Practical issues performing Bronchial Challenge Tests
Transcript of Practical issues performing Bronchial Challenge Tests
Practical issues performing Bronchial Challenge Tests
Why we do what we do
Leanne Rodwell PhD BSc Grad Dip
Phty CRFS Respiratory Scientist
The Lady Cilento Children’s Hospital Brisbane
Speaker Disclosure
• In accordance with the policy of the Thoracic Society of Australia and New Zealand the following presenter has indicated that they have a relationship which in the context of their presentation, could be perceived as a real or apparent conflict of interest but do not consider that it will influence their presentation. The nature of the conflict is listed:
• I have shares I purchased myself in Pharmaxis Ltd
No animals were harmed while preparing for this talk
Why challenge testing
“It is clear that an increase in nonspecific airway responsiveness is an important feature of asthma.”
“It’s measurement should be as essential to the diagnosis and management of asthma as the glucose tolerance test is to diabetes.”
Prof Anne Woolcock 1979
Most commonly used
Clinical Bronchial Challenge tests
Direct stimuli
Inhalation
• Histamine
• Methacholine – non-selective
muscarinic receptor
agonist
– approved by FDA
Provocholine™
Indirect stimuli
Physical
• Exercise
• Eucapnic Voluntary
Hyperventilation (EVH)
(5%CO2, 21%O2, 74%N2)
Inhalation
• Hypertonic saline
• Mannitol (eg Aridol)
“Direct”
Acts on a specific receptor on bronchial smooth muscle
causing it to contract.
Identifies responsiveness to the administered substance.
persistent, structural changes, lung injury not
associated with asthma
“Indirect”
The agonists histamine, leukotrienes, prostaglandins are
released from inflammatory cells (mast cells, eosinophils) in
response to the stimulus
Identifies variable airway hyperresponsiveness
responsiveness to endogenously released
mediators of inflammation airway inflammation
Cockcroft et al. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977:7(3):235-43. Hargreave et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy & Clin Immunol 1981:68:347-55
Yan K et al. Rapid method for measurement of bronchial responsiveness. Thorax. 1983:38(10):760-5.
Standardisation of “direct” bronchial challenge tests
Nebuliser Units to deliver direct challenge aerosols
Nebuliser run off compressed air
(Tidal breathing technique - 2mins each concentration)
Hand held and operated
Inhale increasing doses of challenge aerosol
(Yan 1983)
Dosimeter technique Breathe each concentration for
5 consecutive breathes
Classification of severity of AHR to
direct challenges
Some Factors that determine dose
1. Nebuliser output Nebulisers of different models and different nebulisers of the same model produced different outputs and particle size(aerosol generated/unit time)
(Ryan et al, J Allergy & Clin Immunology 1981)
2. Duration of inhalation Increase in the duration of inhalation ↑dose delivered
(Cockcroft & Berscheid, Chest 1982; 82:572-5)
3. Room temperature influences nebuliser output Nebuliser output ↑23% when room temperature increased 19 to 24oC
(Kongerud J et al. Eur Respir J, 1989;2:681-4
Nebulizers of different models produced different outputs and particle size; output varied with flow rate.
Ryan et al, J Allergy & Clin Immunology 1981
Duration of inhalation affects site of dose delivery. (Ryan et al 1981)
Tidal breathing method
Wright’s nebuliser- 2min
The PC20 for each method was the same.
Dosimeter DeVilbiss 646
Inhale for: 3-5 sec 1-2 sec
Outer zone: 21.2% Outer zone: 15.3% Outer zone: 16.8%
(Ryan et al 1981)
McH responsiveness in elite athletes may be measuring airway trauma
• High prevalence of AHR to direct stimuli in winter athletes.
• ? airway damage or remodelling
• Cause = effects of high intensity exercise.
• Absence of asthma
(Sue-Chu 2010 & Kippelen 2012)
Direct tests for AHR
Technical disadvantages:
•Potential variation in nebuliser output (Calibrate+++)
•Standard inhalation technique by patient
•Challenge setting is stable (temperature control)
Advantages :
•Positive test with airway injury e.g. gases, dry air
•Dose-response curve obtained
•Time for testing can be less than exercise
Identify AHR that is asthma
A positive MCH challenge identifies AHR but it is not specific for asthma Clinicians wanted to monitor the effect of drug therapy on AHR in asthmatic patients What is required are Bronchial Challenge tests that identify AHR and are specific for asthma.
Borg, Thompson & O’Hehir 2014: Interpreting Lung Function tests: A step by step guide
Exercise Induced Bronchoconstriction (EIB)
“If from running gymnasatic exercises, or any other work, the breathing become difficult, it is called Asthma”
Historically….
50-60 years ago many asthmatics avoided exercise:
– Personal experience of EIB
– Parents restricted children’s involvement.
– Lowered aerobic fitness ↑O2 consumption for a task
– Very unfit EIB occurs at low levels of exercise.
Godfrey & Fitch. Immunol Allergy Clin N Am: 2013
The Value of Exercise testing
• Diagnose Exercise Induced Asthma (EIA)
• Block EIA with medications
• Reproduce the symptoms experienced during exercise
• If it is not EIA, demonstrate to:
– Parents the child can exercise
– Child they can exercise
Standardisation of indirect
challenge tests to identify EIB
• 1972 Standardisation of Exercise test • Clinician driven – assess effects of drugs eg:Intal
• Silverman & Anderson Arch Dis Childh 1972
• Clinical guidelines first published in US 1979
Eggleston et al; 1979:J Allergy Clin Immunol
• 1996 Standardisation of Eucapnic
Voluntary Hyperventilation (EVH) • Argyros et al: Chest 1996 (60-80% MVV)
• Modified Anderson et al: Br J Sports Med 2001 -
accommodate elite athletes (85% MVV: FEV1x30)
A good starting point
• Need to understand the mechanism and the stimulus that cause airways to narrow in susceptible people.
THEN
• Control the environment and the stimulus to optimise the challenge
• That’s why we do what we do!!
(Anderson and Kippelen 2013; Immunol Allergy Clin N Am 33:363
Water Loss by Evaporation
from the airway surface
Mucosal Cooling
Vasoconstriction
Reactive hyperemia
Vascular Engorgement
± vascular leakage &
Oedema
Exercise-induced bronchoconstriction
Mucosal Dehydration
Increase [Na+][Cl-][Ca++][ K+]
Increased Osmolarity
Cells Shrink
Mediators Released
Smooth muscle Contraction
± vascular leakage & Oedema
Cough Mucus
Modified from Anderson SD & Holzer K J Allergy Clin Immunol 2000;106:419-428
Airway Injury
AHR
What conditions are required to create the stimulus of evaporative water loss?
1. High ventilation rates = eg high intensity exercise
2. Duration of the stimulus = Needs to be long enough
to dehyrate airways
3. Condition of the inspired air = dry air
4. Refractory period - When did they last exercise
1. Intensity Increase gradient & constant speed
Effect of gradient (work load) on asthma, induced by treadmill running, at a constant speed for 6 min.
Godfrey et al, J Allergy Clin Immunol; 1973
2. Duration of Exercise 6 - 8min constant speed & slope
Godfrey et al, J Allergy Clin Immunol; 1973
3. Condition of the inspired air – dry air
Anderson et al, Lancet 1979: 314; 629
Prevention of severe exercise-induced asthma with hot humid air
Measure room temperature and the humidity prior to Exercise Bronchial challenge
Haby et al, Eur Respir J, 1994, 7, 43–49
Measure laboratory temperature and humidity
Temperature = 22oC Relative Humidity = 45% Absolute water content <10mg H2O/L of air
4. Refractory Period
A refractory period occurs in 50% of subjects when tests are repeated within 2hrs.
Definition
“the time following an airway challenge during which the bronchoconstrictive response to further challenge is diminished” Rosenthal et al Am Rev Resp Dis 1990
Wear Nose-pegs during exercise challenge
R. Shturman-Ellstein, 1978 ARRD:118;1:65-73.
Anderson SD et al Respir Res 2010;11;120
NAEPP II Score 1 = symptoms < 2 times/wk 2 = > 2 times/wk less than daily, 3 = daily
Respiratory symptoms are poor predictors of the presence or severity of EIB in adults.
Exercise-Induced respiratory symptoms are poor
predictors of EIB in children.
Madhuban A et al. J Asthma 2011;3:275
This is what we do!
Measurement : FEV1 Pre Ex & 1,5,10,15,30min post
Mode of Exercise : running on treadmill increasing
speed/slope over 2 to 3 minutes
Target Ventilation: Preferably >17 times FEV1 L
Index of Intensity : HR 80-90% max (220-age) within 2min
and maintain for 6 min
Target Duration : 8 minutes
Inspired Air : Dry air
Positive Response: FEV1 % Fall ≥10% (adults)
FEV1 % Fall ≥13% (children)
Anderson SD et al Respir Res 2009;10:4
Weiler J et al Ann Allergy Asthma Immunol 2005;94:65-72
Anderson SD et al Respir Res 2010;11:120
Pre
Post BD
Other conditions masquerading as EIB
1. Inspiratory stridor (Rundell & Spiering Chest 2003;123)
2. Vocal cord dysfunction (McFadden & Zawadski Am J
Respir Crit Care 1996;153)
3. Exercise induced Laryngeal obstruction (Maat et
al 2011)
4. Tracheobronchomalacia (Moore et al, 2012)
– 93% Negative to mannitol challenge
Eucapnic Voluntary Hyperventilation (EVH)
Why EVH?
Stimulus for EIB is water loss by evaporation. To cause water loss in the airways by evaporation do not need to exercise Just need to “run the lungs” using dry air
Not all patients can: Exercise on a treadmill or bike Maintain exercise intensity Maintain the required ventilation
Equipment
•Special Gas
mixture
4.9-5.0% CO2,
21% O2, balance
N2
•Demand valve or
resuscitator
•BOC
•Two-way valve
Hans Rudolph
2700
•
• Large
Meteorological
balloon 300 gm
•Rotameter
50- 250 or more
L/min
•Tubing at least 3
cm diameter
Equipment
(con’t)
Universal
Ventilation
meter by
Vacumed
Metal tap
Morgan
# PKM
9075010500
Spirometer
Photo Courtesy of Dr SD Anderson
A standard protocol
Inhalation of gas at room temperature
Target Ventilation
i. Athletes & defence force recruits
FEV1 x 30 (75-80% MVV)
ii. Others & known asthmatics
FEV1 x 21 (60% MVV)
• Ventilation time = 6min
• FEV1 post challenge: 1,3,5,10 &15min
• Positive test ≥ 10% decrease in FEV1 Porsberg & Brannan: 2010; Breathe
Multistage protocol
Achieve a dose-response curve – for safety
Progressive – Target Ventilation (MVV = FEV1x35)
30% MVV - 3min
60% MVV - 3min
90% MVV - 3min
Measure FEV1 at 1, 2, 5 & 7min
Positive test ≥ 10% decrease in FEV1
Anderson & Brannan Clin Rev Allergy & Immunology 2003
EVH Beware
1. Potential Refractoriness within the challenge FEV1x 30 (75-80% MVV)
Ventilation time = 2min + 2min + 2min
Result
6 min uninterrupted EVH had greater obstruction than interrupted challenge of 2min repeated 3 times
(Argyros et al 1995)
Recommendation: ..EVH should not be incrementally dosed but should be given as a single challenge….-(Argyros et al 1995)
2. A very potent challenge
In some subjects large falls in FEV1 can occur
Standardisation of indirect
challenge tests to identify EIB
• 1989 Standardisation of hypertonic
nebulised aerosols (Smith & Anderson 1989. J Allergy Clin Immunol)
(Sterk et al,1993 ERJ 6: 53-83)
• 1997 Standardisation of Mannitol
aerosol challenge (Anderson SD et al 1997. AJRCCM)
BHR to Hypotonic & Hypertonic saline
aerosols
Schoeffel et al, 1981: Br Med J
•Particle size = 2m to 6m
•Dose delivered by ultrasonic neb was constant, independent of airflow, time related to volume delivered
Time used for dose schedule
0.5min, 1, 2, 4, 8mins (max 15.5min)
Why use 4.5% NaCl?
• Hypotonic solutions cause excessive cough
• Increase in non-specific AHR (Mattoli et al,1986 : Smith et al, 1987)
• Rate of change of airway osmolarity is important
Concentration ↑ 3.6%(sea water) to 4.5% = faster test
• Positive response 15% fall from baseline FEV1 is
specific for asthma
• Progressive challenge = Dose-response = safe
Generation Number
024681012141618
Cumulative Volume (ml)
0.1
1
10
The potential to change the ion concentration and osmolarity of the
airway surface liquid is possible because the volume of fluid in the
first 10 generations of airways is normally < 1ml.
Anderson SD Chp 29 page 507 In: ASTHMA Eds: Barnes PJ et al 1st Edition 1988
The challenge is used for;
SCUBA diving
assessments,
It has relevance for divers..
…BUT
Problems with a wet aerosol
• Exhaled aerosols into room
- eg issues with infection
• Hygienic issues
- eg saliva
• Cumbersome equipment
- eg scales, tubing
• Particle size change over life of the Ultrasonic Neb
Mannitol inhalation test
Photo Courtesy of Pharmaxis
Why Mannitol
Dry Powder Aerosol? • Naturally occurring, safe
• Commonly used as an excipient
• Not significantly absorbed by the GI tract
• Stimulate release from human lung mast cells
• Portable and easily administered test
• Acquire a Dose-response curve = safe
• Has Therapeutic Goods Administration approval
HOWEVER
• Inhaled osmotic aerosol test result can be false negative
if time taken to inhale doses is too long
• Cough – highlights importance of “0mg capsule”
Anderson 2016; Eur Clin Respir J
Grading Responses to Inhaled Mannitol
1 10 100
% F
all F
EV1
0
5
10
15
20
25 Severe 35 mg
Moderate 155mg
Mild > 155 mg
Normal
Cumulative dose of mannitol (mg)
635
Anderson & Brannan Clin Rev All Immunol 2003; 24: 27-54
Airway Sensitivity PD15 FEV1
Provoking Dose causing a 15%
fall from baseline FEV1
Gregory’s Mannitol Challenge
19% Mild
Why we do what we do
Methods for testing airway hyperresponsiveness in the lab have come from an understanding of the stimulus and potential mechanisms causing AHR. Tests are now • Safer • Less complex • Less expensive • Practical to use routinely • Recommended in guidelines to use in clinical practice.
Anderson 2016: European Clinical Respiratory Journal 3:31096
Take Home Message