Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. (Original Article).

Background: Until recently, only two cases of acute adrenal crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency of this side effect in the United Kingdom.

Methods: Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory, asking whether they had encountered asthmatic patients with acute adrenal crisis associated with CS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs and abnormal hypothalamic-pituitary-adrenal axis function test results.

Results: From an initial 2912 questionnaires, 33 patients met the diagnostic criteria (28 children, five adults). Twenty-three children had acute hypoglycaemia (13 with decreased levels of consciousness or coma; nine with coma and convulsions; one with coma, convulsions and death); five had insidious onset of symptoms. Four adults had insidious onset of symptoms; one had hypoglycoemia and convulsions. Of the 33 patients treated with 500-2000 [micro]g/day ICS, 30 (91%) had received fluticasone, one (3%) fluticasone and budesonide, and two (6%) beclomethasone.

Conclusions: The frequency of acute adrenal crisis was greater than expected as the majority of these patients were treated with CS doses supported by British Guidelines on Asthma Management. Despite being the least prescribed and most recently introduced CS, fluticasone was associated with 94% of the cases. We therefore advise that the licensed dosage of fluticasone for children, 400 [micro]g/day, should not be exceeded unless the patient is being supervised by a physician with experience in problematic asthma. We would also emphasise that until adrenal function has been assessed patients receiving high dose CS should not have this therapy abruptly terminated as this could precipitate adrenal crisis.

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Corticosteroids are highly effective therapy for persistent asthma due to their anti-inflammatory activity. Inhaled corticosteroids (ICS) were developed to reduce the possibility of side effects associated with oral corticosteroids. Side effects are unlikely with beclomethasone (BDP) and budesonide (BUD) using doses of up to 400 [micro]g/day. (7) and with fiuticasone (FP) in doses of up to 200 [micro]g/day. (1,2) In severe asthma, the benefits of controlling symptoms often outweigh the risk of side effects and, in these circumstances, use of ICSs in higher daily dosages is recognised. (3) Although recently it has been suggested that the maximum clinical effect of inhaled FP is achieved in adolescents and adults in a dose of around 500 [micro]g/day, (4) others have suggested benefits of FP in severe asthma at higher dosages (5,6) even up to 1500 or 2000 [micro]g/day. (7) Although both British and international guidelines recommend up to 1000 [micro]g/day in severe cases in children,3 there are no long term stu dies to support this. Despite the use of these high doses, serious systemic effects in patients receiving ICS are extremely rare. There are, however, a few reports of severe growth retardation and adrenal suppression in children taking ICS doses [greater than or equal to] 1000 [micro]/day. (8,9)

Fluticasone was introduced in the UK in 1993 as a potentially safer ICS than those already in use. (10) Oral systemic availability of FP was low because of the almost complete first pass hepatic metabolism (about 99%) (10) of the swallowed fraction (usually at least 70% of the emitted dose) after oral inhalation. However, significant amounts of ICS is also absorbed systemically through the lung, escaping hepatic first-pass metabolism. (1) At high doses ([greater than or equal to] 1000 [micro]g/day) severe growth retardation and adrenal suppression have been attributed to systemic activity of FP. (8,9) We recently described four cases of acute adrenal crisis associated with inhaled FP, including three children presenting with hypoglycaemic coma and convulsions. (1,2)

Until 1999 there were only two published case reports of acute adrenal crisis associated with ICSs in more than 30 years' use. One case was an adult receiving 6400 [micro]g/day BUD, (13) and the other was a child receiving 500 [micro]g/day BUD . (14) However, given our experience of adrenal insufficiency in patients on ICS (12) together with our awareness of other colleagues who were encountering the same problem, we decided to conduct a national survey to investigate the frequency of acute adrenal crisis associated with all ICS. Eleven of the cases identified in our survey have also been published as case reports elsewhere. (12-15-17)

METHODS

An initial questionnaire was sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory in which tertiary care physicians were specifically identified. The questionnaire inquired …