Asthma diagnosis and treatment
Response to inhaled albuterol during nocturnal asthma

https://doi.org/10.1016/j.jaci.2004.03.046Get rights and content

Background

During conventional daytime studies of β2-agonists, 1 puff of a metered-dose inhaler often produces a near maximum bronchodilator response. Consequently, the US Food and Drug Administration–approved dose of albuterol is only 1 to 2 puffs every 4 to 6 hours.

Objective

To determine whether a higher dose of albuterol is required to normalize lung function during nocturnal asthma.

Methods

Fifteen subjects (age, 18-37 years) were treated with albuterol metered-dose inhalers in a randomized crossover manner at the onset of nocturnal symptoms while sleeping in the Clinical Research Center and during the day when they were asymptomatic. The dose was doubled at 15-minute intervals to 16 cumulative puffs.

Results

The mean ± SD predose FEV1 was lower at night than during the day (44% ± 12% vs 68% ± 9% predicted; P = .0001). The maximum FEV1 achieved was also lower at night (84% ± 15% vs 90% ± 12%; P = .02). The nocturnal dose-response curve was shifted to the right. The median (25th, 75th percentiles) dose required to achieve 80% of the subject's personal best FEV1 was substantially higher at night (5 [1, 19] vs 0.4 [<0.25, 2] puffs; P = .02), and the median time to achieve this endpoint was longer (47 [21, 90] vs 10 [0.2, 42] minutes; P = .005). No significant systemic effects were observed.

Conclusion

At night, the response was slower and required a higher dose because more severe airway obstruction was present on awakening. These results suggest that studies establishing the clinical dose of a β2-agonist or assessing the equivalence of different formulations should be conducted in subjects with more severe reversible airway obstruction than is present during conventional daytime studies.

Section snippets

Subject selection

Twenty-two subjects (10 females) age 18 to 44 years with a history of nocturnal asthma were selected. During the screening visit, their FEV1 had to meet American Thoracic Society criteria for acceptability and reproducibility13 and had to be ≥60% of predicted.14 To confirm bronchodilator responsiveness, nebulized albuterol (2.5 mg) was administered at 30-minute intervals until FEV1 improved ≥15% and to ≥80% of predicted, or 3 doses had been inhaled. Subjects were excluded if they had any

Results

Of the 22 subjects randomized to treatment, 15 (8 females) age 18 to 37 years completed the study. Five subjects were excluded because they did not wake from asthma symptoms in the CRC. A sixth subject was excluded because of an asthma exacerbation, and a seventh subject was excluded because of the presence of barbiturates in his urine. At the prestudy screening visit, all of the subjects who completed the study had moderate airway obstruction with the capacity to achieve normal or near normal

Discussion

The results of this study indicate that during nocturnal asthma, response to albuterol was slower, was less complete, and required a larger number of puffs to normalize lung function than during the day when subjects had asymptomatic airway obstruction. These differences were most likely a result of the severe airway obstruction on awakening from nocturnal asthma.

Our results are supported by a previous study of epinephrine in 5 subjects with nocturnal asthma. Barnes et al17 found a steeper

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    Supported in part by an investigator-initiated grant from the GlaxoSmithKline Respiratory Research Institute, Research Triangle Park, NC, by a pulmonary fellowship training grant from the American Lung Association, and by the National Institutes of Health General Clinical Research Center Grant #MO1 RR00082.

    Disclosure of potential conflict of interest: L. Hendeles has a consultant arrangement with Kos Pharmaceuticals and Medicis Pharmaceuticals, has a stock or other equity ownership in Medicis Pharmaceuticals, receives grants or research support from GlaxoSmithKline, Merck, and Novartis, and is on the speaker's bureau for AstraZeneca, GlaxoSmithKline, Merck, and Novartis. R. Ahrens has consultant arrangements with AstraZeneca, Forest Laboratories, GlaxoSmithKline, IVAX, and Skye Pharma, and receives grants or research support from AstraZeneca and GlaxoSmithKline.

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