American Thoracic Societv - Guidelines for Methacholine and

American Thoracic

Societv

Guidelines for Methacholine and Exercise Challenge

Testing-1999

THIS OFFICIAL

STA.TEMENT

OF THE AMERICAN

THORACIC

SOCIETY WAS

ADORED

BY THE ATS BOARD OF DIRECTORS, JULY 1999

I. Purpose and Scope

II. Methacholine Challenge Testing

A. Indications

B. Contraindications

C. Technician Training/Qualifications

D. Safety

E. Patient Preparation

F. Choice and Preparation of Methacholine

G. Dosing Protocols

Two-Minute Tidal Breathing Dosing Protocol

2. Five-Breath Dosimeter Protocol

H. Nebulizers and Dosimeters

I. Spirometry and Other End-point Measures

J. Data Presentation

K. Interpretation

III. Exercise Challenge

A. Indications

B. Contraindications and Patient Preparation

C. Exercise Challenge Testing

D. Assessing the Response

References

Appendix A: Sample Methacholine Challenge Test Consent

Form

Appendix B: Sample Methacholine Challenge Pretest Ques-

tionnaire

Appendix C: Sample Report Format

Appendix D: Equipment Sources

PURPOSE

AND SCOPE

This statement provides practical guidelines and suggestions

for methacholine and exercise challenging testing. Specifi-

cally, it reviews indications for these challenges, details factors

that influence the results, presents brief step-by-step proto-

cols, outlines safety measures, describes proper patient prepa-

ration and procedures, provides an algorithm for calculating

results, and offers guidelines for clinical interpretation of re-

sults. The details are important because methacholine and ex-

ercise challenge tests are, in effect, dose-response tests and

delivery of the dose and measurement of the response must be

accurate if a valid test is to be obtained. These guidelines are

geared to patients who can perform good-quality spirometry

tests; they are not appropriate for infants or preschool chil-

dren. They are not intended to limit the use of alternative pro-

tocols or procedures that have been established as acceptable

methods. We do not discuss the general topic of bronchial

hy-

perresponsiveness (BHR).

Respir Crit Care Med

Vol 161. pp 309-329, 2000

Internet address:

www.atsjournals.org

The bronchial challenge tests chosen for review are the two

most widely used, with enough information in the literature to

evaluate their utility. Of the two, methacholine challenge test-

ing is better established; a number of aspects in the exercise

challenge protocol will benefit from further evaluation. We do

not cover specific challenges with allergens, drugs, or occupa-

tional sensitizers, and recommend that such tests be performed

only in laboratories with considerable experience in their tech-

niques. For more extensive details or other challenge proce-

dures the reader is referred to previously published guidelines

for bronchial challenge testing (l-5) and reviews on the gen-

eral topic of BHR (6-9).

As with other American Thoracic Society (ATS) statements

on pulmonary function testing, these guidelines come out of a

consensus conference. The basis of discussion at the committee’s

September 1997 meeting was a draft prepared by three members

(P.E., C.I., and R.C.). The draft was based on a comprehensive

Medline literature search from 1970 through 1997, augmented

by suggestions from other committee members. The final rec-

ommendations represent a consensus of the committee. For is-

sues on which unanimous agreement could not be reached, the

guidelines reflect both majority and minority opinions.

The committee recommends that the guidelines be reviewed

years and, in the meantime, encourages further research

in the areas of controversy.

II. METHACHOLINE CHALLENGE TESTING

Indications

Methacholine challenge testing is one method of assessing air-

way responsiveness. Airway hyperresponsiveness is one of the

features that may contribute to a diagnosis of asthma. It may

vary over time, often increasing during exacerbations and de-

creasing during treatment with antiinflammatory medications.

Methacholine challenge testing (MCT) is most often consid-

ered when asthma is a serious possibility and traditional meth-

ods, most notably spirometry performed before and after

administration of a bronchodilator, have not established or

eliminated the diagnosis. Symptoms that suggest asthma in-

clude wheezing, dyspnea, chest tightness, or cough in the fol-

lowing circumstances: (I) with exposure to cold air, (2) after

exercise, (3) during respiratory infections, (4) following inhal-

ant exposures in the workplace, and (5) after exposure to al-

lergens and other asthma triggers. A history of such symptoms

increases the pretest probability of asthma. The optimal diag-

nostic value of MCT (the highest combination of positive and

negative predictive power) occurs when the pretest probabil-

ity of asthma is

30-70%

(10). Methacholine challenge testing

is more useful in excluding a diagnosis of asthma than in es-

tablishing one because its negative predictive power is greater

than its positive predictive power.

Methacholine challenge testing is also a valuable tool in the

evaluation of occupational asthma. Methacholine challenge

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testing is sometimes used to determine the relative risk of de-

veloping asthma, assess the severity of asthma, and assess re-

sponse to asthma therapy although its clinical use in these ar-

eas has not been well established.

Rationale. Even asthma specialists cannot accurately pre-

dict MCT results in patients with an intermediate probability

of asthma (I 1). The MCT has excellent sensitivity but medio-

cre positive predictive value for asthma (8). Most subjects with

current asthma symptoms will have BHR. However, bronchial

hyperresponsiveness is also seen in a wide variety of other dis-

eases, including smoking-induced chronic airway obstruction

(COPD), congestive heart failure (CHF), cystic fibrosis, bron-

chitis, and allergic rhinitis (12-14).

Because improvement in the clinical severity of asthma is

associated with improvement in airway responsiveness (1.5,

16) clinical studies of asthma therapies often use change in air-

way responsiveness as an objective outcome measure (9, 17-

25). Sont and colleagues have demonstrated the efficacy of a

treatment program that included measures of airway hyperre-

activity in the management approach (26). However, we be-

lieve the routine use of MCT to examine patients with asthma

in a clinical setting should await further exploration of the util-

ity of such testing.

B. Contraindications

The contraindications to methacholine challenge testing, sum-

marized in Table 1, are all conditions that may compromise

the quality of the test or that may subject the patient to increased

risk or discomfort. They are identified in the pretest interview

or questionnaire.

contraindications are identified, they

should be discussed with the physician who ordered the test or

the medical director of the laboratory before proceeding.

Rationale. Low FEV,. Occasional dramatic falls in FEV,

may occur during MCT and the risk of such events may be in-

creased in individuals with low baseline lung function. Re-

duced lung function is a relative contraindication because the

overall risk of serious adverse events is small, even in patients

with asthma who have severe airway obstruction (27). The

level of lung function at which MCT is contraindicated is con-

troversial. A baseline FEV, of

1.5 L or

60% predicted in

adults is proposed as a relative contraindication by Sterk and

coworkers

(I)

and Tashkin and coworkers (28). Half of 40 in-

vestigators polled in one study considered an FEV, of

70%

predicted to be a contraindication (29); 20% used cutoff

points of 60% of predicted and 20% used 80% of predicted.

The Second National Asthma Expert Panel Report used an

FEV,

65% predicted (30).

Airway obstruction.

is difficult to interpret a “positive”

methacholine challenge result when baseline spirometry shows

airway obstruction (a low FEV,/FVC and low FEV,), because

TABLE 1

CONTRAINDICATIONS FOR

METHACHOLINE CHALLENGE TESTING

Absolute:

Severe airflow limitation

(FEV,

50% predicted or

1 .O L)

Heart attack or stroke in last 3 mo

Uncontrolled hypertension, systolic BP

200, or diastolic BP

100

Known aortic aneurysm

Relative:

Moderate airflow limitation (FEV,

60% predicted or

1.5 L)

Inability to perform acceptable-quality spirometry

Pregnancy

Nursing mothers

Current use of cholinesterase inhibitor medication (for myasthenia

gravis)

airway responsiveness correlates strongly with the degree of

baseline airway obstruction in COPD. In the presence of a

good clinical picture for asthma, if baseline spirometry shows

airflow obstruction and there is a significant bronchodilator

response

12% and

0.2-L increases in either FEV, or

FVC) the diagnosis of asthma is often confirmed and MCT is

usually unnecessary.

Spirometry quality. An acceptable-quality methacholine

challenge test depends on the ability of the patients to perform

acceptable spirometric maneuvers. Patients who cannot per-

form acceptable spirometry tests in the baseline session should

perhaps be rescheduled or be tested using an end-point mea-

sure that is less dependent on patient effort.

Cardiovascular problems. A history of cardiovascular prob-

lems may also be a contraindication, depending on the prob-

lem. The additional cardiovascular stress of induced broncho-

spasm may precipitate cardiovascular events in patients with

uncontrolled hypertension or recent heart attack or stroke. In-

duced bronchospasm causes ventilation-perfusion mismatching

(31,32), which can result in arterial hypoxemia and compensa-

tory changes in blood pressure, cardiac output, and heart rate

(33, 34). On the other hand, cardiac arrhythmia rates actually

fall during the performance of FVC maneuvers (35).

Pregnancy and nursing mothers. Methacholine is a preg-

nancy category C drug, meaning that animal reproductive stud-

ies have not been performed and it is not known whether it is

associated with fetal abnormalities. It is not known whether

methacholine is excreted in breast milk.

C. Technician Training/Qualifications

There is no recognized certification program for persons who

perform methacholine challenge testing. The pulmonary labo-

ratory director is responsible for evaluating and/or verifying

the training and qualification of the person(s) who perform the

test. At a minimum, the technician should:

Be familiar with this guideline and knowledgeable about

specific test procedures

Be capable of managing the equipment including set-up,

verification of proper function, maintenance, and cleaning

Be proficient at spirometry

Know the contraindications to MCT

Be familiar with safety and emergency procedures

Know when to stop further testing

Be proficient in the administration of inhaled bronchodila-

tors and evaluation of the response to them

Rationale. These requirements are standard testing ele-

ments designed to ensure good-quality results and patient

safety. It is estimated that about 4 d of hands-on training and

at least 20 supervised tests are required for a new technician to

become proficient in methacholine challenge testing (36).

D. Safety

Inhaled methacholine causes bronchoconstriction. The safety

of both patients and technicians should be considered in the

design of the test room and the testing procedures.

Precautions for patient safety. The medical director of the

laboratory, another physician, or another person appropri-

ately trained to treat acute bronchospasm, including appropri-

ate use of resuscitation equipment, must be close enough to

respond quickly to an emergency. Patients should not be left

unattended during the procedure once the administration of

methacholine has begun.

Medications to treat severe bronchospasm (30) must be

present in the testing area. They include epinephrine and atro-

pine for subcutaneous injection, and albuterol and ipratro-

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TABLE 2

FACTORS THAT DECREASE BRONCHIAL RESPONSIVENESS

Factor

Medications

Minimum Time Interval

from Last Dose to Study Ref. No.

Short-acting inhaled bronchodilators, such as isoproterenol,

45,46

isoetharine, metaproterenol, albuterol, or terbutaline

Medium-acting bronchodilators such as ipratropium

24 h

20,47

Long-acting inhaled bronchodilators, such as salmeterol,

48 h

48,49

formoterol, tiotropium

(perhaps 1 wk for tiotropium)

Oral bronchodilators

so,51

Liquid theophylline

12h

Intermediate-acting theophyllines 24 h

Long-acting theophyllines

48 h

Standard

pz-agonist

tablets

12h

Long-acting

pz-agonist

tablets 24 h

Cromolyn sodium

Nedocromil

48 h

Hydroxazine, cetirizine

Leukotriene modifiers

24 h

Foods

Coffee, tea, cola drinks, chocolate

Day of study

Note:

The authors do not recommend routinely withholding oral or inhaled corticosteroids, but their antiinflammatory effect may de-

crease bronchial responsiveness (53, 54). Inhaled corticosteroids may need to be withheld depending on the question being asked.

3. Testing.

a. Subjects must be able to understand the procedure and per-

form reliable spirometric maneuvers.

b. Subjects should be seated comfortably throughout the test.

c. A brief physical examination of the chest and lungs may be

useful but is not required.

Rationale. The pretest evaluation will alert the technician

to important issues, including

(1)

the presence of contraindica-

tions to proceeding with the test; (2) conditions or exposures,

such as a recent viral infection, that could temporarily increase

airway responsiveness

(58,

62-64) and cause a false-positive

response; (3) the presence of medications that may alter air-

way responsiveness. Influenza vaccination, the menstrual cy-

cle, antihistamines, and oral contraceptives do not significantly

affect airway responsiveness (65-67). A number of medica-

tions, most notably anticholinergic and P-agonist inhalers, can

temporarily reduce airway responsiveness, potentially causing

a false-negative response (20,23-25,46,52).

F. Choice and Preparation of Methacholine

Methacholine (acetyl-P-methylcholine chloride), available as

a dry crystalline powder, is the agent of choice for nonspecific

bronchoprovocation challenge testing. Food and Drug Ad-

ministration (FDA)-approved methacholine (Provocholine) is

TABLE 3

FACTORS THAT INCREASE BRONCHIAL RESPONSIVENESS

Factor

Duration of Effect

Ref. No.

Exposure to environmental antigens

Occupational sensitizers

Respiratory infection

Air pollutants

Cigarette smoke

Chemical irritants

l-3 wk

Months

55,56

3-6 wk

57,58

1 wk 59

Uncertain*

Days to months

*Studies of the acute effects of smoking on airway hyperreactivity and methacholine

challenge testing are not consistent

(60).

There is some evidence of a brief acute effect

that can be avoided by asking subjects to refrain from smoking for a few hours before

testing.

available in prepackaged, sealed

lOO-mg

vials. Industrial sources

of methacholine appear to work as well as Provocholine (68).

The advantages of FDA-approved methacholine are that it is

approved for human use and is required to meet good manu-

facturing practices for quality, purity, and consistency. The bro-

mide salt of methacholine may be substituted for the chloride

salt, although it is not currently available in an FDA-approved

form. Methacholine powder is very hygroscopic. Bulk powder

should be stored with a desiccator in a freezer. Sealed pre-

packaged vials do not require desiccation or freezing. Sterile

normal saline (0.9% sodium chloride) with or without 0.4%

phenol may be used as the diluent. The committee prefers the

use of normal saline without phenol. Phenol-containing saline

is specified for the dilution of Provocholine. There is no evi-

dence that adding a preservative such as phenol to sterile sa-

line diluent is necessary

(69)

nor is there evidence that use of

phenol adversely affects MCT. Both diluents are widely used.

The potential benefit of adding phenol is reducing the poten-

tial for bacterial contamination. The pH of methacholine in

normal saline solution is weakly to moderately acidic depend-

ing on the concentration of methacholine. Buffered solutions

are less stable and should not be used as the diluent (69-71).

Methacholine solutions should be mixed by a pharmacist or

other well-trained individual using sterile technique. The vials

should be labeled as methacholine with the concentration and

an expiration date and stored in a refrigerator at about 4” C.

When prepared with saline diluent and stored at 4” C, metha-

choline solutions of 0.125

mg/ml

and greater should be stable

for 3 mo (69, 71, 72). The package insert for Provocholine

specifies the use of normal saline containing 0.4% phenol as

the diluent and recommends the solution not be stored longer

than 2 wk and that the 0.025mg/ml solution be mixed on the

day of testing. We are not aware of published information on

the stability of methacholine in normal saline with phenol so-

lution; such studies are needed. In the absence of this informa-

tion, we recommend that the package insert recommendations

for Provocholine storage be followed when methacholine is

mixed with saline containing phenol. Solutions of methacho-

line should be warmed to room temperature before testing be-

gins. Any unused methacholine solution remaining in a nebu-

lizer should be discarded.

American Thoracic Society

Rationale. Choice of agent. Methacholine and histamine

produce bronchoconstriction at nearly equivalent concentra-

tions (73,74). Methacholine is currently more commonly used

(29) and is preferred to histamine because histamine is asso-

ciated with more systemic side effects, including headache,

flushing, and hoarseness. In addition, BHR measurements may

be less reproducible when using histamine (75-77).

Methacholine is a synthetic derivative of the neurotrans-

mitter acetylcholine, a substance that occurs naturally in the

body. Methacholine is metabolized more slowly by cholinest-

erase; its effects can be blocked or lessened by atropine or

similar anticholinergic agents.

Conditions. Acidic methacholine solutions with concentra-

tions greater than 0.3

mglml

(pH

6) remain stable for at least

3 mo when stored at 4” C (69,71,72,78). One committee mem-

ber’s experience is that concentrations of 0.125

mg/ml

are clini-

cally stable for 3 mo, but this observation has not been docu-

mented in the literature and a conservative approach should be

taken until more information is available on the stability of

lower concentrations. Methacholine is rapidly decomposed by

hydrolysis as the solution pH increases above six (71). Lower

concentrations of methacholine lose potency faster when stored

at room temperature because they are less acidic than higher

concentrations (71, 72). The concentration of methacholine

will change during nebulization if cold solutions are not allowed

time to warm to room temperature before use (79). Solution

remaining in a nebulizer after it has been used will concentrate

by evaporation and should not be reused.

Preparing solutions. Accurate sterile mixing is very impor-

tant for the accuracy of the test results and for the safety of pa-

tients. Only trained individuals should mix and label metha-

choline solutions.

C. Dosing Protocols

Many different dosing protocols have been used. Each has ad-

vantages and disadvantages and the committee was unable to

come to a single recommendation. We were able to narrow

the choices to two: (I) the 2-min tidal breathing method and

(2) the five-breath dosimeter method. The FDA approval for

the Methapharm (Brantford, ON, Canada) methacholine

(Provocholine) is based on the five-breath technique and a

dosing schedule using methacholine concentrations of 0.025,

0.25, 2.5, 10, and 25 mg/ml. A dilution scheme provided in

their product information is designed to accurately produce

these concentrations. The concentrations in the Provocholine

product information can be used in the five-breath dosimeter

method, although the committee prefers the dosing schedule

described below because the dosing steps are even and be-

cause of concerns about the safety of the

lo-fold

changes in di-

lution strength in the Provocholine protocol. Dilution schemes

for the two recommended dosing schedules, based on a

lOO-

mg vial of Provocholine, are presented in Table 4.

Rationale. Four common methods of aerosol generation

and inhalation are used (1): (I) dosing during a deep inhala-

tion, using a Y tube occluded by the thumb; (2) five breaths of

a fixed duration, using a dosimeter at the beginning of a deep

inhalation (5, 80,81); (3) a hand bulb nebulizer activated dur-

ing inhalation (82); and (4) continuous nebulization while tidal

breathing for 2 min (4, 83). All of these methods give similar

results (74, 81, 84-88). The two techniques recommended in

this statement are those most widely used in North America

and Europe. The hand bulb nebulizer (Yan protocol) is infre-

quently used in the United States (3) and has poorer repro-

ducibility when used with patients who have not previously

performed methacholine challenge tests (87). It is widely used

for epidemiological surveys.

313

1. Two-minute tidal breathing dosing protocol. The 2-min

tidal breathing method is, with some variation, based on the

protocol recommended by the Canadian Thoracic Society (4,

89). Refer to the flow chart in Figure 2. Details on spirometry

technique are found in the section, Spirometry and Other End-

point Measures.

Prepare the following 10 doubling concentrations of metha-

choline in sterile vials, place them in a holder, and store

them in a refrigerator:

Diluent: 0.03 0.06 0.125 0.25 0.50 1 2 4 8 16

mg/ml (see Table 4)

The use of the diluent step is optional. An optional short-

ened dosing regimen can be used under certain circum-

stances (see Rationale).

Remove the vials from the refrigerator 30 min before test-

ing, so that the mixture warms to room temperature before

use. Insert 3 ml of the first (diluent or lowest) concentra-

tion into the nebulizer, using a sterile syringe.

Perform baseline spirometry and calculate a target FEV,

that indicates a 20% fall in FEV, (baseline [or diluent]

FEV,

0.8).

Use a nebulizer setup such as shown in Figure 1. Use dry

compressed air to power the nebulizer, and set the pressure

regulator to 50

lb/in2.

Flow meter accuracy should be

checked with a rotameter (Matheson Tri-Gas, Montgomer-

yville, PA). Adjust the flow meter to deliver the output es-

tablished during the calibration procedure (0.13 ml/min,

10%). Attach a new exhalation filter (optional).

Instruct the patient to relax and breathe quietly (tidal breath-

ing) for 2 min. Apply a noseclip. Set the timer for 2 min.

Ask the patient to hold the nebulizer upright, with the

mouthpiece in his/her mouth. A face mask with a noseclip

is a valid alternative and may be easier for some subjects

(90). Start the timer and begin nebulization.

Watch the patient to ensure that he/she is breathing com-

fortably and quietly, and not tipping the nebulizer. After

TABLE 4

DILUTION SCHEMES FOR THE TWO RECOMMENDED

METHACHOLINE DOSING SCHEDULES

Label Strength Take

Add

NaCl

(0.9%)

Obtain Dilution

A. Dilution schedule* using 100.mg vial of methacholine chloride and the

2-min

tidal breathing protocol

100

6.25 ml

mg/ml

of dilution

A 3 ml

mg/ml

ml of dilution

3 ml

mg/ml

3 ml

of dilution

3 ml

mglml

3 ml

of dilution

3 ml

mg/ml

ml of dilution

3 ml

0.5

mg/ml

3 ml

of dilution

3 ml

0.25

mg/ml

of dilution

C 3 ml

0.125

mg/ml

of dilution

3 ml

0.0625

mg/ml

3 ml

of dilution

3 ml

0.031

mg/ml

B. Optional dilution schedule using

lOO-mg

vial of methacholine chloride and

five-breath dosimeter protocol

100

100 mg

6.25 ml

mg/ml

ml of dilution

A 9 ml

mg/ml

ml of dilution

9 ml

mg/ml

ml of dilution

9 ml

0.25

mg/ml

ml of dilution

9 ml

0.0625

mg/ml

Schedule obtained from Methapharm (Brantford, ON, Canada).

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(

Perform Barcl;ne Splromeny

Admmrster next dose of methachohne.

and perform sp~omctry after the approprwe delay

figure 2. Methacholine challenge testing sequence (flow chart).

*The choice of the

FEV,

value considered a contraindication may

vary from 60 to 70% of predicted. **The final dose may vary de-

pending on the dosing schedule used. Final doses discussed in this

statement are 16, 25, and 32

mg/ml.

exactly 2 min, turn off the flow meter and take the nebu-

lizer from the patient.

h. Measure the FEV, about 30 and 90 s after the nebulization

is completed. Obtain an acceptable-quality FEV, at each time

point. This may require repeated attempts. Perform no more

than three or four maneuvers after each dose. It should

take no more than 3 min to perform these maneuvers. To

keep the cumulative effect of methacholine relatively con-

stant, the time interval between the commencement of two

subsequent concentrations should be kept to 5 min.

At each dose, report the highest FEV, from the acceptable

maneuvers.

If the FEV, falls less than

20%,

empty the nebulizer, add 3 ml

of the next highest concentration, and repeat steps e-h above.

k. If the FEV, falls more than 20% from baseline (or the high-

est concentration has been given), give no further metha-

choline, note signs and symptoms, administer inhaled

al-

buterol, wait 10 min, and repeat the spirometry. If vocal

cord dysfunction is suspected and the patient’s symptoms

allow it, full inspiratory and expiratory flow volume loops

may be performed before giving the bronchodilator.

2. Five-breath dosimeterprotocol. The five-breath dosimeter

protocol was first standardized by the National Institutes of

Health (NIH) Institute of Allergic and Infectious Diseases in

1975 (5) and is presented as an alternative method by the Eu-

ropean Respiratory Society (1). It is widely used in research

studies. We have modified it by recommending quadrupling

doses rather than doubling doses. The Provocholine dosing

schedule is also acceptable. Refer to the flow chart in Figure 2.

.i.

Set up and check the dosimeter.

Prepare the following five concentrations of methacholine

in sterile vials; place them in a holder; and store them in a

refrigerator. (Note: in contrast to the 2 min tidal breathing

method, only every other concentration is used, resulting in

increments of quadrupling doses.) Use of a 32 mg/mL con-

centration is optional; it would primarily be used for re-

search and epidemiological studies.

Diluent: 0.0625 0.25 1 4 16

mg/ml

(see Table 4)

Use of the diluent step is optional.

Remove the vials from the refrigerator 30 min before test-

ing, so that the contents warm to room temperature before

use. Insert 2.0 ml of the first

concentraGon

into the nebulizer,

using a sterile syringe. (Some nebulizer models may require

more than 2.0 ml of solution for reliable aerosolization.)

The patient is seated throughout the test.

Perform baseline spirometry.

Briefly open the dosimeter solenoid to make sure the nebu-

lizer is nebulizing.

Ask the patient to hold the nebulizer upright with the mouth-

piece in his/her mouth. Watch the patient during the breath-

ing maneuvers to ensure that the inhalation and breathhold

are correct and that the nebulizer is not tipped. The patient

should wear a

noseclip

while inhaling from the nebulizer.

At end exhalation during tidal breathing (functional resid-

ual capacity), instruct the patient to inhale slowly and

deeply from the nebulizer. Trigger the dosimeter soon after

the inhalation begins; dosimeters may do this automati-

cally. Encourage the patient to continue inhaling slowly

(about 5 s to complete the inhalation) and to hold the

breath (at total lung capacity, TLC) for another 5 s.

Repeat step h for a total of five inspiratory capacity inhala-

tions. Take no more than a total of 2 min to perform these

five inhalations.

Measure the FEV, at about 30 and 90 s after the fifth inha-

lation from the nebulizer. Obtain an acceptable-quality

FEV, at each time point. This may require repeated at-

tempts. Perform no more than three or four maneuvers af-

ter each dose. It should take no more than 3 min to per-

form these maneuvers. To keep the cumulative effect of

methacholine relatively constant, the time interval between

the commencement of two subsequent concentrations

should be kept to 5 min.

At each dose, report the highest FEV, from acceptable ma-

neuvers.

If the FEV, falls less than

20%,

empty the nebulizer, shake

it dry, and trigger the dosimeter once to dry the nebulizer

nozzle. Add 2.0 ml of the next higher concentration, and

repeat steps g-j.

m. If the FEV, falls more than 20% from baseline (or the high-

est concentration has been given), give no further metha-

choline, note signs and symptoms, administer inhaled

al-

buterol, wait 10 min, and repeat the spirometry. If vocal

cord dysfunction is suspected and the patient’s symptoms

allow it, full inspiratory and expiratory flow volume loops

may be performed before giving the bronchodilator.

American Thoracic Society

315

3. Rationale. Dosing schedules. Many different dosing pro-

tocols have been used by investigators and laboratories. Dou-

bling concentrations are widely recommended for research

protocols and are mathematically attractive but the smaller

steps increase the time needed for a test. As a compromise, for

clinical testing, we recommended quadrupling increments for

clinical testing with the five-breath dosimeter method. Fewer

concentrations have been used by many investigators in order

to save time

(41,91-9.5)

without any apparent increase in risk

of severe bronchospasm. If MCT is used to determine changes

in airway reactivity after therapy in patients known to have

asthma, using doubling doses will give more precise

PCZo

(pro-

vocative concentration causing a 20% fall in FEV,) values.

Optional shortening of the tidal breathing protocol. The

2-min tidal breathing protocol may be shortened (depending

on the clinical situation) by adjusting the starting concentra-

tion (4). For example, in a diagnostic test for a subject not

known to have asthma, taking no asthma medications, with

normal lung function, and no response to diluent, a starting

dose of 1

mg/ml

is quite safe. In addition, when the FEV, has

fallen less than 5% in response to a dose of methacholine, the

next concentration may be omitted; a fourfold increase in dos-

age is quite safe under these circumstances. Caution: Small

children with asthma symptoms are more likely than adults to

have severe airway hyperresponsiveness and more caution in

increasing the concentration at each step is warranted. This

apparent increased sensitivity in children may reflect an in-

creased dose per unit weight (96).

Test techniques. The speed at which methacholine is in-

haled affects how it is deposited and, consequently, affects test

results. Rapid inhalation flow

L/s), instead of the recom-

mended slow inhalation over 5 s, will reduce measured

PC&

many patients (97,98). Nose clips are used to prevent dilution

of the inhaled solution with air through the nose during the

slow inhalations. The nebulizer is held upright because tipping

may reduce or stop aerosol generation as the fluid intake noz-

zle moves above the fluid line. In addition, the output of some

nebulizer models may depend on a vertical position. Inhala-

tion of the aerosol via face mask (with the nose occluded) gave

equivalent results compared with using a mouthpiece (90).

FEV,: Timing and selection of values for interpretation.

The timing of FEV, measurements at 30 and 90 s after the in-

halation is based on considerable experience with measure-

ments at these times. Recommendations for interpretation are

largely based on measurements performed according to this

timing schedule and use of the largest acceptable FEV, as the

outcome variable is widely accepted. Some investigators pre-

fer to report the lowest FEV,, reasoning this will avoid the ef-

fect of an increase in FEV, as the methacholine wears off (99).

However, this approach assumes the technician will be able to

ensure high-quality tests and discard all unacceptable maneu-

vers before selecting the lowest FEV,. If all FEV, maneuvers

are completed in the recommended time

3 min) it is highly

unlikely that the effect of methacholine will wear off.

Use of a diluent step. The opinions of the committee mem-

bers regarding the desirability of starting with a diluent (con-

trol) were divided; most current protocols start with a diluent

step. An advantage of starting with a diluent is that it gives pa-

tients an opportunity to learn the technique of inhaling from

the nebulizer and practice in performing spirometry. In addi-

tion, most reference data used for interpretation are based on

studies that used a diluent step and use of a diluent step pro-

vides a better link to interpretative data by ensuring technical

comparability. Other committee members felt the rationale

for using a diluent was weak. They argued: the lowest concen-

tration of methacholine was chosen so that only the most

hy-

perresponsive patient with asthma will respond and the use of

a diluent control does not improve the safety of the test. The

PCZO

is not affected by starting with a diluent (100). The addi-

tion of a diluent control adds 5 min to each test. Only 1% of

patients tested using a diluent (control) respond to the diluent

with a 20% or greater fall in FEV, (101) and the clinical mean-

ing of a positive response to the diluent is unknown. Such

patients may be experiencing FVC maneuver-induced broncho-

spasm, but this should have been detected before the metha-

choline study was scheduled.

When a diluent step is used, the postdiluent

FEV,

is the

reference point for comparison. We recommend a 20% fall in

FEV, following diluent as the threshold of significance for

consistency with the thresholds used in the rest of the test. Al-

though some investigators have used a 10% fall in FEV, as the

threshold to determine a positive response to the diluent, this

threshold is close to the 95th percentile confidence interval of

FEV, repeatability in patients with BHR and increases the

chance of a test failure.

Ii.

Nebulizers and Dosimeters

Nebulizers for the tidal breathing method. The nebulizer must

deliver an aerosol with a particle mass median diameter

(MMD) between 1.0 and 3.6

p,rn

[e.g., the English Wright

neb-

ulizer (Roxon Medi-Tech, Montreal, PQ, Canada) (4) gener-

ates particles between 1.0 and 1.5 MMD and is generally used

for this method]. It is acceptable to perform this technique

with other brands of nebulizers with similar characteristics.

For other nebulizer brands, reviews of nebulizer performance

may be useful in making initial selections (102, 103); further

validation of nebulizer performance is recommended. Avoid

the use of nebulizers with MMD less than 1.0 pm. Flow must

be adjusted for each nebulizer to obtain an output within 10%

of 0.13 ml/min. Variation of MMD between 1.3 and 3.6 pm

does not influence measurement of airway responsiveness when

using the 2-min tidal breathing method (104). It is not, there-

fore, necessary to check the particle size generated by each in-

dividual nebulizer once the MMD range for a nebulizer model

has been found to be between 1 .O and 3.0 pm.

To measure nebulizer output for the tidal breathing method,

perform the following steps:

1. Put 3 ml of room temperature saline into the nebulizer.

2. Weight the nebulizer, using a balance accurate to 1.0 mg

(preweight).

3. Adjust the flow meter to 7.0 L/min and nebulize for exactly

2 min.

4. Reweigh the nebulizer (postweight). Empty the nebulizer.

5. Repeat steps

three times for each of the following air

flows: 7.0, 8.0, and 9.0

Umin

(or 4.0, 5.0, and 6.0 L/min for

some nebulizer models).

6. Calculate and plot the average nebulizer output at each air-

flow.

a. The nebulizer output in milliliters per minute, assuming

1 ml of saline equals 1,000 mg, is calculated as

Output

(mUmin)

[

(preweight (mg)

postweight

(mg))/time

(min)]/ 1,000.

(1)

b. By interpolation, determine the airflow that will gener-

ate an output of 0.26 ml over 2 min (0.13

mUmin).

Record

the airflow for the nebulizer and the date of the calibra-

tion check.

7. Subsequent checks of nebulizer output need only test the

nebulizer output at the flow that generates the correct out-

put. If the output is within specification (0.13 ml/min,

10%) testing at other flows is not necessary. Alternative

316

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 161

2000

techniques for nebulizer calibration checks have been de-

scribed that may be more accurate and that are applicable

to respiratory function laboratories (105).

Nebulizers for the five-breath dosirneter method. Nebulizers

for the five-breath method should deliver 9

(0.009 ml)

10% of solution per 0.6-s actuation during inhalation (104).

The DeVilbiss (Somerset, PA) model 646 nebulizer is com-

monly used for this technique (Figure 1). Other nebulizers

with equivalent characteristics and output are acceptable. Be-

cause the DeVilbiss 646 model has high between-unit output

variability (106, 107) each nebulizer must be adjusted and its

output checked before it is put into service. The extra vent on

the DeVilbiss 646 nebulizer must be closed during methacho-

line challenge testing, as the nebulizer output increases and is

variable when air can be entrained into the nebulizer (108). A

flow regulator may be added to the nebulizer to control the

rate of inspiratory flow. If used, the flow regulator must be in-

cluded in the system during calibration. Nebulizer output is in-

fluenced by the gap between the jet orifice and the tip of the

capillary tube (Figure 1). The position of the impinger arm

also influences the output of the nebulizer but the effect varies

from nebulizer to nebulizer, so no single position can be rec-

ommended (107). In the Lung Health Study, the impinger arm

was placed so that its large curve pointed toward the mouth-

piece when the nebulizer was assembled. A jet orifice-capil-

lary tube gap of 0.01 in. (0.254 mm), measured with a spark

plug tool, was used (P. Enright, personal communication).

These are reasonable starting places. Once the nebulizer out-

put is satisfactory, the impinger arm should be carefully glued

in the position used during calibration. An exhalation filter

may be added to the nebulizer cap opposite the mouthpiece

(Figure 1). A single nebulizer may be used for all concentra-

tions, provided it is emptied and the nozzle dried between

doses. Alternatively, six or seven separate calibrated nebuliz-

ers may be filled before the test. If separate nebulizers are

used, they must be carefully labeled to avoid dosing errors.

For the five-breath dosimeter technique, outputs are checked

by weighing the nebulizer containing 2 ml (or the volume used

for testing) of room temperature, sterile normal saline before

and after 10 actuations with a technician simulating the test by

inhaling slowly from the nebulizer. The scale used must be ac-

curate to at least 0.5 mg. For the DeVilbiss 646 nebulizer, the

target output is 90

p_l

+ 10% (0.09 ml

[90

mg] + 10%) for the

10 actuations.

Monitoring nebulizer performance. Nebulizer output varies

from model to model and from unit to unit and may vary with

time depending on how the nebulizer is maintained and cleaned

(109). The actual output of each nebulizer used must be mea-

sured initially and at regular intervals. Because nebulizer perfor-

mance over time may vary depending on individual laboratory

use, maintenance, and cleaning practices, each laboratory should

establish its own nebulizer monitoring schedule. We recommend

that each laboratory check output after every 20 uses until an ap-

propriate testing schedule is established for the laboratory.

The dosimeter. The dosimeter is an electrically valved sys-

tem that enables the technician to administer aerosol for 0.6

during inhalation from the nebulizer. The dose may be trig-

gered manually by pressing a button or by an automatic sys-

tem that delivers a single dose soon after the onset of a deep

breath. Useful dosimeter options include a dose counter dis-

play (to remind the technician how many doses have been

given), a feedback tone slowly increasing in frequency for

after the dose is delivered, followed by a steady tone lasting

for 5

(to encourage a slow inhalation and breath holding at

TLC), and a

5-min

timer.

Dosimeter systems should be set up and checked according

to the manufacturer recommendations. Manufacturers should

give explicit instructions for

(1)

dosimeter and nebulizer setup

and use to deliver the recommended methacholine concentra-

tions and (2) operational checks to ensure proper ongoing

function of the system.

The committee divided on the need for a dosimeter. Do-

simeters may improve the accuracy and repeatability of the

dose delivered to the airways but add additional expense.

They are widely used in both clinical and research challenge

testing. Automatic triggering of the dosimeter during the on-

set of inhalation is an attractive feature but manual triggering

is acceptable. At least one researcher (110) has reported that

exact timing of the dose did not affect the methacholine re-

sponse, an argument against the need for automatic triggering.

Further studies are needed to resolve this issue. It is important

to simulate an actual test when nebulizers are calibrated be-

cause nebulizer output may be less if the dosimeter is acti-

vated without the inhalation.

Rationale. Nebulizers. Commercially available nebulizers

used to deliver bronchodilator drugs have a wide range of

characteristics. Early investigators used DeVilbiss 40 glass

nebulizers. DeVilbiss 646 nebulizers have also been used by

many investigators performing inhalation challenges. Their

output characteristics have been well described ( 111, 112) and

they are relatively inexpensive. Inexpensive plastic nebulizers

are generally not manufactured with tight output tolerances

and their volume output should be checked before use (107,

113,114).

The output of a DeVilbiss 646 nebulizer varies

2:l

with the

extra vent open or closed. It should be permanently closed

(115) for methacholine challenge use, as the output is in-

creased by inhaling through the nebulizer and also varies over

time and after disassembly and reassembly of the baffle (109,

and personal communications from Robert Wise and Paul En-

right). At least 1 ml of solution should remain at the end of

nebulization, because output decreases below this level. A

10% range in nebulizer output is considered acceptable

with doubling or quadrupling concentration increments.

Neb-

ulizer output is also directly proportional to the airflow driv-

ing the nebulizer (115).

Effect of nebulizer and technique differences on test out-

comes. The two proposed techniques appear to give similar re-

sults in both children (116) and adults despite the substantial

differences in administration technique and equipment. The

Wright nebulizer used for the 2-minute tidal breathing has a

very small particle size distribution with close to 80% of the

output in the respirable fraction (RF). The RF is defined as

the fraction of aerosol contained in droplets of

5 pm, which,

if inhaled via a mouthpiece, would have a high probability of

deposition below the vocal cords (117, 118). For a calibrated

output of 0.13 ml/min and a respiratory duty cycle (inspiratory

time divided by total respiratory cycle time, Tt/Ttot) of 0.43,

for 2 min of tidal breathing, approximately 0.089 ml of metha-

choline solution would be delivered below the cords (119).

While much of this would be deposited, many smaller particles

will be exhaled.

For the five-breath method, a DeVilbiss 646 nebulizer is

used with an output of 9

pl(O.009

ml) per 0.6-s activation for a

total delivery of 0.045 ml (104). Approximately 70% of the to-

tal delivery would be within the RF (107) for an estimated

total dose of 0.032 ml delivered below the cords. It would ap-

pear, therefore, that the tidal breathing method should cause

bronchoconstriction at a lower concentration of methacholine.

The reasons such differences are not apparent include the fol-

lowing:

(I)

methacholine is rapidly metabolized. The tidal

American Thoracic Society

317

breathing method ensures that there will be at least 2.5 min be-

tween the start of the inhalation and the first FEV,, while the

five-breath technique moves more quickly with less time for

the effect of methacholine to wear off; (2) many of the small

particles from the Wright nebulizer may either be exhaled or

deposited in the alveoli, where they cannot cause bronchocon-

striction; (3) the logarithmic increase in dose would make

small differences in airway deposition very difficult to detect;

and (4) the repeated deep inhalations in the five-breath tech-

nique may affect airway caliber (see Section I, Rationale).

By chance rather than by design, the two methods appear

to yield very similar results. Because the inspiratory flow of

the subject will greatly exceed the driving flow to the nebu-

lizer, the parameters that will influence deposition will be

TI/

Ttot

for the tidal breathing method and the total duration of

inspiration for the five-breath technique, neither of which is

size dependent. This means that the expected deposition will

be the same but the deposition per unit weight (or lung size)

will be greater in smaller subjects than larger ones. This in-

creased dose per unit size may be one of the factors that ex-

plains the apparent increased sensitivity in small children (96).

Spirometry and Other End-point Measures

Spirometry. Change in FEV, is the primary outcome measure

for MCT. Spirometry should meet ATS guidelines (120). Spe-

cial care should be taken to obtain high-quality baseline FEV,

measurements because unacceptable maneuvers may result in

false-positive or false-negative results. The quality of the flow-

volume curves should be examined after each maneuver. Full

FVC efforts lasting at least 6

should be performed at base-

line (and after diluent, if applicable). If FEV, is the only out-

come being measured, the expiratory maneuver can be short-

ened to about 2 s. If a shortened expiratory time is used,

technicians should take care that the inspiration is complete

because incomplete inhalations will result in a false reduction

in FEV, and abbreviated flow-volume tracings may not show

an inadequate inhalation. If other spirometric outcome vari-

ables are used or if vocal cord dysfunction is suspected, full

FVC maneuvers should be performed throughout the test.

The highest FEV, value from acceptable tests is selected for

the outcome variable after each dose.

The quality of the maneuvers contributes to the confidence

with which an interpretation can be made. The following

scheme of quality control (QC) grades reported (printed) af-

ter each level of methacholine may be used to assist the inter-

preter.

A = two acceptable FEV, values that match within 0.10 L

B = two acceptable FEV, values that match within 0.20 L

C = two acceptable FEV, values that do not match within

0.20 L

D = only one acceptable FEV, maneuver

F = no acceptable FEV, maneuvers

All acceptable quality tests performed at 30 and 90

after

each dose of methacholine are used to calculate repeatability.

Bear in mind that the repeatability criteria are based on tradi-

tional spirometric measurements and may not apply directly

to tests performed after the administration of methacholine.

Failure to meet repeatability standards should be used only to

assist interpretation and not to exclude data from analysis.

Studies are needed to better define FEV, repeatability criteria

for methacholine challenge tests.

Forced inspiratory maneuvers. If vocal cord dysfunction is

suspected, or if inspiratory stridor is noted during the baseline

examination or after the final dose of methacholine, perform

at least three full spirograms that include forced inspiratory

vital capacity (FIVC) maneuvers. Vocal cord dysfunction (VCD)

may be revealed as spontaneous or MCT-induced limitation

of forced inspiratory flow resulting in a plateau in flow on the

FIVC curves (121-124). Patients with vocal cord dysfunction

or central airway obstruction are not common, but often have

a history suggesting asthma and may be referred for bron-

choprovocation testing when the diagnosis of asthma is either

considered or questioned.

Body plethysmography. Measures of airway resistance

(Raw), usually expressed as specific conductance

(sGaw),

are

alternative end points for MCT but should be used primarily in

patients who cannot perform acceptable spirometry maneuvers

(125,126). In patients with asthma and COPD, changes in Raw

usually parallel changes in FEV, with MCT

(127-l

29),

but both

Raw and

sGaw

are more variable than FEV,. A larger percent

change (e.g., 45%) is therefore required for a positive test. It is

not necessary to measure total lung capacity (TLC) during

MCT, because TLC usually does not change

(13s-132).

A de-

crease in vital capacity reflects an increase in residual volume.

Transcutaneous oxygen. Measurements of transcutaneous

oxygen tension

(PtcoZ)

correlated well with measurements of

lung function in children (133-137).

Ptcoz

may be a useful end

point in infants, young children, and adults (138) whose coop-

eration cannot be obtained for spirometry. Use of Ptco, should

be restricted to laboratories with experience in its use as an

MCT end point.

Forced oscillation. Forced oscillation or impulse techniques

and occlusion or interrupter techniques have recently been as-

sessed (136,137). These approaches do not require patient ef-

fort and may be useful in testing patients who cannot perform

acceptable spirometry maneuvers. At this time, their use should

be reserved for patients who cannot perform acceptable

spi-

rometry

maneuvers and should be restricted to laboratories

with expertise in their application and interpretation.

Rationale. The bronchial smooth muscle stimulation in-

duced by methacholine inhalation results in airway narrowing

and airway closure. In healthy persons and patients with mild

asthma, the deep inhalation that precedes an FVC maneuver

causes transient bronchodilation that may last for up to 6 min

(139-141). In patients with more severe asthma, this response is

blunted or absent and the maneuver may result in bronchocon-

striction (132, 141-143). In patients being clinically tested for a

diagnosis of asthma, this difference in the effect of deep inhala-

tions on airways may contribute to the better ability of FEV,, in

comparison with measurements of Raw or

sGaw,

to separate

patients without asthma from patients with asthma (127, 144).

However, because most diagnostic challenge tests are per-

formed on individuals who are either nonasthmatic or mildly

asthmatic, both are likely to have the bronchodilator response.

Changes in peak expiratory flow (PEF) often parallel changes

in FEV, during bronchoconstriction but have the disadvantages

of being

(2)

more effort dependent and less reproducible and

(2) less sensitive in detecting bronchoconstriction

(145-148).

Although not commonly used as an end point, change in FVC is

reported to correlate with disease severity (149).

Changes in airway resistance may be more sensitive than

changes in FEV, for detecting bronchoconstriction, but FEV,

is superior to other parameters for discriminating relatively

healthy persons from those with asthma (127,144). Other end

points such as transcutaneous oxygen and forced oscillation

have promise but are still experimental and are not recom-

mended for routine clinical testing at this time.

Data Presentation

The results are reported as a percent decrease in FEV, from

baseline (or postdiluent if a diluent step is used). Data should

318

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 161 2000

be presented for each step in the protocol, including the

post-

bronchodilator test. At a minimum, all of the elements in the

sample bronchoconstriction report in APPENDIX C should be

included, including volume-time or flow-volume curves. A

single number,

PC&

(with one decimal place), may be used to

summarize the results for clinical purposes. Unless stated oth-

erwise, it may be assumed that the

PC&

is calculated from the

change in FEV,.

If the FEV, does not fall by at least 20% after the highest

concentration (e.g., 16 mg/ml) then the

PC,,,

should be re-

ported as

“>

16 mg/ml.” Do not extrapolate beyond the final

concentration. If the FEV, falls by more than 20% after inha-

lation of the diluent, a

P(&

is not reported. Instead, state

“there was a significant decrease in lung function after inhala-

tion of the diluent and methacholine was not given.”

For manual graphic calculation of

PC&,

the change in

FEV, as a percentage of the reference value may be plotted

on the ordinate against the log concentration on the abscissa.

The following equation can be used to calculate the interpo-

lated

PC&,

(1,4,150):

(logC2-logC,)(20-Rr)

*tj

= antilog

log C, +

R2-RI

(2)

where

= second-to-last methacholine concentration (concen-

tration preceding C,).

= final concentration of methacholine (concentration

resulting in a 20% or greater fall in FEV,)

= percent fall in FEV, after

Rationale. Exponential models are better than linear mod-

els for interpolating between concentrations or doses (150,

151). The provocative concentration that results in a 20% fall

in FEV, (PC,,,) was selected as the outcome variable because

it is simple to calculate and avoids the complicated and con-

troversial aspects of estimating a provocative dose

(PD,).

K. Interpretation

The following factors should be taken into consideration when

interpreting

PC&

results for an individual patient:

Pretest probability of asthma, including current asthma symp-

toms

Presence or degree of baseline airway obstruction

Quality of the patient’s spirometry maneuvers

Pretest questionnaire results (effects modifiers; see Tables 2

and 3)

Symptoms reported by the patient at the end-of-test

Degree of recovery after bronchodilator administration

TABLE 5

CATEGORIZATION OF BRONCHIAL RESPONSIVENESS

PC20

Ow/ml)

4.0-l 6

1.0-4.0

1.0

Interpretation*

Normal bronchial responsiveness

Borderline BHR

Mild BHR (positive test)

Moderate to severe BHR

Before applying this interpretation scheme, the following must be true: (I) baseline

airway obstruction is absent; (2) spirometry quality is good; (3) there is substantial

postchallenge

FEV,

recovery.

Sensitivity and specificity of methacholine challenge tests

Repeatability of methacholine challenge test

A general scheme for categorizing airway responsiveness

using

PC&,

for use when the patient has no baseline airway ob-

struction, is shown in Table 5. The relationship between levels

of airway responsiveness and asthma are discussed below.

Relating the degree of airway responsiveness to questions

about individual patients. Using the degree of airway respon-

siveness to answer questions about individual patients as-

sumes the test is properly performed, that no modifiers that

would artificially alter airway responsiveness were present,

and that the patient’s prior probability of having current asthma

can be reasonably estimated. If the prior probability of asthma

30-70%

and the

PC&

mg/ml

it may be stated with a

high degree of confidence that the patient does not currently

have asthma (Figure 3) (152, 153). If the same patient has a

PC&,

1.0

mg/ml,

the test provides strong confirmation of the

clinical diagnosis of asthma. When the

PC&

is between 1 and

mg/ml,

one must be more cautious about stating whether or

not the patient has asthma. It has been suggested that when

the

PG,

is low and the “asthma-like” symptoms induced by

MCT are similar to those previously reported by the patient,

confidence is a diagnosis of asthma increases. This is intu-

itively attractive but we know of no published evidence sup-

porting it.

In people with a

PC&

between 1 and 16

mg/ml

and who

have no asthma symptoms (an unusual circumstance because

MCT would not be clinically indicated in such a setting) sev-

eral possibilities exist:

(1)

there is mild intermittent asthma

but the patient is a “poor perceive? of asthma symptoms; (2)

after exercise or inhalation challenges, the patient experiences

chest tightness that is perceived but not recognized as abnor-

mal (154); (3) the patient never exercises or experiences envi-

ronmental triggers of bronchospasm; (4) the mild BHR is due

to a cause other than asthma (postviral upper respiratory

in-

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

pre-test probability

Figure 3. Curves illustrating pretest and

posttest

probability of

asthma after a methacholine challenge test with four

PCZO

values.

The curves represents a compilation of information from several

sources (10, 152, 153). They are approximations presented to il-

lustrate the relationships and principles of decision analysis. They

are not intended to calculate precise

posttest

probabilities in pa-

tients.

American Thoracic Society

319

fection [URI], cigarette smoking, etc.); or (5) there is subclini-

cal (asymptomatic) asthma that will become clinical asthma in

the future (155, 156). Between 1.5 and 45% of asymptomatic

persons with BHR may develop asthma during 2-3 yr of fol-

low-up (157, 158).

In patients with a diagnosis of asthma, the correlation be-

tween degree of airway responsiveness and clinical severity of

asthma is significant, but not strong enough by itself to catego-

rize the severity of asthma in individual patients

(83,159-162).

Recent exposures causing airway inflammation or residual ef-

fects of antiinflammatory therapy (systemic or topical to the

airways) can easily change the degree of airway responsive-

ness so that the

PCZo

does not reflect the “usual” untreated se-

verity of the patient’s asthma.

It is difficult to interpret the meaning of a low

PC&,

in a pa-

tient with baseline airway obstruction (163). For instance,

most patients with smoking-related COPD and mild to mod-

erate baseline airway obstruction have BHR, but most have

no acute or chronic bronchodilator response or symptoms of

asthma (28, 128). It is even more difficult to interpret the sig-

nificance of a change in PG,, when there has also been a

change in baseline FEV, (which often occurs after successful

therapy).

Decision

unalysis.

The most common clinical indication for

MCT is to evaluate the likelihood of asthma in patients in

whom the diagnosis is suggested by current symptoms but is

not obvious. The continuous nature of airway responsiveness

and the overlap in

PC&,

between the response of persons with

healthy lungs and patients who have unequivocal asthma re-

quires decision analysis whether this is done formally or intu-

itively (1.52, 164-166).

The pretest probability (prior probability) is the likelihood

that the patient has asthma before MCT results are consid-

ered. The posttest probability is the likelihood of asthma con-

sidering both the pretest probability and MCT results (poste-

rior probability). The difference between the pre- and posttest

probabilities represents the contribution of MCT. The MCT

results can be helpful or misleading (1.52).

From an epidemiologic standpoint, the prior probability of

asthma for a given individual is equal to the prevalence of

asthma when a randomly selected population sample is being

tested and the subject’s medical history is not considered (e.g.,

when methacholine testing is used to screen hundreds or thou-

sands of military recruits or job applicants for asthma). The

prevalence of asthma is relatively low in the general popula-

tion, usually about 5% (1.59, 167,

168),

and the pretest proba-

bility in the example is also likely to be about 5%. In this ex-

ample, an MCT test that is positive with a

PC&

of 1

mg/ml

(using the curves in Figure 3) gives an estimated posttest like-

lihood of asthma of approximately 45%. Note that with pre-

test likelihoods in the

S-15%

range, the curves are steep and

the pretest likelihood is a very strong determinant of the post-

test likelihood of asthma.

When a patient presents with symptoms suggestive of asthma,

the pretest probability is much higher than in the general pop-

ulation and is more difficult to define precisely. However,

when the prior probability is between 30 and 70% MCT can

be quite useful. For example, with a

P&,

of 1

mg/ml,

the

post-

test likelihood of asthma is roughly

90-98%

with pretest likeli-

hood estimates ranging from 20 to 80%

(152;

see Figure 3). If

the prior probability is 30% and the

PCZo

is 4

mg/ml,

the

post-

test likelihood is about 70% (Figure 3). Optimal test charac-

teristics (the highest combination of positive and negative pre-

dictive power) occurs when the pretest probability of asthma

is about 50% (10).

Categorical method of interpreting a methacholine challenge

test. The alternative “categorical” method for the clinical in-

terpretation of methacholine challenge tests makes three as-

sumptions: (I) MCT results are either positive or negative for

BHR; (2) asthma is either present or absent; and (3) there is a

“gold standard” for diagnosing asthma. This popular method

ignores the continuous spectrum of airway responsiveness, the

continuous nature of the degree of uncertainty in the diagno-

sis of asthma, and the lack of a gold standard for the diagnosis.

Using the categorical method, sensitivity is defined as the

fraction (or percentage) of patients with the disease (asthma)

who have a positive test. Specificity is defined as the fraction

of patients without asthma who have a negative test. A nega-

tive methacholine challenge result is commonly defined as

non-

response to the highest concentration (a

PCZo

8-25

mg/ml).

positive test is often defined as a

PCZo

8 or

16 mg/ml. The

optimal cutoff point (threshold) for separating a positive from

a negative test is best accomplished using receiver-operator

characteristic (ROC) curves. When using ROC analysis, the

best

PCZo

cut point to separate patients with asthma from

those without asthma is in the range of 8-16

mgiml

(10, 169).

The false-positive rate for asthma is of concern when inter-

preting MCT results; in such cases the PG,, is

mg/ml

but

the patient does not actually have asthma. In testing general

population samples, patients with allergic rhinitis, and smok-

ers with COPD, MCT has relatively high false-positive rates

and, therefore, poor positive predictive power (8, 169). About

30% of patients without asthma but with allergic rhinitis have

PC&

in the borderline BHR range (144, 170-172). Our rec-

ommendation to use an intermediate area of “borderline

BHR” when the

PCZo

is between 4 and 16

mg/ml

will improve

the specificity of MCT in comparison with previous studies. A

lower false-positive rate (with better test specificity) can be

obtained by considering the pretest probability of asthma (us-

ing decision analysis).

A false-negative methacholine challenge result occurs when

the

PCZo

is greater than

8-25

mg/ml

(no response to the high-

est concentration) in a patient who has asthma. This occurs

much less frequently than false-positive results. The negative

predictive power of MCT is more than 90% when the pretest

probability of asthma is in the range of

30-70%

(153,172) and

most authors conclude that a negative MCT rules out asthma

with reasonable certainly in patients who have had asthma

symptoms during the previous 2 wk. Three factors should be

considered before accepting a negative test as ruling out

asthma: (I) airway responsiveness may have been suppressed

if the patient was taking intensive antiinflammatory medica-

tions prior to the MCT. This issue may not be relevant if the

patient has current symptoms; (2) in patients without current

symptoms, the season for aeroallergen exposure may have

passed (173,174); and (3) a small fraction of workers with oc-

cupational asthma due to a single antigen or chemical sensi-

tizer may respond only when challenged with the specific

agent (175,176).

Effect of test repeatability on interpretation. Optimal repeat-

ability of MCT results is most important when change in air-

way responsiveness is used in clinical research studies to mea-

sure outcome of asthma therapy in clinical research studies.

However, knowledge of short-term repeatability of the

PC&,

also useful when interpreting the results from the first MCT

performed by a single patient for clinical purposes.

Short-term within-subject repeatability studies (l-8 wk)

when patients are in a stable clinical state show that the 95%

confidence intervals for repeat determinations of methacho-

line

PC2,,

lie within 2 1.5 doubling doses (7.5, 81, 82, 87, 88,

320

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161

2000

177-183). In other words, if the

PC&,

is measured as 4

mg/ml

during a baseline clinic visit, repeat MCT 2 wk later will give a

PC&,

between

1.5

and 12

mg/ml

in 95% of cases.

In addition to technical issues in standardization there are a

number of nontechnical or subject-related factors (which will

worsen or improve airway responsiveness) to be considered.

Such factors should either be controlled in order to maximize

repeatability, or recorded if they might explain changes in air-

way responsiveness. Factors that must be considered here in-

clude recent antigen exposure (which may have a considerable

influence on airway responsiveness), exposure to chemical

sensitizers (which may also have a large effect), recent respira-

tory tract infections (likely to have a relatively small effect),

variations in airway caliber (probably a small effect), and al-

teration in asthma medications (may have a large effect de-

pending on the circumstances).

Finally, partial tolerance of methacholine may occur in non-

asthmatic subjects but not in asthmatic subjects when tests are

repeated at less than 24-h intervals (184,

185).

The observed

tolerance may have been related to the higher cumulative

doses of methacholine given to the nonasthmatic subjects (185).

III.

EXERCISE CHALLENGE

Exercise induces airway narrowing in the majority of patients

with asthma. Exercise-induced airway narrowing is called ex-

ercise-induced asthma (EIA) and exercise-induced broncho-

constriction (EIB); the latter term is used here. The major

factors that determine severity of EIB are the pulmonary ven-

tilation reached and sustained during exercise and the water

content and temperature of the inspired air. The stimulus by

which exercise causes the airways to narrow is the loss of wa-

ter in bringing large volumes of air to body conditions in a

short time

86189). The mechanisms whereby water loss causes

the airways to narrow is thought to involve the thermal (cool-

ing and rewarming) and/or osmotic effects (190-195) of dehydra-

tion. While airway cooling during exercise and airway rewarm-

ing after exercise are important determinants of the magnitude

of response in adults breathing air of subfreezing tempera-

tures

(190),

they are not prerequisites for EIB (194). Thus,

EIB can occur when the inspired air temperature is greater

than 37” C and in the absence of airway cooling

(192,196-198).

Rapid rewarming does not enhance EIB in children (199).

Airway cooling and drying are thought to stimulate the re-

lease of inflammatory mediators, such as histamine and the

cysteinyl leukotrienes (200-203). Thus, exercise has become

an important challenge method for assessing the effects of an-

tiinflammatory and other asthma medications. Given the ob-

servations of EIB occurring both in cold and very hot inspired

air conditions, it can be concluded that, for the purposes of ex-

ercise challenges, the most important factor to control is the

rate of water loss from the airways by monitoring ventilation

and controlling inspired water content.

A. Indications

Exercise is used as a challenge test to make a diagnosis of EIB

in asthmatic patients with a history of breathlessness during or

after exertion. Such a diagnosis cannot be made with a metha-

choline test and EIB cannot be excluded by a negative response

to methacholine. When the presence of EIB would impair the

ability of a person with a history suggesting asthma to perform

demanding or lifesaving work (e.g., military, police, or firefight-

ing work), a test for EIB may be indicated (204, 205). Exercise

testing is used to determine the effectiveness and optimal dos-

ages of medications prescribed to prevent EIB. Exercise is also

used to evaluate the effects of antiinflammatory therapy given

acutely (e.g., cromolyn sodium and nedocromil sodium) and

chronically (e.g., steroids and leukotriene antagonists).

B. Contraindications and Patient Preparation

Contraindications. The contraindications for this test are the

same as for methacholine challenge testing (Table 1). In addi-

tion, the patient with unstable cardiac ischemia or malignant

arrhythmias should not be tested. Those with orthopedic limi-

tation to exercise are unlikely to achieve exercise ventilation

high enough to elicit airway narrowing. For patients over 60 yr

old, a

12-lead

electrocardiogram (ECG) obtained within the

past year should be available.

Patientpreparation. The patient should report to the labora-

tory in comfortable clothes and running or gym shoes, having

consumed no more than a light meal and having had pulmo-

nary medications withdrawn as suggested (Table 2). In addi-

tion, antihistamines should have been withheld for 48 h. Vigor-

ous exercise should be avoided for at least 4 h before testing, as

prior exercise has been found to exert a protective effect. The

interval between repeat testing must also be at least 4 h.

Rationale. Fifty percent of individuals with exercise-induced

bronchoconstriction are refractory to a second challenge within

60 min (206). Most lose this refractory state within 2 h. but it

occasionally takes as long as 4 h (207-210).

C. Exercise Challenge Testing

Modes of exercise. The preferred modes of exercise are the

motor-driven treadmill with adjustable speed and grade or

the electromagnetically braked cycle ergometer. Heart rate

should be monitored from a three-lead electrocardiographic

configuration as a minimum. Alternatively, a pulse oximeter

or other device able to reliably determine heart rate may be

used. For those at higher risk for coronary artery disease, a

12-

lead ECG configuration is advisable.

Inhalate. The patient inspires dry air less than 25” C with a

noseclip in place, as nasal breathing decreases the water loss

from the airways (211). This can be accomplished by conduct-

ing the study in an air-conditioned room (with ambient tem-

perature of 20-25” C) with low relative humidity (50% or

less). Inspired air temperature and humidity should be mea-

sured and recorded. Optimally, the water content of the in-

spired air should be less than 10

mg/L.

Alternatively, the sub-

ject can inspire dry air through a mouthpiece and a two-way

breathing valve. A dry inhalate is obtained by filling talc-free

meteorological balloons with gas from a medical-grade com-

pressed air source (195, 212, 213). Dry air can also be inspired

through a demand valve attached to the inspired port of the

two-way valve, although this provides some extra inspiratory

resistance at high flow rates (214).

Treadmill protocol. Treadmill speed and grade are chosen

to produce 4-6 min of exercise at near-maximum targets with

a total duration of exercise of 6-8 min. For children less than

12 yr of age, the time is usually 6 min; for older children and

adults the time is usually 8 min. Starting at a low speed and

grade, both are progressively advanced during the first 2-3

min of exercise until the heart rate is

80-90%

of the predicted

maximum (calculated as 220

age in years) (203, 210, 215-

217). Ventilation rather than heart rate can be used to monitor

exercise intensity. Ventilation should reach 4060% of the

predicted maximum voluntary ventilation (MVV, estimated as

FEV, X 35) (214,218,219). The degree of physical fitness and

body weight will strongly influence the grade and speed neces-

sary to obtain the desired heart rate. A reasonable procedure

is to quickly advance to a rapid, but comfortable, speed and

then raise the treadmill slope until the desired heart rate or

ventilation is obtained. Treadmill speed and slope are chosen

American Thoracic Society 321

to achieve a target ventilation (or heart rate) that is main-

tained for at least 4 min. Children are usually able to reach the

target more quickly than adults and for them the exercise du-

ration may be only 6 or 7 min. For older children and adults

8 min of exercise is usually required to elicit EIB when dry air

temperature is inhaled. A treadmill speed greater than 3 mph

(about 4.5 km/h) and a gradient greater than 15% or an oxy-

gen consumption of 35 ml/min/kg or greater will usually achieve

the target ventilation or heart rate in young healthy subjects.

Nomograms have been proposed to predict speed and grade

that will elicit the desired heart rate (210) but they have not

been extensively validated. It may be preferable to use nomo-

grams relating oxygen consumption per kilogram to speed and

slope of the treadmill

(22@222).

The test ends when the patient has exercised at the target

ventilation or heart rate for at least 4 min. This usually re-

quires a total of 6-8 min of exercise. The test may be termi-

nated by the patient at any time.

Bicycfe ergometer. For bicycle ergometer exercise, a target

work rate to achieve the target ventilation can be determined

from equations relating work rate to oxygen consumption and

oxygen consumption to ventilation (193,219,222). One equa-

tion used to establish the target work rate is watts = (53.76 X

measured FEV,)

11.07. The work rate is set to 60% of the

target in the first minute, 75% in the second minute, 90% in

the third minute, and 100% in the fourth minute (214). Using

this protocol the repeatability of the percent fall in FEV, is

good. For example, the coefficient of variation for two tests

performed within 1 mo is 21%. Thus, a patient who has a 30%

fall in FEV, on one occasion would be expected to have a fall

within 24-36% if tested within 1 mo. Ventilation and/or heart

rate are checked to determine if the exercise targets are

achieved. A valid test requires the target exercise intensity to

be sustained for 4-6 min. To ensure that the target minute

ventilation is sustained, the work rate may need to be reduced

in the final minutes of exercise. It is important for the patient

to reach the target heart rate or ventilation within 4 min be-

cause the rate of water loss is the determining factor for elicit-

ing EIB and refractoriness can develop if exercise is pro-

longed at submaximal work. The test ends when the patient

has exercised at the target work rate for 6 min. The patient

may terminate the test at any time.

Pulmonary gas exchange. Measurement of pulmonary gas

exchange during exercise is helpful, although not required. Mea-

surement of minute ventilation allows an assessment of the

magnitude of the stimulus to airway narrowing (223) and mea-

surement of oxygen uptake makes it possible to quantify the

intensity of exercise as a fraction of predicted peak oxygen up-

take. These data can be used to confirm an adequate exercise

level, which is especially important when a test is negative.

Safety. A licensed physician or an experienced technician

should observe the patient during exercise and the recovery

period and watch for undue stress (e.g., severe wheezing, chest

pain, lack of coordination) or adverse signs (e.g., ECG abnor-

malities, falling blood pressure, severe decrease in

satura-

tion). The choice of who monitors the test and what parame-

ters are monitored depends on the risk for adverse events. In

patients felt to be low risk for adverse events, the test may be

supervised by an experienced technician, provided that a li-

censed physician can be summoned quickly, if problems arise.

The technician should be able to recognize the presence of in-

dicators of respiratory distress and be able to recognize the

presence of significant arrhythmias. In patients felt to be at

higher risk for adverse events, a physician should directly moni-

tor the test. In either case, a resuscitation cart should be imme-

diately available.

Although not always accurate during exercise (224, 225)

estimation of arterial

saturation by pulse oximetry is rec-

ommended both during and after exercise. Measurement of

blood pressure by sphygmomanometry is a useful adjunct but

is not routinely required. ECG monitoring of all subjects is

necessary to ensure accurate heart rate measurements but

12-

lead monitoring is necessary only in high-risk cases.

Rationale. The choice of the recommended technique is

based on physiologic considerations and on substantial experi-

ence reported in the literature (1, 201,210,

213-215,

218, 219,

221,223,226-228).

Mode of exercise.

Although early studies suggested that tread-

mill exercise was preferable to bicycle exercise (226,229,230),

it appears this was most likely due to the more rapid increase

in ventilation in response to treadmill running. Providing the

work rate can raise the ventilation to the target within 4 min,

cycling exercise can be used effectively. Although peak oxy-

gen uptake averages approximately 10% less on the cycle er-

gometer than on the treadmill, peak ventilation is comparable

(231). In those with established EIB, the cycle ergometer has

been used successfully in assessing the effects of drugs (214).

Its role in identifying those with EIB is less well defined. The-

oretically, cycle ergometry should be a satisfactory alternative

testing mode; well-designed comparative studies will be re-

quired to establish this. Free range running has been proposed

as being useful for screening populations

(232-235),

although

safety measures are difficult to provide in this testing mode.

Choice of the inhalate. The tendency to elicit airway narrow-

ing is enhanced when the inhalate is cool and/or dry. However, it

is not clear whether the ambient humidity in the typical air-con-

ditioned laboratory (typically

3&50%

water vapor saturation) is

significantly less likely to induce airway narrowing than perfectly

dry air (as can be obtained from a compressed air source).

Anderson and coworkers (189) found in a group of 12 children a

35 + 13% (SD) fall in FEV, with ambient air (23.3” C, 12 mg

H,O/L)

and a 45 + 16.7% (SD) fall in FEV, with compressed

dry air (25.4” C). Although the difference was not significant, the

greater response to compressed air may help to identify persons

with mild EIB and diminish the chance of a negative test. Cold

air generators, which produce dry air at below-freezing tempera-

tures, are commercially available and are in use in some labora-

tories (236). In patients in whom symptoms are specifically asso-

ciated with exercise in the cold, conducting an exercise challenge

while breathing a cold dry inhalate may be useful.

Work rate profile. A range of testing configurations may

produce a similar degree of bronchoconstriction is susceptible

individuals. However, the target minute ventilation must be

reached quickly and be sustained for 4 min to diminish the

possibility that refractoriness will occur. The intensity of the

exercise should be such that the person cannot exercise much

beyond 6 or 8 min. If they can, it is unlikely that the workload

was sufficiently hard to elicit EIB. The incremental work rate

profile used in cardiopulmonary exercise testing, in which ex-

ercise intensity is progressively increased to tolerance over a

lo-min period (231) is less likely to be effective in evaluating

EIB (237) probably because high levels of ventilation are sus-

tained for a relatively short time. Studies will be required to

evaluate this possibility. The evidence suggests the most effec-

tive exercise is hard and relatively brief. Specifically, prolong-

ing the warm-up period has the potential to induce refractori-

ness to EIB. Sustaining the heavy exercise period for a

prolonged period may actually diminish the bronchoconstric-

tion; a trend for a decreased response has been demonstrated

for exercise periods of 12 min or longer (221).

Using a heart rate target is practical and generally effec-

tive. However, because pulmonary ventilation is more closely

322

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161

2000

related to the stimulus to bronchoconstriction than is heart

rate, some authors prefer measuring ventilation to guide exer-

cise intensity. Anderson and colleagues have suggested that

ventilation be sustained for 4 min at between 40 and 60% of

predicted maximum voluntary ventilation, calculated as FEVl X

35 (214,218,219).

Safely.

The most common problem encountered in exercising

a patient with asthma is severe bronchoconstriction. This can

usually be treated rapidly and successfully by administering

neb-

ulized bronchodilator with oxygen. The appropriate equipment

should be immediately available and a pulse oximeter should be

kept on the subject. As the patients most likely to have the most

severe response are those with less than normal lung function a

minimum FEV, for a patient to be allowed to proceed with the

exercise test must be clearly defined. The European Respiratory

Society (219) suggested an FEV, greater than 75% of the pre-

dicted normal value.

The approach to monitoring will vary depending on the set-

ting in which exercise testing is conducted and an assessment of

risk for the individual being tested. Risk of adverse events

should be minimized and a rapid response should be available in

the event of a serious adverse event. In a hospital setting, where

a resuscitation team is readily available, a young, healthy subject

who has symptoms of exercise-induced bronchoconstriction can

be tested in a laboratory with minimum monitoring and only a

technician present. In a setting with less support and a higher

risk patient, more intense monitoring by individuals with the

skills to appropriately diagnose and treat adverse events would

be necessary. In their procedure manual, testing laboratories

should define the appropriate levels of monitoring and the per-

son who makes the decisions to test individual subjects.

D. Assessing the Response

Forced expiratory volume in

(FEV,) is the primary out-

come variable. Spirometry should be performed in the seated

position before exercise and then serially after exercise, utiliz-

ing the test method recommended by the American Thoracic

Society (120). At least two and preferably three acceptable

tests should be obtained at each testing interval. As a goal, the

highest and second highest FEV, values should differ by no

more than 0.2 L. The highest of the acceptable FEV, values is

selected as the representative value at each interval. One ex-

ception to ATS-recommended techniques for spirometry is al-

lowed. If the only outcome variable to be used is the FEV,,

the duration of the expiration may be limited to 2-3 s. In all

cases it is important to vigorously coach the patient to inhale

fully even in the presence of chest tightness. Incomplete inha-

lations will result in false reductions in FEV,.

If vocal cord dysfunction or other possible causes of central

airway obstruction are suspected, full inspiratory and expira-

tory flow-volume loops should be obtained.

An appropriate postexercise testing schedule is 5, 10, 15, 20,

and 30 min after cessation of exercise. Some investigators in-

clude earlier measurements (1 and 3 min postexercise) because

severe EIB can sometimes be present at the cessation of exercise

(214,219). Early recognition allows it to be dealt with promptly.

If the FEV, has returned from its nadir to the baseline level

or greater, spirometry testing may be terminated at 20 min

postexercise. A P-agonist bronchodilator may be administered

at any time to reverse the bronchoconstrictive response if the

patient experiences appreciable dyspnea, or if the FEV, has

not recovered to within 10% of baseline when the patient is

ready to leave the laboratory.

The presence of exercise-induced bronchoconstriction is

defined by plotting FEV, as a percentage of the preexercise

baseline FEV, at each postexercise interval. A decrease below

90% of the baseline FEV, (i.e., a 10% decrease) is a generally

accepted abnormal response (1,218,221,237-240). Some au-

thors suggest a value of 15% is more diagnostic of EIB, partic-

ularly if exercise has been performed in the field (233).

Rationale. A large number of testing schedules for per-

forming postexercise spirometry have been suggested. In most

cases, the nadir in FEV, occurs within

S-10

min of cessation of

exercise, although it is occasionally not reached until 30 min

postexercise (239). Including a 30-minute postexercise obser-

vation is controversial, because such a delay is infrequently

seen. Some laboratories terminate the test as soon as the

FEV, falls below a certain threshold (e.g., 10%). Without con-

firming the FEV, has reached its nadir, it is not possible to

assess the severity of exercise-induced bronchoconstriction.

Other laboratories define the nadir as when the FEV, has in-

creased from its lowest value at the two subsequent time inter-

vals (e.g., the test is terminated at 15 min when the lo- and

min FEV, values are higher than that measured at 5 min). This

reduces the time of challenge for most patients.

The criterion for a positive response is controversial. A fall

of 10% or more is considered abnormal; a fall of 15% appears

to be more diagnostic of EIB. A fall in FEV, of as little as

10% seems to be a reasonable criterion because healthy sub-

jects generally demonstrate an increase in FEV, after exercise.

Some authors have employed a more stringent criterion (e.g.,

a 15% fall) (223, 227). Three studies in presumably normal

children have demonstrated an upper 95% confidence limit

(defined as 1.96 SD) of the FEV, fall as 8.2%

(241),

10%

(242),

and 15.3% (233). Further studies are needed to estab-

lish the validity of proposed thresholds for a positive test.

A positive response is seen in those with upper airway ab-

normalities such as abnormal posterior motion of the arytenoid

region (243) or vocal cord dysfunction (244). These rare cases

can be distinguished from exercise-induced bronchoconstric-

tion by examining the flow-volume curve (245,246).

ATS Committee on Proficiency Standards for Clinical Pulmonary

Function Laboratories

Committee Members

Ad Hoc Committee Members

ROBERT 0.

CFZAPO,

M.D.,

Choirman

ANDRA

D. A

NDERSON

, Ph.D.

RICHARD

CASABURI,

Ph.D., M.D.

DON W. COCKCROFT, M.D.

ALV\N

COATES,

M.D.

AMES

E. F

ISH

, M.D.

AUL

ENRIGHT,

M.D

PETER

STERK,

M.D.

OHN

L. H

ANKINSON

, Ph.D.

HARLES

RVIN

, Ph.D.

NEIL R.

MAC~NTYRE,

M.D.

T. M

, Ph.D.

JASK

ANGER

, M.S.

Acknowledgment:

The authors thank

janet

Emby

for editorial assistance.

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328

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 161 2000

APPENDIX A

SAMPLE METHACHOLINE CHALLENGE TEST CONSENT FORM

PROCEDURE. The purpose of a methacholine challenge test is to determine the amount of

airway irritability of a patient. You (or your child) will be asked to inhale a mist that contains

different concentrations of methacholine. The mist is produced by a device called a nebulizer and

inhaled through a mouthpiece or facemask. Before the test begins, and after each period of

inhalation, you or your child will be asked to blow forcefully into a spirometer. The test usually

takes about an hour.

DISCOMFORTS AND RISKS. This test does not cause an asthma attack but the inhalation of

aerosols may be associated with mild shortness of breath, caught, chest tightness, wheezing,

chest soreness, or headache. Many subjects do not have any symptoms at all. These symptoms (if

they occur) are mild, last for only a few minutes, and disappear following the inhalation of a bron-

chodilator medication. There is a very small possibility of severe narrowing of your airways. This

could cause severe shortness of breath. If this occurs, you will be immediately treated.

I have read the above information and undertsand the purpose of the test and the associated risks.

With this knowledge I agree to having this test performed on me or my child.

Patient or Guardian

Date

Witness

Date

APPENDIX B

SAMPLE METHACHOLINE CHALLENGE PRETEST QUESTIONNAIRE

Name:

Date of birth:

1. List all medications you have taken in the last 48 hours for asthma, hay fever, heart disease,

blood pressure, allergies, or stomach problems, and the number of hours or days since your

last dose for each medication.

Drug Date and time of last treatment

10.

11.

Has a physician told you that you have asthma?

Have you ever been hospitalized for asthma?

Did you have respiratory disease as a child?

Have you ever experienced asthma symptoms such

as wheezing, chest tightness, or shortness of breath

within the last two weeks?

If a smoker, when did you last smoke?

Yes

Yes No

Yes

Have you had a respiratory infection in the last 6 weeks?

Yes

Have you had a heart attack or stroke within the last three months?

Yes No

Do you have high blood pressure?

Yes No

Do you have an aortic aneurysm?

Yes

Are you pregnant?

Yes

American Thoracic Society

329

APPENDIX C

SAMPLE METHACHOLINE CHALLENGE TEST REPORT FORM

Laboratory name, address, and phone number:

Patient name, ID number, date of birth, sex, height:

Test date, technician initials:

Indication for the test (e.g., rule out asthma):

Test method (e.g., five-breath dosimeter):

Bronchodilator administered and dose:

FEVl

Time

Test Phase

FEV, Score

of baseline)

9:00 Baseline

3.10 A

9:lO

Diluent

3.00 B

100%