METHACHOLINE CHALLENGE TEST“ATS GUIDELINE”

Airway hyper-responsiveness:• Airway hyper-responsiveness to exogenous stimuli is a

characteristic feature of asthma• Symptoms of asthma:

Wheezing

dyspnea

chest tightness

cough in the following:• After exercise• with exposure to cold air• during respiratory infections• following inhalant exposures in workplace• after exposure to allergens and other asthma triggers

• AHR progress from a concept synonymous with variable airflow obstruction, to a physiologic measurement

• AHR is most commonly measured by inhalation provocation challenges

• The various agents which can be used for bronchoprovocation

Methacholine challenge testing content:

• Indications• Contraindications• Technician Training/Qualifications• Safety• Patient Preparation• Choice and Preparation of Methacholine• Dosing Protocols• Nebulizers and Dosimeters• Spirometry and Other End-point Measures• Data Presentation• Interpretation

Indications

The main indication:

• asthma is a serious possibility and traditional methods, notably spirometry performed before and after BD not establish or eliminate diagnosis

Other indications:• asthma with atypical features

• possibility of occupational asthma

• Monitoring asthma therapy

• Identifying specific asthma triggers

• Excluding a diagnosis has social impact

• Objective assessing of asthma severity

Contraindications:

Absolute:• Severe airflow limitation (FEV1 < 50% predicted or <1 L)

• Acute coronary syndrome or stroke within 3 months

• Severe hypertension (SBP > 200 mm Hg or DBP > 100 mm Hg)

• Cerebral or aortic aneurysm

Contraindications:

RELATIVE• Moderate airflow limitation (FEV1 < 60% predicted or <1.5L)• Inability to perform acceptable and repeatable spirometry• Pregnancy• Nursing mothers• Current use of cholinesterase inhibitor medication for MG• Significant hypoxemia (PaO2 < 60)• Recent upper or lower respiratory tract infection (within 6 wk)• Failure to withhold medication that may affect test results• Vigorous exercise on day of test

Technician Training/Qualifications

technician should be:

• familiar with guideline

• capable of managing equipment

• proficient at spirometry

• Know the contraindications

• familiar with safety and emergency procedures

• Know when to stop further testing

• proficient in administration of BD and evaluation response

SafetyPrecautions for patient safety:

• Presence of medical director trained to treat bronchospasm

• Presence of medications to treat severe bronchospasm

• Oxygen must be available

• A nebulizer should be available for administration BD

• A stethoscope, sphygmomanometer and pulse oximeter should be available

Precautions for technician safety:

• Minimize technician exposure

• Testing room must have adequate ventilation.

• Using low resistance filters

• A laboratory fume hood

• dosimeter technique reduce technician exposure

• To stand well away from patient

Patient preparation• Give list of item to avoid

• Explain the test

• Ask would like to urinate before the test

• Evaluate contraindications and medications

• able to understand procedure & perform reliable spirometry

• A brief P/E of the chest and lungs

Choice and Preparation of Methacholine(Provocholine)

• a dry crystalline powder

• choice for nonspecific bronchoprovocation challenge test

• available in100 mg vials

• Sterile N/S +/- 0.4% phenol is used as the diluent

• stored 4°C with0.125mg/ml and greater stable for 3 mo

• warmed to room Tem before test

• sterile mixing is very important

• unused methacholine remain in nebulizer should be discard

Dosing protocols• different protocols have been used

• able to narrow the choices to two: the 2-min tidal breathing method the five-breath dosimeter method

• These give similar results

• FDA approved Provocholine for five-breath technique

Two-minute tidal breathing dosing protocol

• Prepare the following 10 doubling concentrations:

Two-minute tidal breathing (cont…)

• Remove from refrigerator 30 min before test

• Insert 3 ml diluent or lowest concentration,using a sterile

syringe(diluent setup is optional)

• perform baseline spirometry

• Apply a noseclip

• Instruct patient to breathe quietly for 2 min

• holding nebulizer upright

• begin nebulization

Two-minute tidal breathing (cont…)

• after 2 min,turn off the flow meter

• Measure FEV₁,30 and 90s after complete nebulization

• Obtain acceptable FEV₁ at each time

• no more than three or four maneuvers after each dose

• no more than 3 min to perform these

• interval of two subsequent concentrations should be kept to 5 min

• At each dose report the highest FEV₁

Two-minute tidal breathing (cont…)

• If the FEV₁ falls less than 20% go to next concentration

• If the FEV₁, falls more than 20% from baseline (or the highest

concentration has been given), give no further methacholine

• administer albuterol ,wait 10 min and repeat spirometry

Five-breath dosimeter protocol

• Prepare the following five concentrations:

Five-breath dosimeter protocol(cont..)

• Remove vial from refrigerator 30 min before test

• 2 ml of first concentration to nebulizer

• wear a nose clip

• Perform baseline spirometry

• Ask to hold the nebulizer upright

Five-breath dosimeterprotocol(cont..)

• At end exhalation(FRC) encourage patient to inhale slowly and deeply (about 5 s to complete the inhalation) and to hold breath (at TLC) for another 5 s

• Repeat this step for a total of five inhalations

• Take no more than a total of 2 min

Five-breath dosimeterprotocol(cont..)

• Measure FEV₁, at 30 and 90s after the fifth inhalation

• Obtain an acceptable FEV₁, at each time point

• no more than three or four maneuvers,take no more than 3 min

• interval between two subsequent concentrations should be kept to 5 min

Five-breath dosimeter protocol(cont..)

• At each dose, report the highest FEV₁

• If the FEV₁, falls more than 20% from baseline (or the highest concentration has been given),give no further methacholine

• administer albuterol,wait 10 min and repeat spirometry

The effect of increasing the inhaled dose of histamine or methacholine in a healthy subject (red) and an asthmatic patient (blue). The provocative concentration is the amount of inhaled aganist required to drop the FEV1 by 20 percent from the baseline (PC20 FEV1), and is much less in the asthmatic than in the normal subject.

Optional shortening

• 2-min tidal breathing protocol may be shortened depending

on the clinical situation

• subject not known to asthma , no asthma medications, with normal lung function, no response to diluent,start at 1 mg/ml

• when FEV₁ fall less than 5% ,in next concentration fourfold increase is quite safe

Nebulizers

Nebulizers for the tidal breathing method:• deliver aerosol with a particle mass median diameter(MMD)

between 1 and 3.6µm• The English Wright nebulizer• Flow must be adjusted for nebulizer to obtain output within

0.13 ml/min +/- 10%

Nebulizers for the five-breath dosimeter method• deliver 9µl+/-10% of solution per 0.6s actuation during inhalation• The DeVilbiss model 646 nebulizer

A-2 min tidal breathing(English wright nebulizer)

B- five beath dosimetre(Devibiss model 646)

Spirometry and Other End-point Measures

• Change FEV₁ is primary outcome for MCT

• Failure to meet repeatability should be to assist

interpretation and not to exclude data from analysis

• Quality control (QC) report after each level:A = two acceptable FEV₁ values that match within 0.10 L

B = two acceptable FEV₁ values that match within 0.20 L

C = two acceptable FEV₁ values that do not match within0.20 L

D = only one acceptable FEV₁ maneuver

F = no acceptable FEV₁ maneuvers

Other End-point Measures(cont…)

Raw and sGaw• Airway resistance(Raw) express as specific conductance

(sGaw) are alternative end point• Use in patients cannot perform acceptable spirometry • Usually parallel changes in FEV₁ with MCT• Raw and sGaw are more variable than FEV₁• A larger change (e.g 45%) for a positive test

Other End-point Measures(cont…)

Transcutaneous oxygen• Ptc o₂ may a useful end point• Use in patients cannot perform acceptable spirometry

Forced oscillation• have recently been assessed• do not require patient effort• useful in patients cannot perform acceptable spirometry • should be restricted to laboratories with expertise

Data Presentation• Data should be presented for each step in the protocol:

PC ₂₀• PC₂₀ used to summarize results for clinical purposes• PC₂₀=provocative concentration cause 20% fall in FEV₁• If FEV₁ does not fall by at least 20% after 16 mg/ml PC₂₀

should report > 16 mg/ml• For manual calculation of PC₂₀ :

C₁= second to last concentration(concentration preceding C₂)C₂= final concentration result 20% or greater fall in FEV₁ R₁= percent fall in FEV₁ after C₁ R₂= percent fall in FEV₁ after C₂

Interpretation

Factors should take into consideration when interpreting:• Pretest evaluation probability of asthma • Degree of baseline airway obstruction• Quality of spirometry• Pretest questionnaire results (modifiers)• Symptoms at the end of test• Degree of recovery after BD• Sensitivity and specificity of MCT• Repeatability of MCT

Curves illustrating pretest and posttest probability of asthma after a methacholine challenge test with four PC₂₀ values.They are approximations presented to illustrate relationships and principles of decision analysis. They are not intended to calculate precise posttest probabilities in patients.

Relationship between airway responsiveness & asthma

• If clinical probability of asthma is 30-70%and PC₂₀ >16 mg/ml,

patient does not currently have asthma

• If PC ₂₀ < 1 mg/ml, strong confirmation of asthma

• When PC ₂₀ between 1 and16 mg/ml, more cautious about stating asthma

• When PC ₂₀ low and the “asthma-like” symptoms induced by MCT, diagnosis of asthma increase

methacholine dose–response curves for four individuals, one with normal airway responsiveness and one each with mild to moderate and marked airway hyperresponsiveness. These curves demonstrate hyperresponsiveness both in the increase in magnitude of the response and the ease of the response, the latter identified the leftward shift of the curve and the smaller PC20

Relationship (cont…)

when PC ₂₀ between 1 and 16 mg/ml and no asthma symptoms several possibilities exist:

• Mild intermittent asthma but patient is “poor perceive” of asthma symptoms

• After MCT,experience chest tightness but not recognized as abnormal

• Patient never exercises or experiences environmental triggers of bronchospasm

• mild BHR is due to a cause other than asthma(URTI )• there is subclinical asthma will become clinical in future

Relationship (cont…)

• significant correlation between degree of airway responsiveness and severity of asthma

• PC ₂₀ does not reflect the “usual” untreated severity of asthma

• difficult to interpret a low PC ₂₀ with baseline airway obstruction(e.g COPD)

Categorical method of interpreting MCT

• Categorical method for clinical interpretation of MCT makes three assumptions:MCT results are either positive or negative for BHRasthma is either present or absentThere is a“gold standard” for diagnosing asthma

• Sensitivity is fraction of patients with asthma have positive test

• Specificity is fraction of patients without asthma have negative test

Categorical method(cont..)

• Negative MCT is defined as nonresponse to highest concentration (PC ₂₀ > 8-25 mg/ml)

• positive test is defined as a PC ₂₀ < 8 or < 16 mg/ml

• The false-positive when PC ₂₀ is <8 mg/ml but patient does not have actually asthma

• Allergic rhinitis and COPD have high FP rates and poor PPV

Categorical method(cont…)

• A FN result occurs when PC ₂₀ > 8-25 mg/ml in a patient with asthma

• The NPV of MCT is more than 90% when pretest probability of asthma is in range of 30-70%

• Negative MCT rules out asthma certainly in patients have had asthma symptoms during previous 2 wk

Categorical method(cont…)

Consider three factors before negative test rule out asthma:

• taking intensive anti inflammatory medications prior MCT

• season for aeroallergen exposure may have passed

• occupational asthma due to single Ag or chemical sensitizer respond only specific challenge agent