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(Chest. 2005;127:135-142.)
© 2005 American College of Chest Physicians

Deep Inspiration Avoidance and Methacholine Response in Normal Subjects and Patients With Asthma*

Barbara Simard, BSc; Hélène Turcotte, MSc; Donald W. Cockcroft, MD, FCCP; Beth E. Davis, BSc; Marie-Ève Boulay, MSc and Louis-Philippe Boulet, MD, FCCP

* From the Institut de cardiologie et de pneumologie de l’Université Laval (Ms. Simard, Ms. Turcotte, Ms. Boulay, and Dr. Boulet), Hôpital Laval, Quebec City, QC; and Division of Respiratory Medicine (Dr. Cockcroft and Ms. Davis), Royal University Hospital, Saskatoon, SK, Canada.

Correspondence to: Louis-Philippe Boulet, MD, FCCP, Hôpital Laval, 2725, Chemin Sainte-Foy, Québec, QC, Canada, GlV 4G5; e-mail: lpboulet{at}med.ulaval.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Deep inspiration (DI) avoidance and time intervals between inhalation and measurement of FEV1 may influence methacholine challenges.

Objectives: (1) To compare the degree of airway response to methacholine when the initial FEV1 measurements are obtained either 30 s or 3 min after inhalation, (2) to evaluate a simplified method to study the influence of DI avoidance before inhalation on the fall in FEV1, and (3) to determine if methacholine has a cumulative effect.

Participants/methods: Twenty-five patients with asthma and 21 normal subjects without asthma. Four methacholine inhalation tests (MITs) were performed: two standard tidal-breathing MITs, with the first FEV1 measured 30 s (test A) and 3 min (test B) after the end of inhalation; a single-dose MIT, using the last concentration from test B, with no control of DI and the first FEV1 obtained 3 min after inhalation (test C); and an identical single-dose MIT preceded by 20-min of DI avoidance (test D). We compared the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) from tests A and B (aim 1), the percentage fall in FEV1 from tests C and D (aim 2), and the percentage fall in FEV1 from tests B and C (aim 3).

Results: Mean PC20 values from tests A and B were 1.5 mg/mL and 1.0 mg/mL (p = 0.002) in patients with asthma, and 69.8 mg/mL and 29.9 mg/mL (p < 0.0001) in control subjects, respectively. The mean falls in FEV1 for tests C and D were 22.0% and 24.5% (p > 0.05) in patients with asthma, and 22.1% and 38.9% (p = 0.0005) in control subjects, respectively. The mean falls in FEV1 for tests B and C were 30.2% and 22.0% (p = 0.01) in patients with asthma, and 27.5% and 22.1% (p > 0.05) in control subjects, respectively.

Conclusions: In both groups, the longer the time interval between the end of inhalation and the first FEV1 measurement, the greater the fall in FEV1 (lower PC20). DI avoidance before inhalation does not enhance the fall in FEV1 in subjects with asthma, while it does in control subjects. Methacholine has a slight cumulative effect that is significant in patients with asthma (p = 0.007).

Key Words: asthma • bronchoconstriction • deep inspiration • inspiratory maneuvers


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Airway hyperresponsiveness, the exaggerated response to a variety of chemical and physical stimuli, is a cardinal feature of asthma that remains largely unexplained.1 One of the hypotheses offered to explain this phenomenon is that it results from an impaired capacity of deep inspiration (DI) to stretch and relax airway smooth muscle.2345

Airway response to DI in patients with asthma differs from that observed in subjects without asthma.67 Airway narrowing in response to bronchoconstricting agents that can induce bronchoconstriction in patients with asthma does not develop in healthy humans; however, healthy subjects have an exaggerated airway narrowing when they avoid DI during methacholine challenge.2 In patients with asthma, however, the absence of DI seems to have little influence on the airway response during conventional methacholine challenge testing.8

DI has a dual action in control subjects8910: it may prevent a fall in expiratory flows, considered to reflect airway constriction, when it is done before the administration of the bronchoconstrictor agent; and it may act as a bronchodilator, by reversing airway obstruction.6 The magnitude of the bronchoprotective effect is greater than the bronchodilator effect, which may implicate a different mechanism.11 In patients with asthma, a DI maneuver may cause a bronchoconstrictor response.712131415

The present study was motivated by the perceived need to further explore some aspects of methacholine challenge standardization, and to better document the influence of avoidance of DI before and after methacholine inhalation on the airway response. Furthermore, current methods used to explore the influence of DI avoidance on airway responsiveness during methacholine challenge are relatively time-consuming.8 Most require multiple single-dose methacholine inhalation tests (MITs) performed after a 20-min period of DI avoidance to establish the dose reducing FEV1 by ≥ 15%. A method that would allow a simpler evaluation of this mechanism could be useful. Comparison of different MIT protocols shows that the time elapsed between the end of methacholine inhalation and the first FEV1 measurement (eg, 30 s, 1 min, 3 min) is not always standardized. Finally, the possible cumulative effect of methacholine inhalation on airway response16 requires better documentation.

Our hypotheses were as follows: (1) a period of avoidance of DI before methacholine challenge or the variation in time intervals between the end of methacholine inhalation and the first FEV1 may lead to a change in the interpretation of the challenge; (2) normal subjects and patients with asthma behave differently in regard to the magnitude of the response to the various tests; and (3) the cumulative effect of methacholine is more marked in patients with asthma than in subjects without asthma. Consequently, the aims of the present study were as follows: (1) to examine the influence, on the final fall of expiratory flows, of DI avoidance after methacholine inhalation (this will be done in comparing the degree of airway response to methacholine when the initial FEV1 measurements are obtained either 30 s or 3 min after inhalation); (2) to develop a new, simplified method for studying the influence of DI avoidance before inhalation of methacholine on the fall in FEV1; and (3) to evaluate whether methacholine has a cumulative effect.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Forty-eight subjects were recruited from respiratory clinics at the Centre de Pneumologie de l’Hôpital Laval, Québec, QC, Canada, and from the Division of Respiratory Medicine, Royal University Hospital, Saskatoon, SK, Canada. Twenty-five subjects with mild asthma (age range, 17 to 55 years) and 21 healthy control subjects (age range, 19 to 50 years) [Table 1 ] were included. Control subjects were recruited from the community by radio and newspaper advertising. All participants filled out an asthma questionnaire and underwent allergy skin testing and methacholine inhalation challenge.17


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  		Table 1. Participant Characteristics*

 
The patients with asthma were nonsmokers and had stable asthma only using inhaled short-acting ß2-agonists to control symptoms. Control subjects were nonsmoking and nonatopic, had never experienced upper or lower airway respiratory symptoms consistent with asthma or had an asthma diagnosis, and had normal expiratory flows. The provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20) had to be ≤ 16 mg/mL in patients with asthma and between 16 mg/mL and 256 mg/mL in control subjects. The study was approved by the local ethics committees, and written informed consent was obtained.

Study Design
Each subject made four visits to the laboratory within a 10-day period for four different MITs, all at the same time of day in order to minimize circadian variation. Visits were separated by at least 24 h. The first two visits were done consecutively, while the last two visits were conducted in random order.

Visit 1, Screening:
On the first visit, all subjects underwent a screening evaluation including allergy skin-prick tests and a standard tidal breathing MIT (test A)17 (Fig 1 , top, a). FEV1 and FVC were measured at 30 s and 90 s, and then at 3 min and 4 min after each inhalation of methacholine.



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  		Figure 1. Schematic description of tests. M = methacholine.

 
Visit 2:
This part of the study was designed to determine what influence the time interval between the end of each methacholine inhalation and the first FEV1 measurement had on airway responsiveness to methacholine. All subjects underwent another MIT using the identical dosing regimen as for test A, the only difference being that the two first measures of FEV1 and FVC were measured at 3 min and 4 min after each inhalation (test B), instead of 30 s and 90 s (test A), as described in the standard method17 (Fig 1, center, b). DIs were avoided from beginning inhalation until the initial FEV1.

Visits 3 and 4:
Tests C and D were carried out in random order. Test C was performed to determine the cumulative effect of methacholine; all subjects underwent a single-dose methacholine challenge, inhaling tidally for 2 min the final concentration of methacholine administered in test B. FEV1 and FVC were then measured 3 min and 4 min after inhalation. During this time, subjects were asked to breathe normally but to avoid DI from beginning inhalation until the initial FEV1. The maximum percentage fall in FEV1 was calculated and compared with that obtained from test B (Fig 1, center, c).

Test D was performed in order to develop a quicker and simpler method of evaluating the effects of DI avoidance on airway responsiveness to methacholine. We slightly modified the single-dose methacholine challenge initially developed by Malmberg et al10 and modified by Kapsali et al8 and Scichilone et al.11 Briefly, after three baseline spirometric maneuvers, subjects were asked to refrain from taking deep breaths for 20 min, a time shown to be sufficient to allow the bronchoprotective effect of baseline spirometric maneuvers to dissipate.89 Tidal breathing was monitored visually and from a pneumotachograph recording, in order to be sure that DI were avoided. Thereafter, the identical dose of methacholine used for test B was inhaled tidally for 2 min. Again, FEV1 and FVC were measured 3 min and 4 min after the end of inhalation, avoiding DI until the first spirometric measurements. The difference between the lowest FEV1 value after methacholine and the lowest baseline value was expressed as the percentage fall from baseline. The resulting changes from baseline values in spirometric outcomes after methacholine were compared with those of the same single-dose challenge in which DIs were allowed before the inhalation test (test C; Fig 1, bottom, d).

To exclude any difference in response due to variable timing in spirometric measurements between inhalations, the time interval between inhalation starts was kept constant at 6 min on all 4 days. Responses to the different challenges were assessed by changes in spirometry following challenge. Baseline values were defined as the mean of the three measurements obtained prior to challenges. Administration of saline solution (tests A and B) or the first dose of methacholine (test C) followed immediately after baseline measurements. The percentage change from the lowest values of FEV1, FVC, and FEV1/FVC after saline solution were calculated using the lowest set of values after challenges.

Measurement of Expiratory Flows
Spirometry was performed with an American Thoracic Society-approved spirometer. The forced expiratory maneuvers were performed according to standard recommendations.18 Predicted values were obtained from Crapo et al.19

Skin-Prick Tests
Atopic status was determined by skin-prick testing with a battery of 26 common aeroallergens. Normal saline solution and histamine were used as negative and positive controls, respectively. The wheal size was recorded at 10 min as the mean of two perpendicular measures. A positive response was defined as skin wheal diameter ≥ 3 mm.

"Standard" and Modified Methacholine Challenges
Methacholine was administered through a Wright nebulizer (Aerosol Medical; Colchester, UK) [Laval Hospital; Québec] or a Twin jet nebulizer (Puritan Bennett; Los Angeles, CA) [Royal University Hospital, Saskatoon], both calibrated at an output of 0.13 mL/min and attached to a flowmeter (Western Medica; Westlake, OH).20 Airway responsiveness to methacholine was measured using a minor modification of the method described by Juniper and coworkers.17 Briefly, tidal inhalations of physiologic saline solution and methacholine in doubling concentrations from 0.03 to 256 mg/mL were inhaled for 2 min at 6-min intervals, until a 20% fall in FEV1 from the lowest post-saline solution value was observed or until the last concentration of methacholine (256 mg/mL) had been administered. Following each inhalation, FEV1 and FVC were recorded at 30 s and 90 s, and 3 min and 4 min. At each step, the lowest FEV1 and FVC values were recorded. The responses were expressed as the PC20, obtained from the log dose-response curve.

The modification to the method of Juniper and coworkers17 was to set the time interval between the start of the inhalations at 6 min, instead of 5 min. ß2-Agonists were withheld for 12 h before the tests. Coffee and tea were not allowed on the morning of a visit day. All subjects were currently nonsmokers and were tested after a period of at least 4 weeks of seasonal allergen avoidance and 4 weeks without upper respiratory infection.

Data Analysis
PC20 values were log transformed before analysis. The results are expressed as mean ± SEM. Baseline values of FEV1 for the four tests were compared by analysis of variance. Paired t tests were used to compare the following: (1) log PC20 and percentage fall in FEV1 between tests A and B in order to analyze the effect of the time interval between the end of the inhalation and the first FEV1 measurement; (2) the fall in FEV1 between tests C and D to determine the influence of a 20-min DI avoidance before the MIT; and (3) the fall in FEV1 between tests B and C to evaluate the cumulative effect of methacholine. An unpaired t test was used to compare control subjects and patients with asthma.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Among the 48 subjects recruited, 2 control subjects were excluded because their PC20 values were < 16 mg/mL. In the end, 46 subjects were enrolled: 21 nonatopic control subjects (4 men and 17 women) and 25 atopic patients with asthma (10 men and 15 women), showing at least one positive response on allergic skin-prick testing. Mean FEV1 readings for patients with asthma and control subjects were 89.2 ± 1.9% and 95.0 ± 1.9%, respectively. Volunteers were relatively young (age range, 19 to 50 years in control subjects, and 17 to 55 years in patients with asthma), and there was no age difference between the two groups. Patients with asthma had mild-to-moderate airway hyperresponsiveness, with a geometric mean PC20 of 1.5 mg/mL, while control subjects had a geometric mean PC20 of 69.8 mg/mL.

Baseline FEV1 at the Four Visits
Baseline FEV1 (percentage of predicted) did not vary significantly among the four tests in the patients with asthma (89.2 ± 1.9%, 88.7 ± 2.0, 86.6 ± 2.0%, and 87.0 ± 2.2%, respectively; p > 0.05) or control subjects (95.1 ± 1.9%, 94.8 ± 2.0%, 94.2 ± 1.9%, and 93.2 ± 2.4%, respectively; p > 0.05).

Effect of DI After Methacholine Inhalation (3 min vs 30 s)
To evaluate the effect of DI after methacholine inhalation, we compared PC20 values obtained during test A (first FEV1 at 30 s after methacholine) and test B (first FEV1 at 3 min after methacholine); geometric mean (–1 SD, +1 SD) PC20 values after tests A and B were 1.5 mg/mL (0.3–6.4) and 1.0 (0.3–3.4) mg/mL (p = 0.007) in patients with asthma, and 69.8 mg/mL (31.5–159) and 30.0 (15.1–59.3) mg/mL (p < 0.0001) in control subjects, respectively (Table 2 , Fig 2 ). The reduction in PC20 for test B as compared with test A in doubling concentrations was significantly different for control subjects (– 1.22) and patients with asthma (– 0.51) [p = 0.003]. Four control subjects who had PC20 values of 18 mg/mL, 95 mg/mL, 39 mg/mL, and 29 mg/mL on test A had their PC20 reduced to 13 mg/mL, 16 mg/mL, 13 mg/mL, and 9 mg/mL, respectively, on test B. The values for maximum percentage fall in FEV1 following methacholine tests A and B for subjects who received the same final dose of methacholine were 23.0 ± 1.1% and 31.5 ± 2.7% (p = 0.005) in patients with asthma (n = 13), and 20.0 ± 0.9% and 28.1 ± 3.4% (p = 0.08) in control subjects (n = 7), respectively.


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  		Table 2. Effects of the Different Methacholine Inhalation Tests on PC20 and Percentage Fall in FEV1

 


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  		Figure 2. Comparison of PC20 between tests A and B. Test A: 30 s before first FEV1 measurement; multiple doses of methacholine inhalation; no period without DI before methacholine inhalation. Test B: 3 min before first FEV1 measurement; multiple doses of methacholine; no period without DI before methacholine inhalation.

 
Effect of DI Avoidance Before Methacholine Inhalation
To look at the effect of DI avoidance before methacholine inhalation, we compared test C (no DI avoidance before methacholine inhalation) and test D (20 min of DI avoidance before methacholine inhalation). The maximum percentage falls in FEV1 in tests C and D were 22.0 ± 2.8% and 24.5 ± 2.9% (p > 0.05) in patients with asthma and 22.1 ± 2.9% and 37.3 ± 4.7% (p = 0.006) in control subjects, respectively (Fig 3 ). The change in fall in FEV1 (test D – test C) was 2.4 ± 2.5% in patients with asthma and 16.8 ± 5.0% in control subjects (p = 0.0096) [Fig 4 ].



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  		Figure 3. Comparison of PC20 between tests C and D for the final percentage fall in FEV1. Test C: 3 min before first FEV1 measurement; single doses of methacholine; no period without DI before methacholine inhalation. Test D: 3 min before first FEV1 measurement; single doses of methacholine; 20 min without DI before methacholine inhalation.

 


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  		Figure 4. Comparison of the percentage change in FEV1 (test D – test C) between control subjects and patients with asthma.

 
Cumulative Effect of Methacholine
A possible cumulative effect of methacholine was sought by comparing tests B and C. The maximum percentage falls in FEV1 in tests B and C were 30.2 ± 2.0% and 22.0 ± 2.8% (p = 0.007) in patients with asthma, and 27.5 ± 2.0% and 22.1 ± 2.9% (p > 0.05) in control subjects, respectively (Fig 5 ).



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  		Figure 5. Comparison of PC20 between tests B and C for the final percentage fall in FEV1. Test B: 3 min before first FEV1 measurement; multiple doses of methacholine; no period without DI before methacholine inhalation. Test C: 3 min before first FEV1 measurement; single doses of methacholine; no period without DI before methacholine inhalation.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates three important features regarding DI and the timing of methacholine inhalations and spirometry after methacholine challenge. First, avoidance of DI after methacholine inhalation by delaying the first spirogram until 3 min (vs 30 s) enhances methacholine-induced airway obstruction in patients with asthma and control subjects. Second, avoidance of DI (20 min) before methacholine inhalation, by contrast, has different effects in patients with asthma and control subjects, causing no enhancement of methacholine-induced bronchoconstriction in the former but significant enhancement in the latter. Finally, there is a slight cumulative effect of methacholine when doubling concentrations are inhaled at 6-min intervals and when the first FEV1 is not measured until 3 min.

Although it has been previously demonstrated that DI significantly influences methacholine response, particularly in control subjects, our study confirms and extends previous work in this field and shows how it can affect methacholine challenges standardization.2122 It also confirms that a slightly "shortened" method can be used to assess effects of DI avoidance, in finding the dose causing a given fall in FEV1 such as 15%. We did not use methods not involving a full lung inflation to explore the effects of DI, as this has been done before and because our goals were mostly to test current procedures using FEV1 to assess airway obstruction.23 Skloot et al2 developed a modified methacholine challenge using partial forced expiratory maneuvers after incremental doses of methacholine. Kapsali et al8 then reported on repeated single-dose bronchoprovocations that included a 20-min period of avoidance of deep breaths; these methods made it possible to observe the bronchodilatory and bronchoprotective effects of DI.811 In healthy subjects, bronchoprotection is more potent than bronchodilation; in patients with asthma, there was no evidence that DI had a bronchoprotective effect.8 Our study is in keeping with these findings, while using a shortened method to evaluate the effects of DI avoidance before methacholine challenge. Although the mechanisms underlying the above findings remain to be explored, they may be related to the previously described changes in "plasticity" and function of the bronchial smooth muscle.24 It is indeed possible that changes in the structure of the airways observed in asthma lead to a reduced airway distensibility or are associated with a reduced potential for smooth muscle distention during inspiratory maneuvers. The airways could then loose their potential to relax after DI.

Although there is a considerable amount of data on the influence of avoidance of DI on airway function, this should be translated into recommendations for standardization of bronchial challenges. In addition to confirming previous observations that avoiding DI before methacholine challenge significantly increases airway responsiveness in control subjects while not changing airway response in patients with mild asthma, our study shows that the time interval between the last inhalation of methacholine and the first measurement of expiratory flow influences airway response to this agent. In our study, four subjects with a PC20 in the normal range (> 16 mg/mL) on test A (if the first FEV1 was measured at 30 s) had their PC20 reduced on test B (if the first FEV1 was measured at 3 min) to doses corresponding to the gray zone between asthma and normality; this suggests that such difference in methodology can possibly affect diagnostic accuracy in some "borderline" cases. Furthermore, differences in the final results of methacholine challenge tests, even when not significant in terms of final diagnosis, may be important for multicenter studies, especially when comparing tests between different centers. Therefore, this outlines the crucial importance of using the same techniques and same time intervals for the measures performed.

The result of methacholine challenges might also be affected if deep breaths or coughs occurred during the waiting period after the end of inhalation. This possibility, however, is not usually considered when bronchoprovocation tests are performed. We found that the longer the time interval was between the end of inhalation and the first FEV1 measurement, the greater the magnitude of airflow obstruction was, both in asthma patients and control subjects. This may be related to a slower effect of this agent on muscarinic receptors on the smooth muscle. This effect seems to be more marked in patients with asthma. Although it has been reported that total intrapulmonary aerosol deposition and its pattern had no significant effect on responsiveness to methacholine, changes in the distribution of methacholine in the airways over a 3-min period in patients with asthma compared to normal subjects may be involved in these findings.25

Previous studies suggested that there could be a slight cumulative effect of histamine2627 or methacholine16 during challenges. Juniper et al16 demonstrated a slight cumulative effect of methacholine using the doubling concentration protocol, with 5 min between concentrations and the first FEV1 measured at 30 s. Our study shows that there is also a cumulative effect when doubling concentrations of methacholine are administered at 6-min intervals with the first FEV1 measured at 3 min. The cumulative effect of methacholine is dependent on the time interval between dose step-ups and will increase as the time interval is reduced. The apparent cumulative effect may also vary depending on the time to first spirogram, possibly increasing with the later FEV1; this requires further study. This may suggest that the longer the time one waits before the measurement, the greater the airway smooth muscle will shorten. While the cumulative effect demonstrated is of small magnitude and will cause little change in the results, it is yet another reason for standardization of both the time interval between inhalations and the timing of spirograms after inhalation.

In conclusion, in subjects with mild-to-moderate asthma, avoiding DIs for 3 min after (by delaying the first spirogram) but not for 20 min before methacholine inhalation increased the magnitude of methacholine-induced bronchoconstriction. In control subjects, however, avoiding DI both before and after methacholine inhalation enhanced the bronchoconstriction. In both groups, there was a slight cumulative effect of administering doubling concentrations of methacholine at 6-min intervals when the first FEV1 was measured at 3 min.


   Footnotes
 
Abbreviations: DI = deep inspiration; MIT = methacholine inhalation test; PC20 = provocative concentration of methacholine inducing a 20% fall in FEV1

This study was funded by local funds. Dr. Cockcroft is the Ferguson Professor of Respiratory Medicine, supported by the Lung Association of Saskatchewan.

Received for publication February 12, 2004. Accepted for publication August 2, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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N. D. Allen, B. E. Davis, T. S. Hurst, and D. W. Cockcroft
Difference Between Dosimeter and Tidal Breathing Methacholine Challenge: Contributions of Dose and Deep Inspiration Bronchoprotection
Chest, December 1, 2005; 128(6): 4018 - 4023.
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