Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate

doi:10.1016/S0140-6736(96)03339-9

The Lancet

Volume 348, Issue 9019, 6 July 1996, Pages 27-29

https://doi.org/10.1016/S0140-6736(96)03339-9 Get rights and content

Summary

Background

Fluticasone propionate was introduced in 1993 in the UK as a potentially safer inhaled corticosteroid than those already in use. The efficacy and safety of fluticasone has been established at recommended doses of 200μg/day, but not at the higher doses that are often used.

Methods

Growth retardation was observed in six severely asthmatic children after introduction of high-dose fluticasone propionate treatment (dry powder). Assessment of cortisol response was by insulin-induced hypoglycaemia in three cases, by short tetracosactrin test in two, and by low-dose tetracosactrin and 24-hour urinary cortisol/ creatinine ratio in one.

Findings

Six children with growth retardation noted after treatment with high-dose fluticasone propionate were found to have adrenal suppression. In one case the growth rate and cortisol response returned to normal 9 months after the fluticasone dose was reduced to 500μg/day.

Interpretation

When high doses of fluticasone propionate are used, growth may be retarded and adrenal suppression may occur.

Introduction

Side-effects of inhaled corticosteroids such as growth retardation and adrenal suppression have been described in children and are more likely when doses exceed 400 (μg/day of beclomethasone dipropionate or budesonide.¹ In severe asthma the benefits of controlling symptoms often outweigh the risk of side-effects and, in these circumstances, the use of inhaled corticosteroids in daily dosages greater than 1000μg/day is recognised.² Some studies have suggested a better safety profile for fluticasone propionate than beclomethasone or budesonide, with bioavailability approaching zero.3, 4, 5 These claims have recently been challenged.⁶ The efficacy and safety of fluticasone at 200μg/day is established⁷ but the side-effects of high doses (5=1000μg/day) in children are unknown.

We report six children with growth and adrenal suppression during treatment with high-dose inhaled fluticasone.

Section snippets

Patients and methods

The children we report had severe asthma and were attending an asthma clinic. Each child had required high-dose beclomethasone or budesonide (≥800μg/day) which was changed to high-dose fluticasone (≥1000μg/day) as a theoretically safer alternative to oral steroids. The children were also taking short-acting and long-acting inhaled beta 2 agonists and theophyllines (if tolerated). After the introduction of high-dose fluticasone, a reduction in growth velocity was noted. Investigations in four

Patient one

A 7-year-old boy, during the year before starting fluticasone was treated with nebulised budesonide 2 mg/day. At the age of 5·2 years fluticasone 1500μg/day given via a dry powdered device (Diskhaler, Allen and Hanbury, Uxbridge, UK) was substituted. During the next year his asthma was better controlled with minimal requirement for systemic corticosteroids. While on fluticasone, his growth rate decreased and he was found to have a low baseline cortisol which failed to rise after insulin-induced

Discussion

We report six children with asthma whose symptoms improved with a change of inhaled corticosteroids from either budesonide or beclomethasone to high-dose fluticasone (≥1000μg/day) but in whom this change was associated with growth retardation and adrenal insufficiency. In none of the cases could our findings be accounted for by increased use of oral steroids. In patient one, growth and adrenal function returned to normal 9 months after reducing the dose of fluticasone. Both the other inhaled

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However, there are several reports of Cushing syndrome, adrenal suppression and growth failure in association with concomitant use of inhaled corticosteroids and itraconazole [5–7]. While fluticasone has close to 100% first-pass metabolism when administered orally or nasally, the inhaled route is associated with high systemic bio-availability [7,8]. Therefore, the combination of inhaled fluticasone and itraconazole could lead to significant accumulation of fluticasone, and in combination with oral prednisone could lead to significant glucocorticoid excess with resulting insulin resistance.
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Evaluation of adrenocortical function in 3-7 aged asthmatic children treated with moderate doses of fluticasone propionate: Reliability of dehydroepiandrosterone sulphate (dhea-s) as a screening test
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Citation Excerpt :
Inhaled corticosteroids (ICS) are the first-line treatment in the management of persistent asthma.1 Recently there have been reports of symptomatic adrenal insufficiency in children on chronic ICS treatment.2–4 Most of these children were treated with high doses of inhaled fluticasone.
Inhaled corticosteroids (ICS) are the first-line therapy in the treatment of persistent asthma. At medium to high doses and prolonged usage, ICS can supresss the hypothalamic-pituitary-adrenal axis. Dehydroepiandrosterone sulphate (DHEA-S) is a corticotropin-dependent adrenal androgen precursor that is supressible in patients treated with ICS.
To evaluate the adrenal axis in asthmatic children treated with moderate doses of fluticasone propionate and to evaluate the DHEA-S as a possible marker for adrenal axis ın preadrenarchal children.
Twenty-eight children with persistent asthma with a mean age of 4.4 years (median 4.2; range 2.5-7.1) on long term treatment (mean 6.16; median 6; range 4.5-9 months) with moderate doses (mean 250; median 253; range 158-347 (g/m²/day) of inhaled fluticasone propionate were evaluated with low-dose ACTH stimulation test to assess adrenal function, and DHEA-S levels were compared with the results.
One out of 28 patients (3.57%) demonstrated an abnormal cortisol response to low-dose ACTH test. There was no correlation between DHEA-S and peak cortisol, morning cortisol and fasting blood glucose levels. However, mean inhaled corticosteroid dosages were inversely correlated with the DHEA-S.
In most of the children with persistent asthma, mild to moderate fluticazone propionate doses supress the hypothalamic-pituitary-adrenal axis rarely. Chronic moderate doses of ICS may suppress adrenal androgen levels without supression of cortisol production. DHEA-S levels may be used as a practical method to follow adrenal functions and may be an earlier indicator of adrenal dysfunction in children.
Normal and Aberrant Growth
2011, Williams Textbook of Endocrinology, Twelfth Edition
The treatment of asthma in children: Inhaled corticosteroids
2007, Pulmonary Pharmacology and Therapeutics
The evidence that asthma is characterized by extensive inflammation of the airways has warranted the use of inhaled corticosteroid (ICS) in asthma maintenance therapy. Corticosteroid treatment, especially if high or frequent doses are required, is associated with a range of adverse effects including adrenal suppression and impairment in growth and bone metabolism. New corticosteroids are in development, including mometasone furoate, and some of these are predicted to have reduced adverse effects such as the soft steroid ciclesonide. Soft steroids are designed for delivery near to their site of action, to exert their effect and then to undergo controlled and predictable metabolism to inactive metabolites. This review points out the anti-inflammatory effects of corticosteroid in asthmatic airways and the clinical efficacy and safety of ICS in asthmatic children. The development of a soft steroid should help to achieve the aim of improving the therapeutic profile of ICS in asthma and thus alleviate the ongoing problem of poor patient compliance especially in childhood.

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Early ReportGrowth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients and methods

Patient one

Discussion

Resp Med

Resp Med

Inhaled corticosteroid therapy in children: an assessment of the potential for side effects

Thorax

HIgh dose fluticasone proprionate 1 mg daily, versus fluticasone 2 mg daily, or budesonide 1.6 mg daily in patients with severe asthma

Eur Respir J

Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients

Thorax

Early Report
Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate