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Adrenal Suppression, Evaluated by a Low Dose Adrenocorticotropin Test, and Growth in Asthmatic Children Treated with Inhaled Steroids¹

Department of Pediatrics, Kuopio University Hospital, FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Senja Kannisto, M.D., Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FIN-70211, Kuopio, Finland.

	Abstract

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The aim of the present study was to evaluate the prevalence of adrenal suppression and growth retardation in children using moderate doses of budesonide or fluticasone propionate. Seventy-five asthmatic children were randomly divided into three treatment groups: 30 to the fluticasone propionate (FP), 30 to the budesonide (BUD), and 15 to the cromone (CROM) group. FP doses were 500 µg/day during the first 2 months and 200 µg/day thereafter. The respective BUD doses were 800 and 400 µg/day. A low dose ACTH (0.5 µg/1.73 m²) test was performed before treatment and 2, 4, and 6 months later. The test was considered abnormal if the stimulated serum cortisol concentration was more than 2 SD lower than the pretreatment mean (<330 nmol/L).

The low dose ACTH test was abnormal after both the high and low steroid doses in 23% of the children. At the 4 month measurement there were more abnormal tests in the BUD (n = 9) than in the FP (n = 5) group (P < 0.05). At that time also the stimulated concentration of serum cortisol was lower in the BUD than in the CROM group (P < 0.01), whereas the difference between the FP and CROM groups was not significant. During the study year the mean decrease in height SD score was 0.23 in the children treated with BUD, 0.03 in the children treated with FP, and 0.09 in the children treated with CROM; the difference between the BUD and FP groups was significant (P < 0.05).

In conclusion, the low dose ACTH test revealed mild adrenal suppression in a quarter of the children using moderate doses of inhaled steroids. A FP dose of 200 µg/day caused less adrenal and growth suppression than did a BUD dose of 400 µg/day.

	Introduction

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INHALED STEROIDS may have systemic effects and thus suppress adrenal function and growth in children (1, 2, 3, 4, 5). Growth retardation caused by inhaled steroids is a complex phenomenon and is unlikely to be mediated solely through the hypothalamo-pituitary-adrenal axis (2, 5). Adrenal suppression has conventionally been evaluated by high dose ACTH tests, by determining cortisol excretion in the urine, or by measuring basal concentrations of plasma cortisol in the morning. Based on these methods, it has been assumed that budesonide (BUD) and beclomethasone dipropionate (BDP) at doses of 400 µg/day or less and fluticasone propionate (FP) at doses of 200 µg/day or less are safe, with minor or no risk for adrenal suppression (6, 7, 8, 9, 10, 11, 12). However, these assays either are not applicable to clinical practice or are not sensitive enough to reveal incipient adrenal suppression. According to recent studies, low dose ACTH tests seem to be more sensitive than conventional tests in detecting mild adrenal suppression (13, 14, 15, 16).

Studies of the systemic effects of inhaled steroids have given contradictory results; some studies have stressed the adverse effects of FP (17, 18), and others those of BUD (3, 11) or BDP (19). This variation is mainly due to the fact that it is difficult to define with precision the clinically equivalent doses for inhaled steroids. FP has about twice as strong glucocorticoid receptor affinity as BUD or BDP (20), and therefore, FP should be used in lower doses (11, 21, 22).

The aim of the present study was to evaluate the low dose ACTH test for diagnosis of adrenal suppression in children using moderate doses of inhaled steroids. In addition, we compared the suppressive effects of FP and BUD on adrenal function and growth.

	Materials and Methods

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Subjects

The study group consisted of 75 asthmatic children (36 boys and 39 girls) with a mean age of 9.5 yr (range, 5.5–14.7). Sixty-two children (83%) had newly diagnosed asthma and started their first period of maintenance medication. Four children (5%) had used cromone medication continuously during the preceding 3 months, and 9 children (12%) had used inhaled on-demand ß₂=agonists.

The children’s growth data preceding the study period were collected from their health cards. The weights and heights of Finnish children are measured annually in child welfare clinics, preschool, and school health centers and are registered on health cards. Therefore, in all cases exact data on the heights and weights from the preceding year were available. The age and sex distributions as well as the pretreatment growth data of the children are presented in Table 1. The individual heights are expressed as SD score, and the weights are expressed as percentages in relation to the mean weight for height (23).

Study protocol

Sixty asthmatic children were randomly classified to receive either BUD or FP. Fifteen asthmatic children, treated with either cromolyn or nedocromil, formed the control (CROM) group. None of the 75 children had used inhaled or oral steroids during the preceding 12 months.

BUD was administered with a dry powder inhaler (Turbuhaler, Astra S\|[ouml ]\|dert\|[auml ]\|lje, Sweden); the dose was 800 µg/day during the first 2 months and 400 µg/day thereafter. Correspondingly, FP was given as a dry powder (Diskus, Glaxo, Hertfordshire, UK); the dose was 500 µg/day during the first 2 months and 200 µg/day thereafter. In both steroid treatment groups the daily medication was divided into 2 doses. Based on our stepwise maintenance policy (24), 18 (60%) children in the BUD group and 19 (63%) children in the FP group were taken off steroids and put on cromones after 4 months of steroid treatment. The remaining children continued to use either BUD (400 µg/day; n = 12) or FP (200 µg/day; n = 11; Fig. 1).

View larger version (31K): [in this window] [in a new window]   Figure 1. The study protocol. All children were examined at the beginning, at the 4 month visit, and 1 yr after starting the study. In addition, the children in the BUD and FP groups were examined at the 2 and 6 month visits. During all visits the children’s heights and weights were recorded. Blood tests were obtained at the beginning and at the 2, 4, and 6 month visits.

The children in the BUD and FP groups were examined five times: at the beginning of the study and at 2, 4, 6, and 12 months. The children in the CROM group were examined at the beginning and at 4 and 12 months (Fig. 1). At each visit the heights and weights of the children were recorded by the same asthma nurse. Compliance was assessed by a home monitoring diary in which the subjects had recorded the used medication doses. At the baseline forced expiratory volume in one second (FEV₁) was equal in different treatment groups. At 4 months, FEV₁ improved in mean 8.4% (SD 13.9) in the BUD and 5.4% (SD 9.7) in the FP group and decreased 1.5% (SD 7.2%) in the CROM group (P < 0.05 vs. both steroid groups).

Low dose ACTH tests and cortisol determinations

A low dose ACTH test (13) was performed at the beginning of the study and at 2, 4, and 6 months. Before the cannula was inserted, a topical anesthetic cream (Emla, Astra) was used. The basal blood samples for serum cortisol were obtained, and the diluted ACTH (Synacthen, Ciba-Geigy AG, Basel, Switzerland) was injected through the cannula. The ACTH dose was 0.5 µg/1.73 m² body surface area. We assumed this ACTH test (13) to be the most sensitive to find mild adrenal suppression. After ACTH injection, the serum samples for cortisol determinations (Cortisol ¹²⁵I RIA Kit, Orion Diagnostica, Espoo, Finland) were withdrawn at 30 and 60 min. The ACTH tests were performed between 0800–1100 h; for individual patients the tests were performed at the same time on all occasions.

The ACTH test result was considered abnormal if the stimulated cortisol was less than 330 nmol/L after ACTH injection. The criteria for an abnormal test result were calculated from the baseline measurements before maintenance medication; a stimulated cortisol concentration of more than 2 SD below the mean was considered abnormal.

Statistical analysis

The data were analyzed by SPSS version 8.0 (SPSS, Inc., Chicago, IL). The Kolmogorov-Smirnov test was used to check that the continuous variables were normally distributed. The results are presented as means, SD scores, ranges, and 95% confidence intervals (95% CI). The statistical significance of the differences in continuous variables was studied by t test, and that in noncontinuous variables was determined by the ² test.

	Results

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The age, sex, height, and weight data in the three treatment groups at the beginning of the study are presented in Table 1. The study groups did not differ significantly with respect to age, height SD score, or changes in height SD score during the preceding year. The children in the steroid treatment groups were slightly heavier than those in the CROM group.

Baseline serum cortisol

The baseline concentrations of serum cortisol in the three treatment groups are presented in Table 2. At the beginning there were no significant differences between the groups. After 2 months of therapy, the baseline serum cortisol concentrations showed a decreasing trend in both BUD and FP groups. At the 4-month measurements, when the steroid dose had been at a reduced level for 2 months, the basal serum cortisol concentrations rose in the FP group, and the difference between the FP and BUD groups became statistically significant. After inhaled steroids were changed to cromones, the baseline cortisol concentrations were very close to the pretreatment levels within 2 months.

At the beginning of the study the mean serum stimulated cortisol was 516 nmol/L (95% CI, 495–538) in the whole study group. The values did not differ between measurements performed before (518 nmol/L; 95% CI, 483–552) and after (516 nmol/L; 95% CI, 490–541) 1000 h. In most tests (97%) the highest stimulated cortisol value was measured at the 30 min point. The stimulated cortisol concentrations in the three treatment groups are presented in Table 3. At the beginning of the study there were no significant differences between the groups. After 2 and 4 months of medication the stimulated concentrations of serum cortisol decreased significantly in both steroid groups. After the steroid doses were reduced, the stimulated cortisol concentrations showed an trend to increase in the FP group, but not in the BUD group. When inhaled steroids were changed to cromones, the stimulated concentrations of cortisol increased to the level seen at the beginning of the study (Table 3).

The lower normal limit for stimulated cortisol after ACTH injection was calculated from the baseline tests and was 330 nmol/L. By this criterion, 14 (23%) of the 60 steroid users had an abnormal ACTH test result after 2 months of therapy; 6 of them belonged to the FP group, and 8 to the BUD group. Abnormal ACTH test results were equally common after 4 months of therapy, but now 5 cases belonged to the FP group and 9 to the BUD group (P < 0.05). At the 6 month measurement, 4 children, 16% of the steroid users, still had an abnormal ACTH test result. The test was normal in all cromone users, including those 37 children taking steroids for the first 4 months.

Growth

The height SD score decreased during the 4-month treatment period in the BUD group (P < 0.01), but not in the FP and CROM groups (Fig. 2). During the same 4-month period the mean decrease in height was 0.05 SD score (95% CI, -0.16 to +0.06) in the children with an abnormal ACTH test and 0.03 SD score (95% CI, -0.06 to +0.01) in those with a normal ACTH test.

View larger version (16K): [in this window] [in a new window]   Figure 2. Changes in height SD score (mean, 95% CI) in the three study groups during the year preceding the study (broken line) and during the first 4-month treatment period (solid line). During the preceding year the mean changes in height SD score were the same in all treatment groups. At the 4 month measurements the BUD group differed significantly from both FP (P < 0.01) and CROM (P < 0.05) groups.

View larger version (17K): [in this window] [in a new window]   Figure 3. Changes in height SD score (mean, 95% CI) in the three groups for those children who were treated with the same drug throughout the whole year. Broken lines represent mean changes in height SD score during the year before the study, and solid lines represent mean changes during the year after starting asthma medication. The difference between the BUD and FP groups was significant (P < 0.05).

	Discussion

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In the present study almost a quarter (23%) of the children using moderate doses of inhaled steroids had subnormal responses in the low dose ACTH test. Even though there have been many studies on side-effects of inhaled steroids in children, few of them have evaluated the prevalence of abnormal adrenocortical function. We found only three such studies of children using moderate doses of inhaled steroids. Shapiro et al. (12) found that 9–12% of the children using BUD (400–800 µg/day) had subnormal values for basal plasma cortisol. In two other studies 30–35% of the children using inhaled steroids had adrenal suppression. In the study by Priftis et al. (6) children were using BDP (200–900 µg/day), and their adrenal function was evaluated by urinary excretion of cortisol metabolites. Broide et al. (13) used a low dose ACTH test, and the daily BDP or BUD doses were, on the average, 500 µg/m² for both drugs. Thus, according to previous and present observations, 25–30% of the children using moderate doses of inhaled steroids have measurable suppression of adrenal function. This proportion depends on the number and sensitivity of the available tests. Although the clinical importance of these laboratory findings has remained unresolved, the results raise the possibility of significant adrenal suppression in children who are sensitive to steroids and in children with high doses of steroids (25, 26).

Low dose ACTH tests have previously been used in patients with adrenocortical insufficiency (15, 27) and recently also in children using inhaled steroids (13, 25). In the present study the references values for the ACTH test were calculated from the results obtained at the beginning of the study before introduction of inhaled steroids. In this way the lower limit for the normal cortisol response was lower (330 nmol/L) than the 500 nmol/L used previously (13). Despite this strict limit, we identified abnormal test results in as many as quarter of the steroid users.

In many studies of inhaled steroids, adrenal suppression has been evaluated by measuring basal concentrations of serum cortisol, with a result of some decrease (12), as in the present study, or no decrease (28). However, we detected low levels before any steroid treatment even in children with good responses to low doses of ACTH. In addition, basal concentrations of serum cortisol should be measured early in the morning. In contrast, the time of the day does not influence the stimulated concentration of serum cortisol in a low dose ACTH test (29), as was also observed in the present study. Thus, a serum basal cortisol value alone is not a practical and reliable indicator of adrenocortical function, at least not in out-patients with asthma.

The equivalent or equipotent doses of inhaled steroids are difficult to assess. When FP and BUD have been used in equal doses, the efficacy and systemic effects have been found to be similar (28, 30), or FP has exhibited even greater adrenal suppression than BUD (31). However, in recent studies FP has been as effective as double doses of BUD or BDP, with similar (20) or fewer side-effects (32, 33). The theoretical basis for these different doses lies in differences in the glucocorticoid receptor affinities; FP has twice as strong affinity as BUD and BDP have (20). Our patients used 500 and 200 µg/day FP and 800 and 400 µg/day BUD. These doses are commonly used to treat moderate and severe asthma in children and can be considered to be equivalent (11). With these doses BUD caused more adrenal suppression than FP did; there were more abnormal ACTH test results and lower serum baseline or stimulated cortisol concentrations. However, there are confusing results in studies comparing drug delivery via turbuhaler and diskus; some have found turbuhaler (34) and others diskus (35) to be better. Thus, possibly, BUD could be used at lower doses than those we employed. However, it is worth noting that none of these children had any clinical symptoms suggesting impaired adrenal function. In addition, when the inhaled steroid treatment was changed to cromones, the mean stimulated cortisol values returned to the pretreatment level within 2 months.

BUD suppressed longitudinal growth more than FP did. Actually, the children using FP grew as well as those using cromones. The result was similar whether it was based on 4- or 12-month follow-ups. The decrease in height SD score in our BUD group at 12 months was very close to that reported by Saha et al. (4) in their retrospective analysis of children using inhaled BUD or BDP. They found the most profound effect of inhaled glucocorticoids on growth velocity during the first year of treatment, and the growth velocity remained below mean, which caused the height to decrease about 0.5 SD score during the 5-yr treatment period. This significant growth retardation may even have an effect on final adult height if glucocorticoid treatment is continued for years in sufficiently high doses. On the other hand, growth velocity seems to recover rapidly if growth-suppressive glucocorticoid treatment can be changed to cromones (36).

In our study subnormal ACTH test results were not associated with growth retardation during the first 4 study months, probably because the observation period was too short for growth analysis. In contrast, in children who used steroids the whole year, a subnormal ACTH test at 4 months was associated with 1 yr growth suppression. Thus, a low dose ACTH test may be used to predict growth retardation in children receiving long term inhaled steroid treatment.

In conclusion, the low dose ACTH test proved to be a sensitive method for identifying adrenocortical suppression in children treated with inhaled steroids. A quarter of the children using moderate doses of inhaled steroids had mild adrenal suppression. FP (200 µg/day) suppressed adrenal function and longitudinal growth less than did BUD (400 µg/day).

	Footnotes

 
¹ This work was supported by the Finnish Foundation for Pediatric Research and Kuopio University Hospital (Research Contract 5145).

Received July 9, 1999.

Revised October 15, 1999.

Accepted October 15, 1999.

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