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Adrenal Suppression Among Asthmatic Children Receiving Chronic Therapy with Inhaled Corticosteroid with and Without Spacer Device
Adrenal suppression among asthmatic children receiving chronic therapy with inhaled corticosteroid with and without spacer device Shmuel Goldberg, MD*†; Nurit Algur, PhD‡; Mordechai Levi, MD§; Elchanan Brukheimer, MD*†; Harry J Hirsch, MD\; David Branski, MD*; and Eitan Kerem, MD*†
Background: Inhaled corticosteriods have become a first-line treatment for chronic asthma. It has been shown that inhaled corticosteroids can have a measurable effect on the hypothalamic-pituitary-adrenal axis in asthmatic children. Objective: To investigate the prevalence of adrenal suppression among asthmatic children receiving chronic therapy with low to moderate doses (up to 1000 g) of inhaled beclomethasone dipropionate via a metered dose inhaler (MDI) and via MDI attached to a spacer device (MDI-spacer). Methods: The study included 39 asthmatic children currently undergoing therapy; 24 received beclomethasone dipropionate by MDI attached to a spacer, and 15 directly by MDI. All the patients had been treated for at least 4 months. Another 21 children were normal controls. The 24-hour urinary free cortisol excretion was measured to evaluate hypothalamic-pituitary-adrenal axis function. Results: Seven of 15 (47%) patients from the MDI group had reduced 24 hour-urinary free cortisol excretion and 2 of 24 (8%) in the MDI-spacer group (P ⫽ .006). The mean 24-hour urinary free cortisol excretion of the MDI group was 0.0185 ⫾ 0.0089 g/g creatinine, and the MDI-spacer and the control groups were, 0.0290 ⫾ 0.0138 g/g creatinine and 0.0270 ⫾ 0.0118 g/g creatinine, respectively, (P ⫽ .037, f ⫽ 3.51 ANOVA). Conclusion: Chronic inhalation of low to moderate doses of corticosteroids is associated with adrenal suppression in some asthmatic children. This side effect is more common among patients inhaling directly from the MDI and is less frequent when a large volume spacer is attached to the MDI. Ann Allergy Asthma Immunol 1996;76:234–238.
INTRODUCTION Inhaled corticosteroids have become a first-line treatment for chronic asthma.1–3 Their daily use has allowed better control of asthma and reduction in the requirement of oral corticosteroids. Chronic use of inhaled corticosteroids, however, raises concerns over their potential systemic side effects.4 The major concern in children is impairment of linear growth and enhanced bone From the Department of Pediatrics*, Pulmonary and Cystic Fibrosis Clinic†, Endocrine Laboratory‡, Shaare Zedek Medical Center, Jerusalem, Rokach Pulmonary Center, Kuppat Cholim§, and Department of Pediatrics, Hadassah Medical Center\, Jerusalem, Israel. Received for publication March 22, 1995. Accepted for publication in revised form June 25, 1995.
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metabolism, hypothalamic-pituitaryadrenal axis suppression and impairment of immunity. It has been shown in adults that high doses of inhaled corticosteroids have a measurable effect on the hypothalamic-pituitary-adrenal axis.5,6 Studies of the incidence of adrenal suppression in asthmatic children receiving inhaled corticosteroids have revealed conflicting results. Some investigators have found mild to moderate suppression of adrenal function,7–14 while others have observed normal adrenal function.15–19 The results are conflicting mainly because the investigations have often been uncontrolled, patients have previously received oral corticosteroid therapy, the durations of treatment have varied, different inhalers have been used, and
different tests have been applied to monitor changes in hypothalamic-pituitary-adrenal axis function. Attachment of a spacer to the mouthpiece of a metered dose inhaler (MDI) increases the deposition of the inhaled particles in the small airways from 10% to 25%,20 –22 and reduces significantly, from 80% to 20%, the amount of particles deposited in the oropharynx.23,24 The spacer acts as a holding chamber in which the large particles are filtered off, become smaller by evaporation of propellant, and move more slowly when they are inhaled. The net result of these devices is to expose the patient to a significantly lower dose of the inhaled medication.25 Recent studies in adults have suggested that large volume spacers reduce adrenal suppression caused by high doses of inhaled corticosteroids.26 –30 To the best of our knowledge, the effect of spacers to reduce adrenal suppression in asthmatic children receiving chronic inhaled corticosteroids has not been studied. The aim of this study was to investigate the prevalence of adrenal suppression among asthmatic children receiving mild-to-moderate doses of inhaled corticosteroids via an MDI and an MDI attached to a spacer device (MDI-spacer). PATIENTS AND METHODS Patients The study included 39 asthmatic children (5 to 16 years of age) who had stable asthma and had been treated with low to moderate doses of inhaled corticosteroids (maximal dose 1000 g/day) for at least 4 months. Children who had required oral corticosteroids
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
in the month prior to entering the study or had received oral corticosteroids for more than five days in the last 6 months prior to entering the study were excluded. Inhaled corticosteroid beclomethasone dipropionate, was delivered directly from the MDI in 15 patients, or by a large volume spacer (Volumatic, Glaxo) attached to the MDI in 24 patients. The dose of corticosteroids and the type of the inhalation device were determined at least 4 months before they were enrolled in the study by their physician. The control group comprised 18 normal children and three children with stable asthma who never had received corticosteroid treatment. Clinical Assessment Upon enrollment in the study each patient had baseline evaluations, which included clinical history regarding disease activity (presence of cough, wheezing, shortness of breath, -agonist use), height, weight, vital signs, and pulmonary function tests. The inhalation technique was inspected and corrected if necessary. The closed mouth technique is used in our clinic for the MDI. In order to ensure strict compliance during at least 1 month of therapy, the patients were supplied with a pre-weighed MDI, and were asked to continue on their original treatment plan as prescribed by their physician prior to entrance to the study. Other forms of steroids, oral, intranasal, or topical, were banned. A diary card was supplied on which patients were to mark the doses of be-
clomethasone dipropionate taken. This dose was the reported dose. All patients returned 4 weeks later with 24hour urine collection. At this clinic visit the baseline evaluation was repeated by the same investigator and patients were asked regarding compliance with MDI use. The inhalers were collected, weighed, and the expected MDI weight according to the patient’s report, was compared with the actual weight. Adrenal Suppression Study The 24-hour urinary free cortisol excretion was used as the index of the hypothalamic-pituitary-adrenal axis function. This method has been recommended for evaluation of side effects of inhaled corticosteroids on the hypothalamic-pituitary-adrenal axis.31 Patients were asked to collect urine after the first void of the morning until the next morning including the first void. The completeness of the urine samples was ensured by measurement of the urinary creatinine excretion. A urine sample was only used if the creatinine content was in agreement with that expected from the child’s body surface area. All measurements were done with the endocrine laboratory blind to the type of treatment the patient had received. The urinary free cortisol was measured using a solid phase radioimmunoassay kit (DPC Coat-A-Count Diagnostic Products Corporation, LosAngeles, CA) after extraction of samples with dichloromethane. Results were corrected for 24-hour urine cre-
atinine excretion to adjust for differences in weight and height among the patients. Statistical Analysis Results are given as mean ⫾ standard deviation. Differences between groups were calculated using the analysis of variance with repeated measures for the parametric variables. For comparison of proportions chi square was used. Correlation between parameters was calculated using Pearson’s correlation coefficient. RESULTS Of the 60 children enrolled in the study, one subject from the control group was excluded because of disagreement of the urine creatinine content with that expected from the child’s body surface area. No side effects, local or systemic, were reported. There was no difference between both treatment groups in disease severity as indicated by pulmonary function, and activity of the disease as determined at the two clinic visits (Table 1). As shown in the Table, all the patients were compliant with the treatment prescribed. It is also evident from the Table that although patients from the MDI-spacer group were younger than the MDI group, the mean beclomethasone dipropionate dosage in the MDIspacer group was slightly higher. Seven of the 15 (47%) patients from the MDI group and 2 out of 24 (8%) in the MDI-spacer group had reduced 24hour urinary free cortisol excretion, P ⫽ .006 (considering the lower value
Table. Clinical Data on Study Patients (mean ⫾ SD)
Number of patients Males, % Age, yr FEV1 pre-study, % predicted FEV1 post-study, % predicted Prescribed dose of BDP, g/day range Dose of BDP reported taken, g/day Dose of BDP actually taken, g/day
MDI
MDI-Spacer
Control
15 58 11.87 ⫾ 3.25 78.6 ⫾ 11.2 75.8 ⫾ 11.0 500 ⫾ 240 200–1000 478 ⫾ 217 474 ⫾ 220
24 60 8.56 ⫾ 2.46* 75.2 ⫾ 10.4 75.3 ⫾ 18.7 608 ⫾ 224 300–1000 591 ⫾ 227 563 ⫾ 249
20 50 10.1 ⫾ 3.41
* P ⫽ .017, analysis of variance. Abbreviations: MDI ⫽ metered dose inhaler, MDI-spacer ⫽ metered dose inhaler attached to a spacer, BDP ⫽ beclomethasone dipropionate, and FEV1 ⫽ forced expiratory volume in 1 second.
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of the control group, above 0.0132 g/g creatinine, as a cutoff value). Figure 1 shows the 24-hour urinary free cortisol excretion in all three groups. The MDI group had a mean 24-hour urinary free cortisol of 0.0185 ⫾ 0.0089 g/g creatinine, significantly lower compared with the MDI-spacer group 0.0290 ⫾ 0.0138 g/g creatinine and with the control group 0.0270 ⫾ 0.0118 g/g creatinine (P ⫽ .037, f ⫽ 3.51). The three asthmatic children from the control group had 24-hour urinary free cortisol excretion above the mean of the group. There was no correlation between beclomethasone dipropionate dose, as measured by the inhalers’ weights before and after the use, or beclomethasone dipropionate dose corrected for weight, and the 24-hour urinary free cortisol level. Fourteen children were treated by three doses of beclomethasone dipropionate per day and 25 patients by two doses per day. There was no significant difference in 24-hour urinary free cortisol between these groups.
DISCUSSION Our study shows that inhalation for at least 4 months of low-to-moderate doses of corticosteroids can cause adrenal suppression in asthmatic children. The use of a large volume spacer with the MDI was associated with lower rates of adrenal suppression. Adrenal suppression occurred in 47% of the patients inhaling corticosteroids directly from the MDI, and in only 8% of the patients using MDI with a large volume spacer. Since all our patients had stable asthma, treated with similar doses of beclomethasone dipropionate and did not receive oral steroids during 6 months before the measurements, it is likely that the reduced rate of low 24-hour urinary free cortisol excretion observed in the MDI-spacer group resulted from lower systemic absorption of the inhaled steroid. Adrenal suppression has been observed previously in adults and in children receiving inhaled corticosteroids.7,8,12–15 In a recent study, Nicolaizik et al.32 found that low-dose inhaled steroids in the form of beclomethasone dipropionate or budes-
Figure 1. Box plots presentation of 24-hour urinary free cortisol excretion in asthmatic children receiving inhaled beclomethasone dipropionate via metered dose inhaler only (MDI), n ⫽ 15; via MDI attached to a large volume spacer (MDI-spacer), n ⫽ 24; and in a control group, n ⫽ 20. The box represents the middle 50% of the data. The horizontal line inside the box is the median value. The upper and lower ends of the box show the upper and lower quartiles. The vertical lines show the 95% range. Asterisks represent points outside this range.
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onide caused reduction in nocturnal serum cortisol production and urinary free cortisol excretion after 2 and 4 weeks of treatment. Its clinical significance is uncertain, although cases of clinical adrenal insufficiency have been reported in patients treated with inhaled corticosteroids.33,34 The attachment of a spacer to the MDI has been shown to decrease the oropharyngeal deposition of inhaled isotope-labelled aerosols and to increase their intrapulmonary deposition20 –24,35–37 thus, the net result is to expose the patient to a lower dose of the inhaled medication. In addition, it has been shown to augment the bronchodilator response of asthmatic patients38 and to reduce local side effects.25 Previous results of studies in adults receiving high doses of inhaled steroids via large volume spacers have been contradictory. Toogood et al25 found lower levels of morning serum cortisol in adult asthmatic patients receiving high-dose budesonide (1600 g/day) via spacers compared with those receiving it directly from the MDI; however, half of their patients received oral prednisone regularly. Three other studies showed that large volume spacers reduced adrenal suppression caused by inhaled corticosteroids. Farrer et al26 studied healthy adults who inhaled a single dose of 2 mg beclomethasone dipropionate. The morning serum cortisol level was reduced when beclomethasone dipropionate was inhaled by MDI alone and unchanged when it was inhaled from a spacer device. Brown et al27 studied asthmatic adults receiving high-dose beclomethasone dipropionate (15002500 g/day) by MDI alone; half of them had been treated previously by oral steroids for long periods. Twentyfive percent had impaired adrenal function. In the latter group, a change to inhale the same dose of beclomethasone dipropionate through a large volume spacer, caused an increase in morning serum cortisol and mean 24hour urinary free cortisol levels, although in nearly half of them evidence of adrenal suppression remained.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Selroos and Halme28 showed that asthmatic adults inhaling beclomethasone dipropionate, 1000 g/day, with a spacer device, had less adrenal suppression compared with those inhaling similar doses without spacer. In addition they showed that mouth-rinsing caused less adrenal suppression, emphasizing the importance of oropharyngeal and gastrointestinal absorption as the main cause of systemic side effects. Our study shows adrenal suppression among some asthmatic children receiving chronic inhalation of low to moderate doses of corticosteroids. The attachment of a large volume spacer to the MDI may reduce the risk of this unwanted side effect. The clinical relevance of the adrenal suppression is uncertain, however. Although this report only adresses adrenal suppression, it would be prudent to monitor linear growth in all children receiving chronic treatment with inhaled corticosteroid. Further investigations of the importance of the adrenal suppression observed during the treatment of inhaled steroids in children are needed. These studies should be prospective, blinded, and randomized plus include measurements of hypothalamic-pituitary-adrenal axis function before and after treatment. REFERENCES 1. Barnes PJ. A new approach to the treatment of asthma. N Engl J Med 1989;321:1517–27. 2. Reed CE. Aerosol steroids as primary treatment of mild asthma. N Engl J Med 1991;325:424 –5. 3. Geddes DM. Inhaled corticosteroids: benefits and risks. Thorax 1992;47: 404 –7. 4. Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148: S1–S26. 5. Gordon ACH, Mcdonald CF, Thomson SA, et al. Dose of inhaled budesonide required to produce clinical suppression of plasma cortisol. Eur J Respir Dis 1987;71:10 – 4. 6. Smith MJ, Hodson ME. Effects of long term inhaled high dose beclomethasone dipropionate on adrenal function. Thorax 1983;38:76 – 81.
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7. Vaz R, Senior B, Morris M, Binkiewicz A. Adrenal effects of beclomethasone inhalation therapy in asthmatic children. J Pediatr 1982;100: 660 –2. 8. Springer C, Avital A, Maayan CH, et al. Comparison of budesonide and beclomethasone dipropionate for treatment of asthma. Arch Dis Child 1987; 62:815–9. 9. Law CM, Honour JW, Marchant JL, et al. Nocturnal adrenal suppression in asthmatic children taking inhaled beclomethasone dipropionate. Lancet 1986:i:942– 4. 10. Pederson S, Fugslang G. Urine cortisol excretion in children treated with high doses of inhaled corticosteroids: a comparison of budesonide and beclomethasone. Eur Respir J 1988;1: 433–5. 11. Bisgaard H, Nielsen MD, Andersen B, et al. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J Allergy Clin Immunol 1988: 81:1088 –95. 12. Wyatt R, Wascher J, Weinberger M, Aherman B. Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitaryadrenal function in children with chronic asthma. N Engl J Med 1978; 299:1387–92. 13. Tabachnic E, Zadik Z. Diurnal cortisol secretion during therapy with inhaled beclomethasone dipropionate in children with asthma. J Pediatr 1991;118: 294 –7. 14. Phillip M, Aviram M, Leiberman E, et al. Integrated plasma cortisol concentration in children with asthma receiving long-term inhaled corticosteroids. Pediatr Pulmonol 1992;12;84 –9. 15. Goldstein DE, Konig P. Effect of inhaled beclomethasone dipropionate on hypothalamic-pituitary-adrenal axis function in children with asthma. Pediatrics 1983;72:60 – 4. 16. Prahl P, Jensen T. Adrenocortical function in children on high dose steroid aerosol therapy. Allergy 1987;42: 541– 4. 17. Kerebbijn KF. Beclomethasone dipropionate in long-term treatment of asthma in children. J Pediatr 1976;89: 821– 6. 18. Volovitz B, Amir J, Malik H, et al. Growth and pituitary-adrenal function in children with severe asthma treated with inhaled budesonide. N Engl J
Med 1993;329:1703– 8. 19. Gleeson JGA, Price JF. Controlled trial of budesonide given by the Nebuhaler in preschool children with asthma. Br Med J 1988;297:163– 6. 20. Newman SP, Pavia D, Clarke SW. Improving the bronchial deposition of pressurized aerosols. Chest 1981; 80(Suppl 65):909 –11. 21. Newman SP, Pavia D, Garland N, Clarke SW. Effects of various inhalation modes on the deposition of radioactive pressurized aerosols. Eur J Respir Dis 1982;63(Suppl 119):57– 65. 22. Newman SP, Moren F, Pavia D, et al. Deposition of pressurized aerosols inhaled through extension device. Am Rev Respir Dis 1981;124:317–20. 23. Moren F. Drug deposition of pressurized inhalation aerosols: 1. influence of actuator tube design. Int J Pharmacol 1978;1:205–12. 24. Dolovich M, Ruffino RE, Roberts R, Newhouse MT. Optimal delivery of aerosols from metered dose inhalers. Chest 1981;80(Suppl 65):911–5. 25. Toogood JH, Baskerville J, Jennings B, et al. Use of spacers to facilitate inhaled corticosteroid treatment for asthma. Am Rev Respir Dis 1984;129: 723–9. 26. Farrer M, Francis AJ, Pearce SJ. Morning serum cortisol concentration after 2 mg inhaled beclomethasone dipropionate in normal subjects: effect of 750 ml spacing device. Thorax 1990;45:740 –2. 27. Brown PH, Blundell G, Greening AP, Crompton GK. Do large volume spacer devices reduce the systemic effect of inhaled corticosteroids? Thorax 1990;45:736 –9. 28. Selroos O, Halme M. Effect of volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from a metered dose inhaler and dry powder inhaler. Thorax 1991;46: 891– 4. 29. Prahl P, Jensen T. Decreased adrenocortical suppression utilizing the nebuhaler for inhalation of steroid aerosol. Clin Allergy 1987;17:393– 8. 30. Gleeson JGA, Price JF. Controlled trial of budesonide given by nebuhaler in preschool children with asthma. Br Med J 1988;297:163– 6. 31. Holt PR, Lowndes DW, Smithies E, Dixson GT. The effect of inhaled steroid on the hypothalamic-pituitary-adrenalaxis-which test should be used? Clin Exp Allergy 1990;20:145–9.
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32. Nicolaizik WH, Marchant JL, Preece MA, Warner JO. Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Dis Crit Care Med 1994;150:624 – 8. 33. Zwaan CM, Odink RJH, Delemarrevan de Waal HA, et al. Acute adrenal insufficiency after discontinuation of inhaled corticosteroid therapy. Lancet 1992;340:1289 –90. 34. Wong J, Black P. Acute adrenal insufficiency associated with high dose inhaled steroids. Br Med J 1992;304: 1415.
35. Lindgren SB, Formgren H, Moren E. Improved aerosol therapy of asthma: effect of actuator tube size on drug availability. Eur Respir Dis 1980;61: 56 – 61. 36. Gurwitz D, Levison H, Mindorff C, et al. Assessment of a new device (aerochamber) for use with aerosol drugs in asthmatic children. Ann Allergy 1983; 50:166 –70. 37. Rivlin J, Mindorff C, Reily P, Levison H. Pulmonary response to a bronchodilator delivered from three inhalation devices. J Pediatr 1984;104:470 –3.
38. Kerem E, Levison H, Schuh S, et al. Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma. J Pediatr 1993; 125:321–16. Request for reprints should be addressed to: Eitan Kerem MD Department of Pediatrics Pulmonary and Cystic Fibrosis Clinic Shaare Zedek Medical Center P.O. Box 3235 Jerusalem Israel 91031
APPROPRIATENESS OF INTERMITTENT INHALED CORTICOSTEROIDS To evaluate responses to discontinuation of inhaled corticosteroids the authors studied 14 patients with asthma or chronic obstructive pulmonary disease who had had decreases in FEV1 of at least 80 mL per year and at least one exacerbation per year during 2 years of continual treatment with bronchodilators (1600 g albuterol or 160 g ipratropium bromide per day). Each then had received beclomethasone, 400 g bid by inhalation for 2 years in addition to the bronchodilators. The inhaled corticosteroid then was discontinued and observation continued for another year. No significant differences in mean annual changes in FEV1, bronchial responsiveness to histamine, morning peak expiratory flow rate, diurnal variation in peak expiratory flow rate, symptom scores, or rate of exacerbations followed discontinuation of inhaled corticosteroid as compared with the two years during which they had received inhaled beclomethasone. Only week-to-week variation in peak expiratory flow rate increased significantly after discontinuation of beclomethasone (paired t test, P ⫽ .02). These observations indicate it is safe to discontinue an inhaled corticosteroid in some patients with mild asthma or chronic obstructive pulmonary disease after the inhaled steroid has improved control of the disease. The authors propose intermittent rather than continual treatment with inhaled corticosteroids is appropriate for some patients. —RMS van Schayck CP, van den Broek PJJA, den Otter JJ, et al. Periodic treatment regimens with inhaled steroids in asthma or chronic obstructive pulmonary disease. JAMA 1995;274:161– 4.
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ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: Inhaled corticosteriods have become a first-line treatment for chronic asthma. It has been shown that inhaled corticosteroids can have a measurable effect on the hypothalamic-pituitary-adrenal axis in asthmatic children. Objective: To investigate the prevalence of adrenal suppression among asthmatic children receiving chronic therapy with low to moderate doses (up to 1000 g) of inhaled beclomethasone dipropionate via a metered dose inhaler (MDI) and via MDI attached to a spacer device (MDI-spacer). Methods: The study included 39 asthmatic children currently undergoing therapy; 24 received beclomethasone dipropionate by MDI attached to a spacer, and 15 directly by MDI. All the patients had been treated for at least 4 months. Another 21 children were normal controls. The 24-hour urinary free cortisol excretion was measured to evaluate hypothalamic-pituitary-adrenal axis function. Results: Seven of 15 (47%) patients from the MDI group had reduced 24 hour-urinary free cortisol excretion and 2 of 24 (8%) in the MDI-spacer group (P ⫽ .006). The mean 24-hour urinary free cortisol excretion of the MDI group was 0.0185 ⫾ 0.0089 g/g creatinine, and the MDI-spacer and the control groups were, 0.0290 ⫾ 0.0138 g/g creatinine and 0.0270 ⫾ 0.0118 g/g creatinine, respectively, (P ⫽ .037, f ⫽ 3.51 ANOVA). Conclusion: Chronic inhalation of low to moderate doses of corticosteroids is associated with adrenal suppression in some asthmatic children. This side effect is more common among patients inhaling directly from the MDI and is less frequent when a large volume spacer is attached to the MDI. Ann Allergy Asthma Immunol 1996;76:234–238.
INTRODUCTION Inhaled corticosteroids have become a first-line treatment for chronic asthma.1–3 Their daily use has allowed better control of asthma and reduction in the requirement of oral corticosteroids. Chronic use of inhaled corticosteroids, however, raises concerns over their potential systemic side effects.4 The major concern in children is impairment of linear growth and enhanced bone From the Department of Pediatrics*, Pulmonary and Cystic Fibrosis Clinic†, Endocrine Laboratory‡, Shaare Zedek Medical Center, Jerusalem, Rokach Pulmonary Center, Kuppat Cholim§, and Department of Pediatrics, Hadassah Medical Center\, Jerusalem, Israel. Received for publication March 22, 1995. Accepted for publication in revised form June 25, 1995.
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metabolism, hypothalamic-pituitaryadrenal axis suppression and impairment of immunity. It has been shown in adults that high doses of inhaled corticosteroids have a measurable effect on the hypothalamic-pituitary-adrenal axis.5,6 Studies of the incidence of adrenal suppression in asthmatic children receiving inhaled corticosteroids have revealed conflicting results. Some investigators have found mild to moderate suppression of adrenal function,7–14 while others have observed normal adrenal function.15–19 The results are conflicting mainly because the investigations have often been uncontrolled, patients have previously received oral corticosteroid therapy, the durations of treatment have varied, different inhalers have been used, and
different tests have been applied to monitor changes in hypothalamic-pituitary-adrenal axis function. Attachment of a spacer to the mouthpiece of a metered dose inhaler (MDI) increases the deposition of the inhaled particles in the small airways from 10% to 25%,20 –22 and reduces significantly, from 80% to 20%, the amount of particles deposited in the oropharynx.23,24 The spacer acts as a holding chamber in which the large particles are filtered off, become smaller by evaporation of propellant, and move more slowly when they are inhaled. The net result of these devices is to expose the patient to a significantly lower dose of the inhaled medication.25 Recent studies in adults have suggested that large volume spacers reduce adrenal suppression caused by high doses of inhaled corticosteroids.26 –30 To the best of our knowledge, the effect of spacers to reduce adrenal suppression in asthmatic children receiving chronic inhaled corticosteroids has not been studied. The aim of this study was to investigate the prevalence of adrenal suppression among asthmatic children receiving mild-to-moderate doses of inhaled corticosteroids via an MDI and an MDI attached to a spacer device (MDI-spacer). PATIENTS AND METHODS Patients The study included 39 asthmatic children (5 to 16 years of age) who had stable asthma and had been treated with low to moderate doses of inhaled corticosteroids (maximal dose 1000 g/day) for at least 4 months. Children who had required oral corticosteroids
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
in the month prior to entering the study or had received oral corticosteroids for more than five days in the last 6 months prior to entering the study were excluded. Inhaled corticosteroid beclomethasone dipropionate, was delivered directly from the MDI in 15 patients, or by a large volume spacer (Volumatic, Glaxo) attached to the MDI in 24 patients. The dose of corticosteroids and the type of the inhalation device were determined at least 4 months before they were enrolled in the study by their physician. The control group comprised 18 normal children and three children with stable asthma who never had received corticosteroid treatment. Clinical Assessment Upon enrollment in the study each patient had baseline evaluations, which included clinical history regarding disease activity (presence of cough, wheezing, shortness of breath, -agonist use), height, weight, vital signs, and pulmonary function tests. The inhalation technique was inspected and corrected if necessary. The closed mouth technique is used in our clinic for the MDI. In order to ensure strict compliance during at least 1 month of therapy, the patients were supplied with a pre-weighed MDI, and were asked to continue on their original treatment plan as prescribed by their physician prior to entrance to the study. Other forms of steroids, oral, intranasal, or topical, were banned. A diary card was supplied on which patients were to mark the doses of be-
clomethasone dipropionate taken. This dose was the reported dose. All patients returned 4 weeks later with 24hour urine collection. At this clinic visit the baseline evaluation was repeated by the same investigator and patients were asked regarding compliance with MDI use. The inhalers were collected, weighed, and the expected MDI weight according to the patient’s report, was compared with the actual weight. Adrenal Suppression Study The 24-hour urinary free cortisol excretion was used as the index of the hypothalamic-pituitary-adrenal axis function. This method has been recommended for evaluation of side effects of inhaled corticosteroids on the hypothalamic-pituitary-adrenal axis.31 Patients were asked to collect urine after the first void of the morning until the next morning including the first void. The completeness of the urine samples was ensured by measurement of the urinary creatinine excretion. A urine sample was only used if the creatinine content was in agreement with that expected from the child’s body surface area. All measurements were done with the endocrine laboratory blind to the type of treatment the patient had received. The urinary free cortisol was measured using a solid phase radioimmunoassay kit (DPC Coat-A-Count Diagnostic Products Corporation, LosAngeles, CA) after extraction of samples with dichloromethane. Results were corrected for 24-hour urine cre-
atinine excretion to adjust for differences in weight and height among the patients. Statistical Analysis Results are given as mean ⫾ standard deviation. Differences between groups were calculated using the analysis of variance with repeated measures for the parametric variables. For comparison of proportions chi square was used. Correlation between parameters was calculated using Pearson’s correlation coefficient. RESULTS Of the 60 children enrolled in the study, one subject from the control group was excluded because of disagreement of the urine creatinine content with that expected from the child’s body surface area. No side effects, local or systemic, were reported. There was no difference between both treatment groups in disease severity as indicated by pulmonary function, and activity of the disease as determined at the two clinic visits (Table 1). As shown in the Table, all the patients were compliant with the treatment prescribed. It is also evident from the Table that although patients from the MDI-spacer group were younger than the MDI group, the mean beclomethasone dipropionate dosage in the MDIspacer group was slightly higher. Seven of the 15 (47%) patients from the MDI group and 2 out of 24 (8%) in the MDI-spacer group had reduced 24hour urinary free cortisol excretion, P ⫽ .006 (considering the lower value
Table. Clinical Data on Study Patients (mean ⫾ SD)
Number of patients Males, % Age, yr FEV1 pre-study, % predicted FEV1 post-study, % predicted Prescribed dose of BDP, g/day range Dose of BDP reported taken, g/day Dose of BDP actually taken, g/day
MDI
MDI-Spacer
Control
15 58 11.87 ⫾ 3.25 78.6 ⫾ 11.2 75.8 ⫾ 11.0 500 ⫾ 240 200–1000 478 ⫾ 217 474 ⫾ 220
24 60 8.56 ⫾ 2.46* 75.2 ⫾ 10.4 75.3 ⫾ 18.7 608 ⫾ 224 300–1000 591 ⫾ 227 563 ⫾ 249
20 50 10.1 ⫾ 3.41
* P ⫽ .017, analysis of variance. Abbreviations: MDI ⫽ metered dose inhaler, MDI-spacer ⫽ metered dose inhaler attached to a spacer, BDP ⫽ beclomethasone dipropionate, and FEV1 ⫽ forced expiratory volume in 1 second.
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of the control group, above 0.0132 g/g creatinine, as a cutoff value). Figure 1 shows the 24-hour urinary free cortisol excretion in all three groups. The MDI group had a mean 24-hour urinary free cortisol of 0.0185 ⫾ 0.0089 g/g creatinine, significantly lower compared with the MDI-spacer group 0.0290 ⫾ 0.0138 g/g creatinine and with the control group 0.0270 ⫾ 0.0118 g/g creatinine (P ⫽ .037, f ⫽ 3.51). The three asthmatic children from the control group had 24-hour urinary free cortisol excretion above the mean of the group. There was no correlation between beclomethasone dipropionate dose, as measured by the inhalers’ weights before and after the use, or beclomethasone dipropionate dose corrected for weight, and the 24-hour urinary free cortisol level. Fourteen children were treated by three doses of beclomethasone dipropionate per day and 25 patients by two doses per day. There was no significant difference in 24-hour urinary free cortisol between these groups.
DISCUSSION Our study shows that inhalation for at least 4 months of low-to-moderate doses of corticosteroids can cause adrenal suppression in asthmatic children. The use of a large volume spacer with the MDI was associated with lower rates of adrenal suppression. Adrenal suppression occurred in 47% of the patients inhaling corticosteroids directly from the MDI, and in only 8% of the patients using MDI with a large volume spacer. Since all our patients had stable asthma, treated with similar doses of beclomethasone dipropionate and did not receive oral steroids during 6 months before the measurements, it is likely that the reduced rate of low 24-hour urinary free cortisol excretion observed in the MDI-spacer group resulted from lower systemic absorption of the inhaled steroid. Adrenal suppression has been observed previously in adults and in children receiving inhaled corticosteroids.7,8,12–15 In a recent study, Nicolaizik et al.32 found that low-dose inhaled steroids in the form of beclomethasone dipropionate or budes-
Figure 1. Box plots presentation of 24-hour urinary free cortisol excretion in asthmatic children receiving inhaled beclomethasone dipropionate via metered dose inhaler only (MDI), n ⫽ 15; via MDI attached to a large volume spacer (MDI-spacer), n ⫽ 24; and in a control group, n ⫽ 20. The box represents the middle 50% of the data. The horizontal line inside the box is the median value. The upper and lower ends of the box show the upper and lower quartiles. The vertical lines show the 95% range. Asterisks represent points outside this range.
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onide caused reduction in nocturnal serum cortisol production and urinary free cortisol excretion after 2 and 4 weeks of treatment. Its clinical significance is uncertain, although cases of clinical adrenal insufficiency have been reported in patients treated with inhaled corticosteroids.33,34 The attachment of a spacer to the MDI has been shown to decrease the oropharyngeal deposition of inhaled isotope-labelled aerosols and to increase their intrapulmonary deposition20 –24,35–37 thus, the net result is to expose the patient to a lower dose of the inhaled medication. In addition, it has been shown to augment the bronchodilator response of asthmatic patients38 and to reduce local side effects.25 Previous results of studies in adults receiving high doses of inhaled steroids via large volume spacers have been contradictory. Toogood et al25 found lower levels of morning serum cortisol in adult asthmatic patients receiving high-dose budesonide (1600 g/day) via spacers compared with those receiving it directly from the MDI; however, half of their patients received oral prednisone regularly. Three other studies showed that large volume spacers reduced adrenal suppression caused by inhaled corticosteroids. Farrer et al26 studied healthy adults who inhaled a single dose of 2 mg beclomethasone dipropionate. The morning serum cortisol level was reduced when beclomethasone dipropionate was inhaled by MDI alone and unchanged when it was inhaled from a spacer device. Brown et al27 studied asthmatic adults receiving high-dose beclomethasone dipropionate (15002500 g/day) by MDI alone; half of them had been treated previously by oral steroids for long periods. Twentyfive percent had impaired adrenal function. In the latter group, a change to inhale the same dose of beclomethasone dipropionate through a large volume spacer, caused an increase in morning serum cortisol and mean 24hour urinary free cortisol levels, although in nearly half of them evidence of adrenal suppression remained.
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Selroos and Halme28 showed that asthmatic adults inhaling beclomethasone dipropionate, 1000 g/day, with a spacer device, had less adrenal suppression compared with those inhaling similar doses without spacer. In addition they showed that mouth-rinsing caused less adrenal suppression, emphasizing the importance of oropharyngeal and gastrointestinal absorption as the main cause of systemic side effects. Our study shows adrenal suppression among some asthmatic children receiving chronic inhalation of low to moderate doses of corticosteroids. The attachment of a large volume spacer to the MDI may reduce the risk of this unwanted side effect. The clinical relevance of the adrenal suppression is uncertain, however. Although this report only adresses adrenal suppression, it would be prudent to monitor linear growth in all children receiving chronic treatment with inhaled corticosteroid. Further investigations of the importance of the adrenal suppression observed during the treatment of inhaled steroids in children are needed. These studies should be prospective, blinded, and randomized plus include measurements of hypothalamic-pituitary-adrenal axis function before and after treatment. REFERENCES 1. Barnes PJ. A new approach to the treatment of asthma. N Engl J Med 1989;321:1517–27. 2. Reed CE. Aerosol steroids as primary treatment of mild asthma. N Engl J Med 1991;325:424 –5. 3. Geddes DM. Inhaled corticosteroids: benefits and risks. Thorax 1992;47: 404 –7. 4. Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148: S1–S26. 5. Gordon ACH, Mcdonald CF, Thomson SA, et al. Dose of inhaled budesonide required to produce clinical suppression of plasma cortisol. Eur J Respir Dis 1987;71:10 – 4. 6. Smith MJ, Hodson ME. Effects of long term inhaled high dose beclomethasone dipropionate on adrenal function. Thorax 1983;38:76 – 81.
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7. Vaz R, Senior B, Morris M, Binkiewicz A. Adrenal effects of beclomethasone inhalation therapy in asthmatic children. J Pediatr 1982;100: 660 –2. 8. Springer C, Avital A, Maayan CH, et al. Comparison of budesonide and beclomethasone dipropionate for treatment of asthma. Arch Dis Child 1987; 62:815–9. 9. Law CM, Honour JW, Marchant JL, et al. Nocturnal adrenal suppression in asthmatic children taking inhaled beclomethasone dipropionate. Lancet 1986:i:942– 4. 10. Pederson S, Fugslang G. Urine cortisol excretion in children treated with high doses of inhaled corticosteroids: a comparison of budesonide and beclomethasone. Eur Respir J 1988;1: 433–5. 11. Bisgaard H, Nielsen MD, Andersen B, et al. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J Allergy Clin Immunol 1988: 81:1088 –95. 12. Wyatt R, Wascher J, Weinberger M, Aherman B. Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitaryadrenal function in children with chronic asthma. N Engl J Med 1978; 299:1387–92. 13. Tabachnic E, Zadik Z. Diurnal cortisol secretion during therapy with inhaled beclomethasone dipropionate in children with asthma. J Pediatr 1991;118: 294 –7. 14. Phillip M, Aviram M, Leiberman E, et al. Integrated plasma cortisol concentration in children with asthma receiving long-term inhaled corticosteroids. Pediatr Pulmonol 1992;12;84 –9. 15. Goldstein DE, Konig P. Effect of inhaled beclomethasone dipropionate on hypothalamic-pituitary-adrenal axis function in children with asthma. Pediatrics 1983;72:60 – 4. 16. Prahl P, Jensen T. Adrenocortical function in children on high dose steroid aerosol therapy. Allergy 1987;42: 541– 4. 17. Kerebbijn KF. Beclomethasone dipropionate in long-term treatment of asthma in children. J Pediatr 1976;89: 821– 6. 18. Volovitz B, Amir J, Malik H, et al. Growth and pituitary-adrenal function in children with severe asthma treated with inhaled budesonide. N Engl J
Med 1993;329:1703– 8. 19. Gleeson JGA, Price JF. Controlled trial of budesonide given by the Nebuhaler in preschool children with asthma. Br Med J 1988;297:163– 6. 20. Newman SP, Pavia D, Clarke SW. Improving the bronchial deposition of pressurized aerosols. Chest 1981; 80(Suppl 65):909 –11. 21. Newman SP, Pavia D, Garland N, Clarke SW. Effects of various inhalation modes on the deposition of radioactive pressurized aerosols. Eur J Respir Dis 1982;63(Suppl 119):57– 65. 22. Newman SP, Moren F, Pavia D, et al. Deposition of pressurized aerosols inhaled through extension device. Am Rev Respir Dis 1981;124:317–20. 23. Moren F. Drug deposition of pressurized inhalation aerosols: 1. influence of actuator tube design. Int J Pharmacol 1978;1:205–12. 24. Dolovich M, Ruffino RE, Roberts R, Newhouse MT. Optimal delivery of aerosols from metered dose inhalers. Chest 1981;80(Suppl 65):911–5. 25. Toogood JH, Baskerville J, Jennings B, et al. Use of spacers to facilitate inhaled corticosteroid treatment for asthma. Am Rev Respir Dis 1984;129: 723–9. 26. Farrer M, Francis AJ, Pearce SJ. Morning serum cortisol concentration after 2 mg inhaled beclomethasone dipropionate in normal subjects: effect of 750 ml spacing device. Thorax 1990;45:740 –2. 27. Brown PH, Blundell G, Greening AP, Crompton GK. Do large volume spacer devices reduce the systemic effect of inhaled corticosteroids? Thorax 1990;45:736 –9. 28. Selroos O, Halme M. Effect of volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from a metered dose inhaler and dry powder inhaler. Thorax 1991;46: 891– 4. 29. Prahl P, Jensen T. Decreased adrenocortical suppression utilizing the nebuhaler for inhalation of steroid aerosol. Clin Allergy 1987;17:393– 8. 30. Gleeson JGA, Price JF. Controlled trial of budesonide given by nebuhaler in preschool children with asthma. Br Med J 1988;297:163– 6. 31. Holt PR, Lowndes DW, Smithies E, Dixson GT. The effect of inhaled steroid on the hypothalamic-pituitary-adrenalaxis-which test should be used? Clin Exp Allergy 1990;20:145–9.
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32. Nicolaizik WH, Marchant JL, Preece MA, Warner JO. Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Dis Crit Care Med 1994;150:624 – 8. 33. Zwaan CM, Odink RJH, Delemarrevan de Waal HA, et al. Acute adrenal insufficiency after discontinuation of inhaled corticosteroid therapy. Lancet 1992;340:1289 –90. 34. Wong J, Black P. Acute adrenal insufficiency associated with high dose inhaled steroids. Br Med J 1992;304: 1415.
35. Lindgren SB, Formgren H, Moren E. Improved aerosol therapy of asthma: effect of actuator tube size on drug availability. Eur Respir Dis 1980;61: 56 – 61. 36. Gurwitz D, Levison H, Mindorff C, et al. Assessment of a new device (aerochamber) for use with aerosol drugs in asthmatic children. Ann Allergy 1983; 50:166 –70. 37. Rivlin J, Mindorff C, Reily P, Levison H. Pulmonary response to a bronchodilator delivered from three inhalation devices. J Pediatr 1984;104:470 –3.
38. Kerem E, Levison H, Schuh S, et al. Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma. J Pediatr 1993; 125:321–16. Request for reprints should be addressed to: Eitan Kerem MD Department of Pediatrics Pulmonary and Cystic Fibrosis Clinic Shaare Zedek Medical Center P.O. Box 3235 Jerusalem Israel 91031
APPROPRIATENESS OF INTERMITTENT INHALED CORTICOSTEROIDS To evaluate responses to discontinuation of inhaled corticosteroids the authors studied 14 patients with asthma or chronic obstructive pulmonary disease who had had decreases in FEV1 of at least 80 mL per year and at least one exacerbation per year during 2 years of continual treatment with bronchodilators (1600 g albuterol or 160 g ipratropium bromide per day). Each then had received beclomethasone, 400 g bid by inhalation for 2 years in addition to the bronchodilators. The inhaled corticosteroid then was discontinued and observation continued for another year. No significant differences in mean annual changes in FEV1, bronchial responsiveness to histamine, morning peak expiratory flow rate, diurnal variation in peak expiratory flow rate, symptom scores, or rate of exacerbations followed discontinuation of inhaled corticosteroid as compared with the two years during which they had received inhaled beclomethasone. Only week-to-week variation in peak expiratory flow rate increased significantly after discontinuation of beclomethasone (paired t test, P ⫽ .02). These observations indicate it is safe to discontinue an inhaled corticosteroid in some patients with mild asthma or chronic obstructive pulmonary disease after the inhaled steroid has improved control of the disease. The authors propose intermittent rather than continual treatment with inhaled corticosteroids is appropriate for some patients. —RMS van Schayck CP, van den Broek PJJA, den Otter JJ, et al. Periodic treatment regimens with inhaled steroids in asthma or chronic obstructive pulmonary disease. JAMA 1995;274:161– 4.
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