Adrenal Suppression with High-Dose Fluticasone

Abstract

Source: Paton J, Jardine E, McNeill E, et al. Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone. Arch Dis Child. 2006;91:808–813; doi:10.1136/adc.2005.087247Inhaled fluticasone is an effective maintenance therapy for asthmatic children but in recent years there have been several disturbing case reports of morbidity due to adrenal suppression among children treated with >400 μg/day, the maximum dose licensed by the FDA in the US for children with asthma.1–3 Investigators from Royal Hospital for Sick Children, Glasgow, UK studied asthmatic children receiving high-dose inhaled fluticasone to determine the prevalence of adrenal suppression. Records of all children treated in the respiratory clinics at the Royal Hospital for Sick Children were reviewed to identify patients who were prescribed inhaled fluticasone >400 μg/day from January 2000 to April 2002. Because of significant morbidity and mortality due to adrenal suppression previously encountered in their practice, the authors considered adrenal testing to be clinically indicated, and all identified patients were requested to come in for testing. Adrenal function was assessed following administration of low-dose synthetic ACTH (Synacthen). Cortisol response was defined as normal (peak >18.2 μg/dL), impaired (≤18.2 μg/DL), or flat (peak ≤18.2 μg/dL with increment <7.3 μg/dL and basal morning cortisol <7.3 μg/dL).Initial record review identified 422 children prescribed high-dose fluticasone. Further inquiry revealed that 161 of these were no longer receiving doses >400 μg/day, and of the remaining 261 children, 220 (84%) were tested for adrenal suppression. Of 192 children receiving fluticasone >500 μg/day, 6 (3%) had flat responses, 82 (43%) had impaired responses, and 104 (54%) had normal responses. Of 25 children taking fluticasone <500 μg/day, none had flat responses, 4 (16%) had impaired responses, and 21 (84%) had normal responses. No relationship was found between fluticasone dose and height or weight. Two patients had had symptoms of adrenal insufficiency. Both symptomatic patients and all those with flat ACTH responses were taking fluticasone doses >1000 μg/day. The authors concluded that monitoring for adrenal suppression is indicated among children taking fluticasone at doses >400 μg/day.Dr. Aldous has disclosed no financial relationship relevant to this commentary. This commentary contains a discussion of an unapproved use of a commercial product – doses of fluticasone above the maximum dose licensed by the FDA.This study from the UK provides a population-based estimate of the prevalence of adrenal suppression among children taking higher doses of inhaled fluticasone. Although the study “population” is relatively small (children of a single clinic system in Scotland), the authors attempted to identify all children in this population receiving fluticasone at doses >400 μg/day and were successful at studying 84% of those identified. The prevalence of abnormal adrenal responses, 42%, is surprisingly high, and while the clinical significance of these laboratory abnormalities is unknown, the case reports presented in the article make clear that some of these children are at increased risk for catastrophic events. The authors chose to study children taking doses >400 μg/day because such doses exceed the licensed pediatric dose for fluticasone in Scotland. In the US the approved dose for children 4–11 years of age is up to 200 μg/day. A systematic review of the efficacy of inhaled fluticasone in treating children with asthma found that the dose-response curve “appears to plateau between 100 and 200 μg per day” but that there was some evidence for “additional efficacy at the 400 μg per day dose in children with severe asthma.”4 In practice it is easy to exceed these doses.Asthma causes hundreds of deaths and hundreds of thousands of hospitalizations annually among US children.5 Inhaled fluticasone is one of the most important advances in the treatment of children with persistent asthma, and fears about growth suppression and other side effects (eg, cataracts, glaucoma6) must not cause us to abandon its use in children who need it. The present study is a reminder to prescribe inhaled fluticasone at doses in the approved range, at least initially, and to attempt to step down to the lowest possible doses after control is achieved. When higher doses appear necessary, it is important to remember the potential adrenal effects and consider all treatment options carefully, including consultation with a specialist experienced in treating children with severe asthma.