AARC GUIDELINE: METHACHOLINE CHALLENGE TESTING: 2001 REVISION & UPDATE

AARC Clinical Practice Guideline

Methacholine Challenge Testing: 2001 Revision & Update

MCT 1.0 PROCEDURE: 4.5 the need to assess response to therapeutic Methacholine challenge test. This guideline does interventions;2 not address other bronchial challenges (eg, his- tamine, exercise, occupational exposures, specific MCT 5.0 CONTRAINDICATIONS: antigens, isocapnic hyperventilation.) 5.1 Absolute contraindications are: 5.1.1 ventilatory impairment: FEV1 <50% MCT 2.0 DESCRIPTION/DEFINITION: of predicted or < 1.0 L;2 [This may be a 2.1 The methacholine challenge test is one relative contraindication depending on the method of assessing airway responsiveness. In age or size of the patient or on the pres- this test, the patient inhales an aerosol of one or ence of a restrictive disorder (re- more concentrations of methacholine. Results duced forced , or FVC, with of pulmonary function tests (eg, spirometry, a relatively normal FEV1/FVC)]; specific conductance) performed before and 5.1.2 heart attack or stroke within the pre- after the are used to quantitate re- vious 3 months;1,2 sponse. This guideline applies to adults and 5.1.3 known aortic or cerebral aneurysm;1,2 children capable of adequately performing 5.1.4 uncontrolled hypertension [The spirometry or body plethysmography and of co- American Thoracic Society (ATS) sug- operating during the course of the challenge. gests systolic pressure > 200 and/or dias- 2.2 A positive test is defined as a decrease from tolic pressure >110 mm Hg.].2 the baseline forced expiratory volume in the 5.2 Relative contraindications are: first second (FEV1) or of the postdiluent FEV1 5.2.1 ventilatory impairment: FEV1 > value of 20%, or of a decrease in specific con- 50% or > 1.5L but < 60% of predicted;2 ductance of 35-45% from the baseline or post- 5.2.2 inability to perform spirometry of diluent value.1-4 acceptable quality;2 5.2.3 significant response to the diluent, if MCT 3.0 SETTINGS: administered (ie, > 10% fall in FEV1 from Possible settings include: baseline);10 3.1 pulmonary function laboratory;RETIRED 5.2.4 upper- or lower-respiratory-tract in- 3.2 clinic or physician’s office; fection within previous 2 to 6 weeks;1,11,12 3.3 field site (eg, occupational setting or work- 5.2.5 current use of -inhibitor place). medication (for ); 2 5.2.6 pregnancy (The effect of metha- MCT 4.0 INDICATIONS: on the fetus is unknown.);13 Indications for testing include: 5.2.7 lactation;13 4.1 the need to exclude a diagnosis of airway 5.3 Failure to withhold medications may affect hyperreactivity (ie, );1,2,5-9 the methacholine challenge test. Recommended 4.2 the need to evaluate ;1,2 periods for withholding medications are gener- 4.3 the need to assess the severity of hyperre- ally based on their duration of action.1,2 Labora- sponsiveness;1,2 tories may choose to develop a simplified with- 4.4 the need to determine the relative risk of de- holding schedule that makes allowances for any veloping asthma;2 of the following used by the patient:

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Agent Withholding Time not be sensitive enough or specific short-acting inhaled 6-8 hours enough to detect response, and other mea- surements such as airways resistance long-acting inhaled 48 hours (Raw) and/or specific conductance (sGaw) bronchodilators (eg: salmeterol, may be used. Differences of opinion exist formoterol) regarding the spirometric values that best aerosols 24 hours track response in particular airways.1,2,24 (eg: ipratropium) 7.1.2 Deep inspiration taken while perform- tiotropium up to 1 week14 ing spirometry variably alters bronchial disodium cromoglycate 8 hours tone and may result in either bronchocon- nedocromil 48 hours striction or .25-27 oral beta2-adrenergic agonists 24 hours 7.1.3 Poor patient effort during pul- theophyllines, depending on 12-48 hours monary function testing can produce specific preparation2 false-positive results and make interpreta- leukotriene modifiers 24 hours2 tion more difficult or impossible. Results corticosteroids, inhaled or oral Duration of effect from spirometry should be acceptable ac- (may decrease is unknown but cording to the most recent ATS recom- hyperresponsiveness) may be prolonged.15,16 mendations, and the quality of the flow- 5.4 Foods: Ingestion of coffee, tea, cola drinks, volume curves should be examined after chocolate, or other foods containing each maneuver.2,28 may decrease bronchial responsiveness. These 7.1.4 Spirometry should be performed ac- substances should be withheld on the day of test. cording to the current acceptability guide- 5.5 Other factors that may confound results in- lines of the ATS. Alternatively, the expira- clude: tory maneuver can be shortened to about 2 5.5.1 smoking,17 seconds after the methacholine doses are 18 5.5.2 occupational sensitizers, inhaled if FEV1 is the only outcome mea- 5.5.3 respiratory infection,11,12 sure. If this shortened expiratory maneu- 5.5.4 specific antigens,19 ver is used, care should be taken to assure 5.5.5 vigorous exercise.20-22 (Performing that the inspiration is maximal.2 After the other bronchial challenge procedures or of diluent (if used) and of each exercise testing immediately prior to dose of methacholine, FEV1 measure- methacholine challenge may affect inter- ments should be made at 30 and 90 sec- pretation.) onds after the last inhalation. The time in- terval between doses should be standard- MCT 6.0 HAZARDS/COMPLICATIONS: ized at 5 minutes to keep cumulative Possible hazards or untoward reactions include: effect constant. 6.1 , hyperinflation,RETIRED severe 7.2 A limitation of the method is the variability coughing; due to the effects of various factors including 6.2 hazards associated with spirometry, such as medications, time of day, and differences in dizziness, light-headedness, chest pain;23 technique and equipment. 6.3 possible exposure of testing personnel to 7.3 Inconsistencies in technique and equipment provocative substance. can affect the amount of agonist reaching the airways and, thus, the subject’s response— MCT 7.0 LIMITATIONS OF METHOD & making meaningful interpretation difficult or VALIDATION OF RESULTS: impossible. Factors influencing response that 7.1 Limitations of pulmonary function testing must be controlled and held constant across used to quantitate response including intralabo- testing include output and particle ratory variability for each pulmonary function size, volume inhaled, length of breath-hold, and test variable: inspiratory flow.2,29,30 7.1.1 In some patients, spirometry may 7.4 If clinical suspicions are not confirmed by

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one test, additional tests may be indicated. scribed in the NCCLS GP26-A A Quality System 7.5 The final test report should include: Model for Health Care.31 (Fig. 1) The document de- 7.5.1 PC20FEV1 (ie, the provocative con- scribes a laboratory path of workflow model that in- centration that causes a 20% fall in FEV1). corporates all the steps of the procedure. This pro- 7.5.2 comment on the adequacy of spiro- cess begins with patient assessment and the genera- metric effort and quality of other mea- tion of a clinical indication for testing through the surements; application of the test results to patient care. The 7.5.3 notation regarding medications quality system essentials defined for all health care known to confound interpretation of re- services provide the framework for managing the sults (Section 5.3) taken by the patient path of workflow. A continuation of this model for prior to testing; respiratory care services is further described in 7.5.4 presence or absence of other factors NCCLS HS4-A A Quality System Model for Respi- known to confound interpretation of re- ratory Care.32 In both quality models the patient is sults (Section 5.4); the central focus. 7.5.5 clinical and 9.1 General considerations include: clinical appearance during the course of 9.1.1 As part of any quality assurance pro- the test and after final dose; gram, indicators must be developed to 7.5.6 and dose adminis- monitor areas addressed in the path of tered at end of challenge; workflow. 7.5.7 tabular display of data for each test 9.1.2 Each laboratory should standardize phase including response to bronchodila- procedures and demonstrate intertechnol- tor at end of challenge. ogist reliability. Test results can be con- sidered valid only if they are derived ac- MCT 8.0 ASSESSMENT OF NEED: cording to and conform to established lab- Need is established by documenting in a subject the oratory quality control, quality assurance, presence of one or more of the listed indications or and monitoring protocols. as established by progression through the institu- 9.1.3 Documentation of results, therapeu- tion’s or the laboratory’s protocol decision tree. tic intervention (or lack of) and/or clinical decisions should be placed in the patient’s MCT 9.0 ASSESSMENT OF TEST QUALITY . & VALIDITY OF RESULTS: 9.1.4 The type of medications, dose, and The consensus of the committee is that all diagnos- time taken prior to testing and the results tic procedures should follow the quality model de- of the pretest assessment should be docu-

RETIREDPulmonary Diagnostics Path of Workflow Pretest Testing Session Post-test Quality Patient Assessment Patient Training Results Report Test Request Test Performance Interpretation System Patient Preparation Results Review and Selection Clinical Consult Essentials Equipment Preparation Patient Assessment for Further Testing Organization Personnel Information Management Equipment Information System Purchasing/ Inventory Process control Documents/ Records Occurence management Quality system essentials Internal apply to all operations assessment in the path of workflow Process improvement Service and Satisfaction

Fig. 1. Structure for a Quality System Model for a Pulmonary Diagnostics Service (From Reference 31, with permission)

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mented. 10.1.2 A high quality nebulizer with con- 9.1.5 Report of test results should contain sistent output should be used to produce a statement by the technician performing the aerosol. The particles produced by the the test regarding test quality (including nebulizer should have a mass median aero- patient understanding of directions and dynamic diameter (MMAD) of 1-4 mi- effort expended) and, if appropriate, crons.1 If more than one nebulizer is used which recommendations were not met. in the testing of a given subject, nebulizer 9.1.6 Test results should be interpreted by output should be measured for each nebu- a physician, taking into consideration the lizer to assure a consistent dose. If output clinical question to be answered. measurement is not possible, we recom- 9.1.7 Personnel who do not meet annual mend the use of the same nebulizer to de- competency requirements or whose com- liver all concentrations to a given patient. petency is deemed unacceptable as docu- 10.1.3 The gas powering the nebulizer mented in an occurrence report should not and/or dosimeter should be at the correct be allowed to participate, until they have driving pressure or flow (as specified by received remedial instruction and have the manufacturer) and should be main- been re-evaluated. tained at that pressure or flowrate consis- 9.1.8 There must be evidence of active re- tently throughout the test. view of quality control, proficiency test- 10.1.4 Reagents: ing, and physician alert, or ‘panic’ values, 10.1.4.1 The Food & Drug Administra- on a level commensurate with the number tion (FDA) approved form of metha- of tests performed. choline powder (Provocholine) is avail- 9.2 Calibration and quality control measures able in prepackaged vials ready for dilu- specific to equipment used in methacholine tion. Provocholine and diluent can be challenge include: obtained from Methapharm Inc, 131 9.2.1 the size of the dose received and, Clarence St, Brantford, Ontario, Canada, thus, the response and its interpretation N3T 2V6; Telephone 800.287.7686. include nebulizer output, particle size, in- 10.1.4.2 The recommended diluent used spiratory flow, lung volume at beginning to dissolve the methacholine is sterile nor- of inspiration, and breath-hold time mal saline (0.9% sodium chloride) with or (These factors must be held constant without a preservative (eg, 0.4% phenol).2 across the testing procedure and from one 10.1.4.3 Various strategies have been de- test to another.); scribed for dosing schemes.10,13,34-38 The 9.2.2 excessive variability in measured range of doses is 0.02-25.0 mg/mL, gen- values including a nonreproducible base- erally given in doubling doses1,10,13,24,29 line (FEV1 variation of more than 0.2 L (ie, 0.02 mg/mL, 0.04 mg/mL, 0.08 after repeated efforts) makesRETIRED test results mg/mL.). The dosing scheme most re- more difficult to interpret.28 cently recommended by the ATS is: dilu- 9.3 Recommendations related to equipment ent, 0.03, 0.06, 0.125, 0.25, 0.5, 1, 2, 4, maintenance and calibration made in the Clini- 8, and 16 mg/mL.2 If a shortened dosing cal Practice Guidelines for spirometry23 and protocol is desired, the ATS recom- measurement of specific conductance33 should mends: diluent, 0.06, 0.25, 1, 4, and 16 be addressed. mg/mL.2 Caution should be used with the shortened protocol when testing MCT 10.0 RESOURCES: small children with asthma symptoms. 10.1 Equipment: The use of the diluent step is optional.2 10.1.1 must meet or exceed 10.1.4.4 In general, higher concentra- ATS requirements28 and be calibrated ap- tions of methacholine solution (ie, > propriately. All other equipment must be 1.25 mg/mL) are stable for at least 4 appropriately calibrated and maintained. months when stored at 4d C.39-41 The

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package insert for Provocholine recom- MCT 11.0 PATIENT MONITORING: mends that solutions > 0.25 mg/mL be 11.1 The FEV1 is the primary variable to be stored for no longer than 2 weeks, with monitored, and the results of spirometry should weaker solutions mixed on the day of meet acceptability and reproducibility recom- testing.13 mendations proposed by the ATS.28 A short- 10.1.4.5 A pharmacist or other well- ened expiratory maneuver can be used in some trained individual should prepare the situations and may be acceptable, and repro- methacholine reagents according to the ducibility after inhalation of some metha- manufacturer’s recommendations, choline concentrations may be difficult.2 using sterile technique. 11.2 The test should be administered according 10.1.4.6 Reagents should be clearly la- to the specific protocol, with the number of beled with dose, date prepared, and ex- breaths and the pattern documented. piration date. 11.3 Breath sounds, pulse rate, , 10.1.4.7 The test should be adminis- and/or blood pressure may be monitored to as- tered in a well-ventilated room (with at sist in patient evaluation and test interpreta- least 2 complete air exchanges per tion.42-45 Patients should not be left unattended hour).28 A filter to collect excess parti- during the procedure. cles or an exhaust system to remove 11.4 In the case of a positive response to provo- provocative material from the room cation (ie, ≥ 20% fall in FEV1), bronchodilator may be desirable. may be administered to speed recovery. 10.1.4.8 Oxygen, bronchodilators, and Spirometry should be repeated after bron- resuscitation equipment should be chodilator administration to ensure that ventila- readily available.1,24 tory function has returned to near baseline (ie, 10.1.4.9 The need for written consent at least 85% of baseline).46 should be determined within the specif- ic institution. MCT 12.0 FREQUENCY: 10.1.4.10 A pretest questionnaire 12.1 To ensure that a previous methacholine chal- should be used. An example of a ques- lenge test does not affect a later test, 230 minutes tionnaire can be found in the ATS should be allowed to elapse before the test is re- Methacholine Challenge Guideline.2 peated.47 Tolerance of methacholine may occur in 10.2 Personnel: patients who are not asthmatic when tests are re- 10.2.1 Methacholine challenge tests peated at less than 24-hour intervals.48,49 should be performed under the direction 12.2 When a test is to be repeated, medications, of a physician trained in pulmonary func- exposures, time of day, and nebulizer employed tion testing and experienced in bronchial should be held constant, if possible. provocation. Personnel performing the test should be experiencedRETIRED in patient as- MCT 13.0 INFECTION CONTROL: sessment, knowledgeable of and have 13.1 The staff, supervisors, and physician-di- demonstrated competency in performing rectors associated with the pulmonary laborato- this challenge (including reversal of ry should be conversant with “Guideline for methacholine response), know the associ- Isolation Precautions in Hospitals”50 and devel- ated hazards, and be certified in basic life op and implement policies and procedures for support. Attainment of the CPFT and/or the laboratory that comply with its recommen- RPFT credentials is recommended. dations for Standard Precautions and Transmis- 10.2.2 During the testing procedure, a sion-Based Precautions. physician knowledgeable in provocation 13.2 The laboratory’s manager and its medical testing procedures and trained to treat director should maintain communication and acute bronchospasm and use resuscitation cooperation with the institution’s infection con- equipment must be close enough to re- trol service and the personnel health service to spond in an emergency. help assure consistency and thoroughness in

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complying with the institution’s policies related sensitizing stimuli in adults. Report Working Party Stan- to immunizations, post-exposure prophylaxis, dardization of Lung Function Tests, European Community and job- and community-related illnesses and for Steel and Coal. Official Statement of the European Res- exposures.51 piratory Society. Eur Respir J Suppl 1993 Mar;16:53-83. 13.3 Primary considerations include adequate 2. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson handwashing,52 provision of prescribed ventila- JL, Irvin CG, et al. Guidelines for methacholine and exer- tion with adequate air exchanges,53 careful han- cise challenge testing, 1999. This official statement of the dling and thorough cleaning and processing of American Thoracic Society was adopted by the ATS Board equipment,50 and the exercise of particular care of Directors, July 1999. Am J Respir Crit Care Med in scheduling and interfacing with the patient in 2000;161(1):309-329. whom a diagnosis has not been established.50 3. Chatham M, Bleeker ER, Smith PL, Rosenthal RR, Mason 13.4 Sterility of reagents should be maintained P, Norman PS. A comparison of histamine, methacholine, by proper storage and aseptic handling. and exercise airway reactivity in normal and asthmatic sub- jects. Am Rev Respir Dis 1982;126(2):235-240. MCT 14.0 AGE-SPECIFIC ISSUES: 4. Greenspon LW, Gracely E. A discriminate analysis applied Test instructions and techniques should be given in to methacholine bronchoprovocation testing improves clas- a manner that takes into consideration the learning sification of patients as normal, asthma, or COPD. Chest ability and communication skills of the patient 1992;102(5):1419-1425. being tested. 5. Cockcroft DW, Hargreave FE. Airway hyperresponsive- 14.1 Neonatal: This CPG does not apply to ness: relevance of random population data to clinical use- neonatal populations. fulness. Am Rev Respir Dis 1990;142(3):497-500. 14.2 Pediatric: This CPG is appropriate for 6. Cockcroft DW, Murdock KY, Berscheid BA, Gore BP.

children who can perform good quality spirom- Sensitivity and specificity of histamine PC20 determination etry or body plethysmography ≥ 5 years of age). in a random selection of young college students. J Allergy 14.3 Geriatric: This CPG is appropriate for the Clin Immunol 1992;89(1 Pt 1):23-30. geriatric population. 7. Backer V, Groth S, Dirksen A, Bach-Mortensen N, Hansen KK, Laursen EM, Wendelboe D. Sensitivity and specificity Pulmonary Function Testing Clinical Practice of the histamine challenge test for the diagnosis of asthma Guidelines Committee (principal author is listed in an unselected sample of children and adolescents. Eur first): Respir J 1991;4(9):1093-1100. Jack Wanger MS RRT RPFT, Lenexa KS 8. Perpina M, Pellicer C, de Diego A, Compte L, Macian V. Susan Blonshine BS RRT RPFT, Mason MI Diagnostic value of the bronchial provocation test with Catherine M Foss, BS RRT RPFT, Ann Arbor MI methacholine in asthma: a Bayesian analysis approach. Carl Mottram, BA RRT RPFT, Chair, Rochester MN Chest 1993;104(1):149-154. Gregg Ruppel MEd RRT RPFT, St Louis MO 9. Fish JE. Bronchial challenge testing. In: Middleton E, edi- tor. Allergy: principles and practice, 4th ed. St Louis: The current Pulmonary Function ClinicalRETIRED Practice Mosby Year Book: 1993. Guidelines Committee updated an earlier version 10. Chai H, Farr RS, Froehlich LA, Mathison DA, McLean JA, (Bronchial provocation. Respir Care 1992;37 Rosenthal RR, et al. Standardization of bronchial inhala- (8):902-906) and gratefully acknowledge the con- tion challenge procedures. J Allergy Clin Immunol tributions of Robert Brown, Michael Kochansky, 1975;56(4):323-327. and Kevin Shrake who provided input to that earlier 11. Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel JA. version. Mechanisms of bronchial hyperreactivity in normal sub- jects after upper infection. Am Rev Respir REFERENCES Dis 1976;113(2):131-139. 12. Cheung D, Dick EC, Timmers MC, de Klerk EP, Spaan 1. Sterk PJ, Fabbri LM, Quanjer PH, Cockcroft DW, O’Byrne WJ, Sterk PJ. Rhinovirus inhalation causes long-lasting ex- PM, Anderson SD, et al. Airway responsiveness: standard- cessive airway narrowing in response to methacholine in ized challenge testing with pharmacological, physical and asthmatic subjects in vivo. Am J Respir Crit Care Med

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