Effective management of the asthmatic child depends on identification and avoidance of specific allergens and irritants, judicious drug therapy, and immunotherapy when hypersensitivity is present to inhalant allergens that cannot be avoided.
Avoidance of exposure to the offending allergen is the most effective form of treatment for any allergic disease, whether the allergen is a food or an inhalant. The frequency with which asthma is due to food allergy is uncertain, but asthma is much more likely to be due to food allergy in infants than in older children. Once the offending food has been completely eliminated from the diet for a period of several months, it can often be tolerated. Parents must be supplied with lists of dietary sources of common food allergens, such as cow's milk, egg, and wheat, when implicated (Tables 1-3). Wheat-free, egg-free, and milk-free recipes, available in textbooks or from the American Dietetic Association,1 are also helpful.
One of the several commercial soybean formulas can be substituted for cow's milk, but allergy to soybean can also develop. Pregestimil and Nutramigen are casein hydrolysates with added corn oil, sugar, starch, minerals, and vitamins. Allergy to the peptides in these formulas is rare but may necessitate substitution of meatbase formula. It is not known how often corn oil in formula may cause symptoms in infants with allergy to corn, but if intolerance is thought to be due to this, I-Soyalac can be substituted.
DIETARY SOURCES OF COWS MILK
DIETARY SOURCES OF EGG
DIETARY SOURCES OF WHEAT
When food allergy is considered likely but no specific food can be implicated by history, use of a diet eliminating the common allergenic foods may be helpful. One that is commonly recommended eliminates milk, egg, and cereals.2 After three weeks, individual foods are restored to the diet at weekly intervals and the youngster is observed closely for an exacerbation of his symptoms. Any incriminated food is withdrawn from the diet again for two additional trials, each followed by challenge, before the conclusion is established that the child has an allergy or intolerance.
Complete avoidance for 12 months is then usually recommended. The diagnosis can be established with greater certainty by observation oi the patient after double-blind challenge with food in opaque, dye-free capsules if he is old enough to swallow the capsules.
Highly restricted diets must not be imposed for prolonged periods without assessment of their nutritional adequacy. Supplemental vitamins and minerals may be necessary.
Hypersensitivity to dog or cat dander is best treated by complete elimination of the animal from the house. Restriction of the animal to a single room is usually inadequate because dander is then carried or circulated by forced-air heating or cooling systems throughout the rest of the house. Other furbearing animals and birds are also common household sources of inhalant allergens. Any asthmatic should be discouraged from acquiring such pets because of the likelihood of development of hypersensitivity following a period of exposure.
It is also important for asthmatics to avoid exposure to house dust, which often abounds with certain mites, Dermatophagoides farinae or D. pteronyssinus. The allergenic potency of house dust correlates often but not always with its mire content. Because a typical child spends at least eight to 1 0 hours each day in his bedroom, most of it continuously at night, and much of the rest of his day outdoors or at school, control of exposure to dust in the bedroom substantially reduces his total exposure to dust. Observance of the usual precautions to minimize exposure to dust also greatly reduces a child's exposure to mites (see box).
Such precautions must receive more than lip service if cooperation of the patient and parents is to be expected. Home visits usually disclose unsuspected breaches in environmental control. Compliance with recommendations is most likely when written instructions are supplemented by a thorough discussion of the problem, including its relevance to the particular child.
High-efficiency particulate-air (HEPA) filters and electronic air filters are effective in removing dust, mold, and pollen particles from air. Electronic filters produce ozone, which may impair pulmonary function, so use of HEPA filters is preferable. A central unit is most desirable, but use of a room unit at the bedside can assure that the child at least breathes clean air at night. Clinical improvement does not necessarily follow installation of such units, probably because of the numerous other variables. The use of such a unit in no way obviates the need for other precautions to minimize exposure to household inhalant allergens.
Smoke, perfume, and any strong odor may act as irritants, causing reflex bronchoconstriction in asthmatics. Cigarette smoking should not be permitted in the home of an asthmatic.
The role of industrial and motor vehicular air pollution in aggravating or provoking asthmatic symptoms is less well established except in cases of extremely polluted air, but it is likely that these types of air pollution also cause airway obstruction. During episodes of extreme air pollution the asthmatic should be encouraged to remain indoors in an airconditioned environment, breathing filtered air if possible. If this is impossible, physical exertion should be minimized as far as possible.
A trial of immunotherapy is indicated when frequent or severe asthmatic attacks cannot be controlled by measures to prevent or to minimize exposure to allergens, and hypersensitivity to inhalant allergens has been established by history and allergy skin testing, radioallergosorbent testing (RAST), or (rarely) bronchial provocation testing.
Immunotherapy with ragweed or grass pollen and house dust or mite extract is of demonstrated efficacy, and it is inferred that treatment with tree pollen and mold extracts is probably also effective. There is some evidence that treatment with animal dander extracts may be beneficial, but their inclusion in extract mixtures may limit the maximal dose tolerated to one that may not be optimal for other ingrethents of the extract. Almost all controlled studies of bacterial vaccine have disclosed they have no beneficial effects in reducing or preventing asthmatic attacks.
The use of active extracts is essential to a good response to immunotherapy. Both aqueous and alum-precipitated extracts are of established efficacy, but both lose their potency over a period of months, especially when highly diluted. Refrigeration favors retention of potency.
Because of the possibility of local or systemic reactions when starting treatment, immunotherapy must begin with the subcutaneous injection of 0.1 ml. of an extract diluted to approximately 1:100,000, or 5 proteinnitrogen units (PNU)/ml., and gradually increased at weekly or twice-weekly intervals to the maximal tolerated dose (usually 0.5 to 1.0 ml. of extract diluted to 1:100, or approximately 5,000 PNU). With extreme hypersensitivity an even greater initial dilution may be necessary. The maximal dose tolerated without systemic or large local reactions also depends upon the degree of hypersensitivity as well as the number of allergens in the extract. Unfortunately neither weight by volume nor the total protein content of the extract correlates well with allergenic potency.
After the maintenance dose has been reached and administered several times, intervals between injections can usually be increased gradually to four weeks. If more than six weeks has elapsed, however, it is prudent to reduce the dose by at least one step. Continued treatment is recommended until the youngster has been free of significant symptoms for one or two years. Improvement is usually evident during the first year if the recommended schedule is maintained. There is evidence that some who do not improve during the first year improve during the second year. A period of improvement followed by worsening of symptoms may suggest a need for further diagnostic testing to identify additional allergens to which hypersensitivity may have developed. On the other hand, exacerbations of wheezing occurring repeatedly several hours after administration of allergy injections may indicate a need for a reduction in dosage.
Pharmacologic therapy may consist of theophylline, terbutaline, cromolyn sodium, beclomethasone dipropionate aerosol, and (rarely) oral adrenal corticosteroids.*
Theophylline. Most asthmatic attacks respond to treatment with an oral theophylline preparation in appropriate dosage. Liquid preparations or tablets or capsules of micronized theophylline (Theolair tablets, Bronkodyl capsules), permit the rapid attainment of therapeutic serum concentrations (10 to 20 PgJmL) necessary for the patient receiving the drug intermittently. Usually they must be administered every six hours, however. In some patients a serum concentration of 5 /ig JmI. will be adequate. Since some airway obstruction persists for several days after chest auscultation has become normal, continued administration of theophylline is recommended for at least five to seven days after overt wheezing has subsided.4
Sustained-release preparations (Theo-Dur tablets, Theolair-SR tablets, Theophyl-SR capsules, Slo-Phyllin Gyrocaps) are most effective in maintaining adequate serum concentrations after therapeutic concentrations have been reached, and usually need to be administered only every eight hours. Adequate concentrations can be maintained in some patients with administration of some of the preparations at 12-hour intervals, (e.g., Theo-Dur tablets). For optimal treatment the initial therapy may consist of both the first dose of a q 12 h sustained-release preparation (half the total usual 24-hour dose), and approximately two-thirds the calculated usual q 6 h dose of a preparation that provides therapeutic levels of theophylline rapidly. After the first dose, the rapidly acting preparation is discontinued, and treatment consists of the sustained-release preparation taken (usually) every 12 hours.
The dosage a child will need to take in order to maintain serum theophylline concentrations at 10 to 20 /LIgJmL varies with age and other factors. The usual doses average children will need to maintain therapeutic concentrations after the first one or two days are shown in Table 4. Thus, an 11 -year-old youngster weighing 37.5 kg. would receive 375 mg. of a sustained-release preparation every 12 hours. At the time of the initial dose, he could also receive about 125 mg. of a rapidly acting preparation. Dosage calculations are based on anhydrous theophylline content.
It must be emphasized that these doses are appropriate only for the average child. Individual rates of metabolism and elimination of theophylline vary widely in children, and if the response is inadequate at these doses (or if signs or symptoms of toxicity occur) serum theophylline concentrations must be measured. The dose should then be adjusted as necessary. Peak serum concentrations are usually found within one to two hours after administration of a rapidly absorbed preparation, and within four to eight hours after a sustained-release preparation has been given, so these would be the appropriate times to obtain serum specimens to see if toxic levels had been reached. To determine whether an increased dosage is needed, the specimen should be obtained immediately before the administration of the next scheduled dose.
When liquid theophylline preparations are used, one that does not contain alcohol is preferred - e.g. Slo-Phyllin syrup, Somophyllin Oral Liquid, Quibron liquid.
Theophylline treatment should be started at the onset of coughing or wheezing, and even earlier in children in whom symptoms of allergic rhinitis are regularly followed within a few hours by bronchoconstriction.
Children with frequently recurrent asthmatic attacks benefit from continual treatment with theophylline. In fact, adequate control with theophylline may be impossible to achieve in some children unless treatment is given continually in dosages that will maintain serum concentrations of 10 to 20 /xg./ml. Terbutaline. If response to treatment with optimal doses of theophylline alone is inadequate, an oral sympathomimetic is added. Terbutaline (Brethine, Bricanyl) is probably the most effective of those commercially available in the United States. The muscle tremor that often occurs as a side effect can sometimes be minimized or prevented by starting with half the calculated dose, and gradually increasing the dose until the recommended level is reached. For example, the usual dose for children in the 12 to 15-year group is 2.5 mg.. If side effects are particularly disturbing, the dose may be reduced to half this three times daily, and still provide a clinically significant improvement in pulmonary function.
DAILY DOSAGE NEEDED TO MAINTAIN SERUM THEOPHYLLINE CONCENTRATIONS (BY AGE)
Metaproterenol. Terbutaline has not been approved by the Food and Drug administration for use in children under the age of 12. Oral metaproterenol (Alupent, Metaprel), however, can be used in younger children at a dose of 0.5 mg./kg. body weight every six or eight hours. Thus, for children in the 6 to 9 age group weighing 27 kg. (60 pounds) or less, the dose would be 10 mg. three or four times a day; for children over 9 years, or weighing more than 27 kg., the maximum dosage would be 20 mg. four times a day.
The sympathomimetic is usually prescribed as an adjunct when response to theophylline alone is inadequate in the child receiving either continual or intermittent theophylline therapy, but continued treatment with both theophylline and an oral sympathomimetic is occasionally necessary.
Cromolyn sodium. If asthmatic attacks continue to recur at intervals of one week or less despite continual treatment with theophylline and an oral sympathomimetic, cromolyn sodium (Intal) may be helpful. Inhalation of the contents of one capsule (20 mg.) four times a day often is followed by a decrease in the frequency of asthmatic attacks within two weeks. If improvement has not been recognized within four weeks it should be discontinued. Use of cromolyn should be temporarily discontinued during acute asthmatic attacks.
Improvement due to use of cromolyn is sometimes maintained with decreases in the frequency of dosage to three times a day or even twice a day, but continued regular usage is necessary due to the prophylactic nature of its action.
Beclomethasone dipropionate. If adequate control cannot be achieved with bronchodilators and cromolyn, treatment with beclomethasone dipropionate aerosol (Vanceril, Beclovent) is indicated for children six years old or older.5 Although control of asthmatic symptoms in children 6 to 12 years of age is usually possible with one or two inhalations (50 to 100 /Ag.) given three or four times a day, abuse is possible. The maximum daily intake should not exceed ten inhalations (500 µg.) in children 12 years of age or younger, or twice that (20 inhalations, 1000 µg.) in adults. Excessive doses can cause adrenal suppression. Accordingly, this drug should be reserved for the rare patient who continues to have substantial difficulty despite optimal therapy with bronchodilators and cromolyn when there has been sufficient time for a trial with cromolyn.
Treatment with beclomethasone aerosol cannot be started when substantial airway obstruction is present because of its route of delivery. Bronchodilation must first be elicited even if use of an oral corticosteroid becomes necessary. Even at recommended doses, beclomethasone dipropionate aerosol may cause continued adrenal suppression if this has already been induced by treatment with systemic adrenal corticosteroids. Adequate doses of oral corticosteroids must be prescribed during exacerbations of asthma in children receiving beclomethasone aerosol.
Adrenal corticosteroids. Continued treatment with oral adrenal corticosteroids is necessary for the rare asthmatic child for whom even the addition of beclomethasone aerosol does not afford adequate relief. Adrenal suppression and side effects can be minimized by choosing a steroid with intermediate duration of activity such as prednisone for administration as a single morning dose on alternate days.
If the decision to start oral steroids is made during an asthmatic episode that has been inadequately controlled by other measures, control is achieved initially with administration of large doses (2 mg./kg./day, maximum 80 mg., divided into four equal doses) for a few days with subsequent gradual reduction in dosage as tolerated, substitution of alternate-day therapy as soon as possible, and further gradual reductions to the least dose consistent with adequate control.
Complete freedom from symptoms is not the goal of steroid therapy. Absence of any signs or symptoms of asthma for prolonged intervals would suggest that the child was receiving too large a dose. Abnormal pulmonary function tests despite optimal therapy might be a possible indication for continued steroid therapy in some patients.
Expectorants. Glyceryl guaiacolate and other "expectorants" are of unproved efficacy, but maintenance of adequate hydration is important to prevent inspissation of tracheobronchial secretions. Encouraging oral fluids is usually adequate.
Postural drainage. During convalescence from acute asthmatic attacks, gravity-assisted postural drainage facilitates removal of excessive tracheobronchial secretions. The cupped hand is clapped vigorously over the segment to be drained after the child has been positioned appropriately. Detailed, illustrated instructions are available in some textbooks,6 and from other sources. *
Anthihistamines. Although antihistamines are not recommended for the treatment of asthma, their use is urged for the treatment of allergic rhinitis in asthmatics. It is especially important to facilitate nasal breathing in such patients because of the resultant filtration, warming, and humidification of inspired air. Antihistamines are contraindicated during status asthmaticus because of their potential inspissation of tracheobronchial secretions.
Exercise-induced asthma is usually inhibited by administration of theophylline 30 minutes to an hour before anticipated exercise, or by inhalation of cromolyn shortly before exercise. In children for whom the time of exercise cannot be predicted, the treatment most suitable is a sustained-release theophylline preparation that may afford protection throughout the day.
Patients and parents must understand that if moderate or severe wheezing does not lessen or stop within 30 to 60 minutes after administration of an oral bronchodilator, prompt further treatment at a physician's office or a hospital emergency room must be sought.7
Most acute asthmatic attacks respond promptly to 1:1000 aqueous epinephrine, 0.01 ml./kg. given by subcutaneous injection (maximum dose 0.3 ml.) If necessary, this same dose can be repeated twice at 20-minute intervals. If sufficient improvement follows administration of epinephrine, it can be followed 30 minutes later with Sus-Phrine (1:200 aqueous epinephrine suspension) in a dose of 0.005 ml. /kg. body weight for a more sustained effect. The maximum single dose for children between the ages of 2 and 12 and weighing 30 kg. or less is 0.15 ml.
Terbutaline is somewhat more effective and longer-acting than epinephrine. The dose for acute asthma is 0.01 ml./kg. body weight by subcutaneous injection. The maximum pediatric dose is 0.25 ml. A second dose can be given 20 or 30 minutes later if necessary, but a third dose should not be given until at least four hours after the second. That is, a total dose of 0.5 mg. should not be exceeded within a four-hour period.
Terbutaline probably will replace epinephrine for the treatment of asthma in adolescents and adults. It has not been approved by the Food and Drug Administration for use in children below the age of 12, but studies are now in progress to define the safe and effective dose in prepubescent children.
Ethylnorepinephrine hydrochloride (Bronkephrine) may be more suitable than epinephrine for use in infants because it has less vasoconstrictive activity. The dose is 0.01 to 0.02 ml./kg. body weight by subcutaneous injection, with the maximum dose in children 0.5 ml. The dose may be repeated once, after a 20-minute interval.
If a child fails to improve satisfactorily following administration of the recommended doses of these sympathomimetics, it is diagnostic of status asthmaticus. Management of status asthmaticus is outlined in Table 5.
The drug of choice among those available for treatment of status asthmaticus in the United States is aminophylline given by intravenous infusion. A loading dose of 5 mg./kg. is diluted to 30-50 ml. and infused over 20 to 30 minutes if the youngster has received no theophylline in the previous six to eight hours and no sustained-release theophylline in the previous 12 hours and has not been receiving continual theophylline therapy. This is followed by a constant infusion at a rate expected to maintain the serum theophylline concentration at 10-20 /xg./ml. Because such rates may vary from 0.5-1.1 mg./kg./hour, depending on age and other variables, the serum theophylline concentration is determined after the constant infusion has been started and adjustments in its rate are made as necessary. If a therapeutic concentration of 10-20 µg./ml. is not found, an additional infusion expected to increase the concentration to an appropriate concentration is administered over 20 to 30 minutes after dilution. An additional dose of 2 mg./kg. is expected to increase the serum concentration by approximately 4 /xg./ml.
If the child has received theophylline recently a constant infusion can be started at an appropriate rate, but the serum concentration is determined before any loading dose is given. If the patient has been receiving continual therapy with theophylline it is usually reasonable for the infusion to be administered at the same rate with allowance for the fact that aminophylline is only approximately 85 percent theophylline.
If dehydration is present, intravenous fluids should consist of 360-400 ml./sq. m. of 5 or 10 percent glucose in one- fourth or one-third normal saline or 5 percent glucose in normal saline given during the first hour. After renal flow has been established, this is followed by a polyionic, potassium-containing hypotonic solution (between 2,400 and 3,000 ml./sq. m. every 24 hours). If there is no dehydration, administration of fluids at the rate of 1,500 ml./sq. m. every 24 hours is adequate. Additional fluids are infused as indicated by the clinical state and by serum electrolyte determinations.
MANAGEMENT OF STATUS ASTHMATICUS
Sufficient supplemental humidified oxygen is necessary to maintain the arterial PO~ at 65 to 100 torr.* Hypoventilation due to elimination of the hypoxic drive to ventilation in a subject with hypercapnia would necessitate immediate artificial ventilation, but this rarely if ever occurs in children with uncomplicated asthma, probably because of the intermittent nature of the airway obstruction.
Administration of mist is not likely to be beneficial and may even provoke bronchoconstriction in asthmatic children.
Prompt, intravenous administration of hydrocortisone, 4 mg./kg. every four hours is vital for any asthmatic at risk for adrenal insufficiency because he has been treated with adrenal corticosteroids during the previous nine months. It is prudent to administer hydrocortisone even to youngsters whose exogenous steroids have previously consisted only of beclomethasone dipropionate aerosol. Hydrocortisone is also administered whenever adequate improvement has not followed intravenous administration of aminophylline at appropriate dosage.
Inhalation of nebulized isoproterenol or isoetharine (Bronkosol) is followed often by bronchodilation even in youngsters who are unresponsive to administration of epinephrine by subcutaneous injection. Oxygen should be administered simultaneously to prevent the decrease in arterial PO2, which has sometimes followed inhalation of isoproterenol. Use of Intermittent Positive Pressure Breathing Apparatus (IPPB) is avoided because it can cause bronchoconstriction in asthmatics as well as pneumomediastinum or pneumothorax.
The dose of 1:200 isoproterenol or isoetharine is 0.01 ml./kg. diluted to 5 to 10 ml., depending on the nebulizer capacity, and administered as often as every four hours if necessary. More frequent use is not recommended without very close observation of the patient and use of a cardiac monitor. It is safest to avoid administration of isoproterenol within two hours of use of epinephrine, since it may increase the risk of cardiac arrhythmia.
The main problem with isoproterenol or isoetharine when used in this way is that they both have a short duration of action. A selective, longer-acting sympathomimetic, such as terbutaline, offers substantial advantages.
Correction of metabolic acidosis with sodium bicarbonate sometimes restores responsiveness to such catecholamines as epinephrine and may be helpful if there has not been a satisfactory response to intravenous aminophylline. The dose of 1.5-2 mEq./ kg. is diluted and infused over 15 to 20 minutes. This dose can be repeated over the next 45 minutes and repeated each hour as long as the metabolic acidosis persists with pH less than 7.35, plasma bicarbonate less than 20 mEq./L. and serum sodium less than 145 mEq ./L.
Antibiotics are indicated only if there is evidence of bacterial infection.
Sedatives, tranquilizers, and opiates are contraindicated because of their depressant effect on the respiratory center. Restlessness and agitation should be recognized as the signs of hypoxemia that they usually are and should be treated with oxygen instead of a sedative.
Antihistamines are considered contraindicated in the patient with status asthmaticus because of their potential inspissating effect on tracheobronchial secretions as well as their sedative effect.
Progression of the airway obstruction to respiratory failure is an indication for endotracheal intubation and controlled ventilation.
A clinical scoring system that organizes clinical observations facilitates recognition of impending respiratory failure (Table 6). Serial blood gas determinations will also be vital in recognizing impending respiratory failure, as well as essential for monitoring oxygen therapy. Hypoxemia is usually found in children with status asthmaticus, but respiratory alkalosis due to overventilation of the less obstructed portions of lung is commonly present early. As airway obstruction progresses, the pH and pC02 may gradually return to normal, and hypercapnia and respiratory acidosis may then follow quickly.
A CLINICAL SCORING SYSTEM FOR THE DIAGNOSIS OF RESPIRATORY FAILURE IN CHILDREN WITH ASTHMA
Respiratory failure has been treated at some centers with constant intravenous infusions of isoproterenol because of the short duration of action of isoproterenol and complications of mechanical ventilation. Adolescents and adults have died suddenly while receiving intravenous isoproterenol despite every possible precaution, however. It seems most prudent to defer this form of therapy at least until /3-adrenergic drugs with less cardiac activity are available for use in the United States, but some allergists and pulmonologists consider it an alternative preferable to mechanical ventilation.
1. American Dietetic Association, Allergy Recipe Booklet. Chicago: American Dietetic Association, 430 N. Michigan Avenue, Zip 60611. Revised edition, 1978, 64 pp., $1.50.
2. Siy, R. M., Pediatrie Allergy. Flushing, N.Y. Medical Examination Publishing Company, 1977, p. 241.
3. Sly, R. M., supra, p. 287.
4. Wyatt, R., Weinberger, M., and Hendeles, L. Oral theophylline dosage for the management of chronic asthma. /. Pedtatr. 92 (1978), 125.
5. Wein, R., Waldman, D., Kershnar, H., et al. Treatment of chronic childhood asthma with beclomethasone dipropionate aerosol. I. a double-blind crossover trial in nonsteriod-dependent patients. Pediatrics 60 (1977), 7.
6. Sly, R. M., supra.
7. Siegel, S. C, and Richards, W. Status asthmatkus in children. Int. Anesthesia. Cl 9 (1971), 99.
8. Wood, D. W., Downes, J. )., and Leeks, H. I. A clinical scoring system for the diagnosis of respiratory failure. Am. ]. Dis. Child 123 (1972), 227-228.
DIETARY SOURCES OF COWS MILK
DIETARY SOURCES OF EGG
DIETARY SOURCES OF WHEAT
DAILY DOSAGE NEEDED TO MAINTAIN SERUM THEOPHYLLINE CONCENTRATIONS (BY AGE)
MANAGEMENT OF STATUS ASTHMATICUS
A CLINICAL SCORING SYSTEM FOR THE DIAGNOSIS OF RESPIRATORY FAILURE IN CHILDREN WITH ASTHMA