Clinical relevance of inhaled corticosteroids and HPA axis suppression

doi:10.1016/S0091-6749(98)70157-5

Journal of Allergy and Clinical Immunology

Volume 101, Issue 4, Supplement, April 1998, Pages S447-S450

https://doi.org/10.1016/S0091-6749(98)70157-5 Get rights and content

Abstract

Although hypothalamic-pituitary-adrenal (HPA) axis suppression has traditionally been viewed as an adverse event after long-term administration of corticosteroids, this effect can also be used to compare the potency of different inhaled corticosteroids. However, various factors such as the dose, frequency of administration, treatment duration, study population (patients with asthma versus normal volunteers), and prior systemic steroid therapy influence adrenal suppression with inhaled corticosteroids. The different adrenal function tests available and the results produced with these tests also must be considered along with the clinical relevance of such results. Whereas low doses of inhaled corticosteroids are likely to cause minimal or no HPA axis suppression, long-term high-dose inhaled corticosteroid use may result in significant suppression by effectively replacing endogenous steroid production. The risk of acute adrenal insufficiency in patients taking low/medium-dose inhaled corticosteroids is minimal, but patients receiving long-term high-dose treatment may require supplementary systemic steroids during stress challenges, especially if they have previously received long-term systemic steroid treatment. (J Allergy Clin Immunol 1998:101;S447-50.)

Section snippets

Tests of adrenal function

When assessing HPA axis suppression, it is important to understand the various tests of adrenal function that are available as well as the implications of the results of each test. Adrenal function tests can either assess basal secretory functions (morning cortisol, 24-hour cortisol profiling, or 24-hour urinary free cortisol) or involve stimulation testing (e.g., short [60-minute] or long [6- to 8-hour] exogenous adrenocorticotrophic hormone, or metyrapone- or insulin-induced hypoglycemia).

Clinical relevance of hpa axis suppression

When analyzing the results of HPA axis suppression with inhaled corticosteroids, it is important to define the study end points as well as the clinical implications of the findings (Table III).

. Clinical assessment of HPA axis suppression

End-point assessment of HPA axis suppression	Functional status of HPA axis
Statistical significance	Normal
Physiological perturbation	Partial suppression
Clinical relevance	Complete suppression (adrenocortical atrophy)

For example, the low-dose (1 μg)ACTH test is more

High-dose inhaled corticosteroid and hpa axis suppression

Few published studies have addressed the issue of HPA axis suppression in patients with asthma during long-term, high-dose treatment with inhaled corticosteroids. The cross-sectional report of Brown et al. evaluated morning cortisol, urinary free cortisol, and short ACTH stimulation testing in 74 patients with asthma who had been treated with a median dose of 1600 μg of either BDP or BUD for a median duration of 13 months.⁶ Approximately 30% of these patients had received prior courses of

Risk of Adrenal Crisis

Finally, the risk of acute adrenal insufficiency culminating in adrenal crisis in patients taking steroids (systemic and/or inhaled corticosteroids) is probably exaggerated. There are several studies of patients taking long-term systemic steroids in which treatment was withheld for 36 hours (before and during major surgeries); cortisol levels and blood pressure were recorded during and after surgery. Despite subnormal cortisol responses in a large number of patients, hypotension was extremely

Conclusions

HPA axis suppression should be viewed as a marker of the systemic bioavailability of inhaled corticosteroids, and the focus should be on the clinical relevance of these alterations (Table IV). The clinical relevance of inhaled corticosteroid treatment at a defined dose should also be viewed in the context of HPA axis suppression after long-term inhaled corticosteroid use, that is, months rather than days, because adrenocortical atrophy usually requires weeks or months or exogenous

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Citation Excerpt :
This demonstrates that performance of comparative studies at the steady state is needed, as the HPA axis effects of single dosing will be much less for a drug with long elimination half-life. In a 1998 article, Dluhy35 recommends that the clinical relevance of ICS treatment at a defined dose be viewed in the context of HPA axis suppression after long-term ICS use (months rather than days) as adrenocortical atrophy usually requires weeks or months of exogenous glucocorticoid exposure. The author also states that although unexpected adrenal responses may occur at moderate doses of corticosteroids, clinically relevant HPA axis suppression should only occur after high-dose, long-term treatment in a subset of patients.
Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single-ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (< 6 weeks) for adult trials and blinded, placebo controlled, and long term (≥ 6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained.
Efficacy and safety of triamcinolone acetonide aqueous nasal spray in children aged 2 to 5 years with perennial allergic rhinitis: A randomized, double-blind, placebo-controlled study with an open-label extension
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Intranasal corticosteroids (INSs) are the most effective treatment for allergic rhinitis (AR). However, available INS safety and efficacy data in children younger than 6 years are limited.
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In a 4-week, multicenter, double-blind, parallel-group study, patients were randomized to receive triamcinolone acetonide aqueous nasal spray (TAA AQ), 110 μg once daily, or placebo. A subset of children continued into a 6-month, open-label phase. Efficacy end points included total nasal symptom scores. Safety measures included reports of adverse events, morning serum cortisol levels before and after cosyntropin infusion, and growth as measured using office stadiometry.
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Use of TAA AQ, 110 μg once daily, for up to 6 months offers a favorable efficacy to safety ratio in children aged 2 to 5 years with perennial AR.
Effect on growth of long-term treatment with intranasal triamcinolone acetonide aqueous in children with allergic rhinitis
2008, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
In published guidelines,1,3–5 intranasal corticosteroids (INSs) are recommended as a first-line treatment for AR. However, the possibility that INS treatment can increase corticosteroid serum levels and reproduce the well-known adverse effects of long-term systemic corticosteroid use, including decreased bone density,6 increased risk of glaucoma or subcapsular cataracts,7 and suppression of hypothalamic-pituitary-adrenal (HPA) axis function,8 raises concerns about the safety of long-term INS treatment.9 For example, treatment of children with AR for 1 year with the INS beclomethasone dipropionate significantly decreased growth velocity by 0.9 cm per year.10
Guidelines recommend treatment with intranasal corticosteroids for patients with allergic rhinitis (AR), but concerns remain about possible adverse effects.
To present the 1- and 2-year growth results for children with AR treated with triamcinolone acetonide aqueous nasal spray.
Thirty-nine children (aged 6.1–14.3 years at study entry) were treated with triamcinolone acetonide aqueous for 1 year, and a subset of 30 children completed a second year of treatment. The dose was physician titered to achieve control over AR symptoms. For each child, statural heights at baseline and at the 1- and 2-year (where available) visits, together with growth rates, were measured and were compared with predicted values.
There were no significant differences between measured and predicted heights at the 1- and 2-year visits. The mean (SD) measured − predicted difference was 0.3 (2.2) cm (95% confidence interval, −0.4 to 1.0 cm) at the 1-year visit and 0.5 (3.0) cm (95% confidence interval, −0.6 to 1.6 cm) at the 2-year visit. Mean differences in measured and predicted growth rates were nonsignificant at the 1- and 2-year visits.
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2008, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
Individual studies 9-16 have shown inconsistent effects of ICSs on cortisol suppression, a sensitive marker of HPA axis function. The inconsistencies seen across studies may be due to factors such as differences in dose, formulation, frequency of administration, treatment duration, previous systemic corticosteroid therapy, method of cortisol measurement used, and patient population studied. 17 Systematic reviews and meta-analyses have been used in an effort to overcome the limitations associated with the individual studies. 5,18
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Thirty-one studies providing information on 216 measures of cortisol suppression were included in this meta-analysis. Cortisol suppression in the low-, medium-, and high-dose groups were estimated to be 17.92% (95% confidence interval [CI], 11.08%-24.77%), 26.55% (95% CI, 17.29%-35.80%), and 36.31% (95% CI, 26.48%-46.13%), respectively.
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The purpose of the present study was to investigate the effectiveness of chemosurgery with 80 w/v% trichloroacetic acid (TCA) for the treatment of Japanese cedar pollenosis. The effectiveness of this treatment was evaluated in terms of the levels in the nasal washings of the chemical mediators histamine and eosinophil cationic protein, and the reactivity in the nasal provocation test.
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^☆: From Brigham and Womens Hospital, Boston, Mass.

^☆☆: Reprint requests: Robert G. Dluhy, MD, Brigham and Womens Hospital, 221 Longwood Ave., Boston, MA 02115.

^★: 1/0/86610

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Clinical relevance of inhaled corticosteroids and HPA axis suppression☆,☆☆,★

Abstract

Section snippets

Tests of adrenal function

Clinical relevance of hpa axis suppression

High-dose inhaled corticosteroid and hpa axis suppression

Risk of Adrenal Crisis

Conclusions

Respir Med

Respir Med

Br J Anesth

Inhaled glucocorticoids for asthma

N Engl J Med