Measuring
Lung Volumes and AHR
James Zangrilli MD
Topics
• Measuring lung volumes by tracer gas dilution
– Single breath
– Multiple breath
– Nitrogen washout
• Plethysmography
• Airway hyperresponsiveness
– Physiologic basis
– Measurement
SLE with DOE and orthopnea
FVC 1.22 L (pred 3.79)
Reasons to measure Lung Volumes?
• To confirm/support your clinical diagnosis of restrictive
airway disease
– Hx, physical, radiograph, low FVC with FEV1/FVC (> ~ 85%)
• Utility in obstruction?
– Gas trapping: ‘nice to know’
• To ascribe some level of severity to the restriction after
you decide the test is abnormal
– % predicted
• Monitor disease progression or response to treatment
When is lung function value is abnormal?
• Based on percent predicted values (i.e. w.i. 80-120%)
– common but deemed less rigorous
• A restrictive ventilatory defect is characterised by a
reduction TLC below the 5th percentile of the predicted
value, and a normal FEV1/VC.
ATS-ERS Interpretive Strategies, Eur Respir J 2005; 26: 948–968
http://www.spirxpert.com/expressing3.htm
Subdivisions of lung volume
Calculating lung volume by gas dilution
• Wash-in: diluting a tracer gas in a lung compartment
– Breathing helium mix via a closed circuit spirometer
• Single breath helium dilution includes a vital capacity breath hold
– Included as part of the DLCO
• Multiple breath helium dilution: rebreathing of the helium mix at FRC until
the lung and spirometer have equilibrated
– Determination of lung volume is based on
•
knowing the initial volume of gas in the spirometer
– Or VI for for single breath technique
•
the amount of helium dilution that has occurred during the test.
• Wash out: washing gas out of the lung compartment
– utilize endogenous nitrogen as “tracer”
Tracer gas
• Properties of a good tracer
– Should be relatively insoluble and biologically inert
• Does not leave the alveoli
– Not normally present in the alveolar gas
• E.g. He, CH4
Single breath helium dilution and VA
• The amount of tracer inspired = the final amount
in lung
• Vi·Fi,He = VD·Fi,He+ VA·FA,He
F
• VA = (Vi - VD) · i,He
FA,He
Estimated (2.2ml/kg IBW)
Volume of gas inspired
VI – Rapid inhalation from RV to TLC
Multi-breath helium dilution technique and TLC
• Person breathes in and out of a spirometer filled with a
mixture of helium and oxygen until the exhaled and
inhaled He concentrations reach equilibrium
• The test is stopped at the end of a normal tidal expiration
(i.e. at the FRC)
CLOSED CIRCUIT
Multi-breath helium dilution technique and TLC
• The total volume of helium initially = total volume at the
end of the test
– Vsp • FHei = FHef (Vsp + Vfrc)
Nitrogen washout technique for lung volume
determination
• Breath 100% O2 in and out through a one-way valve (open
circuit)
– collect all of the exhaled breath until the exhaled
nitrogen registers 0 (i.e. FRC washed out)
• The volume of N2 in the lung initially = volume of N2 washed
out
• 0.8 FRC = FN2 final·V2
O2
– FRC = 1.25·FN2·V2
final N2
Ni
V2
VA vs TLC
• Total Lung Capacity (TLC) is routinely measured with the
multiple-breath closed-circuit helium dilution technique.
• Single-breath helium dilution provides an estimate of
TLC, commonly referred to as alveolar volume (VA).
– VA is automatically included with measurement of DLCO
– relatively rapid and simple
• VA can underestimate the multiple-breath TLC in
patients with obstructive lung disease
– Helium may not mix thoroughly in 10 seconds
– All gas dilution techniques can underestimate volume in slowly
emptying/noncommunicating lung
VA underestimates TLC as degree of
obstruction worsens
…but its pretty close in normal
and restricted subjects where
VA + VDest ≈ TLC
Chest Punjabi et al. 1998, 114 (3): 907
Thoracic Gas Volume via plethysmography
• Volume of gas contained in the thorax whether
communicating or not
• Principle: Boyles Law P1V1=P2V2
– Closed container
Mouth pressure
FLOW
Panting against a closed shutter
• compresses and decompressed the lung
• reciprocal change in the body box pressure
corresponds to → ΔV
Box
Pressure
Transducer
P1·FRC = P2 (FRC+ ΔV)
FRC = P2 ΔV
P1-P2
Calibration syringe
Body box bonus: gives airway
resistance
• Obstruction can be assessed by
– Flow during conditions of maximal effort (spirometry)
– Airway resistance under low flow conditions
• Panting with shutter open gives airflow at the mouth (Vm)
• Occlude the airway: record pressure at the mouth ≈ alveolar
pressure
Palv
Raw = Vm
Airway hyperresponsiveness
Definition of AHR
• A condition in which the airway reacts too readily and
too much to nonspecific bronchoconstricting stimuli
– Reflective of the variable airway obstruction seen in asthma
• exercise, cold, irritant, etc (a specific stimulant would be allergen)
– Mimic in the lab with bronchial challenge
• AHR is closely associated with - but not identical to - the
diagnosis of asthma
– Common in COPD and can be seen in other diseases
Reasons to measure AHR
• Adjunct to initial asthma assessment
– Help to determine if asthma is present or not
– Special situations: Cough, occupational
• Exploratory endpoint for research
– Novel drug trials (particularly early phase clinical)
– Common in preclinical asthma studies
• Emerging: a complement to asthma control assessment
in treated patents
– Potential to guide therapy
ARH and airway structure
Circular bands of smooth muscle surround the
airway epithelium as far peripherally as the
respiratory bronchioles
Physiologic coupling of the parenchyma to
the AWSM
• Healthy lungs
– In vivo evidence that airway diameter varies in
proportion to lung volume
– Suggests that airway smooth muscle, airway wall,
and lung parenchyma are mechanically coupled
Remodeling in asthma: changes in lung volume have
diminished effect on airway diameter or ASM contractility
• Structural
remodeling
– SM hypertrophy
– Subendothelial
thickening
– Matrix alteration
– Epithelial
abnormlality
• Inflammation
Persistent and variable factors affect AHR
Remodeling
Epithelial dysfunction
Inflammatory mediators
• Mast cell
• Inflammatory cells
• Neuroendocrine cells
Busse W W Chest 2010;138:4S-10S
How structure is believed to affect AHR
Remodeling: Inflammation  injury  repair
– Subepithelial thickening
– Proteases: decreased stiffness of the elastic elements
– Smooth muscle hypertrophy
Loss of effective tethering between muscle cells and
dynamic physical environment
Adaptation of the shortened muscle to its new length in
chronic disease
– Increased ability of the shortened muscle to generate force
Measuring airway hyperresponsivness by
provocation
•
•
Persistent component primarily reflects smooth muscle function:
sensitive to agonists that act directly on SM receptors
• Relatively low dose needed
• Airway caliber important
Variable component critically depends on presence of inflammation
with attendant mediator release
– Clinical correlates: drying of the airways during exercise, cold air etc.
Assessing airway hyperresponsiveness
• Four hypothetical dose response curves for a smooth muscle agonist
• Degree of hyperresponsiveness characterized by
– Too readily: Ease of the response (sensitivity): leftward shift in PC20
– Too much: threshold typically set at ≥ 20% fall in FEV1
When is disease
present?
Sensitivity and specificity of histamine PC20: 500 randomly
selected college students, 17 with current asthma Sx
• For current symptomatic asthma as
the diagnosis and PC20≤ 8 mg/ml
– Sensitivity 100%
– Specificity 93%
– Negative predictive value 100%
– PPV only 39%
 Strength is high sensitivity: i.e.
PC20 ≥ 8 mg/ml likely to indicate
that current asthma not present
PC20 ≤ 8
Cockroft DW, JACI1992 ;89:23-30.
More general population: cut-offs for methacholine*
bronchoprovocation
• Sensitive test with high negative predictive value for asthma
– False negative ~16% - consider repeat if suspicion high
• Relatively non-specificity unknown
Am J Respir Crit Care Med Vol 161. pp 309-329, 2000
*Histamine ≈ methacholine
Direct (structure) and indirect (inflammation)
comparisons
•
•
Direct challenge: (arbitrary) cut points define a highly sensitive, less
specific test
– Useful to r/o asthma
Indirect challenge: studies support high specificity for asthma but low
sensitivity relative to methacholine
– Useful to confirm asthma
Cockroft DW, Chest 2010;138;18S-24S
Indirect bronchoprovocation using dry powder
mannitol inhalation (initial trial)
• Mannitol induced bronchoconstriction correlated well
with hypertonic saline (n=43) and MeCh (n=25)
challenge in asthma patients
• Well tolerated
• Spontaneous recovery of FEV1 wi 60
minute (10 with SABA)
 Major advantages:
• greater specificity for detecting disease
driven by inflammation
• ease of use
Anderson SD, AM J RESPIR CRIT CARE MED 1997;156:758–765
Mannitol believed to increased airway surface osmolarity
leading to the release of inflammatory mediators from
inflammatory cells and sensory nerves
• Mannitol induced bronchoconstriction was inhibited by nedocromil
– Similar to other drying (e.g. exercise) and osmotic challenge (e.g
hypertonic saline)
Brannan JD, Am J Respir Crit Care Med
2000, 161: 2096–2099,
Mannitol AHR as a potential marker of asthma control
Tracks with ICS usage
Distinguished
ICS step-down
failures
Correlates well with EIB
Leuppi JD Am J Respir Crit Care Med Vol 163. pp
406–412, 2001
Brannan JD Am J Respir Crit Care Med
1998;158:1120–1126
Brannan JD Respirology (2002) 7, 37–44
Aridol Bronchial Challenge Test
• Indicated for the assessment of bronchial hyperresponsiveness in
patients 6 years of age or older who do not have clinically apparent
asthma
• A positive response is achieved when the patient experiences a
15% reduction in FEV1 from (0 mg) baseline (or a 10% incremental
reduction in FEV1 between consecutive doses). The test result is
expressed as a PD15.