Correspondence

Life-Threatening Asthma during Treatment with Salmeterol

N Engl J Med 2006; 355:852-853August 24, 2006

Article

To the Editor:

Although the addition of a long-acting β₂-agonist such as salmeterol to an inhaled corticosteroid has been demonstrated to provide greater control of asthma than does a substantially increased dose of the inhaled corticosteroid,1 this medication was associated with an increased risk of asthma-related death in a large population study.2 We have identified two adolescent boys with poorly controlled asthma and a history consistent with sudden asphyxial episodes during modest exertion while receiving inhaled corticosteroids and salmeterol. In addition to reporting an inadequate response to their rescue inhaler when symptomatic, they had no apparent bronchoprotective effect from shorter-acting β₂-agonists administered before exercise. Because of the life-threatening nature of their acute episodes (which were associated with cyanosis, a loss of consciousness, and repeated calls for emergency care), they were admitted to the Children's Hospital of Iowa for evaluation.

We found that both boys had profound bronchospasm within a few minutes after treadmill exercise despite pretreatment with albuterol or pirbuterol while they were receiving high doses of inhaled corticosteroid and salmeterol. Moreover, their recovery from the severe bronchospasm induced by relatively brief exertion required repeated inhalations of albuterol, with what appeared to be a blunted response to this agent. Once salmeterol was replaced for two days with slow-release theophylline, which has also been demonstrated to have an additive effect with inhaled corticosteroids,3 there was adequate blocking of exercise-induced bronchospasm with a β₂-agonist (Table 1Table 1Results of Four Exercise Studies in Two Patients Receiving Inhaled Corticosteroids, with and without Concurrent Administration of Salmeterol.). Moreover, both patients subsequently had improved control of their asthma, tolerated exercise after pretreatment with albuterol or pirbuterol, and had virtually no acute symptoms during 10 days of inpatient observation (in the case of the first patient) or during several months of outpatient follow-up (in the case of the second patient).

More than a decade ago, Grove and Lipworth reported that continuous exposure to salmeterol resulted in subsensitivity of the acute bronchodilator response to albuterol.4 Consistent with that report, our two patients reported having had previous poor responses to bronchodilators, which resulted in repeated trips for emergency care.

Although our two patients had particularly severe asthma, they may represent a subgroup at risk for life-threatening episodes or death in association with the use of salmeterol.2 Although uncommon, such reactions provide support for the recent recommendation of Martinez for close medical monitoring of patients with sufficiently severe asthma to justify the addition of a long-acting β₂-agonist to maintenance inhaled corticosteroids.5

Miles Weinberger, M.D.
Mutasim Abu-Hasan, M.D.
University of Iowa, Iowa City, IA 52242
miles-weinberger@uiowa.edu

5 References

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   Nelson HS, Weiss SC, Bleecker ER, Yancey SW, Dorinsky PM, SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26[Erratum, Chest 2006;129:1393.]
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   Nassif EG, Weinberger MM, Thompson R, Huntley W. The value of maintenance theophylline for steroid-dependent asthma. N Engl J Med 1981;304:71-75
   Full Text | Web of Science | Medline

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   Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995;346:201-206
   CrossRef | Web of Science | Medline

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   Martinez FD. Safety of long-acting beta-agonists -- an urgent need to clear the air. N Engl J Med 2005;353:2637-2639
   Full Text | Web of Science | Medline

Citing Articles (9)

Citing Articles

1. 1

   E.T.G. Kersten, J.M.M. Driessen, J.C. van Leeuwen, B.J. Thio. (2010) Pilot study: The effect of reducing treatment on exercise induced bronchoconstriction. Pediatric Pulmonology 45:9, 927-933
   CrossRef

2. 2

   Lalita Jindal, Michael D Shields. (2010) Is there a role for intermittent use of long-acting β ₂ -agonists in childhood asthma?. Pediatric Health 4:3, 287-293
   CrossRef

3. 3

   Fanta, Christopher H., . (2009) Asthma. New England Journal of Medicine 360:10, 1002-1014
   Full Text

4. 4

   Miles Weinberger. (2008) Pediatric asthma and related allergic and nonallergic diseases: patient-oriented evidence-based essentials that matter. Pediatric Health 2:5, 631-650
   CrossRef

5. 5

   Miles Weinberger. (2008) Long-acting β-agonists and exercise. Journal of Allergy and Clinical Immunology 122:2, 251-253
   CrossRef

6. 6

   Sandra D. Anderson, Pascale Kippelen. (2008) Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes. Journal of Allergy and Clinical Immunology 122:2, 225-235
   CrossRef

7. 7

   Chris Randolph. (2008) Exercise-induced Bronchospasm In Children. Clinical Reviews in Allergy & Immunology 34:2, 205-216
   CrossRef

8. 8

   (2007) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 16:3, i-xii
   CrossRef

9. 9

   Lawyer, Matthew C., . (2006) More on Life-Threatening Asthma and Salmeterol. New England Journal of Medicine 355:20, 2157-2158
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