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PRIORITY PRESS - 86th Annual Meeting of the Canadian Paediatric Society

Ottawa, Ontario / June 23-27, 2009

New Canadian Paediatric Asthma Consensus Guidelines which were recently accepted for publication in the Canadian Medical Association Journal (CMAJ) have reaffirmed that inhaled corticosteroids (ICS) is the cornerstone and the first-line maintenance therapy for asthma not adequately controlled with short-acting beta agonists (SABAs), according to Dr. Wade Watson, Head, Division of Allergy, IWK Health Centre, Halifax, Nova Scotia, and Professor of Paediatrics, Dalhousie University. However, he stressed that not all children who require ICS need to be maintained indefinitely on medication. Rather, ICS should be up-titrated when control is poor and down-titrated when possible in patients who have stable disease. If there are no exacerbations of asthma on a low dose of ICS over three to six months, discontinuation of ICS can be considered. “It is a dynamic process and we should be monitoring these children and not expect to be treating them forever,” indicated Dr. Watson.

Even though systemic absorption is not as efficient when steroids are inhaled than when ingested, particularly at low doses, there does appear to be a relationship between increasing doses and increasing risk of systemic exposure. Citing results of a study that associated high doses of the ICS fluticasone with reduced height gains in pre-school age children (Ducharme et al. N Engl J Med 2009;360:339-53), Dr. Watson cautioned that he would avoid very high dosages when possible. Rather, he would seek to add a second controller when possible if symptom control is inadequate. In children who do require prolonged or high doses of an ICS, he advised physicians to monitor growth and intensify efforts to taper steroids when growth deviates from accepted norms.

It may also be possible to switch steroids, because the relative risk of systemic absorption is not shared equally among ICS preparations. When a hierarchy of relative risk for hypothalamic-pituitary-adrenal (HPA) suppression by ICS preparations is created from published studies (Figure 1), fluticasone is followed by budesonide and the combination of beclomethasone/triamcinolone. According to Dr. Alexandra Ahmet, Children’s Hospital of Eastern Ontario, and Associate Professor of Paediatrics, University of Ottawa, ciclesonide poses the least risk. Moreover, she reported that some steroids, such as dexamethasone, appear to be associated with a particularly high potency for HPA suppression relative to anti-inflammatory effect.

Figure 1.

There are several variables that account for a hierarchy of HPA suppression among ICS agents, including the pharmacodynamics and pharmacokinetics that alter the lung-to-gut ratio of distribution. The difference in these ratios may be particularly important during an exacerbation when lung constriction can further reduce the proportion of drug that reaches the lung. While only 10% to 40% of an inhaled dose is distributed to the lung in relatively well-controlled disease, lung constriction redirects more drug to the gut where it is available for intestinal absorption and HPA suppression. For agents with a low relative risk of systemic absorption through the gut, the advantage for avoiding adrenal suppression increases as disease worsens.

The importance of pharmacological differences is illustrated with the properties of ciclesonide, which is a relatively recent addition to the ICS drug class. According to Dr. Ahmet, ciclesonide is 99% protein-bound and produces a relatively high rate of lung deposition, but it also remains inactive until metabolized in the lungs. If ciclesonide reaches the gut, it is rapidly metabolized by the liver before reaching the systemic circulation, preventing it from HPA suppression. Although the reduced risk of systemic absorption is not related to diminished anti-inflammatory effects in the lung relative to other ICS agents, Dr. Ahmet cited several studies indicating that ciclesonide might prevent the growth effects associated with high doses of other ICS agents.

To illustrate the clinical evidence that ICS agents are not interchangeable for relative risks of HPA suppression, Dr. Ahmet recounted a case study in which a patient experiencing adrenal suppression was switched from a standard dose of fluticasone to a standard dose of ciclesonide. Rapid normalization of HPA was achieved with a correlating increase in growth. Although she cautioned that more follow-up is needed to confirm that ciclesonide may be the first ICS to avoid adverse effects on growth, she reported that ciclesonide has not shown to have any adrenal-suppressive effects in treatment doses.

Generally, HPA suppression is an insidious condition that requires periodic monitoring, but physicians should also be vigilant for detecting adrenal crises. According to Dr. Ahmet, there have been 50 recent reports of adrenal crisis on ICS, almost all of which occurred in children. All were taking fluticasone 500 mcg/day or its equivalent. Although the optimal management for adrenal crisis has not been established in controlled trials, Dr. Ahmet advised tapering the corticosteroid dose, particularly when patients have been exposed to a super-physiological dose for over three weeks. She recommended testing HPA function after tapering.

HPA Suppression Recommendations

There are several strategies with which to reduce the risk of adrenal crisis or HPA suppression regardless of ICS, according to Dr. Ahmet. The most important is to employ the lowest dose that allows for good asthma control. Timing of the medication also appears to be important.

“Due to our circadian rhythms, the best time to give steroids to avoid adrenal suppression is early morning. Decreasing the dose, using a short-acting steroid or reducing the frequency of dosing also reduces the risk. It can take up to one year for complete recovery from suppression, but it varies greatly between patients,” according to Dr. Ahmet.

It is also important to educate parents about the signs and symptoms of adrenal suppression. If adrenal suppression is suspected, an ACTH stimulus test should be used to confirm the diagnosis and then employed to follow patients as steroid doses are tapered.

Both the type and dose of steroid are important variables for the risk of HPA suppression, but there are practical clinical issues in ICS administration particularly relevant to children. These include compliance with the regimen and proper technique with inhaler use. Before increasing the dose of an ICS, it is important to verify that patients are using their medication properly. According to Dr. Watson, inadequate compliance due to missed doses or poor technique can be identified in very high proportions of children who are not controlled on standard dosages. He indicated the problem is age-related. “Little children, bad technique; bigger child, better technique,” he remarked, noting that recommended starting doses of ICS (Table 1) do not
ed.

Table 1.

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In addition to compliance, physicians should also check for untreated comorbidities such as rhinitis, sinusitis or an exposure to a new allergen, before increasing an ICS dose. Again, the goal is to keep doses of ICS low whenever possible. Although Dr. Watson suggested that higher doses or a change of medication are warranted in patients with poor asthma control after ruling out inadequate compliance or comorbidities, he warned that the increased risk of adrenal suppression or other adverse events with higher doses should be accompanied by closer patient monitoring.

Summary

Strategies to avoid adrenal suppression in children who require steroids for adequate asthma control are improving. The recognition that ICS agents differ in relative potential for adrenal suppression permits physicians to select agents with lower relative risk, while greater attention to dose adjustments is allowing children to remain controlled at the lowest possible steroid dose. With most of the commonly used agents, dose of ICS correlates with risk of adrenal suppression. Children who face life-threatening exacerbations of asthma should not be denied adequate steroids to control disease, but monitoring of HPA should become more rigorous as doses of steroids increase.