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(Chest. 2001;119:370-375.)
© 2001 American College of Chest Physicians

Regular Inhaled Salbutamol*

Effect on Airway Responsiveness to Methacholine and Adenosine 5'-Monophosphate and Tolerance to Bronchoprotection

Ruzica Jokic, MD; Veronica A. Swystun, BSc; Beth E. Davis, BSc and Donald W. Cockcroft, MD, FCCP

* From the Division of Respiratory Medicine, Department of Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada.

Correspondence to: Donald W. Cockcroft, MD, FCCP, Royal University Hospital, Division of Respiratory Medicine, 103 Hospital Dr, Ellis Hall, Saskatoon, SK S7N 0W8 Canada; e-mail: cockcroft{at}sask.usask.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: Regular treatment with inhaled {beta}2-agonists increases airway responsiveness consistently to indirect bronchoconstrictors (allergen, exercise, hypertonic saline solution, etc) and inconsistently to direct bronchoconstrictors (histamine, methacholine). Studies demonstrating tolerance to {beta}2-agonist bronchoprotection against the indirect bronchoconstrictor adenosine 5'-monophosphate (AMP) have not examined changes in baseline AMP responsiveness. This study assessed the effect of regular salbutamol on AMP and methacholine responsiveness and on tolerance to bronchoprotection.

Design: Double-blind, randomized, crossover study.

Setting: University hospital bronchoprovocation laboratory.

Patients: Fourteen atopic asthmatic subjects with FEV1 > 65% predicted, and methacholine provocative concentration causing a 20% fall in FEV1 (PC20) < 8 mg/mL.

Interventions: Salbutamol, 100 µg, and placebo inhalers, two puffs qid, each for 10 days.

Measurements: Methacholine PC20 and AMP PC20 measured 12 h after blinded inhaler after each treatment period. Methacholine PC20 and AMP PC20 repeated 10 min after salbutamol, 200 µg (eight subjects).

Results: There was no difference between placebo and salbutamol treatment in geometric mean methacholine PC20 (0.85 mg/mL vs 0.82 mg/mL, p = 0.86) or AMP PC20 (22 mg/mL vs 17.4 mg/mL, p = 0.21; n = 14). The acute bronchoprotective effect of salbutamol was greater vs AMP than vs methacholine (5.1 doubling concentrations vs 3.5 doubling concentrations, p = 0.06) and loss of protective effect of salbutamol (mean ± SD) was greater vs AMP than vs methacholine (2.4 ± 0.33 doubling concentration loss vs 0.8 ± 0.21 doubling concentration loss, p = 0.008; n = 8).

Conclusion: Regular salbutamol (mean ± SD) treatment did not enhance airway responsiveness to either the indirect bronchoconstrictor AMP or the direct bronchoconstrictor methacholine. Compared to its effect on methacholine, salbutamol had a greater acute protective effect vs AMP and produced greater loss of protection vs AMP when used regularly.

Key Words: adenosine 5'-monophosphate • airway hyperresponsiveness • asthma • {beta}2-agonists • bronchoprotection • methacholine • tolerance


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Bronchoconstrictor stimuli used to measure airway hyperresponsiveness (AHR) are either direct acting (act on receptors on airway smooth muscle, eg, histamine, methacholine) or indirect acting (act through intermediate pathways, eg, exercise, nonisotonic aerosols, adenosine 5'-monophosphate [AMP], allergen, etc). Airway responsiveness demonstrated by indirect stimuli may be more clinically relevant to asthma.1 Studies of regular inhaled {beta}2-agonists have produced conflicting results regarding airway responsiveness to direct agents.2 Several often-referenced studies2 3 4 5 6 have documented increased airway responsiveness; many more studies2 7 8 9 10 11 12 13 14 15 have not. Although less well studied, regular inhaled {beta}2-agonists have more consistently increased airway responsiveness to indirect stimuli, including exercise,16 hypertonic saline solution,14 15 and allergen, both early10 11 12 13 17 and late,17 18 19 responses. In one study, increased early asthmatic response (EAR) was seen only in conjunction with inhaled corticosteroid treatment.11 Several of these studies have documented no {beta}2-agonist effect on direct airway responsiveness at the same time that indirect airway responsiveness was increased.10 11 12 13 14 15

When compared to the effect on direct-acting stimuli, inhaled {beta}2-agonists provide greater protection against indirect stimuli that act via mast cells (eg, AMP, allergen) and their regular use results in greater tolerance; this may be due to a {beta}-agonist mast cell stabilizing effect that is more susceptible to down-regulation.10 20 21 In a previous study10 comparing the effect of regular salbutamol on airway responses to methacholine and allergen, we found that the large reduction in postsalbutamol allergen provocation concentration causing a 20% fall in FEV1 (PC20) was due in part to the reduction in baseline allergen PC20 and in part to reduced magnitude of bronchoprotection; baseline methacholine PC20 was unchanged. In the studies20 21 demonstrating similar marked reduction in postterbutaline AMP PC20 after regular {beta}2-agonist use, baseline AMP PC20 was presumed not to have changed but was not measured.

The current study examined the effect of regularly inhaled salbutamol on (baseline) airway responsiveness to AMP and methacholine and on the acute bronchoprotective effect of salbutamol against the two stimuli.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Fourteen subjects with asthma volunteered for this study. All were atopic, as documented by history and confirmed by allergen prick skin tests. Asthma was well controlled, and subjects were studied outside of allergen exposure and with no respiratory tract infection for at least the previous 4 weeks. Two subjects used low-dose inhaled corticosteroids, and one subject used leukotriene-receptor antagonist in stable dose for several weeks before and throughout the study. All subjects were able to discontinue inhaled {beta}2-agonist treatment for 2 weeks before and throughout the study, and were able to substitute ipratropium bromide for rescue bronchodilation. Ipratropium therapy was withheld for at least 8 h prior to all study visits. This study was approved by the University of Saskatchewan Ethics Committee, and signed informed consent was obtained.

Methacholine Inhalation Test
The methacholine challenge was performed using the 2-min tidal breathing method.22 Spirometry was initially measured in triplicate. Aerosols were generated using a jet nebulizer (Bennett Twin; Puritan-Bennett; Overland Park, KS) calibrated to deliver an output of 0.13 mL/min, and were inhaled for 2 min of tidal breathing beginning with the diluent isotonic saline solution followed by doubling concentrations of methacholine from 0.03 to 128 mg/mL at 5-min intervals. The FEV1 was measured once at 30 s and once at 90 s after each inhalation. The percent fall in FEV1 was calculated from the lower postsaline solution FEV1 to the lowest postmethacholine FEV1, and the methacholine PC20 was interpolated23 or extrapolated24 using validated formulas.

AMP Inhalation Test
AMP inhalation testing was done in the same fashion as the methacholine challenge, using the same nebulization system, inhalation technique, and spirometry measurements. The doubling concentrations of AMP (Professional Compounding Centers of America; Houston, TX) used ranged from 0.5 to 512 mg/mL.

Methacholine Dose Shift
The bronchoprotective effect of a single dose of salbutamol was assessed by measuring methacholine dose shift on a single day as previously validated.25 Baseline methacholine PC20 was initially established but not reversed with bronchodilator. Fifty minutes after the completion of the initial methacholine inhalations, two puffs of salbutamol, 100 µg/puff, were administered under supervision. Ten minutes later, the FEV1 was measured and a second methacholine PC20 was determined. The methacholine dose shift was calculated in doubling concentrations from the following formula20 :

AMP Dose Shift
We measured the bronchoprotective effect of salbutamol vs AMP using the AMP dose shift measured in the identical fashion to the methacholine dose shift. This method was validated in 10 subjects in our laboratory (data not shown).

Study Design
The study was a double-blind, placebo-controlled, randomized, crossover comparison of placebo metered-dose inhaler, two puffs qid, and salbutamol, 100 µg two puffs qid for 10 days, with a minimum washout period of 10 days between the two treatments. At the start of each treatment, we ascertained that the asthma was stable and that the FEV1 was within 10% of baseline. Concomitant medication use was documented throughout the study. At the end of each treatment period, the subjects attended the laboratory on 2 consecutive days. On one day, a methacholine PC20 and methacholine dose shift were measured; on the other day, AMP PC20 and AMP dose shift were measured. The order of the challenges was randomized between subjects but kept constant within subjects. All challenges were done 12 h after the last dose of blinded medication; following the first series of challenges, treatment with the blinded medications was continued for that last day and stopped 12 h prior to the second set of challenges. All tests were done at the same time of day for each subject. Starting concentrations of methacholine and AMP both before and after salbutamol were kept the same for each individual.

The end points that were examined in all individuals were the FEV1, bronchodilation, baseline methacholine PC20, and baseline AMP PC20. We were only able to measure dose shift to AMP in 8 of the 14 subjects, as 6 subjects had no response measurable at the top concentration after salbutamol. We only measured the methacholine dose shift in the same eight subjects.

Analysis
Logarithmic transformation was done for all PC20 values. Computerized analysis of variance and pairwise comparison of means were done using statistical software (Excel 97; Microsoft; Redmond, WA, and SPSS Version 6.0; SPSS; Chicago, IL). The study was designed to have a 90% power to detect a 0.5 concentration change in baseline methacholine or AMP PC20 at the 5% level.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All 14 subjects completed the investigation without adverse events (anthropometric data are shown in Table 1 ). Rescue ipratropium was required by only four subjects during the placebo treatment period and by no subjects during the active treatment. Mean (± SD) baseline FEV1 (range, 3.37 ± 1.08 to 3.45 ± 1.06 L) and bronchodilation ({Delta}FEV1 after 200 µg of salbutamol range, 6.8 ± 3.1% to 7.3 ± 7.3%) were not significantly different on the 4 days. Baseline methacholine PC20 or AMP PC20 was also not significantly different. The difference between methacholine PC20 after placebo (geometric mean, 0.85 mg/mL) and salbutamol (geometric mean, 0.82 mg/mL) was 0.02 doubling concentrations (95% confidence interval [CI], - 0.36 to 0.18, p = 0.86), and for AMP PC20 (geometric mean PC20, 22.0 mg/mL and 17.4 mg/mL after placebo and salbutamol, respectively) was 0.1 doubling concentration (95% CI, - 0.07 to 0.27, p = 0.21). The baseline methacholine and AMP PC20 values after the two treatments are shown in Figure 1 .


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  		Table 1. Anthropometric Data and Baseline Physiology

 


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  		Figure 1. Treatment effect of placebo and salbutamol on airway responsiveness (PC20) to methacholine and AMP in the 14 subjects.

 
The methacholine and AMP dose-shift data are shown for eight subjects in Figure 2 . Following the placebo treatment, salbutamol provided greater protection against AMP than against methacholine (5.1 doubling doses vs 3.5 doubling doses, p = 0.06). Significant tolerance developed for bronchoprotection against both stimuli after 10 days of regular use of salbutamol. The methacholine dose shift fell 0.8 doubling concentrations, from 3.5 to 2.7 (95% CI, 0.34 to 1.3, p = 0.01); the AMP dose shift fell 2.4 doubling concentrations, from 5.1 to 2.7 (95% CI, 1.7 to 3.2, p = 0.0004). Tolerance was greater for AMP than for methacholine by 1.6 doubling concentrations (95% CI, 0.70 to 2.5, p = 0.008).



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  		Figure 2. Loss of acute bronchoprotection (reduction in dose shift) to methacholine and AMP following regular treatment with salbutamol in eight subjects.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study confirms that in subjects not using {beta}2-agonists, the acute bronchoprotective effect of inhaled {beta}2-agonist against AMP is greater than against methacholine; following regular inhaled {beta}2-agonist use, there is greater tolerance to the bronchoprotective effect against AMP as compared to methacholine. The novel finding of this study is that, contrary to our expectations, there was no increase in baseline airway responsiveness to AMP.

We hypothesized that regularly inhaled salbutamol, in a dose and duration adequate to cause significant tolerance to bronchoprotection, would result in increased airway responsiveness to AMP but not methacholine. This was based on the consistency of the relatively small number of published reports on the effects of regular use of inhaled {beta}2-agonists on airway responsiveness to indirect bronchoconstrictors.10 11 12 13 14 15 16 17 The greatest number of these involve airway responsiveness to allergen.10 11 12 13 17 The mechanism of airway responsiveness to AMP involves mast cell-mediator release.26 The allergen-induced EAR also involves mast cell-mediator release. Since {beta}2-agonists inhibit mast cell-mediator release,27 down-regulation of mast cell {beta}2-receptors might enhance allergen-induced degranulation.10 This is supported by the recent observation17 that allergen challenge after a period of regular use of inhaled salbutamol results in an increase in mast cell-derived serum tryptase when compared with allergen challenge after placebo. Although AMP and allergen share mast cell-mediator release as a mechanism of induction of bronchoconstriction, there are differences. The AMP response has a shorter time course,28 is more completely inhibited by H1-blockers,28 and is not associated with late asthmatic responses.26 The failure to increase AMP responsiveness with regular use of {beta}-agonists, if confirmed by other studies, is another way in which AMP differs from allergen.

Mast cell {beta}2-receptor down-regulation following regular use has been suggested as the explanation for both the greater tolerance to the bronchoprotective effect of {beta}2-agonist against AMP (vs methacholine)20 and the enhanced allergen-induced EAR.10 17 The current study unequivocally shows greater tolerance to the bronchoprotective effect of salbutamol vs AMP than vs methacholine (p = 0.008), while previous studies10 12 13 using similar dose/duration of salbutamol have repeatedly shown a 0.5 to 0.9 doubling concentration fall in allergen provocative concentration causing a 15% fall in FEV1 or PC20. We believe the study was adequately powered at 90% to detect a 0.5 concentration change in AMP PC20 at the 5% level. Based on the outlined logic, we expected mast cell {beta}2-receptor down-regulation would enhance responsiveness to AMP. At this point, we are not able to speculate regarding the reason for mechanisms behind this incongruency.

The failure to detect a significant change in airway responsiveness to methacholine reproduces findings from several studies in our laboratory.10 12 13 17 This is in contrast to several well-recognized and well-referenced studies that have documented regular inhaled {beta}2-agonists increase airway responsiveness to either histamine or methacholine.3 4 5 6 The topic has been reviewed in a clinical commentary by van Schayck et al.2 They have concluded that the variable effects of inhaled {beta}2-agonists on airway responsiveness to histamine and methacholine may relate to variability in allergen exposure between studies. The allergen-induced late asthmatic response is associated with allergen-induced increases in airway responsiveness to histamine or methacholine29 30 and allergen-induced increases in airway eosinophilic inflammation.30 Regular use of inhaled {beta}2-agonists appears to enhance all of these late inflammatory sequelae.17 19 In our studies, we stress allergen avoidance as an important control in maintaining stability of airway responsiveness in asthma. This is done by studying subjects remote from their allergen season, and interdicting exposure to avoidable allergens such as house pets. This is further aided by our geographic location in a very dry area with particularly low levels of house dust mite allergen. It has been hypothesized that studies in which regular {beta}-agonists have increased airway responsiveness to histamine or methacholine may have occurred in subjects with concomitant allergen exposure,2 and a review of these studies suggests that this is at least a possible mechanism.

The clinical relevance of these findings is uncertain and has been reviewed previously.31 Tolerance to {beta}2-agonist bronchoprotection is ubiquitous for all {beta}2-agonists and all bronchoconstricting stimuli.31 The partial loss of bronchoprotection vs chemical stimuli used to measured AHR (eg, histamine, methacholine, AMP) may have limited clinical relevance. However, important loss of bronchoprotection vs natural clinically important stimuli, particularly allergen10 32 and exercise,16 33 may have clinical implications. Although peripheral to the current article, increased airway responses to allergen, particularly the late sequelae, may have even more important clinical implications.

In conclusion, this study documents that regularly used inhaled salbutamol, in doses adequate to cause tolerance to its bronchoprotective effect against both AMP-induced and methacholine-induced bronchoconstriction (greater for AMP), did not cause significant increase in airway responsiveness to the indirect mast cell-dependent stimulus AMP. The reasons are uncertain.


   Acknowledgements
 
The authors thank Jacquie Bramley for assisting in the preparation of this article.


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; AMP = adenosine 5'-monophosphate; CI = confidence interval; EAR = early asthmatic response; PC20 = provocation concentration causing a 20% fall in FEV1

Supported by a research fellowship from Boehringer Ingelheim Canada Ltd.

Received for publication December 16, 1999. Accepted for publication August 4, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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