Clinical aspects of allergic disease Normal diurnal variation in serum cortisol concentration in asthmatic children treated with inhaled budesonide Benjamin Volovitz, MD, Arieh Kauschansky, MD, Moshe Nussinovitch, MD, Liora Harel, MD, and Itzhak Varsano, MD Petah Tiqva and Tel Aviv, Israel Background: Twenty-four-hour serum cortisol secretion is a sensitive parameter for the assessment of the pituitary-adrenal function of asthmatic children treated with inhaled corticosteroids. This study was undertaken to determine the effect of the long-term administration of inhaled budesonide on 24-hour cortisol production in young children with asthma. Methods: We studied 11 children, aged 7 to 12 yeats, with severe perennial asthma. All had been receiving 100 ixg of inhaled budesonide twice daily, administered with a spacer device, for 3 to 5 years. Serum cortisol concentration was measured at 8:00 A~ 60 minutes' after intravenous administration of 0.25 mg of corticotropin, and every 30 minutes for 24 hours in an open-design study. Urinary cortisol secretion was measured by 24-hour urine collection. All determinations were made with a radioimmunoassay kit. Results: The individual morning serum cortisol concentration and the serum cortisol concentration at 60 minutes after corticotropin stimulation were within normal limits in all children. The 24-hour urinary cortisol excretion was also normal The individual 24-hour serum cortisol concentration showed a normal pattern in all children, with no evidence of nocturnal suppression of serum cortisol concentration. Conclusion: Prolonged (3 to 5 years) administration of 200 ixgday of inhaled budesonide in young children with severe asthma does not impair pituitary-adrenal function, even according to the sensitive test for 24-hour serum cortisol secretion. (J ALLERGY CLIN IMMUNOL 1995;96: 874-8.) Key words: Diurnal variation, serum cortisol, children, asthma inhaled corticosteroids, budesonide The effect of long-term treatment with inhaled corticosteroids on growth and pituitary-adrenal function is an important consideration in young children. The assessment of pituitary-adrenal function on the basis of a single measurement of serum From the Department of Pediatrics C, Children's Medical Center of Israel, Beilinson Medical Campus, Petah Tiqva; and Sackler School of Medicine, Tel Aviv University. Presented in part at the XIV International Congress of Allergology and Clinical Immunology, October 13-18, 1991, Kyoto, Japan. Received for publication Aug. 10, 1994; revised Jan. 26, 1995; accepted for publication Jan. 27, 1995. Reprint requests: Benjamin Volovitz, MD, Department of Pediatrics C, The Shenieder Children's Medical Center of Israel, 14 Kaplan St., Petah Tiqva, 49202, Israel. Copyright 1995 by Mosby-Year Book, Inc. 0091-674995 $5.00 + 0 1163844 874 Abbreviation used ACTH: Adrenocorticotropic hormone cortisol is inadequate because of the dynamic nature of the system, and the mean 24-hour serum cortisol concentration better reflects daily integrated cortisol production. Studies of daily doses of 300 to 800 txg of beclomethasone have indicated decreased serum cortisol concentrations during the early morning hours in some children. 1-3 This study was undertaken to determine the effect of long-term administration of inhaled budesonide, 200 p~gday, on the diurnal variation in plasma cortisol concentration in young children with asthma.
J ALLERGY CLIN IMMUNOL VOLUME 96, NUMBER 6, PART 1 METHODS Patients We studied 11 children, aged 7 to 12 years, who had severe perennial asthma that was not controlled by prolonged continuous treatment with cromolyn sodium together with terbutaline sulfate, sustained-release theophylline, and occasional 3- to 5-day courses of oral prednisone. 4 All of the children were continuously treated in our outpatient asthma clinic for a period of 3 to 5 years with inhaled budesonide. Inhaled budesonide was administered in two puffs of 50 ~xg each, twice daily, for a total daily dose of 200 Ixg with a spacer device (Multispacer; Medic-aid, Sussex, U.K.). These children were part of a group of patients described in previous publications.4. 5 The research protocol was reviewed and approved by the hospital ethics committee for clinical investigation, and written informed consent was obtained from the parents of each child. Cortisol measurements Serum cortisol concentration was measured after an overnight fast at 8:00 AM and 60 minutes after intravenous administration of 0.25 mg of corticotropin. For determination of the mean 24-hour serum cortisol secretion, the following protocol was used. On the morning of the test, serum cortisol concentration was measured after an overnight fast at 8:00 AM; thereafter, blood samples were taken every 30 minutes for 24 hours. The morning dose of budesonide was given only after the 8:00 AM cortisol measurement. All other cortisol measurements were performed while the children continued to take their usual dose of budesonide. The next morning, serum cortisol concentration was again measured, after an overnight fast, at 8:00 AM and 60 minutes after intravenous administration of 0.25 mg of corticotropin. Thereafter, 24-hour urine collection was conducted for the determination of urinary cortisol secretion. Serum and urinary cortisol concentrations were measured by the Coat-A-Count cortisol radioimmunoassay kit (Diagnostic Products Corporation, Los Angeles, Calif.). All samples for each 24-hour study from each child were analyzed at the same time. Cortisol values are expressed in micrograms per deciliter, as they were initially measured, and are given together with the values converted, with a factor of 27.6, to nanomoles per liter, as acceptable today. In our laboratory in normal children of a comparable age, the fasting 8:00 AM serum cortisol concentration ranged from 4 to 23 ixgdl (110 to 635 nmoll); serum cortisol at 60 minutes after corticotropin administration ranged from 18 to 50 ~gdl (497 to 1380 nmoll); and mean 24-hour urinary cortisol excretion ranged from 12 to 55 ixgday (330 to 1520 nmolday). The inter- and intra-assay coefficients of variation in serum cortisol concentration are 4.5% to 6.5% and 3% to 8%, respectively. Statistical analysis Volovitz et al. 875 Analysis of differences between groups was performed with Student's t test (unpaired data). All tests were two-tailed, and p values below 0.05 were considered significant. RESULTS Eleven children (nine boys and two girls), aged 7 to 12 years, who had severe asthma were studied. The individual 24-hour serum cortisol concentration, measured every 30 minutes, showed a normal pattern in all of the patients. Highest concentrations occurred in the early morning, and there were several high and low concentration peaks during the day, with no evidence of nocturnal suppression (Fig. 1). The overall mean 24-hour serum cortisol pattern was found to be similar to that observed in healthy adults and children 2, 6-9 (Fig. 2). The mean 24-hour serum cortisol concentration observed in the childre, n in our study, after 3 to 5 years of budesonide therapy (8.4 + 4.2 txgdl [232 +_ 116 nmoll]), was similar to the mean 24-hour serum cortisol concentration observed in children with chronic asthma not taking corticosteroids (9.7 _+ 3.6 ~gdl) 2 and to that of two healthy control groups of children (7.6 +_ 2.0 ixgdl and 9.17 _+ 1.9 txgdl).2. 3 Before starting budesonide therapy, the fasting serum cortisol concentration at 8:00 AM in all of the children was within the normal range (4.3 to 11.3 p~gdl [119-312 nmoll]). The cortisol concentration at 1 hour after adrenocorticotropic hormone (ACTH) stimulation (intravenous administration of 0.25 mg of corticotropin) was also within the normal range (13.9 to 34.00 ixgdl [384 to 938 nmoll]) in all of the children, except two (patients 1 and 10 in Fig. 1 [13.9 and 16.3 ixgdl cortisol, respectively]). During this study these two children had a normal response to ACTH stimulation (41.6 and 25 ~gdl cortisol, respectively). Before the 24-hour test, the mean fasting morning cortisol concentration was 13.5 _+ 3.2 txgdl (373 + 88 nmoll), with a range of 8.5 to 18 txgdl (234 to 497 nmoll); this was much above the minimal normal range. At the end of the 24-hour test, the mean serum cortisol concentration at 60 minutes after the 0.25 mg intravenous corticotropin stimulation test was 27.8 _+ 5.2 ixgdl (767 _+ 144 nmoll), with a range of 22.7 to 41.6 ~gdl (627 to 1148 nmoll); this too, was much above the minimal normal range (Fig. 3). The mean 24-hour urine cortisol concentration was within normal limits in all 11 children, measuring 34.3 _+ 8.9
...... 876 Volovitz et al. J ALLERGY CLIN IMMUNOL DECEMBER 1995 4 k I(TL) _ 251 3(RE) I _ :,AI 2<KE, I\1 '7 '",1... ' ']o i o3o n,,,,, 12 O c... i...,... O (j ~. ~1 6(RN) E 2 II If} Jt F\ 8(RM) 25 20 15 ;0 5 0 lo (RO). I AII 11 (AN) 25 2O 11 ",o i12... i6 4 i 12 16 20 24 4 8 TIME (HOURS) 3 8 12 16 20 24 4 8 FIG, 1. Circadian rhythm of serum cortisol secretion. The serum cortisol concentrations of all the children, measured every 30 minutes during 24 hours, showed a normal pattern, including high concentrations in the early morning, several concentration peaks during the day, and no evidence of nocturnal suppression. ixgday (950 + 250 nmolday), with a range of 24 to 53 ixgday (660 to 1460 nmolday). The growth patterns of all of the children (including height, weight, height-velocity, and increment of boneage) were normal throughout the entire treatment period. 4 DISCUSSION The most important safety consideration in young children treated with inhaled corticosteroids for long periods is the effect of the treatment on growth and pituitary-adrenal function. Serum cortisol concentration varies over a 24-hour period. Cortisol is secreted into the blood in spurts, resulting in a number of high and low concentration peaks. The peaks are relatively low during the day, decrease even further at night, and then increase toward the morning. Because of the dynamic nature of this system, a single measurement of serum cortisol during the day is inadequate for assessment of serum cortisol concentration, and samples should preferably be obtained repetitively during the day and night. The resulting "time concentra- tion profile" better reflects individual daily cortisol production. Recently Law et al. 1 have shown that in some children treated with relatively low doses of inhaled corticosteroids (beclomethasone dipropionate, 300 to 600 Ixgday), nocturnal cortisol secretion was decreased. Moreover, this suppression of cortisol secretion was dose-dependent. 1 Two other studies of the same drug in children have shown similar results. 2,s In one of these studies, s an abnormal response to the ACTH test was found in one of the children treated with 400 txgday of inhaled beclomethasone. In our group of children, who were treated with a relatively low dose of budesonide (200 txgday), we did not find evidence of suppression of serum cortisol concentrations at any point during a 24-hour period (Fig. 1). The data presented in this article are important because they were collected after 3 to 5 years of continuous treatment with inhaled corticosteroids. Because we could not find a group of children who had continuously taken antiasthma medications other than corticosteroids for 3 to 5 years and
J ALLERGY CLIN IMMUNOL Volovitz et al. 877 VOLUME 96, NUMBER 6, PART 1 25 50 ~'20 "0 ',,.J o} 40 J... --... -, El0,= a) or) 5 "~ 30._= 1:: o 0 E20 O0 10 " )< O i i i i i I I J I I ~ I I i i i i i [ i i i i i i i i i i i i i i F i i i i i i [ i i i 8 12 16 20 24 4 8 HOURS -- Lacerda ---Migeon Perkoff --We tzman --Tabachnik --Volovitz FIG. 2. Mean 24-hour serum cortisol concentration. The mean 24-hour serum cortisol time concentration profile was normal, including highest concentrations in the early morning, several concentration peaks during the day, with a decrease during the night and an increase toward the morning. The pattern in our group of children (bod dne) was similar to that observed in healthy adults and children (fineines). 7,9-~2 because data on 24-hour cortisol concentration in normal and asthmatic children not taking corticosteroids were available to us from two other studies performed in our country, 2, 3 we did not include a control group. The mean 24-hour serum cortisol concentration observed in the children in our study after 3 to 5 years of budesonide therapy was similar to the mean 24-hour serum cortisol concentration observed in healthy children 2, 3 and in children with chronic asthma not taking corticosteroids. 2 Individual patterns of the mean 24-hour serum cortisol "time concentration profile" were found to be similar to the pattern observed in healthy adults and children 2, 6-9 (Fig. 2). The response to corticotropin stimulation was also normal in all of the children (Fig. 3). This preservation of the circadian cortisol secretion pattern, including the high and low concentration peaks, indicates that the hypothalamus-pituitary-adrenal axis remained intact and that the negative feedback system of this axis was functioning on a physiologic basis? The relatively short-lasting low serum cortisol concentration observed in some of our patients during the night (Fig. 1) was considered by us to Lower Normal Limit 4 ugdl i s am TIME 1hr. post ACTH FIG. 3. Corticotropin stimulation test. The mean morning cortisol concentration ranged from 8.5 to 18 i~gdl (234 to 497 nmoll), much above the 8:00 AM low normal limit of 4 i~gdl (110 nmoll) in our laboratory. The mean serum concentration at 60 minutes after the 0.25 Fgdl intravenous corticotropin stimulation test ranged from 22.7 to 41.6 i~gdl (627 to 1148 nmoll), much above the low normal limit of 18 Fgdl (4.97 nmoll) in our laboratory. have no clinical significance for several reasons. First, a short physiologic nocturnal decrease in serum cortisol concentration is common and found in healthy individuals (Fig. 2). 8, 9, 11 In contrast, in all of the studies demonstrating significant nocturnal suppression of cortisol secretion, 1-3 nearly undetectable concentrations of cortisol during the night, which lasted for many hours, were reported. Second, all of the children, including those with relatively short-lasting low serum cortisol concentrations during the nig]ht, had other indications of the integrity of their hypothalamus-pituitary-adrenal axis function, such as a normal response to ACTH stimulation, normal 24-hour urine cortisol secretion, and a normal circadian serum cortisol secretion pattern with high and low diurnal concentration peaks. Finally, all of these children showed normal growth and weight gain during the 3 to 5 years of treatment with inhaled budesonide. 4 The adverse effects of inhaled corticosteroid therapy are dose-dependent, a, 12-~5 Recent studies have shown some slowing of linear growth, especially when relatively high doses (800 p~gday) of inhaled corticosteroids were used? 2,13 Treatment with even higher doses (1000 to 1800 ixgday)
878 Volovitz et al. J ALLERGY CLIN IMMUNOL DECEMBER 1995 usually caused pituitary-adrenal suppression. 1,14 However, as shown by us and others, the use of low doses of inhaled corticosteroids (budesonide, 200 txgday) are both clinically effective and safe. 4, 15 There were no adverse effects on the pituitaryadrenal function even according to the sensitive test for 24-hour serum cortisol secretion. We conclude that the prolonged administration of inhaled budesonide in a dose of 200 txgday to young children with severe asthma has no adverse effect on either serum or urinary cortisol concentration including, 24-hour serum cortisol secretion, and consequently, has no adverse effect on pituitary-adrenal function. REFERENCES 1. Law CM, Marchant JL, Honour JW, Preece MA, Warner JO. Nocturnal adrenal suppression in asthmatic children taking inhaled beclomethasone dipropionate. Lancet 1986; 1:942-4. 2. Tabachnik E, Zadik Z. Diurnal cortisol secretion during therapy with inhaled beclomethasone dipropionate in children with asthma. J Pediatr 1991;118:294-7. 3. 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. 4. Volovitz B, Amir J, Malik H, Kaushansky A, Varsano I. Growth and pituitary-adrenal function in children with severe asthma treated with inhaled budesonide. N Engl J Med 1993;329:1703-8. 5. Varsano I, Volovitz B, Malik H, Amir Y. Safety of one year with budesonide in young asthmatic children. J ALLERGY CLIN IMMUNOL 1990;85:914-20. 6. Lacerda L, Kowarski A, Migeon CJ. Integrated concentration and diurnal variation of plasma cortisol. J Clin Endocrinol Metab 1973;36:227-38. 7. Migeon CJ, Tyler FH, Mahoney JP, et al. The diurnal variation of plasma levels and urinary excretion of 17- hydroxy corticosteroids in normal subjects, night workers and blind subjects. J Clin Endocrinol Metab 1956;16:622-33. 8. Perkoff GT, Eiknes K, Nugent CA, et al. Studies of the diurnal variation of plasma 17-hydroxycorticosteroids in man. J Clin Endocrinol Metab 1959;19:432-43. 9. Weitzman ED, Fukushima D, Nogeire C, et al. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab 1971;33:14-22. 10. Prahl P. Adrenocortical suppression following treatment with beclomethasone and budesonide. Clin Exp Allergy 1991;21:145-6. 11. Wallace WHB, Crowne EC, Shalet SM, et al. Episodic ACTH and cortisol secretion in normal children. Clin Endocrinol 1991;34:215-21. 12. Wolthers OD, Pederson S. Controlled study of linear growth in asthmatic children during treatment with inhaled glucocorticosteroids. Pediatrics 1992;89:839-42. 13. Littlewood JM, Johnson AW, Edwards PA, Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate. Lancet 1988;1:115-6. 14. Pedersen S, Fuglsang 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. 15. Agertoft L, Pedersen S. Importance of the inhalation device on the effect of budesonide. Arch Dis Child 1993;69:130-3. Bound volumes available to subscribers Bound volumes of THE JOURNAL OF ALLERGY- AND CLINICAL IMMUNOLOGY are available to subscribers (only) for the 1995 issues from the Publisher, at a cost of $73.00 for domestic, $99.51 for Canadian, and $93.00 for international subscribers for Vol. 95 (January-June) and Vol. 96 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318; phone 1 (800) 453-4351 or (314) 453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.