LUNG MECHANICS

PET IMAGING

Correlation of Lung Mechanics and Ventilation with Positron Emission Tomography During BronchoconstrictionN.T. Tgavalekos1, R.S. Harris2, M. F. Vidal Melo2, G. Musch2, J. D. Layfield2, K.R. Lutchen1 and J. G. Venegas2

1Department of Biomedical Engineering, Boston University, Boston, MA2Dept. of Anesthesia and Medicine, Massachusetts General Hospital, Boston, MA

SUMMARY

END WASHOUT PET IMAGE: TRACER RETENTION

BASELINE POST CHALLENGE

Figure 2: The PET imaging technique for human subjects requires a bolus of 13NN labeled saline solution to be injected intravenously. The 13NN is forced into the saline solution and injected into the patient during a short apnea using a “salsa generator”. Because of the low solubility of 13NN in blood and tissues, upon reaching he pulmonary capillaries, the gas diffuses out of the blood and into the alveolar gas. After a period of imaging, the subject is asked to resume breathing and the rate of local tracer wash out corresponds to regional ventilation. In units distal to closed airways 13NN is retained during the washout period

Figure 1: The mean level and frequency dependence of lung resistance(RL) and elastance (EL) are amplified in asthmatics after methacholine (MCh) challenge. Differences in low and high frequencies for both RL and EL are indicative of heterogeneities in the airway disease. Increases in low frequency EL may also be indicative of airway closure.

Figure 3: PET scan images taken at the end of the washout period. PET scans are shown for one mild-moderate asthmatics at baseline (left) and after a methacholine challenge (right). Each set of images contain 15 slices of the lung, the top left is the apex of the lung and the bottom right the base of the lung. Regions of gas trapping correspond to red colors. At baseline, much of the lung has very little tracer remaining at the end of the washout period. After methacholine challenge, a significant portion of the lung in both asthmatics display large amounts of tracer retention, indicating those alveoli that lay behind close or highly constricted airways

Figure 4: Corresponding baseline and post challenge RL and EL. Post challenge mechanics reveal increased levels and frequency dependence in RL and EL. In particular, ELow is elevated because some of the airways are allowed to close, causing less of the lung to be probed mechanically. Also increases in RLow-RHigh post challenge, reflect a highly heterogeneous airway constriction pattern.

QUANTIFYING VENTILATION HETEROGENEITY

Figure 5: The rate at which tracer washes out of the entire imaged lung can be fit be with a double exponential decay model for both baseline and post challenge curves. From this model we can define a relationship comparing the differences between the two compartments before and after challenge

Tracer kinetics of the entire imaged lung during the washout period may be fit with a two compartment exponential decay model :

fvslow,fast: fraction of blood flow to the lung region associated with each compartmentsVslow,fast: specific ventilation(1/slow,fast)

Figure 6: Correlations of frequency dependence of RL (Rlow-High) (left) and EL(Ehigh-low )(right) with ventilation heterogeneity (HI). Results indicate that increases in mechanical heterogeneity and heterogeneity in ventilation are related (r=.82,.87).

By measuring pressure across the lung and flow at the airway opening, total lung impedance can be defined as:

Z jP j

Q jLtp

( )( )

( )

where = 2f, f = forcing frequency, and one can calculate total lung resistance (RL) and elastance (EL) as:

Tracer Activity= fvf*e (-t/f)+ fvs*e (-t/

s)

PROTOCOLIn 14 mild-moderate asthmatics:I. Measure frequency dependence of RL and EL before and after MCh challengeII. Collect PET images to quantify tracer retention before and after MCh challenge

- All measurements performed in the supine position- MCh dose equal to upright PC20 dose.

Heterogeneity Index (HI) fvi(sVi-sV)2

Increases in HI will correspond to increased differences between sVfast and sVslow

•Ventilation heterogeneity of whole lung washout may be quantified with a Heterogeneity Index

Frequency(Hz)

0 2 4 6 8

Res

ista

nce(

cmH

20/l/

s)

0

10

20

30

40

50

Frequency(Hz)

0 2 4 6 8

Ela

stan

ce(c

mH

20/l)

0

150

300

450

600

POST CHALLENGE

BASELINE

Frequency(Hz)

0 10 20 30 40

Ehi

gh-lo

w(c

mH

20/l)

0

80

160

240

320

400

480 R=.87

HI HI

0 10 20 30 40

RLo

w-H

igh(

cmH

20/l/

s)

-10

0

10

20

30

40 R=.82

QUANTIFYING AIRWAY CLOSURE

Figure 7: Increases in low frequency EL are related to increases in retention fraction(RF), the amount of gas trapped at the end of washout, after methacholine challenge. These results imply that low frequency EL measurements are sensitive to the fraction of alveoli that are not communicating with the airway opening.

To use Positron Emission Tomographic (PET) imaging techniques, to quantify regions of gas trapping and correlate ventilation heterogeneity, with measurements of lung mechanics sensitive to mechanical heterogeneity

GOAL

LUNG MECHANICS

The primary dysfunction in asthma is that the airways are hyperreactive which causes extreme constriction throughout the airway tree. Recent studies suggest that a crucial clinical phenotype of asthma is heterogeneity in the pattern of constriction which amplifies degradation in mechanics throughout the lung by creating functional airway closures and severe hypo-ventilation in some regions of the lung. To date, no one has confirmed whether hypoventilation associated with heterogeneous airway constriction correlates with alterations in lung mechanics.

MOTIVATION

Tra

cer

Act

ivity

R ZL L R e E f ZL L 2 Im

QUANTIFYING VENTILATION HETEROGENEITY

•PET imaging confirms that during airway constriction there is a significant increase in the number of regions where hypoventilation occurs. The images suggest hypoventilation occurs in large contiguous regions and heterogeneously through the lung.

•Qualitative mechanical measures sensitive to heterogeneity, increase significantly with physical evidence of ventilation heterogeneity (Figures 3 and 4).

•Frequency dependence of RL and EL are related to changes with ventilation heterogeneity (Figure 6). Likewise, increases in low frequency elastance, which are indicative of airway closure, are related to the amount of tracer retained in the lung after bronchoconstriction (Figure 7).

•We conclude that acute heterogeneity of constriction is a crucial phenotype of asthma. The heterogeneity leads to functional changes in the lung consequent to hypoventilation associated with closed or nearly closed airways

Tracer Activity apnea

Tracer Activity end washout

RF =

(See Figure 2)

sV

Frequency(Hz)

0 2 4 6 8

Ela

stan

ce(c

mH

20/l)

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0.0 0.5 1.00

15

30

HETEROGENITY

0 2 4 6 8

Res

ista

nce(

cmH

20/l/

s)

4

8

12

16

20

24

28

HETEROGENITY

AIRWAY CLOSURE AND HETEROGENITY

BASELINE

POST CHALLENGE

Frequency(Hz)

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Mea

n T

race

r A

ctiv

ity (

Ci/m

l)

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BASELINE

TRACERRETENTION

POST CHALLENGE

TRACER WASHOUT

APNEA

Time (s)50 100 150 200

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TRACER WASHOUT:sV = fvf*sVf + fvs*sVs

sVfast

Time (s)

sVslow

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ean

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cer

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ivity

(C

i/ml)

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BASELINE

TRACERRETENTION

POST CHALLENGE

TRACER WASHOUT

APNEA

Time (s)