In spite of breakthroughs in pharmacologie management of asthma with the availability of theophylline serum level monitoring, inhaled β-adrenergic agents, and cromolyn, there remains a subset of severe asthmatics who require steroids for control of asthma. Corticosteroids have been available for the treatment of severe asthma for over 25 years, but their proper use is still a difficult clinical problem. Pediatricians are particularly hesitant to use steroids, and recent studies of growth suppression1,2 and osteoporosis in children3 have shown that concern is warranted. On the other hand, there is now evidence that asthma is an inflammatory disease, and steroids as potent anti- inflammatory agents are more than ever recognized as necessary for management of severe asthma.4 The reluctance to use steroids in chronically disabled patients may lead to unnecessary chronic respiratory distress and a predisposition to recurrent episodes of acute asthma. However, steroids may be prescribed in higher dosages and for longer periods than necessary when the clinician is faced with a patient refractory to usual management. In chronic asthma particularly, the dilemma is to balance the therapeutic benefits of steroids with the potential side effects. This requires frequent office visits and objective measurement of pulmonary function.
RATIONALE FOR USE OF STEROIDS IN ASTHMA
The hallmark of asthma is airway obstruction caused by bronchoconstriction, mucosal edema, and increased mucus secretions. Recent studies of the late asthmatic response have provided some insight into these well-known pathologic findings, which correlate with the clinical course and response to treatment.5 Acute bronchospasm may reverse spontaneously, as is frequently seen in exercise-induced asthma, or respond within minutes to epinephrine or inhaled ßadrenergic agents. Chronic bronchoconstriction usually responds well to maintenance bronchodilation with inhaled β-adrenergic agents or theophylline.
Viral infections and occasionally intense exposure to potent allergens, such as dust mite, may be associated with severe, delayed, and prolonged wheezing. Bronchial challenge studies in humans6,7 and now in an animal model8,9 have confirmed that a late-phase response is associated with histologie findings of an inflammatory process and the presence of inflammatory mediators in lavage fluid. The mucosal edema and inflammatory exúdate produce severe airway obstruction that does not respond to bronchodilators or recurs after a partial response, as in status asthmaticus during a viral infection. Steroids are required to reverse this process and to restore responsiveness to β-adrenergic agents.
Another implication of pulmonary inflammation in severe asthmatic reactions is that such inflammation leads to increased bronchial reactivity.10,11 Bronchial hyperreactivity in turn predisposes the patient to heightened sensitivity to any précipitants of wheezing. Bronchial hyperreactivity explains the frequent relapses following a viral respiratory infection or the more subtle chronic disability in a patient sensitized to a constant potent allergen exposure, such as cat or dust mite in the home.
The beneficial effect of steroids in preventing the late-phase response in challenge studies and their clinical corollaries support the hypothesis that inflammation is a central feature of the severe, prolonged asthmatic reaction.12
MECHANISM OF STEROID ACTION
Steroids inhibit nearly every aspect of the inflammatory response, but a specific mechanism in asthma is as yet unknown. Steroids decrease mucus secretion, decrease leakage of fluid and cells from the vasculature, and may suppress the polymorphonuclear response to chemotactic stimuli. A probable major action of steroids in asthma is the inhibition of synthesis of products of arachidonic acid metabolism -prostaglandins» leukotrienes, and platelet-activating factor - by inhibiting the action of phospholipase enzyme on membrane phospholipids.13
Another hypothesis of pathogenesis of asthma is a defect in autonomie nervous system control.14 This suggests that decreased β-adrenergic responsiveness and increased cholinergic responsiveness increase airway reactivity. This theory is validated clinically by the beneficial response of asthmatics to β-adrenergic and anticholinergic agents (atropine sulfate, ipratropium). In addition, evidence from in vitro and in vivo studies shows that steroids increase β-receptor number and affinity. This may explain the often observed clinical situation that steroids dramatically improve the condition of an acutely or chronically ill asthmatic who has not responded to frequent β-adrenergic agents. Recent studies of the importance of inflammatory mediators in the pathogenesis of asthma do not negate the role of the autonomie nervous system. Abnormalities in autonomie receptor response may be secondary to a primary inflammatory process, and airway inflammation may stimulate reflex cholinergic bronchoconstriction by activation of afferent nerve endings, or ß-receptors could be inactivated by effects of inflammatory mediators.
When asthma is not responsive to bronchodilation with β-adrenergic agents and theophylline, steroids are necessary. They decrease the effects of inflammation in the acutely ill asthmatic and can also attenuate the underlying chronic inflammation that is the cause of bronchial hyperreactivity in the chronic asthmatic, thereby preventing the tendency for severe exacerbations. The indications for the use of systemic steroids are:
1. Status asthmaticus;
2. Exacerbations of asthma due to viral infections or intense exposure to allergens;
3. Chronic severe asthma; OT
4. Prevention of adrenal insufficiency.
Systemic steroids should be considered in the management of every patient in status asthmaticus. They should definitely be given to patients who are not responding to repeated administration of bronchodilators and to any patient who has been on maintenance steroids because of the potential of adrenal insufficiency. Asthmatics presenting with wheezing to an emergency room or outpatient clinic are usually by definition in status asthmaticus, in that they have been unresponsive to previously administered inhaled β-agonists at home. The old definition of status asthmaticus, ie, refractoriness to two injections of epinephrine administered 15 minutes apart in the emergency room, is no longer applicable or safe in most cases. With the widespread availability of inhaled β-agonists, most patients will have used their inhaler at home two or three times, taken their theophylline, and still be in distress by the time they decide to seek help. The administration of oxygen and then corticosteroids, in addition to further inhaled ß-adrenergic agents, epinephrine, and theophylline, is necessary to manage the acute bronchospasm and inflammation.
There is sometimes a reluctance to administer steroids even in the acute situation because of the concern about side effects and the fear that steroid "dependency" will ensue. Neither hypothesis is accurate. Short-term, high dose steroids are not associated with long-term side effects and in the doses recommended below are not generally associated with the short-term effects of hypertension, hypokalemia, and hyperglyCeItIiS1 although patients should be monitored. The term "steroid-dependent asthmatic" connotes addiction, but in fact it was coined to describe the asthmatic who requires maintenance steroids because of severity of symptoms, not because of physical dependency. The failure to use steroids early enough during acute severe exacerbations may lead to continued refractory asthma and predisposition to further attacks. Ultimately, a longer course of steroids is prescribed than would have been necessary had they been used early and discontinued when the exacerbation was subsiding.
Steroids for status asthmaticus should be the potent short-acting intravenous preparations of cortisol sodium succinate (Solu-Cortef®) or methylprednisolone sodium succinate (Soiu-Medrol®). Suggested dosages are: Solu-Cortef 5 mg/kg (4 to 8 mg/kg) as a loading dose, and then 2 to 4 mg/kg every 4 to 6 hours. H A typical dose for a 70-kg adult would be 250 mg and for a 35-kg child 125 mg every 6 hours. The dosage of Solu-Medrol is usually 1 to 2 mg/kg as a loading dose, then 0. 5 to 1 mg/kg every 4 to 6 hours. In our experience, Solu-Medrol 20 to 60 mg every 4 to 6 hours has produced beneficial results in patients from 2 to 18 years of age. In infants and children less than 2 years of age, we use 5 to 10 mg every 4 to 6 hours.
There is no reason to give intramuscular depot preparations for asthma except in the most unusual circumstances. These long-acting preparations add no benefit to intravenous or even oral preparations and produce even greater potential for side effects. Some physicians continue inhaled steroids during status asthmaticus, but these cannot substitute for systemic steroids for patients in acute distress, and there has not been proven efficacy of inhaled steroids continued during periods of high dose systemic steroids.
Dose-response curves have not been constructed for adults or children, but dosage ranges have been derived from several studies and long empirical use. One study of status asthmaticus in adults comparing 15, 40, and 125 mg of intravenous methylprednisolone showed a marked improvement in FEVj with the medium or high dose regimens as compared with the low dose regimen and only a modest difference between 40 mg and 12.5 mg, suggesting that a dosage range somewhere between 40 and 125 mg every 6 hours would be optimal for adults.15 A study of children in status asthmaticus compared a high dose regimen of intravenous methylprednisolone (300 mg/m2) with a more conventional dose of 30 mg/m2. The authors found no difference in degree or rate of improvement between the two dosages. 16 A recent study in children found a faster rate of improvement in small airway obstruction in a group treated with intravenous methylprednisolone 1 mg/kg every 6 hours versus placebo; the stero id- treated group also showed less relapse after discharge.17 Two placebo controlled studies in adults demonstrated a reduction in symptoms, hospitalizations, and relapse following emergency room discharge after treatment of status asthmaticus with steroids.18,19
ORAL STEROIDS FOR EXACERBATIONS OF ASTHMA
Oral steroids are necessary for exacerbations of asthma when bronchodilators are insufficient to reverse clinical symptoms and pulmonary function. The most common, prolonged, and severe exacerbations of asthma are produced by viral infections, from rhinovirus to influenza. Even a mild rhmovirus can cause an increase in bronchial hyperreactivity in an asthmatic, which persists long beyond the initial nasal congestion, sore throat, and cough of the acute illness. Likewise, an intense exposure to allergens, such as cat, mold, or dust mite, may precipitate an acute and sometimes prolonged exacerbation of asthma. A short course of oral prednisone, started early, will nearly always restore responsiveness to bronchodilators and can usually be discontinued within several days, as the patient begins to show greater response to inhaled β-adrenergic agents and an increase in peak flow measurements.
Patients who already require maintenance steroids will nearly always require a "burst." Those who have been taking steroids previously, ie, greater than 2 weeks of high dose steroids, should receive a short course of steroids during the exacerbation to cover for potential adrenal insufficiency. A burst of steroids consists of oral prednisone 1 to 2 mg/kg a day in divided doses for 2 to 7 days, average 3 to 5 days. In practice, this is usually achieved by an average dose range of 10 to 40 mg b.i.d. from ages 3 years to adults. If the patient has been taking maintenance prednisone and has been stable prior to the exacerbation, the maintenance dose can be resumed after a burst without tapering. If the patient has been unstable prior to the exacerbation or if the exacerbation is particularly severe or prolonged, the maintenance dose should be increased slightly or the high dose required during exacerbation tapered over 10 days.
Patients who do not require systemic steroids for maintenance can have the burst dose abruptly discontinued if fewer than 14 days have passed, without concern about adrenal suppression.20 The mild to moderate asthmatic with an exacerbation responds very well to a brief course of high dose steroids instituted early and to abrupt discontinuation. This has been documented in several studies in children.21-24
When steroids are prescribed in high doses during exacerbations, the main concern should be documentation of improvement; decreasing the steroid dose back to maintenance in the steroid-requiring asthmatic and discontinuation in the mild to moderate asthmatic as soon as improvement occurs. Improvement should be evaluated by office spirometry measurement of FEV1 when possible or peak expiratory flow rate measurements, in addition to physical examination of the chest for adventitious sounds and quality of air exchange. Without frequent office visits it is impossible to measure improvement, and the physician is often unsure about steroid tapering. If the patient cannot visit the physician weekly following an acute exacerbation, then daily diaries of symptom scores and peak flow measurements at home can be reported to the physician by phone. It is impossible to make effective medication adjustments otherwise, particularly regarding steroid tapers. Without close follow-up the patient suffers from either too rapid tapering and the likelihood of another exacerbation or prolonged tapering of steroids leading to unnecessary exposure to steroid side effects. A suggested regimen is outlined in Table 1.
CHRONIC SEVERE ASTHMA
Severe asthma, by definition, is refractory to bronchodilators and requires steroids to maintain freedom from chronic wheezing and disability. We attempt to avoid steroids on a chronic basis by using long-acting theophylline preparations and inhaled β-adrenergic agents 3 to 4 times daily as maintenance bronchodilators; we frequently use cromolyn 3 to 4 times daily. If a patient cannot be maintained free of daily wheezing or frequent exacerbations on these medications, we add inhaled steroids.
A frequent problem in referral practices is the patient who presents with severely decreased pulmonary functions and wheezing and whose symptoms are not able to be reversed with bronchodilator treatment. After eliminating other causes of reactive airway disease and airway obstruction (tracheoesophageal fistula, hypersensitivity pneumonitis, bronchiectasis, cystic fibrosis, aspiration, gastroesophageal reflux, immunodeficiency), a decision regarding ultimate reversibility often requires a short course of high dose steroids to establish that the diagnosis is severe asthma. If the patient's flow rates on pulmonary function testing are reversed to near normal with the optimum use of bronchodilators and steroids, the diagnosis of asthma is likely. Having ruled out other causes and established reversibility as close as possible to baseline with high dose steroids, the next step in management requires tapering systemic steroids to a threshold dose that will prevent breakthrough wheezing.
A typical difficult pediatrie asthmatic, who has not had a maintenance steroid dose previously established, is placed on a dosage of 20 to 30 mg b.i.d. of prednisone for 3 to 7 days to gain control. If symptoms and FEV1 or peak flows improve, steroids are typically tapered as follows: the dose is changed to 40 to 60 mg once daily in the morning for 2 to 3 days. The high daily dose is then decreased by 5 mg every 1 to 2 days, down to a daily dose of 10 mg daily. The daily dose is then double or tripled and given as an alternate-day dose, eg, 10 mg every day is changed to 30 mg every other day. Once an alternate-day regimen is established, the dose is decreased by 5 mg increments every 7 to 14 days, generally down to 20 mg every other day without difficulty. At this point, inhaled steroids may be added. If the patient is a mild to moderate asthmatic, institution of inhaled steroids enables the systemic steroid dose to be tapered further, and, in most cases, discontinued. If the patient is a severe asthmatic, the inhaled steroids allow maintenance at a lower systemic dose.
Oral Steroids During Exacerbations of Asthma
PREVENTION OF ADRENAL INSUFFICIENCY
Patients who have been taking daily oral steroids are invariably adrenally suppressed. If acute asthma, trauma, infection (severe gastroenteritis), or need for a surgical procedure (tooth extraction) occurs, they should receive systemic steroids to cover for adrenal insufficiency at the time of the acute insult. A recent study in children not on maintenance steroids investigated the effect on the hypothalamic-pituitary-adrenal (HPA) axis after a single course of prednisone for 5 days. This produced HPA suppression for fewer than 10 days.20 This is reassuring for the mild or moderate asthmatic who requires infrequent bursts of steroids. However, frequent steroid bursts in patients on maintenance alternate-day prednisone would be expected to produce some degree of adrenal suppression.25 If there is any doubt, the patient should receive a 2 to 3 day course of intravenous or oral steroids. This is much safer than risking adrenal insufficiency, especially in patients whose illness might mimic an addisonian crisis. The possibility of adrenal insufficiency must always be kept in mind when substituting inhaled for oral steroids.
SIDE EFFECTS OF STEROID THERAPY
Adverse effects of steroid therapy must be continually balanced against therapeutic benefit, particularly in children. The adverse effects of steroids on adrenal suppression, weight gain and fluid retention, hypertension, and electrolyte and glucose metabolism are well known. The long-term side effects of chronic steroids in children are more serious and more subtle. Cataracts,26 growth suppression,1'27 and delayed puberty and osteoporosis28 may not be recognized for many years after chronic high dose usage. The clinician dealing with children taking chronic steroids should have a checklist of steroid side effects available and monitor these during office visits, in addition to measurements of pulmonary function (Table 2).
Although the cosmetic effects of high dose steroids are the most distressing to the patient and the adverse metabolic effects on glucose, electrolytes, and fluid metabolism of most concern for physicians in the short term, the insidious side effects of cataracts, growth suppression, and osteoporosis are the most serious. Ulcers and pancreatitis are rare. A decrease in immunoglobulins and absence of response to delayed hypersensitivity skin testing occur fairly frequently in patients on high dose steroids. Such abnormalities appear not to affect functional immune status, as these patients can usually produce an antibody and cellular immune response to infection in spite of these abnormalities. A possible exception might be varicella infection in children taking very high dose steroids. There have been previous rare case reports of fatal disseminated varicella infection in children on very high dose steroids for nonmalignant diseases. 29 On the other hand, there is ample evidence of morbidity and mortality from failure to treat severe asthma with systemic steroids, and steroids should not be withheld because of fear of increased infection.
Adrenal suppression is invariably present in patients on daily steroids, but this side effect can be managed by covering the patient with supplemental steroids during times of stress. Cataracts usually produce symptoms when they become large, but may develop insidiously. All patients on maintenance systemic steroids should have an ophthalmologist's split- lamp exam every 6 to 12 months. The only way to detect osteoporosis early is to measure bone densitometry of the radius in children. 30 To decrease the osteopenic effects of steroids the patient should be on a regular exercise program of walking, bicycling, low-impact aerobics, or swimming. The recommended allowance of dietary calcium and vitamin D should be ensured. Endocariologie consultation should be obtained for patients with severe growth or pubertal deïay. Most adverse effects can be decreased, if not reversed, by decreasing or discontinuing systemic steroids. This is often not possible in severe asthmatics, but every consideration should be given to maximizing other modes of therapy and removing environmental precipitants if these are contributing factors.
Side Effects of Oral Steroids
INDICATIONS FOR USE OF INHALED STEROIDS
Inhaled steroids have been an important breakthrough in chronic asthma treatment. Increasing evidence from clinical studies indicates that they are particularly effective in decreasing bronchial hyperreactivity, perhaps to an even greater extent than systemic steroids.31 Side effects are markedly less with use of current aerosolized steroids because of their potent bioavai lability at the site of application and limited systemic activity. These compounds are rapidly absorbed by the lung but then rapidly degraded or cleared to the systemic circulation, where they are rapidly metabolized by first-pass effect through the liver.32 Long-term studies have now demonstrated the lack of significant local or systemic adverse effects in adults and older children.33,34 In addition, their efficacy and safety in comparison with oral steroids have been demonstrated in young children and infants m countries where a solution for nebulization is available.35,36
Recommended Doses of Aerosol Steroids In Children 6-12
Steroids for inhalation are not officially approved for use by the Food and Drug Administration for children less than 6 years old. However, they are being used with increased frequency in the US by physicians caring for young severe asthmatics who are faced with the alternative of high dose prednisone. In young children, the limiting factor is mastery of technique of the metered-dose inhaler, as a nebulizer solution is not available in the US. With patience and the use of a spacer, however, a toddler can be taught to use a metered-dose inhaler. The use of inhaled steroids in children younger than 2 to 3 years of age awaits the approval of a nebulizer solution in the US.
Inhaled β-adrenergic agents are generally sufficient for mild episodic asthma, and cromolyn or theophylline if a maintenance drug is required. If these medications and attention to removal of environmental precipitants are not effective, inhaled steroids are added to the treatment regimen. In the severe asthmatic on maintenance steroids, inhaled steroids should be added in an attempt to decrease systemic steroids and reduce potential side effects. If the patient is clinically unstable or has markedly decreased spirometry, acute asthma should be treated by administering a short course of high dose prednisone, as above, and then inhaled steroids should be initiated. For patients who require large doses of systemic steroids, the use of inhaled steroids is beneficial if systemic steroids can be reduced to any degree even if they cannot be discontinued. If use of maximum doses of inhaled steroids cannot prevent unstable asthma and frequent steroid bursts are needed, there is no reason not to use the combination. More moderate asthmatics can usually discontinue prednisone with the use of inhaled steroids.
The patient must be cautioned of the need for systemic steroids during severe exacerbations of asthma and surgery, trauma, or infection. Deaths from asthma attributed to adrenal insufficiency37 have been reported in patients changed from oral to inhaled steroids, and the present aerosol preparations are not sufficient to provide the increased exogenous steroids needed during such times of stress.
The maximum dosages reported have been tolerated without systemic side effects, although steroid side effects should still be monitored. The primary side effects of inhaled steroids have been oropharyngeal candidiasis and dysphonia or hoarseness from a poorly understood effect on the vocal cords, which seems to can be exacerbated by excessive vocal stress, such as shouting. These effects are reversible and, except in the case of severe dysphonia, do not require discontinuing inhaled steroids. The incidence of candidiasis has been greatly decreased by the recent development of dispersion chambers or spacers, which minimize impaction of the aerosolized steroid in the pharynx and increase delivery to the lung.38 Should candidiasis occur, the inhaled steroid may usually be continued with concomitant administration of antifungal agents such as nystatin or ketoconazole.
Aerosolized steroids can be most effectively used by following these guidelines:
1. Initial treatment with oral steroids to reverse to baseline, if unstable.
2. Begin inhaled steroid at highest recommended dose while attempting to decrease oral steroids.
3. Demonstrate effectiveness by monitoring FEV1 or peak flow rates.
4. Use spacers, and gargle or rinse mouth after use.
5. Watch for adrenal insufficiency when changing patients from oral to inhaled steroids.
Types of generalized steroids available in the US are listed in Table 3.
Steroids are necessary for treatment of chronic asthma. They are life-saving in many acute exacerbations and enable daily functioning free of wheezing and disability for the chronic asthmatic. The beneficial effect of steroids for asthma is increasingly thought to be due to their anti- inflammatory effect on hyperreactive airways. Attempts have been made to develop synthetic steroids to maximize the antiinflammatory effect on the target tissue while decreasing adverse effects on other tissues. Inhaled steroids with potent topical and minimal systemic effects have been the most important breakthrough in this regard. Long-term follow-up studies for over ten years of beclomethasone have not shown serious local or systemic side effects. Intravenous or oral steroids are still needed for acute exacerbations, and prednisone may be needed in combination with inhaled steroids for the severe asthmatic. Treatment of this complex, variable disease with any type of steroid should be accompanied by objective measurements of benefit (pulmonary function) and risk (steroid side effects).
1. Nassif E, Wemberger M, Sherman B, et al: Extrapulraonary effects of maintenance corticosteroni therapy with al ternate -day prednisone and inhaled beclomethasone in children with chronic asthma. j Allergy Clin lmmuool 1987; 80:518-529.
2. Hollman GA, Allen DBi Overt glucocomcaid excess due to inhaled corticosteroid therapy. Peduancs 1988; 81:452-455.
3. Brenner AM. HoM ister JR: Osteoporosis in steroid-treated children. J ASergy Clin lmmunof 1984; 73:137.
4. Morris HO: Mechanisms of action and therapeutic role of corticosteroidi in asthma. J Allergy Clin Immunol 1985; 75:1-13.
5. Kaliner MM: Hypotheses on the contribution of late-phase allergic responses to the understanding and Ir eat men t of allergic disease. J Allergy Clin Immunol 1984; 73:311-315.
6. Booj-Nord H, One NGM, de Vries K: Immediate and late bronchial obstructive reactions to inhalation of house dust and protective effects of disodiutn cromoglycate and prednisolone. J Afleigj Clin inanimai 1971; 48:344-354.
7. Cartier A, Thomsen NC, Frith PA, et al: Allergen- induced bronchial responsiveness from seasonal allergen exposure. J Allergy Clin Immune! 1982; 70:170-177.
8. Shampain MP, Behrens BL, Larsen GL, et al: An animal model of late pulmonary responses CD Aktnuaia challenge. Am Rev Hespir Dis 1982; 126:493-498.
9. Marsh WR, Irvin CG, Murphy KR, el al: Increases in airway reactivity to histamine and inflammatory cells in bronchoalveolar lavage after the late asthmatic response in an animal model. Am Rev Resprr Dis 1985; 131:875-879.
10. Boushey HA, Hohnnan M], Sheller JK, et al: Bronchial hyperreactivity. Am Rev Rispir Dis 1980; 121:389-413.
11. Hargreave FE, O'Byme PM, Ramsdale EH: Mediators, airway responsiveness, and asthma. J Allergy CKn ImmunoJ 1985; 76:272-276.
12. BhaghatRG, StmnkRC, Larsen GL: The late asthmatic response. AnnASergy 1985; 297-301.
13. Schleimer RP: The mechanisms of antiinflammatory steroid action m allergic diseases. Artnn RCT Phannocot TOKCO! 1985; 25:381-412.
14. Siegel SC: Overview of corticosteroid therapy. J Allergy Clin Immunol 1985; 76:312-320.
15. Basket I RJ, Wong BM, Hansen JE: A double-blind, randomized clinical trial of methylprednisolone in status asthmaticus. Arch Intern Med 1983; 143:1324-1327.
16. HarfiH, HanissianAS,CrawfordLV:Treatmentofstatusasthmaticusiiichildrenwitri high doses and conventional doses of methylprednuolone. ftdiomci 1978; 61:829-831.
17. Younger RE, Gerber PS, Herrad HG, et al: Intravenous methylprednisobne efficacy in status asthmaticus of childhood. Fediomcs 1987; 80:225-230.
18. FanraCH, RossingTH. Mcfodden ER: Glucocorticoids in acute asthma. AmJ Med 1983; 74:845-851.
19. Littenberg B, Gluck EH: A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J MeJ 1986; 314:150-152.
20. Zora JA, Zinunerman D, Carey TL, er al; Hyporhalamic-piruirary-adrenaJ axis suppression after short-term high-dose glucocorticoid therapy in children with asthma. J Allergy CIm Immunol 1986; 77:9-13.
21. Loten ML, Chai H, Leung P, et al: The use of corticoslCraiJs during an acute exacerbation of asthma. Ann AUergy 1980; 45:67-71.
22. Shapiro GG, Furakawa CT, Pierson WE, et al: Double-blind evaluation of methylprednisolone versus placebo for acute asthma episodes. fWioirKs 1983; 71:510-514.
23. Harris JB, Wfeinberger MM. Nassif E, et al: Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilatois. J Pediatr 1987; 110:627-633.
24. Brunette MG, Lands L, Thibodeau LP: Childhood asthma: Prevention of artrcks with short-term conicosteroid treatment of upper respiratory infection. Biomed 1988; 81:624-629.
25. Chamberlain P, MeyerWJ: Management of pituitary-adrenal suppression secondary to cotticosieroid therapy, ftdúüria 1981; 67:245-251.
26. Bhaghat RG, Chai H; Development of posterior subcapsulat cataracts in children, Pediatrcs 1984, 73:626-630.
27. Reimer LG, Mortis HG, EllisEF; Growth of asthmatic children during treatment with alternate-day steroids. J Allergy Clin ímmimoí 1975; 55:224-231.
28. Adinoff AD, Hol lis ter JR: Steroid- induced fractures and bone losses in patienis with asthma. N EneU Med 1983; 309:265-268.
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Oral Steroids During Exacerbations of Asthma
Side Effects of Oral Steroids
Recommended Doses of Aerosol Steroids In Children 6-12