Date Published: August 25, 2011
Publisher: BioMed Central
Author(s): Alexandra Ahmet, Harold Kim, Sheldon Spier.
Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory agents available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. Although these medications are considered safe at low-to-moderate doses, safety concerns with prolonged use of high ICS doses remain; among these concerns is the risk of adrenal suppression (AS). AS is a condition characterized by the inability to produce adequate amounts of the glucocorticoid, cortisol, which is critical during periods of physiological stress. It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy that can persist for up to 1 year after cessation of corticosteroid treatment. If left unnoticed, AS can lead to significant morbidity and even mortality. More than 60 recent cases of AS have been described in the literature and almost all cases have involved children being treated with ≥500 μg/day of fluticasone.
Asthma is the most common chronic disease among the young, affecting 10% to 15% of Canadian children and adolescents [1-3]. It is also a major cause of pediatric hospital admissions and emergency department visits [4,5]. Despite significant improvements in the diagnosis and management of asthma over the past decade, as well as the availability of comprehensive and widely-accepted national and international clinical practice guidelines for the disease [6,7], asthma control in Canada remains suboptimal. Approximately 50-60% of Canadian children and adults have uncontrolled disease according to guideline-based asthma control criteria [8,9].
Although the various ICSs available for the treatment of asthma are believed to have similar clinical efficacy when used at equivalent therapeutic doses, significant differences in their pharmacokinetics (PK) and pharmacodynamics (PD) exist which can impact their respective safety profiles. These differences warrant careful consideration when determining the benefits and risks of each ICS medication in an individual patient, particularly as they relate to the risk of systemic side effects such as AS . Table 3 provides an overview of the PK and PD parameters that influence the safety of ICSs, such as oral bioavailability, lung deposition, protein-binding, half-life and systemic clearance .
As highlighted previously, AS often goes unrecognized until physiologic stress precipitates an adrenal crisis. As a result, the frequency of AS in the asthma population is not well documented. Currently, there are no national guidelines for AS screening in children with asthma. Evidence suggests that screening approaches vary widely, and that many children with asthma who are at risk for AS are not screened. Guidelines in the UK state that the use of fluticasone at doses ≥400 μg/day should be accompanied with screening for AS . Brodlie and McKean investigated the screening practices of 14 tertiary pediatric respiratory centres in the UK and found that, despite these guidelines, less than 60% had an official policy for screening children with asthma. The investigators also found significant differences in the threshold ICS dose used to start testing for AS, the type of screening tests performed, and the interpretation of test findings. In children prescribed fluticasone, 50% of centres tested for AS at ≥500 μg/day, 21% at ≥1000 μg/day and, in 29%, the cut-off dose for testing varied. For beclomethasone, 50% of centres tested at ≥1000 μg/day, 14% at ≥1500-2000 mg/day and, in 36% of centres, various cut-off doses for testing were used. When considering AS testing, the use of oral prednisolone was taken into consideration by less than 60% of centres. A low-dose ACTH stimulation test was performed in 50% of centres, a high-dose test in 21%, and a morning cortisol measurement in only 8%; in 21% of centres, the screening test used varied. In total, only 57% of respondents regarded AS as a significant problem .
In spite of the measurable effects of ICS therapy on the HPA axis, it is important to remember that effective anti-inflammatory therapy is essential for the treatment of asthma, that ICSs are the most effective anti-inflammatory agents available, and that the suppressive effects of ICS therapy on the HPA axis is markedly less than clinically equivalent doses of oral corticosteroids. At low-to-moderate doses, ICS therapy does not present any significant risk for systemic side effects. However, when high doses are used for prolonged periods, serious adverse events, including AS, are possible. The risk for AS can be minimized through increased awareness and early recognition of at-risk patients, regular patient follow-up to ensure the lowest effective ICS doses are utilized, and by choosing an ICS medication with minimal systemic effects. When high-dose ICS therapy is required, important differences in the PK and PD characteristics of the available ICSs warrant consideration in clinical practice. For patients with proven AS, family education and stress steroids during times of illness, injury or surgery are imperative and will help reduce the morbidity associated with this serious complication of ICS therapy.
Dr. Alexandra Ahmet has received honoraria for continuing education from Nycomed, MD Briefcase and Peer Review.
AA contributed to the conception, drafting and writing of the manuscript and to revising it for important intellectual content. HK and SS contributed to the drafting and development of the manuscript and to revising it critically for important intellectual content. All authors read and approved the final manuscript.