31. 25, 100, !O3 The slow-release formulations are today the most clinically relevant formulations for maintenance therapy. Because of their widespread clinical

ANTIASTHMATIC THERAPY IN CHILDREN

1263

use, many unique formulations have been developed and marketed under even a wider variety of brand names. Despite commercial claims for formulation-specific dosing intervals, it is the characteristic rate of absorption of the product combined with the rate of elimination of the patient at a selected dosing interval that results in the consequent fluctuations in serum concentration. The methodology for evaluating products is extensively reviewed elsewhere. 47. 137 Formulations reliably and completely absorbed at the rate described for Theo-Dur tablets and Slo-Bid capsules permit 12-hour dosing for most patients with fluctuations that generally can maintain serum concentrations between 10 and 20 ""g per ml. Patients with more rapid theophylline elimination, however (identifiable by above-average dose requirements), may benefit from decreased fluctuations expected during 8-hour dosing. 47. 139 Most other reliably absorbed formulations are absorbed more rapidly than these two formulations, whereas more slowly absorbed formulations have thus far frequently been erratic or incomplete in their absorption characteristics. 52 Slow-release formulations available as bead-filled capsules have been extensively used opened and "sprinkled" on spoonfuls of soft food for administration to young children. Whereas previously described methodology47, 130, 140 permits reasonably accurate prediction of fluctuations in serum concentration during multiple dosing based on single-dose absorption studies, confounding factors complicate clinical decision making. Specifically, absorption from some formulations may not be the same for doses given at different times of the day. 39 Moreover, food has specific effects on some formulations that may result in adverse consequences, 53, 65, 77, 97 while little in the way of clinically important effects of food may be present for other formulations (Fig, 6). Slow-release theophylline is now being marketed for 24-hour dosing. The relationship between marketing claims and facts has been extensively reviewed elsewhere. 131, 133 Regardless of marketing claims, the principles of product selection require identification of the rate and extent of absorption, and the fluctuations in serum concentration for patients with defined rates of elimination can then be predicted as previously described. 47, 140 This provides at least a minimal estimate of expected fluctuations in serum concentration at the dosing interval to be selected. A more precise estimate could be made by the same methodology if the rate of absorption following an evening dose of the formulation were incorporated into the equation; unfortunately, these data are not available for most products. Formulations with major defects in rate or extent of absorption resulting from food are best avoided. Dosage Selection of dosage for theophylline must consider rate of theophylline elimination, which varies, on average, with age, and the large variability even within age groups is mirrored by the consequent wide range in dosage (Fig, 7).78 An additional confounding factor that influences the dosing schedule is the observation that the frequency of minor adverse effects is diminished greatly when initial dosage is low and the final therapeutic dosage is approached slowly by clinical titration over a 1- to 2-week period (Fig. 8).78, 139 When this is done, the frequency of even minor adverse

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(Sips et.al. 1984)

6

9

12

15

18

21

24

.27

30

Time (hrs)

Figure 6. Contrasting effects of food on Theo-24 (upper left'f' and Theo-Our Sprinkle (upper right)." Major but paradoxic effects on botb tbe extent and rate of absorption are apparent. In contrast, no effect on extent and only a modest effect on rate are associated with Slo-Bid Gyrocaps (lower left; original data by Weinberger et al., 1984 on file at Rorer Pharmaceuticals), 143 Theo-Our tablets (lower right),I20 or plain tablets or liquid formulations. 145 These results also are supported by otber studies. 55. 72. 77. 92. 131

75

75

50

50

25

Percentage of

Patients

IlL.

0

75[ 50

25

o

•

25

0 75

50

25

o

-t""'"--1--

L'

6

I-'

ffi

10

14

18 22 26 30 Dose (mg/kg/day)

34

38

Figure 7. Frequency distribution for elimination half-life (left) and dose requirements (right) for adults (upper) and children (lower). In the absence of identifiable exogenous factors (see text), elimination rate and dose requirements generally remain stable for extended periods. 7s

1266

MILES WEINBERGER

INITIAL DOSE Adults and children over 1 year old: The lesser of 400 mg/day or 16 mg/kg/day

I

after 3 days

~

FIRST INCREMENTAL INCREASE Adults and children <: 45 kg: 600mg/day Children < 45 kg: The lesser of 600 mg/day or-20 mg/kg/day for ages 1 to 9 16 mg/kg/day for ages>9

I

after 3 days

t

SECOND INCREMENTAL INCREASE Adults and children <: 45 kg: 800ri1g Children < 45 kg: The lesser of 800 mg/day or-22 mg/kg/day for ages 1 to 9 20 mg/kg/day for ages 9 to 12 18 mg/kg/day for ages 12 to 16

I

Check serum concentration about 4 hours after a dose when none have been missed or added for 3 days

~

SERUM CONCENTRATION 10 to 20 mcg/ml.

DIRECTIONS .. Maintam dose if tolerated. RECHECK SERUM THEOPHYLLINE CONCENTRATION AT 6 TO 12 MONTH INTERVALS.'

20 to 25 mcg/ml. 25 to 30 mcg/ml. Over 30 mcg/ml.

.Decrease dose at least 10% .Skip next dose and decrease subsequent doses at least 25% .Skip next 2 doses, decrease subsequent doses 50%, and RECHECK SERUM THEOPHYLLINE FOR GUIDANCE IN FURTHER DOSE ADJUSTMENT.

7.5 to 10 mcg/ml. Below 7.5 mcg/ml.

Increase dose about 25% if tolerated . .Increase dose about 25% and RECHECK SERUM THEOPHYLLINE FOR GUIDANCE IN FURTHER DOSE ADJUSTMENT.

"Fmer adJustments In dosage may be needed for some pallents. drug interactions or phYSiOlogic abnormalIties may "mandate earlier reexamination

Figure 8. Scheme for establishing optimal oral theophylline dosage in ambulatory patients. This is a conservative application of recommendations incorporated into the FDA-approved package inserts. Ideal body weight should be used for obese patients. Initial dosage (mg per kg per day) for infants from 6 weeks to 1 year is 0.2 X age in weeks + 5; average dose to attain serum concentrations of 10 to 20 ILg per ml will be 0.3 x age in weeks + 8. (From Weinberger M, Hendeles L: N Engl J Med 308:706-764, 1983; with permission.)

effects detectable by history is less than 3 per cent so long as serum concentrations are under 20 Ilg per m!. 78 Subsequently, final dosage is guided by measurement of serum concentration, and dosage requirements generally remain stable for extended periods. However, sustained fever, macrolide antibiotics (erythromycin, troleandomycin), quinoline antibiotics (ciprofloxacin), cimetidine, heart failure, and liver disease slow theophylline elimination and thus will result

ANTIASTHMATIC THERAPY IN CHILDREN

1267

in consequent increases in steady state serum concentration. 48, 50, 113, 146 On the other hand, phenytoin, phenobarbital, and cigarette (or marijuana) smoking will increase theophylline elimination, thereby decreasing steadystate serum concentrations. (It is important to consider that patients initially titrated to appropriate dosage based on serum concentration while smoking or receiving phenytoin or phenobarbital will have slower theophylline elimination and increased serum concentrations should these exogenous factors be discontinued.) Prevention and Management of Theophylline Poisoning Despite decades of clinical experience with theophylline, iatrogenic overdosage continues to occur. 81, 147 The importance of prevention by careful patient instruction regarding product selection, dosage, and confounding factors described in the previous sections cannot be overemphasized. When an overdose is inadvertently administered, further absorption can be stopped with activated charcoal. 119 Repeated doses of charcoal also can double the rate of theophylline elimination. 9 Dosage is 1 gm per kg of Super-Char Liquid every 2 to 4 hours. Many patients survive very high serum theophylline concentrations unscathed. However, when seizures occur, death and permanent brain damage are common sequelae. 17,45, 150 Charcoal hemoperfusion can increase the rate of theophylline elimination even more than oral charcoal95, 138 and may be clinically indicated when the serum concentration is over 60 J.1g per ml following repeated doses. Since single overdoses appear less likely to cause seizures at serum concentrations below 100 J.1g per ml,35, 45, 91 charcoal hemoperfusion may need to be considered for these patients only when that higher level is approached. Phenobarbital has been shown to protect laboratory animals from theophylline-induced seizures,34 but this effect has not been evaluated clinically. Nonetheless, a lO- to 20-mg per kg intravenous loading dose administered slowly over 30 minutes should be considered for patients of all ages with serum theophylline levels greater than 40 J.1g per ml, even if asymptomatic. When seizures occur, they should be terminated rapidly with intravenous diazepam, paraldehyde, thiopental, or a general anesthetic, if necessary, while oxygenation and respiratory support are maintained.

CROMOLYN SODIUM

Cromolyn sodium was introduced into the U.S. market in 1973, 5 years after its introduction in the United Kingdom by Fisons. The drug was initially promoted inappropriately for patients with severe steroiddependent asthma. Consequently, the favorable reports in the literature regarding the efficacy of this medication were not generally shared by U. S. physicians. Subsequent studies and greater clinical experience have permitted cromolyn to be placed into appropriate clinical perspective as an exceedingly safe form of treatment for many patients that is often satisfactory for those with milder manifestations of chronic asthma.

1268

MILES WEINBERGER

Cromolyn is unique among the classes of antiasthmatic drugs in that it has no bronchodilator, anti-inflammatory, or antihistaminic effect. As a result, cromolyn sodium has no effect on acute symptoms. Cromolyn's major and best understood mode of action appears to be its protective effect on mast cell degranulation with prevention of the release of chemical mediators that result in bronchospasm and mucous membrane inflammatory changes. The drug is administered topically as a dry powder via a Spinhaler device, as an aerosol solution via nebulizer, or as a fine mist via metereddose inhaler. Topically applied cromolyn has been demonstrated to prevent antigen-induced bronchospasm in addition to bronchospasm induced by other challenges to the airways thought to be mediated by nonantigeninduced mediator release. Specifically, exercise-induced bronchospasm, cold air-induced bronchospasm, and bronchospasm induced by sulfur dioxide have been partially inhibited to varying degrees with cromolyn. There is controversy over the ability of cromolyn to inhibit nonspecific airway reactivity induced by methacholine or antihistamine, but at least short-term use appears to have no effect.lI6 Multiple controlled studies have demonstrated that cromolyn decreases the frequency and severity of daily wheezing, cough, and shortness of breath, when used at doses of 20 mg 4 times daily by the Spinhaler device (when cromolyn is administered with lactose-filler as a dry powder) or at a dose of 2 mg by pressurized metered-dose inhaler spray. Open uncontrolled studies have suggested that less frequent administration may maintain efficacy in many patients. Limited data have suggested that higher doses may provide greater degrees of efficacy for some patients. Comparative studies have demonstrated cromolyn to be similar to theophylline in degree of efficacy for patients with milder asthma. 23, 33, 39 One of these studies using a nebulized solution of cromolyn in young children even suggested an unsustained trend toward somewhat greater efficacy in association with cromolyn. 89 A study of more severe patients, however, demonstrated a greater frequency of asymptomatic days in association with theophylline. 41 Moreover, theophylline has been associated with clinically important additive effect in those who could not be adequately controlled without the use of maintenance corticosteroids, 21 receiving a mean dose of 550 j..lg per day of beclomethasone dipropionate and 10 receiving a mean dose of 30 mg prednisone on alternate mornings,84 whereas cromolyn has not added therapeutic benefit to patients receiving maintenance therapy with inhaled corticosteroids. 19, 55,125 In contrast to these placebo-controlled studies, some open trials have suggested a steroid-sparing effect for patients receiving oral steroids. Many clinicians and investigators experienced in the use of cromolyn have been impressed that, to a large extent, cromolyn tends to be an "allor-nothing" drug in that efficacy is either impressively present or, for a substantial number of patients, is strikingly absent. This is in contrast to the bronchodilator and anti-inflammatory medications, in which degrees of efficacy are more readily apparent, Attempts have been made, therefore, to identify the clinical characteristics of "responders." In spite of the welldefined mechanism of action by preventing antigen-induced mast cell release of chemical mediators, cromolyn has not been consistently more

ANTIASTHMATIC THERAPY IN CHILDREN

1269

effective in preventing symptoms in patients identified as having "extrinsic asthma" as compared with those that do not have defined responses to inhalant allergens. In fact, at least one controlled evaluation could demonstrate statistically significant clinical effect in a group of 30 patients identified as having "intrinsic" perennial disease but not in a group of 29 patients with well defined and characterized seasonal allergic asthma. 11 There have been inconsistent results related to differential effects With regard to age of patients. The clinical impression of many has been that efficacy is greater in children and young patients than in older patients, but controlled evaluation has not consistently supported that impression. 127 Side effects from cromolyn appear to be relatively uncommon and minor 115 with at least some being immunologically mediated.117 Symptoms include transient airway irritation, skin eruptions, myositis, and pulmonary infiltrates. Cromolyn thus appears to be a clinically useful first-line drug for patients with chronic disease (i. e., daily symptoms of asthma). It should be initiated as four times daily therapy in one of its three currently available forms for asthma, 20-mg powder-filled capsules administered via the Spinhaler device, 2 mg by inhalation from the pressurized metered-dose inhaler, or 20 mg inhaled via the nebulizer solution. Acute symptoms of asthma initially need to be cleared with other measures such as inhaled sympathomimetic brOl1chodilators or corticosteroids if bronchodilator unresponsive. In at least one study that demonstrated reduced daily symptoms with nebulized cromolyn in wheezy preschool children, there was no decrease in the frequency or severity of apparent viral-induced acute exacerbations of asthma. 16 Thus, it is important that acute exacerbations of asthma duripg otherwise successful maintenance therapy with cromolyn be treated promptly and appropriately. While the duration of time until optimal clinical effect has been extensively debated, it would appear reasonable to abandon" therapy if clearly evident clinical effect is not apparent within 1 month of initiation. Moreover, the need to add additional maintenance measures should generally be regarded as evidence of a cromolyn "failure" with discontinuation of the medication. Although some have argued that the frequency of cromolyn use can be decreased to as little as twice daily once a good response has been observed, others suggest that continued absence of asthmatic symptoms during reduced dosage indicates remission ()f disease and lack of need for medication. Cromolyn also appears to be effective for a sub!itantial number of patients with allergic rhinitis and conjunctivitis wilen topically applied. Frequent administration is needed, and response appears to be neither as consistent nor as impressive as that seen with topically applied corticosteroids, but the essential absence of potential for serioqs Ildverse effects makes this medication an attractive option. Since the development and introduction of cromolyn sodium, other drugs with cromolyn-like activity have been sought, and several have reached varying stages of clinical investigation. Ketotifen is an orally administered drug with both antihistaminic and cromolyn-like activity. The data supporting the efficacy of this agent have thus far been equivocal, with

1270

MILES WEINBERGER

the antihistaminic effects along with accompanying drowsiness being more prominent than antiasthrpatic effects. To the extent that antiasthmatic effects are qualitatively present, they are generally quantitatively small in magnitude, almost certainly less than that of cromolyn. 76. 116 Other cromolyn-like drugs are under investigation but so far have generally been less effective than cromolyn.

CORTICOSTEROIDS

Corticosteroids are the only drugs currently used for asthma that can reverse airway obstruction that is unresponsive to bronchodilators. Changes in pulmonary function following a single dose usually begin slowly and progress to peak effect over 9 to 12 hours. 26 Return of bronchodilator responsiveness as early as 1 hour after a dose of parenteral prednisolone has been described in stable adult asthmatics unresponsive to inhaled bronchodilators.27 When systemic corticosteroids are used for acute exacerbations of disease, maximal response takes several days (Fig. 9).44 Concern for adverse effects and questions regarding efficacy have served to make corticosteroid therapy often controversial. 28,29,79 An examination of available data, however, enables benefits and risks to be put into proper perspective. 134 Although a list of adverse effects of corticosteroids includes many that are potentially serious, including suppression of endogenous adrenal function, cushingoid changes in appearance, growth suppression, posterior subcapsular cataracts, osteoporosis, aseptic necrosis of the femoral head and others, these all appear to be predominantly related to extended daily therapy. Short courses (i.e., up to 10 to 14 days) appear to be associated with little more than some occasional mood changes along with some facial edema and erythema that may develop by the end of a course of this duration. On the other hand, the benefits of short courses of high doses for acute exacerbations of asthma are such that emergency care and hospitalizations can be avoided. 12, 28, 29, 44, 74, 134 Whereas toxicity is not an important consideration for infrequent short courses of corticosteroids used to treat acute exacerbations of asthma, this issue becomes of major importance when steroids are used for maintenance therapy. As a result, indications for maintenance steroids must be carefully considered (Table 3), and dosage and formulation strategies have been developed to increase the safety during long-term use. One of the earlier strategies developed was based on the observation that suppression of corticosteroid-responsive diseases could be obtained by intermittent therapy. Single doses of a short-acting steroid such as prednisone, prednisolone, or methylprednisolone on alternate mornings appeared not to cause persistent adrenal suppression and was relatively free of the more serious adverse effects associated with long-term therapy. Studies as early as the late 1960s showed little in the way of cushingoid changes or adrenal suppression, and growth in children appeared to be normal at doses averaging 40 mg every other morning. I, 112 More recently, a new generation of inhaled corticosteroids with potent topical effect at doses that have little systemic effect at usual dose have

1271

ANTIASTHMATIC THERAPY IN CHILDREN

100

90

Percent of Predicted

80

Prednisone treated (n = 22) . . - . Placebo treatedno further intervention (n = 11) 0--0 Placebo treatedintervention needed (n = 8)

70

60

6

.. - ... Prednisone treated (n=22) . . - . Placebo treatedno further intervention (n 11) 0--0 Placebo treatedintervention needed (n =8)

=

(7)

4

Mean Number Per Day 2

2

3

4

5

6

7

8

9

10

11

12

13

14

Day Figure 9_ Mean ± SEM peak expiratory flow rate (upper panel) among 22 patients randomly assigned to receive 1 week of prednisone 30 to 40 mg b. i. d., and 19 placebo at the onset of symptoms incompletely responsive to inhaled bronchodilator added to maintenance therapy with oral theophylline. Although all of the prednisone-treated patients improved, it required the 7-day period of treatment for mean peak flows to reach near normal values. The frequency of wheeze, cough, intolerance of activity, nocturnal awakening from asthma, and p.r.n. use of inhaled albuterol (lower panel) mirrored the peak flows. Although many of the placebo-treated patients recovered spontaneously at about the same rate as those receiving prednisone, 40 per cent either persisted in having symptoms or deteriorated despite a continuing high rate of inhaled beta. agonist, thereby eventually requiring rescue intervention. Parenthetic values by data points refer to those for whom data were available; further data were not tabulated once rescue intervention required the addition of unblinded prednisone. (From Harris JB, Weinberger M, NassifE, et al: J Pediatr 110:627-644, 1987; with permission).

become available for clinical usage. While not totally free of measurable systemic effects, these drugs nonetheless have a high margin of safety in clinical use. Comparisons of alternate-morning prednisone and inhaled beclomethasone, the first of the new generation of inhaled corticosteroids,

1272

MILES WEINBERGER

Table 3. Indications and Therapeutic Strategies for Maintenance Corticosteroids Indications Repeated relapse of bronchodilator-unresponsive symptoms after short cOurse of high-dose oral steroids Therapeutic alternatives Oral prednisone (or prednisolone or methylprednisolone) on alternate mornings Inhaled topically active steroids Beclomethasone dipropionate Budesinide Flunisolide Triamcinolone acetonide Dosages Start high Lower slowly to establish maintenance dose Mean (usual range) dosage* Alternate day prednisone-30 (20-40) mg q.o.d.t Inhaled beclomethasone-550 (200-900) jLg/day

*At University ofIowa. tq.o.d.---every other morning.

have been made. Doses required for control of disease in our hands have ranged most commonly froin 20 to 40 mg (mean 30 mg) of alternate-morning prednisone and from 400 to 800 IJ.g per day (mean 550 IJ.g per day) inhaled beclomethasone dipropionate. At these usual doses, little difference in adrenal suppression or growth has been observed. 85, 148 Early morning serum cortisols, although transiently depressed 24 hours after a dose of prednisone, were essentially identical before the next dose of prednisone with children receiving inhaled corticosteroids, Urinary-free cortisols, on the other hand, Were more impressively suppressed but to a virtually identical degree among children receiving the alternate-day prednisone and the inhaled beclomethasone dipropionate. Potentiation of adrenal suppression was apparent when the inhaled steroid and alternate-day oral steroid were used in conjunction. Relative efficacy of the two regimens is often similar, although at least uncontrolled observations suggest that soine patients inadequately controlled on acceptable doses of alternate-day prednisone may be more likely to attain control with the inhaled agents. Moreover, our experience supports the studies by others demonstrating that much higher than usual doses of inhaled corticosteroids can be given with substantial benefit and little in the way of clinically important risk despite the measurable adrenal suppression that almost certainly will occur, 22, 121, 126 Besides beclomethasone dipropionate, two additional corticosteroids have been introduced to the U.S. market. Triamcinolone acetonide is available with a retractable tubelike spacer that may decrease fallout of the aerosol in the mouth, thereby improving delivery with the potential for increased efficacy with decreased detectable systeinic effects. Flunisolide ha.s been marketed as a "twice-daily" product in contrast to the initial labeling of beclomethasone dipropionate and triamcinolone acetonide for four times daily use. Nonetheless, there is evidence that four times daily use was associated with greater clinical benefit than twice daily use for

ANTIASTHMATIC THERAPY IN CHILDREN

1273

another inhaled steroid, budesinide, that is marketed for twice daily usage in Europe. Moreover, it has been common practice to use both beclomethasone dipropionate and triamcinolone acetonide twice daily with adequate benefit for many patients. The three inhaled corticosteroids have recently been compared by examining dose-response relationships for both topical and systemic effect (Fig. 10). Flunisolide appeared to be perhaps eight times as potent per puff for both topical and systemic effect. 37 Thus, this agent may be analogous to the 250 J.1g per inhalation beclomethasone dipropionate inhaler that has been used with effect in European studies to attain greater doses than are readily practical with the usual 50 J.1g per puff preparation currently marketed in the United States.

ANTICHOLINERGIC AGENTS

Ipratropium bromide, a quarternary ammonium congener of atropine, recently has been introduced into the United States as a metered dose inhaler for use as a bronchodilator. The use of anticholinergic, anti muscarinic compounds as bronchodilators for asthma has its roots in 19th century medicine. In fact, the leaves of Datura stramonium, a naturally occurring anticholinergic, were smoked until the middle of this century. Although these and other anticholinergic compounds have measurable bronchodilator effect,38, 94 their role in asthma therapy remains limited because of lesser potency than inhaled beta2 agonists and no defined subgroup of asthmatic patients uniquely responsive to their effect.

INVESTIGATIONAL AGENTS

During the last 4 years, numerous studies have been published on the effects of the calcium channel blockers, verapamil, diltiazem, and nifedipine, on experimentally induced asthma.!O Although none affect resting bronchomotor tone, effects on the increased airway responsiveness of asthma to various stimuli have been demonstrated. 14, 18,36,54,66,108, 1ll While one study has suggested a degree of clinical effect from the use of nifedipine, 93 there are insufficient data to yet support a role for calcium channel blockers in the clinical management of asthma. Future studies or newer calcium channel blockers with more specific effect on bronchial smooth muscle may offer more promise for calcium channel blockers as pharmacotherapeutic agents for asthma. Ketotifen has been on the world market as an antiasthmatic agent. It has antiasthmatic effects and also appears to have effects as a mast cell stabilizer with inhibition of release of mediators. 100 Clinical trials, however, have shown little or no benefit. 76 There are active investigations of specific antagonists of mediators involved in asthma. Because of the multiple mediators involved in asthma, there is reason to be skeptical that these will be much more effective than antihistamines in asthma therapy.

1274

MILES WEINBERGER

100

75 Percent Blocking

f

50 • _. 0 Ftunisolide (n=9) - -

•

-

•

Triamcinolone (0=8)

Beclomethasone (n=9) me.n. SEM least sQuare regression Indicated by dashed hnes

25

!

0 Initial Dose

2x

4x

Initial Dose

Initial Dose

30 20 10 0 Percent Change

-10 -20 -30 -40 -50 -60

r= 90

. _. 0

Flunisolide (n=9)

- -

•

TriamCinolone (n=8)

-

•

r=98

~r=.87

8eclomethasone (n=9) mean t SEM Least sQuare regression Indicated by dashed lines

I

Initial Dose

2x

4x

Initial Dose

Initial Dose

Figure 10. Dose-response curves for topical effect, the blocking of drop in FEV, from an inhaled allergen challenge (upper panel) and systemic effect, 24-hour urinary free cortisol (lower panel) for three inhaled corticosteroids currently on the U.S. market. Beclomethasone dipropionate and triamcinolone were administered at a dose of 2, 4, and 8 puffs q. i. d.; flunisolide, because of lower package insert dosage recommendations, was administered at doses of 1, 2, and 4 puffs q.i.d. The triamcinolone acetonide was administered via the commercially available retractable spacer integrated into the metered-dose inhaler delivery device for that product. The data suggest a somewhat steeper dose-response curve for triamcinolone acetonide and about eight times as great effect per puff of flunisolide as compared with beclomethasone dipropionate for both systemic and topical effect. 37

At times there have been reports of highly toxic substances such as high-dose iodides or arsenic (in low doses) being effective for asthma. The latest in this tradition is methotrexate. 82 While the investigators defend the use of this toxic agent in patients with severe asthma requiring corticoste-

1275

ANTIASTHMATIC THERAPY IN CHILDREN

roids, the lay press picked up this New England Journal of Medicine publication and portrayed it as a breakthrough. It should instead be considered as an act of desperation. Troleandomycin, TAO, is a macrolide antibiotic that has had repeated reports of benefit for steroid-dependent asthmatics when used in conjunction with methylprednisolone. 149 The earliest reports of clinical benefitl22 did not appreciate the effects on slowing theophylline l44 or methylpredniso10nel24 elimination. Further data are still required to define its mechanism of action. Because some methylprednisolone appears to be needed for clinical efficacy of TAO, demonstration of effect other than simply increasing systemic corticosteroid effect from lower doses still needs to be confirmed.

DELIVERY OF CARE TO THE PATIENT WITH ASTHMA Because of variability in both clinical pattern, severity, and physiologic abnormality, the treatment of asthma must be individualized according to frequency and chronicity of symptoms. It is helpful to consider a sequential selection procedure for the pharmacotherapeutic alternatives (Table 4).134. Perhaps most important with regard to immediate threat to patients is the management of acute symptoms. In fact, satisfactory management of acute symptoms may be all that is needed when symptoms occur only on a relatively infrequent, intermittent basis, regardless of severity when they do occur. Efficacy requires measures that relieve respiratory distress rapidly and effectively. Promptness of action, potency, and safety over the short run are the major considerations. On this basis, an inhaled beta2 adrenergic agonist is the bronchodilator of first choice. In contrast, orally administered bronchodilators require time to be absorbed and are therefore slower in onset of action. Acute symptoms not relieved by adequately delivered inhaled be~ agonists require short-term use of corticosteroids. 12. 28. 29. 44. 74.134 For management of the patient with chronic asthma, theophylline has been shown to be highly effective as maintenance therapy. Cromolyn is an alternative to theophylline for the prevention of asthmatic symptoms. Although generally less effective than theophylline in more severe disease, efficacy may be as adequate for milder disease; moreover, dosage is standardized, and toxicity is virtually nonexistent. Oral or inhaled sympaTable 4. Sequential Selection of PharmacologiC Agents to Match PharmacologiC Potential with Physiologic Abnormality TREATMENT STRATEGY PHYSIOLOGIC ABNORMALITY

Bronchodilator response complete and sustained Bronchodilator subresponsive

Interoention

Inhaled beta. agonist Add high-dose oral corticosteroids

Maintenance

Theophylline, cromolyn, or inhaled beta. agonist Add alternate-morning prednisone or inhaled corticosteroids

(From Weinberger M: Managing Asthma. Baltimore, Williams & Wilkins, 1989, p 134; with permission.)

1276

MILES WEINBERGER

STUDY PATIENTS

$0

(n=13)

COMPARISON PATIENTS (n

$ 2500

= 13) o

5 10 15 20 HOSPITAL DAYS"

STUDY PATIENTS (n=13)

$ 35

COMPARISON PATIENTS ( n = 13 ) 0

5

10 15 20 ER VISITS t

* $ 250/DAY t$35/VISIT Figure n. Comparison of hospital days and emergency visits for asthma among 26 patients receiving the same initial treatment recommendations. The 13 randomly assigned study patients differed from the 13 comparison patients only in repeated contacts with a nurseeducator to reinforce initial medical recommendation designed to provide the patient with the means to manage their asthma. (From Fireman P, Friday GA, Gira C, et al. Pediatrics 68:341-349, 1981; with permission.)

1277

ANTIASTHMATIC THERAPY IN CHILDREN

EMERGENCY CARE 100%

~ Once

o More than Once

75 Percentage of Patients

HOSPIT ALiZATIONS 100%

75

50

50

25

25

0

0 Prior

Subsequent

Year

Prior

Subsequent

Year

Figure 12. Frequency of emergency department visits and hospitalizatipns among 169 patients the year before and after entering the asthma management program of the University of Iowa Pediatric Allergy and Pulmonary Division. (From Weinberger M: Managing Asthma. Baltimore, Williams & Wilkins, 1989, p 184; with permission.)

thomimetic bronchodilators also are used to treat chronic asthma. Data supporting control of symptoms with continuous use of these agents are limited, however, and their relatively rapid decrease in effect over time gives reason for concern that drug activity may not be sustained over a dosing interval. Corticosteroids also may be needed when continuous or frequently recurring symptoms and signs of chronic asthma are controlled inadequately with bronchodilators. Because of the potential long-term adverse effects of daily corticosteroid therapy, alternative strategies for increased safety have been developed; these include short-acting oral steroids on alternate mornings and the newer generation of irihaled corticosteroids. As might be expected, more medications may be required for adequate control of more severe disease. Management of asthma that is active only intermittently may require only inhaled sympathomimetic bronchodilators, but those whose symptoms have progressed to the stage at which emergency care or hospitalization has been required may need early intervention with corticosteroids to prevent progressiori of the airway obstruction. Most patients with chronic disease require as maintenance only a single medication such as scheduled use of an inhaled beta2 agonist, cromolyn, or theophylline. Patients with a history of more severe morbidity, however, are more likely to require additi()nal intervention or maintenance measures. 24 Finally, strategies must be developed to ensure that appropriate measures are provided when needed. It is patients or their families that are best suited to provide the actual treatment, both by their proximity and the chronic and episodic pature of asthmatic symptoms. The patient needs to be educated explicitly and, equally important, that education needs to be reinforced (Fig. 11).30

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MILES WEINBERGER

In our own asthma management program utilizing systematic assessment, sequential selection of medication, defined outcome criteria, and repeated reinforcement of self-management techniques, we have demonstrated dramatic reduction of emergency care requirements and hospitalizations (Fig. 12). 134a, 141 Moreover, we have accomplished this with a targeted medication program that requires no maintenance medication for those with only intermittent symptoms and single-drug maintenance therapy for most patients with chronic disease.

REFERENCES 1. Ackerman GL, Nolan CM: Adrenocortical responsiveness after alternate-day corticosteroid therapy. N Engl J Med 278:405-409, 1968 2, Ahrens RC, Bonham AC, Maxwell GA, et al: A method for comparing the peak intensity and duration of action of aerosolized bronchodilators using bronchoprovocation with methacholine. Am Rev Respir Dis 129:903-906, 1984 3. Ahrens RC, Harris JB, Annis L: Effect of metaproterenol and albuterol administered by metered dose inhaler on non-specific airway responsiveness. Part 2. J Allergy Clin Immunol 75:161, 1985 4. Ahrens RC, Jenne JW: Pharmacokinetics of beta, adrenergic compounds. In Jenne JW, Murphy S (eds): Drug Therapy for Asthma: Research and Clinical Practice. New York, Marcel Dekker, 1987, pp 213-253 5. Ahrens RC, Smith GD: Albuterol: An adrenergic agent for use in the treatment of asthma: Pharmacology, pharmacokinetics and clinical use. Pharmacotherapy 4:105121, 1984 6. Anderson SD, Seale JP, Rozea P, et al: Inhaled and oral salbutamol in exercise-induced asthma. Am Rev Respir Dis 114:493-500, 1976 7. American Thoracic Society: Committee on diagnostic standards for non-tuberculosis respiratory disease: Definition and classification of chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Respir Dis 84:762-768, 1962 8. Berdel D: Comparison of a new beta, agonist with salbutamol in the treatment of bronchospasm in asthmatic children. Presented at a symposium as part of the XIIth World Congress of Asthmology in Barcelona, 1987 9. Berlinger WG, Spector R, Goldberg MJ, et al: Enhancement of theophylline clearance by oral activated charcoal, Clin :pharmacol Ther 33:351-354, 1983 10. Barnes PJ: Clinical studies with calcium antagonists in asthma, Br J Clin Pharmacol 20:289-298, 1985 11. Blumenthal MN, Schoenwetter WF, MacDonald FM, et al: Cromolyn in extrinsic and intrinsic asthma. J Allergy Clin Immunol 52:105-113, 1973 12. Brunette MG, Lands L, Thibodeau LP: Childhood asthma: Prevention of attacks with short-term corticosteroid treatment of upper respiratory tract infection. Pediatrics 81:624-629, 1988 13. Campbell AH: Mortality from asthma and bronchodilator aerosols. Med J Aust 1:386391, 1976 14. Cerrina J, Denjean A, Alexandre G, et al: Inhibition of exercise-induced asthma by a calcium antagonist, nifedipine. Am Rev Respir Dis 123:156-160, 1981 15. Chatterjee SS, Perry AE: Salbutamol: Clinical application as pressure-packed aerosol. Postgrad Med (Suppl) 47:53-55, 1971 16. Cogswell JJ, Simpkiss MJ: Nebulised sodium cromoglycate in recurrently wheezy preschool children, Arch Dis Child 60:736-738, 1985 17. Culberson CG, Langston JW, Herrick M: Aminophylline encephalopathy: Clinical, electroencephalographic and neuropathological analysis. Trans Am Neurol Assoc 104:224-226, 1979 18. Cuss FM, Barnes PJ: The effect of inhaled nifedipine on bronchial reactivity to histamine in man. J Allergy Clin Immunol 76:718-723, 1985

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Pediatric Department, JCP University of Iowa Hospital Iowa City, IA 52242