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(Chest. 2004;125:453-458.)
© 2004 American College of Chest Physicians

Methacholine Challenge Testing*

Comparison of the Two American Thoracic Society-Recommended Methods

Catherine Wubbel, MD; Michael J. Asmus, PharmD; Gary Stevens, PhD; Sarah E. Chesrown, MD, PhD and Leslie Hendeles, PharmD

From the Pulmonary Division, Department of Pediatrics (Drs. Wubbel, Chesrown, and Hendeles), College of Medicine; the Asthma Research Laboratory, College of Pharmacy (Dr. Asmus); and the Department of Statistics (Dr. Stevens), University of Florida, Gainesville, FL.

Correspondence to: Catherine Wubbel, MD, DeVos Children’s Hospital, 330 Barclay, Suite 200, Grand Rapids, MI 49503; e-mail: Catherine.wubbel{at}spectrum-health.org


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Recent American Thoracic Society guidelines recommend two different methods of methacholine challenge testing: the 2-min tidal breathing method with twofold increases in concentration, and the five-breath dosimeter method with fourfold increases. Since the tidal breathing method delivers more methacholine to the mouthpiece, we hypothesized that the provocative concentration of methacholine required to decrease FEV1 by 20% (PC20) would be lower than with the dosimeter method.

Design: Twelve subjects 18 to 45 years old with stable asthma were selected on the basis of a screening PC20 (by tidal breathing) of < 1 mg/mL, 1 to 4 mg/mL, or 4 to 16 mg/mL (4 subjects in each concentration range). On subsequent visits within a 7-day period, methacholine challenge testing with tidal breathing or dosimeter were performed on separate days, in a randomized crossover manner.

Results: The geometric mean PC20 was 1.8 mg/mL (95% confidence interval [CI], 0.7 to 4.3) after tidal breathing and 1.6 mg/mL (95% CI, 0.7 to 3.7) after dosimeter (p = 0.2). There was no significant difference between the screening PC20 and the PC20 obtained by either method on randomized study days. The maximum decrease in FEV1 from diluent baseline after the last concentration was 27.8% (range, 20 to 50%) during tidal breathing and 27.9% (range, 16 to 47%) during the dosimeter method (p = 0.35).

Conclusions: Both methods give similar results. Fourfold increases in methacholine concentration with the dosimeter method are as safe as twofold increases with the tidal breathing method.

Key Words: asthma • bronchial challenge • bronchoprovocation • dosimeter • methacholine


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Methacholine challenge testing is a well-established means of evaluating the degree of airway responsiveness.1 2 3 4 It is commonly used to confirm the diagnosis of asthma in patients with a history of asthma symptoms but a normal FEV1. Also, it is used in research studies5 6 7 to measure the effects of asthma therapies over time. A recent American Thoracic Society (ATS) guideline1 recommends two different methods of methacholine challenge testing: the 2-min tidal breathing method, and the five-breath dosimeter method. In the 2-min tidal breathing method, up to 10 twofold increases in concentration of methacholine are placed in a nebulizer attached to a constant-output compressor. Patients are instructed to perform tidal breathing for 2 min. Measurement of response (ie, decrease in FEV1) is performed over a subsequent 3-min period. In the five-breath dosimeter method, the patient slowly inhales five breaths from functional residual capacity to total lung capacity (ie, a deep slow breath) through a dosimeter-driven nebulizer containing up to five fourfold increases in concentration of methacholine. The dosimeter is an electrically valved system that enables one to administer aerosol for 0.6 s during inhalation from the nebulizer. The dose may be triggered manually by pressing a button or by an automatic system that delivers a single dose soon after the onset of a deep breath. After each of five inhalations, the patient is instructed to hold his or her breath for 3 to 5 s. FEV1 is measured before and 3 min after each inhalation challenge. In both protocols, challenges are repeated at 5-min intervals until the subject experiences at least a 20% decrease in FEV1. The primary outcome from each challenge is expressed as the lowest provocative concentration of methacholine required to decrease FEV1 by 20% (PC20) from baseline.

Each method utilizes a unique nebulizer with specific performance characteristics. The nebulizer for the 2-min tidal breathing method must deliver an aerosol with an aerodynamic mass median diameter (AMMD) between 1.0 µm and 3.6 µm, with a calibrated output of 0.13 mL/min (± 10%).1 The Wright nebulizer (Roxon Medi-Tech; Montreal, PQ, Canada) generates particles between 1.0 µm and 1.5 µm AMMD and is recommended for this method,8 but other nebulizers that meet these specific criteria may also be acceptable.1 The nebulizer used in the five-breath dosimeter method should deliver 9 µL (0.009 mL) [± 10%] of solution per 0.6-s actuation during inhalation.9 The DeVilbiss model 646 nebulizer (Sunrise Medical; Somerset, PA) is recommended for this technique.1

Approximately 80% of the aerosol produced by the Wright nebulizer (2-min tidal breathing method) is within the ideal size range (ie, < 5 µm) for optimal delivery to the small airways of the human lung.10 For a calibrated output of 0.13 mL/min and a respiratory cycle (inspiratory time divided by total respiratory cycle time) of 0.34 for 2 min of tidal breathing, approximately 0.089 mL of solution would be delivered to the mouthpiece.11 While much of this would be deposited in the airways, many smaller particles will be exhaled. Approximately 70% of the aerosol produced by the DeVilbiss 646 nebulizer (five-breath dosimeter method) is < 5 µm.4 For a calibrated output of 9 µL (0.009 mL) per 0.6-s actuation for five breaths, a total of 0.045 mL of solution would be delivered to the mouthpiece.4 Thus, twice the volume of methacholine solution is available for inhalation with the tidal breathing method. Consequently, it was our hypothesis that the PC20 would be lower with the tidal breathing method than with the dosimeter method.

Although previous studies2 4 have compared these two methods, the results are not consistent and no study has been conducted under the current guidelines with the newer equipment now commercially available. Previous studies used only doubling methacholine concentrations,2 4 12 13 and did not test the quadrupling concentrations now recommended as an option for the dosimeter method.1 In addition, previous studies were conducted with the original English-made Wright nebulizer, which is no longer manufactured. The Wright nebulizer currently available is manufactured by a different company in Canada, and that company has no data on the performance of their product. Thus, the present study was conducted to test our hypothesis using the equipment and methods specified in the recent ATS guidelines.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Twelve subjects with stable asthma recruited from the community with baseline FEV1 >= 60% and PC20 <= 16 mg/mL (Tables 1 , 2 ) were randomized. Subjects had to be nonsmokers, not pregnant or breast feeding, able to withhold medications that could have an acute effect on PC20, and able to perform acceptable and reproducible spirometry.14 Subjects were excluded if they had an asthma exacerbation requiring oral steroids, an emergency department visit or hospitalization for asthma within 3 months, an upper respiratory tract infection in the past 6 weeks prior to or during the study, or a history of hypertension, life-threatening asthma, or anaphylaxis. Also, subjects were excluded if they had a history of any disease or medication use that might interfere with the results, or place the subject in jeopardy if withheld. General screening included review of allergic status and allergen exposure. Specific allergen testing for atopy was not performed. Although seasonal exposure to allergens can play a role in the overall degree of airway hyperresponsiveness,15 this would not be a confounding factor since all visits were completed within 14 days within the same season. Subjects were selected on the basis of a tidal breathing screening PC20 that fell within the strata of airway responsiveness: < 1 mg/mL, 1 to 4 mg/mL, and 4 to 16 mg/mL.1 The study was approved by the Institutional Review Board at the University of Florida, and all subjects gave witnessed, written, informed consent.


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  		Table 1. Demographic Characteristics and Medication History During the Screening Visit for Randomized Subjects*

 

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  		Table 2. Responses to Methacholine Challenge Tests

 
Study Design
This was an unblinded, randomized, crossover study consisting of three visits. Each visit was at least 24 h but not more than 7 days apart. Thus, for any given subject, the study was completed within 14 days. Testing sessions were performed in the morning hours. The first visit was a screening visit to determine eligibility and baseline PC20, followed by two subsequent study visits using tidal breathing and dosimeter. Before each randomized methacholine challenge test, FEV1 had to be within 10% of the value obtained during the screening visit. Albuterol was withheld for 8 h, and leukotriene modifiers were withheld for 24 h. The morning dose of inhaled corticosteroids was not withheld. None of the subjects were receiving long-acting ß-agonists. No changes in maintenance medication were made during the study, and adherence was not measured.

Test Products
Methacholine solutions were prepared from a commercial powder (Provocholine; Methpharm; Brantford, ON, Canada) using aseptic technique by the Investigational Drug Unit of Shands Hospital Pharmacy. Each concentration (2 mL) was dispensed in a sterile unit-dose syringe and stored frozen until use. Solutions stored in this manner are stable for 4 to 6 months, depending on the concentration.16 Solutions were allowed to warm to room temperature before testing, and unused dilutions were discarded.

Tidal Breathing Method
Concentrations of 0.03, 0.06, 0.125, 0.25, 0.50, 1, 2, 4, 8, and 16 mg/mL were prepared for use with the tidal breathing method. These solutions were delivered to subjects over 2 min by a Wright nebulizer (Roxon Medi-Tech), calibrated to an outflow of 0.13 mL/min (± 10%), powered by dry compressed air. A Hans Rudolph one-way valve (Hans Rudolph; Kansas City, MO) was interposed between the nebulizer and the mouthpiece.

Dosimeter Method
Methacholine concentrations of 0.06, 0.25, 1, 4, and 16 mg/mL were prepared for the dosimeter method. These solutions were delivered to subjects through a mouthpiece attached to a DeVilbiss 646 nebulizer (Sunrise Medical) driven by the KoKo Digidoser system (Pulmonary Data Service; Louisville, CO). The KoKo Digidoser/nebulizer was calibrated to produce an output of 0.009 mL (± 10%) per 0.6-s actuation. After normal tidal expiration to functional reserve capacity, the technician triggered the dosimeter at the onset of inspiration, and the subject was asked to inhale slowly and deeply over 5 s to total lung capacity. Subjects held their breath for 5 s, followed by slow exhalation for 5 s. This procedure was repeated four times for a total of five cycles at each concentration.

Procedures Common to Both Methods
All challenge procedures were performed according to the recent ATS guideline.1 A minimum of three but no more than four FEV1 measurements were performed at 30 to 90 s after each challenge. All subjects wore a nose clip and inhaled the methacholine through a mouthpiece.

When baseline FEV1 was within 10% of screening baseline, each subject received, at 5-min intervals, the respective concentrations of methacholine via either method. Each challenge began with diluent followed by the lowest concentration of methacholine for the respective method, and was increased until either a 20% decline in FEV1 was achieved, the maximum methacholine concentration was administered without at least a 20% change in FEV1, or the subject requested inhaled albuterol. Spirometry was performed using the KoKo Pneumotach Spirometer and software (Pulmonary Data Service). Nebulizer particle sizes were not measured in this study. Each study visit ended when the subject’s FEV1 returned to at least 90% of the baseline value after administration of albuterol from a metered-dose inhaler through a valved holding chamber (Aerochamber; Monaghan Medical; Plattsburgh, NY).

Data Analysis and Statistical Methods
The PC20 was calculated by interpolating the last two FEV1 values plotted on the y-axis vs the noncumulative log concentration of methacholine on the x-axis. PC20 values were log-transformed since they were not normally distributed.

Data analysis was performed using SAS version 8 (SAS Institute; Cary, NC). Two statistical procedures were used to determine and compare the relationship between the two methods. The first was to calculate the concordance correlation coefficient (CCC) of Lin17 and a 95% confidence interval (CI) for the CCC, which tests for both differences in mean response and variability. The CCC method evaluates the degree to which the pairs of data fall on the line of identity, where the PC20 of one method is plotted on the x-axis and PC20 of the other method on the y-axis. It contains both measures of accuracy and precision. In short, CCC = {rho}Cb where rho ({rho}) is the Pearson correlation measure of precision or how far each observation deviated from the best fit line, and Cb is a measure of accuracy: how far the best fit line deviates from the line of identity, also referred to as the bias. This bias measure (Cb) contains a location and a scale shift parameter. The location shift parameter should be close to zero, indicating that the means are equal, and the scale shift parameter should be close to one, indicating that the variances of the two methods are equal. Values of CCC close to one indicate that there is good agreement between the two methods.

A paired t test was used to compare the maximum decrease from diluent baseline after the last concentration of methacholine as well as the geometric mean PC20 after each method. {alpha} < 0.05 was required to reject the null hypothesis.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of 25 subjects screened, 12 subjects were randomized (Table 1) . The results for subject 9 after tidal breathing were unreasonable based on clinical experience. Her PC20 values were as follows: screening, 0.23; dosimeter, 0.54; and tidal breathing, 11.7. Therefore, we suspected surreptitious use of albuterol before the randomized tidal breathing test day. Initially, statistical analyses were performed twice, once including this subject and once excluding this subject. Since including this data affected the results of CCC and the value on the tidal breathing day was probably spurious, data for this subject were excluded from analysis.

ATS criteria for acceptability and reproducibility14 of all measured FEV1 values were met 93% of the time. The geometric mean PC20 for the 11 evaluated subjects was 1.8 mg/mL (95% CI, 0.7 to 4.3) after randomized tidal breathing and 1.6 mg/mL (95% CI, 0.7 to 3.7) after dosimeter (not significantly different, p = 0.2) [Fig 1 , Table 2 ]. The CCC provided three possible contrasts: (1) screening vs randomized tidal breathing PC20, (2) screening vs dosimeter PC20, and (3) randomized tidal breathing vs dosimeter (Table 3 ). The location shift parameter, reflecting accuracy, was not significantly different from zero, and the scale shift parameter, reflecting precision, was not significantly different from 1.0. These results imply that there was no significant difference between the two methods in measuring PC20.



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  		Figure 1. PC20 values. The tidal breathing and dosimeter methods were performed in a randomized manner on different study days. The geometric mean PC20 was 1.8 mg/mL (95% CI, 0.7 to 4.3) after tidal breathing and 1.6 mg/mL (95% CI, 0.7 to 3.7) after dosimeter (p = 0.2) with data from subject 9 deleted. It is our suspicion that subject 9 surreptitiously took albuterol before the challenge on the randomized tidal breathing day. According to the ATS guidelines,1 airway responsiveness is categorized as moderate to severe (< 1 mg/mL), mild (1 to 4 mg/mL), borderline (4 to 16 mg/mL), and normal bronchial reactivity (> 16 mg/mL).

 

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  		Table 3. Estimates From the CCC Analysis*

 
Similarly there were no significant differences by t test of the mean differences in PC20 between tidal breathing and dosimeter on randomized days (p = 0.52). With a sample size of n = 11, the power to detect a twofold difference in mean PC20 with a SD of the log difference of 0.5 was 98%.

The two methods induced a similar degree of bronchospasm. The mean maximum decrease in FEV1 after the last concentration of methacholine was 27.8% (range, 20 to 50%) from diluent during the tidal breathing method and 27.9% (range, 16 to 47%) during the dosimeter method (p = 0.88) [Table 2 ].

Four subjects previously stratified into the 1 to 4 mg/mL group during screening changed strata during the actual testing procedures (Table 2) . During the tidal breathing, randomized, test day, two subjects moved from 1 to 4 mg/mL to 4 to 16 mg/mL and two subjects moved from 1 to 4 mg/mL to < 1 mg/mL. The same pattern occurred during the dosimeter treatment. The proportion of subjects changing categories was not significantly different between the two methods, and only one subject who was < 16 mg/mL during screening had a value > 16 mg/mL on the dosimeter randomized day.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study indicate that the two methods of methacholine challenge recommended in the recent ATS guideline provide similar PC20 values. Estimates of accuracy and precision of the two methods are similar. Differences found between individuals are more likely a result of day-to-day differences in airway responsiveness than the method used to assess this. Moreover, both methods were equally safe. The maximum bronchospasm induced by increasing concentrations in fourfold steps with the dosimeter method was no greater than that produced by twofold increases with the tidal breathing method.

We calculated that the tidal breathing procedure would deliver approximately twice as much methacholine to the mouthpiece than dosimeter. However, the results suggest that similar amounts of drug reach the relevant muscarinic receptors in the airways. The difference, therefore, is likely a result of one or two possibilities. Either the dosimeter method results in greater retention and distribution of aerosol or more methacholine is left in the equipment and/or lost to the atmosphere with the tidal breathing method, or tidal breathing may be associated with greater loss of methacholine due to greater mouth deposition.

Ryan and colleagues9 demonstrated that variation in particle sizes between 1.3 µm and 3.6 µm in AMMD as produced by the English-made Wright nebulizer did not affect PC20 measurement. There are no published data on the particle size distribution with the currently available Wright nebulizer, and the manufacturer could provide no data. Since our results are similar to those of Ryan et al,9 we can only speculate that the Canadian-made Wright nebulizer used in our study delivers particles in the 1.3- to 3.6-µm range.

Although the guidelines state that 3 mL of methacholine should be used,1 we chose 2 mL to decrease the cost of the methacholine. The difference in fill volume should not affect nebulizer performance since the volume nebulized is small (13% for tidal breathing and 3.4% for dosimeter), and thus most of the fill volume remains in the nebulizer at the completion of the challenge.

The ATS guidelines recommend quadrupling concentrations for the dosimeter method,1 and parenthetically state that it is safe to use the shorter procedure with the tidal breathing method. A few studies18 19 20 have determined the usefulness and safety of shorter protocols for the methacholine challenge test with the tidal breathing method. The protocols are shortened by starting at a higher concentration when FEV1 is initially normal (eg, 2 mg/mL) and skipping concentration steps when the previous dilution resulted in < 10% decrease in FEV1. However, there are no previous studies of fourfold steps with the dosimeter method. Since the emphasis of the guidelines was on a twofold increasing concentration with tidal breathing and fourfold steps with dosimeter, we chose to conduct the study in this manner.

Ryan et al9 found no difference between the tidal breathing and dosimeter, whereas Bennett and Davies2 reported lower PC20 values with tidal breathing. One reason for the difference between their studies may have been related to the nebulizers employed. Bennett and Davies2 used the same DeVilbiss nebulizer for both methods, whereas Ryan et al9 used the English-made Wright nebulizer for the tidal breathing method and a DeVilbiss nebulizer for the dosimeter method. Our study was similar to Ryan et al9 using the equipment, dilutions, and protocol recommended in the ATS guidelines.

There are some inherent pitfalls in performing methacholine challenges with either method. These include errors in dilution, erroneous spirometry values, and inaccurate delivery if equipment is not calibrated. Subject factors that may lead to inaccurate results include variation in performance of spirometry as well as day-to-day variation in lung function. To minimize the effects of these factors, several steps were taken. All methacholine dilutions were prepared by one pharmacist at the same time and stored frozen in unit-dose syringes, equipment was calibrated, baseline FEV1 had to be within 10% of the screening value on each study day, and only subjects capable of performing acceptable and reproducible spirometry were selected.

We conclude that the two methods give similar results. Fourfold increases in concentration with the dosimeter method are as safe as twofold increases in concentration with the tidal breathing method when ATS guidelines are followed and potential causes of variability minimized.


   Acknowledgements
 
We thank the study participants; Linda Olander, research assistant in the Asthma Research Laboratory, for assistance in scheduling subjects and assisting with methacholine challenges; and Kathy Rice for editorial assistance.


   Footnotes
 
Abbreviations: AMMD = aerodynamic mass median diameter; ATS = American Thoracic Society; CCC = concordance correlation coefficient; CI = confidence interval; PC20 = provocative concentration of methacholine required to decrease FEV1 by 20%

Received for publication February 21, 2003. Accepted for publication August 12, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Crapo, RO, Casaburi, R, Coates, AL, et al (2000) Guidelines for methacholine and exercise challenge testing, 1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 161,309-329[Free Full Text]
  2. Bennett, JB, Davies, RJ A comparison of histamine and methacholine bronchial challenges using the DeVilbiss 646 nebulizer and the Rosenthal-French dosimeter. Br J Dis Chest 1987;81,252-259[CrossRef][Medline]
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  4. Ryan, G, Dolovich, MB, Roberts, RS, et al Standardization of inhalation provocation tests: two techniques of aerosol generation and inhalation compared. Am Rev Respir Dis 1981;123,195-199[ISI][Medline]
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  7. Leff, JA, Busse, WW, Pearlman, D, et al Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339,147-152[Abstract/Free Full Text]
  8. Juniper, EF, Cockcroft, DW, Hargreave, FE Histamine and methacholine inhalation tests: tidal breathing method; laboratory procedure and standardisation. 1994,5-25 Astra Draco AB. Lund, Sweden:
  9. Ryan, G, Dolovich, MB, Obminski, G, et al Standardization of inhalation provocation tests: influence of nebulizer output, particle size, and method of inhalation. J Allergy Clin Immunol 1981;67,156-161[CrossRef][ISI][Medline]
  10. Clay, MM, Pavia, D, Newman, SP, et al Assessment of jet nebulisers for lung aerosol therapy. Lancet 1983;2,592-594[ISI][Medline]
  11. Brannan, JD, Subbarao, P, Ho, B, et al Inhaled mannitol identifies methacholine responsive children with current asthma [abstract]. Am J Respir Crit Care Med 1999;159,A911
  12. Cockcroft, DW, Berscheid, BA Standardization of inhalation provocation tests: dose vs concentration of histamine. Chest 1982;82,572-575[Abstract/Free Full Text]
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  16. Asmus, MJ, Vaughan, LM, Hill, MR, et al Stability of frozen methacholine solutions in unit-dose syringes for bronchoprovocation. Chest 2002;121,1634-1637[Abstract/Free Full Text]
  17. Lin, LI A concordance correlation coefficient to evaluate reproducibility. Biometrics 1989;45,255-268[CrossRef][ISI][Medline]
  18. Cockcroft, DW, Marciniuk, DD, Hurst, TS, et al Methacholine challenge: test-shortening procedures. Chest 2001;120,1857-1860[Abstract/Free Full Text]
  19. Izbicki, G, Bar-Yishay, E Methacholine inhalation challenge: a shorter, cheaper and safe approach. Eur Respir J 2001;17,46-51[Abstract/Free Full Text]
  20. Troyanov, S, Malo, JL, Cartier, A, et al Frequency and determinants of exaggerated bronchoconstriction during shortened methacholine challenge tests in epidemiological and clinical set-ups. Eur Respir J 2000;16,9-14[Abstract]



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