December 6, 2012 December 6, 2012 Adult Bronchoprovocation TestsAdult Bronchoprovocation Tests

Lanny J. Rosenwasser, M.D.Dee Lyons/Missouri Endowed Chair in Immunology Research

Professor of Pediatrics Allergy-Immunology Division

Childrens Mercy Hospital Kansas City, Missouri

Professor of Pediatrics, Medicine and Basic ScienceUniversity of Missouri Kansas City School of Medicine

Working Definition of AsthmaWorking Definition of Asthma

Asthma is a disorder of the airways with theAsthma is a disorder of the airways with thefollowing pathophysiological characteristicsfollowing pathophysiological characteristics

• Chronic inflammationChronic inflammation

• Variable airflow obstructionVariable airflow obstruction

• Hyperresponsiveness to a variety of “triggers”Hyperresponsiveness to a variety of “triggers”

““Twitchy” AirwaysTwitchy” Airways

Bronchial hyperresponsiveness is:Bronchial hyperresponsiveness is:

• An abnormal increase in airflow limitation followingAn abnormal increase in airflow limitation followingexposure to a stimulus;exposure to a stimulus;

• Alternatively, a threshold response (e.g., Alternatively, a threshold response (e.g., 20% fall20% fallin FEV1) which occurs at a lower point (dose) in FEV1) which occurs at a lower point (dose) than in a healthy individual.than in a healthy individual.

Types of StimuliTypes of Stimuli

• Direct StimulusDirect Stimulus Cause airflow limitation by a direct actionCause airflow limitation by a direct action on effector cells (e.g., airway smooth muscleon effector cells (e.g., airway smooth muscle cells, mucus producing cells).cells, mucus producing cells).

• Indirect StimulusIndirect StimulusCause airflow limitation by an action of cellsCause airflow limitation by an action of cellsother than effector cells, which then interact other than effector cells, which then interact with the effector cells.with the effector cells.

Direct stimulusDirect stimulus

Effector cellsEffector cells• Airway smooth muscle cellsAirway smooth muscle cells• Bronchial endothelial cellsBronchial endothelial cells• Mucus producing cellsMucus producing cells

Airflow limitationAirflow limitation

Indirect stimulusIndirect stimulus

Intermediary cellsIntermediary cells• Inflammatory cellsInflammatory cells• Neuronal cellsNeuronal cells

Direct StimuliDirect Stimuli

• AcetycholineAcetycholine

• MethacholineMethacholine

• CarbacholCarbachol

• HistamineHistamine

• Prostaglandin DProstaglandin D22

• LeukotrienesLeukotrienes

Indirect StimuliIndirect Stimuli

• AdenosineAdenosine

• BradykininBradykinin

• Metabisulfite / SOMetabisulfite / SO22

• ExerciseExercise

• Hyper/hypotonic aerosolHyper/hypotonic aerosol

• Isocap. hyperventilationIsocap. hyperventilation

• MannitolMannitol

• Propanolol (Propanolol (-blockers)-blockers)

What do most people use to What do most people use to evaluate airway hyperreactivity?evaluate airway hyperreactivity?

??

Scott GC, Braun SR. Scott GC, Braun SR. Chest 1991;100:322-328.Chest 1991;100:322-328.

• Questionnaire to prominent and active Questionnaire to prominent and active investigators using bronchial provocationinvestigators using bronchial provocationtechniques.techniques.

• 44 of 94 responses44 of 94 responses

• Methacholine (63%)Methacholine (63%) Histamine (17%)Histamine (17%) Exercise (8%)Exercise (8%) Specific antigens (5%)Specific antigens (5%)

Direct StimuliDirect Stimuli

MethacholineMethacholine• Most widely usedMost widely used• Well standardizedWell standardized• Easy to obtain todayEasy to obtain today• Better differentiates reactive/nonreactive airwaysBetter differentiates reactive/nonreactive airways

HistamineHistamine• Good correlation with methacholineGood correlation with methacholine• More side effectsMore side effects• Development of tachyphylaxisDevelopment of tachyphylaxis

Exercise-induced Exercise-induced BronchoconstrictionBronchoconstriction

(EIB)(EIB)

Exercise-inducedExercise-inducedAsthmaAsthma

(EIA)(EIA)

• Exercise needs to be continuousExercise needs to be continuous

• Type of exercise mattersType of exercise matters

• Intensity: 60-80% max causes greatest severityIntensity: 60-80% max causes greatest severity

• DurationDuration

• Air temperature and humidityAir temperature and humidity

EIB FactorsEIB Factors

Specific AntigenSpecific Antigen

• Performed when proof of sensitivity,Performed when proof of sensitivity,avoidance, or immunotherapy requiredavoidance, or immunotherapy required

• Most commonly used in researchMost commonly used in research

• Immediate and late responsesImmediate and late responses

• Strong and lasting responsesStrong and lasting responses

AdenosineAdenosine

• Adenosine 5’ – monophosphate (AMP)Adenosine 5’ – monophosphate (AMP)

• Indirect stimulantIndirect stimulant

• Releases histamine & other mediators fromReleases histamine & other mediators frommast cellsmast cells

• Action is blocked by antihistaminesAction is blocked by antihistamines

• May reflect extent of airway inflammationMay reflect extent of airway inflammationbetter than methacholinebetter than methacholine

AdenosineAdenosine

• Inhalation of aerosolInhalation of aerosol

• Diluent usually 0.9% salineDiluent usually 0.9% saline

• Dosing scheme range 0.04 to 320 mg/mLDosing scheme range 0.04 to 320 mg/mL

• Quadrupling doses reported to be safeQuadrupling doses reported to be safeand efficient - and efficient - DeMeer et al., Thorax 2001;56:362-365DeMeer et al., Thorax 2001;56:362-365

MannitolMannitol

• Indirect stimulantIndirect stimulant

• Dry powderDry powder

• Osmotic stimulant Osmotic stimulant ( osmolarity of airway surface liquid)( osmolarity of airway surface liquid)

• Special dry-powder inhalers neededSpecial dry-powder inhalers needed

• Procedure not well standardizedProcedure not well standardized

• Reports are mainly from AustraliaReports are mainly from Australia

Oral ChallengesOral Challenges

• Performed when proof of sensitivity neededPerformed when proof of sensitivity needed

• Common agents and prevalenceCommon agents and prevalence• Metabisulfite: 5 – 10% in adultsMetabisulfite: 5 – 10% in adults• Tartrazine: <5%Tartrazine: <5%• ASA: 4 to 20%ASA: 4 to 20%

• Time for reaction variesTime for reaction varies

Occupational ChallengesOccupational Challenges

• Specific challenges considered the goldSpecific challenges considered the goldstandard for dx of occupational asthmastandard for dx of occupational asthma

• Agents Agents • Natural organic (flour, wood dust)Natural organic (flour, wood dust)• Pharmaceuticals (cimetidine)Pharmaceuticals (cimetidine)• Organic chemicals (isocyanates)Organic chemicals (isocyanates)• Inorganic chemicals (nickel salts)Inorganic chemicals (nickel salts)

• Immediate and late responsesImmediate and late responses

• Need for controls (placebo)Need for controls (placebo)

Methacholine ChallengeMethacholine Challenge

BaselineBaseline

PlaceboPlacebo

0.07 mg/mL0.07 mg/mL

0.15 mg/mL0.15 mg/mL

0.31 mg/mL0.31 mg/mL

BronchodilatorBronchodilator

FEV1 (L)FEV1 (L)

3.153.15

3.143.14

2.962.96

2.752.75

2.162.16

3.603.60

% Change% Change

------

------

- 6- 6

- 12- 12

- 31- 31

Contraindications Absolute

• Severe airflow limitation (FEV1 <50% pred., or < 1.0 L)

• Heart attack or stroke in last 3 months• Uncontrolled hypertension• Known aortic aneurysm

Relative• Moderate airflow limitation

(FEV1 <60% pred., or < 1.5 L)

• Inability to perform acceptable spirometry• Pregnancy• Nursing mothers

Martin, Wanger, Irvin, et al. Chest 1997;112:53-56Martin, Wanger, Irvin, et al. Chest 1997;112:53-56

Safety of a Low Starting FEVSafety of a Low Starting FEV11

• 88 patients with FEV88 patients with FEV1 1 <60% predicted (22% - 59%)<60% predicted (22% - 59%)

• Mean baseline FEVMean baseline FEV11 1.39 1.39 0.28 L (0.64 – 2.4 L) 0.28 L (0.64 – 2.4 L)

• Testing was safe and successfulTesting was safe and successful

• 84 patient’s FEV84 patient’s FEV11 returned to 90% of baseline, returned to 90% of baseline,

and 4 required a 2and 4 required a 2ndnd treatment treatment

Patient PreparationPatient Preparation

• Withhold medications that will interfereWithhold medications that will interfere

• Explain the test, but don’t over do it Explain the test, but don’t over do it

• They aren’t going to have an asthma attack!!They aren’t going to have an asthma attack!!

• Avoid the impact of suggestion.Avoid the impact of suggestion.

• Consent formConsent form

• Pre-test questionnairePre-test questionnaire

• Withhold coffee, tea, cola drinks, chocolate Withhold coffee, tea, cola drinks, chocolate for day of studyfor day of study

Medication Withholding Schedule

• Short-acting inhaled bronchodilators 8 hrs

• Med.-acting bronchodilators (e.g., ipratropium) 24 hrs

• Long-acting bronchodilators 48 hrs

• Oral bronchodilators 12-48 hrs

• Cromolyn sodium 8 hrs

• Nedocromil 48 hrs

• Leukotriene modifiers 24 hrs

Technical Factors and Aerosols

• Nebulizer output

• Aerosol particle size

• Tubing

• Lung volume

• Inspiratory flow rate

• Breathhold time

Dosing ProtocolsDosing Protocols

CanadianProtocol(mg/ml)

168421

0.50.25

0.1250.060.03

Diluent

Chai,et al.

(mg/ml)

25105

2.51.25

0.6250.310.150.07

Diluent

Provoch.Package(mg/ml)

25102.5

0.250.025

Diluent

Chatham,et al.

(mg/ml)

4 br-251 br-254 br-51 br-5

Diluent

Corrao,et al.

(mg/ml)

4 br-251 br-25

Dosing ProtocolsDosing Protocols

CanadianProtocol(mg/ml)

168421

0.50.25

0.1250.060.03

Diluent

Chai,et al.

(mg/ml)

25105

2.51.25

0.6250.310.150.07

Diluent

Provoch.Package(mg/ml)

25102.5

0.250.025

Diluent

Chatham,et al.

(mg/ml)

4 br-251 br-254 br-51 br-5

Diluent

Corrao,et al.

(mg/ml)

4 br-251 br-25

ATS1999

(mg/ml)

16

4

1

0.25

0.0625

Diluent

SpirometrySpirometry

• Change in FEVChange in FEV11 is the primary outcome measure is the primary outcome measure

• Spirometry should meet ATS guidelines for acceptabilitySpirometry should meet ATS guidelines for acceptability

• The quality of the spirogram should be examined after The quality of the spirogram should be examined after each maneuvereach maneuver

• Full FVC efforts lasting Full FVC efforts lasting >> 6 sec should be performed at 6 sec should be performed at baseline and after diluentbaseline and after diluent

• If the FEVIf the FEV11 is the only outcome measure, the expiratory is the only outcome measure, the expiratory

maneuver can be shortened to about 2 sec at other maneuver can be shortened to about 2 sec at other stagesstages

• If shortened maneuver is used, assure If shortened maneuver is used, assure inspiration is completeinspiration is complete

Calculation of Percent ChangeCalculation of Percent Change

% Change = Post-diluent FEV1 - Post-methacholine FEV1

Post-diluent FEV1

Provocative Concentration (PC)Provocative Concentration (PC)

The exact concentration that causes a specific fall in a PFT parameter:

PC20FEV1

Concentration that causes a 20% fall in FEV1

PC40SGaw

Concentration that causes a 40% fall in specific conductance

Quality ControlQuality Control

• Nebulizer outputNebulizer output• Verify output initially & after every 20 uses, until anVerify output initially & after every 20 uses, until an

appropriate testing schedule is established for lab.appropriate testing schedule is established for lab.• Output for 2-min. TB neb. = 0.13 to 0.15 mL/min Output for 2-min. TB neb. = 0.13 to 0.15 mL/min ++ 10% 10%• Output for DeVilbiss neb. = 0.009 mL/actuation Output for DeVilbiss neb. = 0.009 mL/actuation ++ 10% 10%

• Verify concentrations of solutionsVerify concentrations of solutions

• Verify challenge procedureVerify challenge procedure

• Keep records of QC proceduresKeep records of QC procedures

SafetySafety

Precautions for Patient SafetyPrecautions for Patient Safety

• Trained staff close enough to respond quicklyTrained staff close enough to respond quicklyto an emergencyto an emergency

• Medications to treat bronchospasm must beMedications to treat bronchospasm must bepresent in testing areapresent in testing area

• A stethoscope, sphygmomanometer, A stethoscope, sphygmomanometer, and pulse oximeter should be availableand pulse oximeter should be available

Precautions for Technician SafetyPrecautions for Technician Safety

• Try to minimize technician exposureTry to minimize technician exposure

• Testing room should have adequate ventilation Testing room should have adequate ventilation (> 2 AC/hr)(> 2 AC/hr)

• Use of exhalation filters useful in TB methodUse of exhalation filters useful in TB method

• Those with asthma are at increased risk and Those with asthma are at increased risk and should take extra precautions to minimize should take extra precautions to minimize their exposuretheir exposure

SafetySafety

Categorization of Response

PCPC2020 (mg/mL) (mg/mL) InterpretationInterpretation

> 16> 16 Normal BHR Normal BHR

4.0 - 164.0 - 16 Borderline BHR Borderline BHR

1.0 - 4.01.0 - 4.0 Mild BHR (positive test) Mild BHR (positive test)

< 1.0< 1.0 Moderate to severe BHR Moderate to severe BHR