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

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