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In a recent paper published inThorax Fitzgerald and co-authors purport to have examined the effects of fluticasone propionate and beclomethasone dipropionate on adrenal function in children with asthma.1They state that they have used Dickstein’s low dose ACTH test 2 to do this. However, the dose of ACTH (500 ng/1.73 m2) used in Fitzgerald’s paper is a dose taken from a different paper describing a dose-response relationship between ACTH and serum cortisol concentration published by Crowleyet al 3 and a later paper by the same author comparing low dose with high dose ACTH cortisol secretory dynamics.4 Dickstein’s paper described a low dose ACTH test in adults using a test dose of 1 μg. This dose was not standardised for body surface area and is approximately twice the size of the dose used by Crowley et al. The cortisol secretory dynamics in the two low dose tests are likely therefore to differ as timing of the peak cortisol response is partly dependent on the dose of ACTH administered. The low dose ACTH test described by Crowley showed that 80% of the time the peak cortisol response after bolus intravenous injection of 500 ng/1.73 m2 ACTH has occurred by 20 minutes, and the test protocol calls for sampling at five minute intervals from 10 to 30 minutes after injection to optimise identification of the peak cortisol response. It is also important to note that the rise in serum cortisol concentration at 20 minutes is identical after both high and low dose ACTH injection in normal volunteers. It is likely that, by taking samples at 30 and 60 minutes only, Fitzgerald has missed the peak cortisol response to 500 ng/1.73 m2 ACTH. Taken in this context, the higher serum ACTH levels observed in the children during treatment with fluticasone may be important. Thus, Fitzgerald’s findings regarding adrenal function may not be relevant and should be challenged.
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authors’ reply We thank Dr Crowley for her interest in our recent article regarding the use of a low dose synacthen test (LDST) in monitoring moderately severe paediatric asthmatic subjects with the potential for adrenal suppression.1-1 Dr Crowley challenges the interpretation of our results based upon data in her two papers in “eight healthy young male volunteers aged 20–22 years”1-2 and “six healthy adult males aged 20–22 years”.1-3
Firstly, the ACTH dosing regime used in our study was arbitrarily chosen at the time of designing the study following communication with Dickstein’s group in Israel. Dickstein and colleagues published papers in 1991 using ACTH doses of 1 μg in 20 adults1-4 and in 1995 using 0.5 μg/1.73 m2 in a population of healthy volunteers (n = 33) and asthmatic children and adults (n = 46).1-5 In our paper1-1 we referenced this work. We are aware of the work of Crowley et alfrom 19911-2 and 19931-3 using LDST (0.5 μg/1.73 m2) and are happy to acknowledge their contribution of patients to the literature. However, the relevance of the papers by Crowley et al 1-2 1-3to our paediatric asthmatic population is unclear. Indeed, the data presented by Crowley et al are not in asthmatics, nor in subjects chronically exposed to high dose inhaled and intermittent systemic corticosteroids. Whether their data are directly applicable to an entirely different cohort of paediatric patients with chronic disease should be further investigated.
In our study an additional cortisol sample 14 minutes after ACTH administration would have answered the question about a possible missed cortisol peak. However, Broide et al 1-5 measured serum cortisol levels at 20, 30, and 45 minutes after 0.5 μg/1.73 m2 ACTH and found similar levels at 20 and 30 minutes in both healthy controls and asthmatic subjects on inhaled corticosteroids. Thus, we believe it unlikely that we have missed the peak cortisol response. Furthermore, we could not demonstrate a difference between treatment sequences in other measures of adrenal suppression including the baseline and 60 minute cortisol levels and the 24 hour urinary free cortisol levels. The marginally higher ACTH levels (p<0.04) in the subjects who did not receive systemic corticosteroids during the study whilst on fluticasone propionate therefore remain of uncertain significance.
We believe that to suggest our data are “largely irrelevant” seems harsh based upon the evidence currently available.