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n recent studies, the measurement of the lung clean
ance of aerosolized technetium-99m diethylene
tniaminepentaacetic acid ([99mTc]DTPA) has been used to assess the alveolobronchiolar permeability in
both smoking and nonsmoking normal subjects and in
patients (1-5). Technetium-99m DTPA is a small hy
drophilic molecule (molecular weight 492 daltons) rap
idly cleared by the lungs and, supposedly, crossing the alveolar capillary barrier through interepithelial junc tions (6). However, little is known about the variations
of this clearance with regards to pharmacologic or
physiologic conditions which lead to changes of the distribution, perfusion, or ventilation within the lung
(7). Exercise is known to induce drastic changes of
regional ventilation and perfusion of the lung which have been thoroughly studied (8, 9). Therefore, we studied the effect of a mild exercise performed in seated posture on the regional lung clearance of [99mTc]DTPA
in order to better understand the mechanism involved in
the transport of this molecule.
Received Dec. 5, 1984; revision accepted Oct. 15, 1985. For reprints contact: Michel Meignan, MD, Départementde Me decine NuclCaire et de Biophysique, Centre Hospitalo-Universitaire Henri-Mondor, 51, avenue du MarCchal de Lattre de Tassigny Crc teil 94000, France.
- This work was presented at the 32nd Annual Meeting of The Society of Nuclear Medicine.
MATERIALS AND METHODS
Experimental Group
Seven healthy nonsmoking volunteers, three men and four women, age ranging from 25 to 36 yr. were selected for the experimental procedure. An aerosol ofdroplets was generated from a 30 mCi (1.1 1 X lO9Bq) [99mTc]DTPA solution in 10 ml 9% sodium chloride using a glass nebulizer under 1.5 bar pressure and at a flow rate of 25.1 mint. The droplets were then dried by flowing through a fenestrated pipe surrounded by silicagel. The air stream containing the dry residue contin uously flowed through a broad-bore tube where the subject inhaled this dry aerosol through the inspiratory valve ofa face mask. The radioactivity from the tube and from the expira tory line was removed by means ofa low-resistance filter. The characteristics of the dry particles were measured with an electrical mobility analyzert as described (10). The particles had a count median diameter of 0.045 @,a geometric dcvi ation of I .7 resulting in a mass median diameter of 0.6 @. The subjects were submitted to the following procedure. They breathed the aerosol with a normal tidal volume for 5 mm. The expiratory gases were collected from the expiratory line during the inhalation. The subjects then sat on an ergo metric bicycle, their backs in front of a large field gamma cameras linked to a minicomputer1. A surgical strip placed under their shoulders prevented the subjects from moving. The lung field radioactivity data were framed at I mm inter vals during a resting and an exercising period; resting period
274 Meignan,Rosso,Leveauetal The Journal of Nuclear Medicine
Exercise Increases the Lung Clearance
of Inhaled Technetium-99m DTPA
Michel Meignan, Jean Rosso, Jean Leveau, AndréKatz, Luc Cinotti, Guy Madelaine,
and Pierre Galle
Dêpartement de MédecineNuc/êaire et de Biophysique, Centre Hospitalo-Universitaire Henri -Mondor, Creteil; and Laboratoire de Physique et de Mêtro/ogie des aerosols, Institut de Protection et de Suireté Nucléaire,Cen, Fontenay Aux Roses France
The regional lung clearance of a depOSited aerosol of [99@Tc]diethylenetriaminepentaacetic acid
was successively computed at rest and at exercise in seven nonsmoking volunteers in upright
posture. The subjects were seated on a bicycle with their backs against a gamma camera. At rest
there was a gradient of clearance from the apex to the base of the lung, the apical clearance
being significantlyhigher. At exercise this regional gradient was enhanced by a large and
significant increase of the apical clearances (3.40 ±0.63% min1 s.d. compared with 1.82 ±
0.75% min1 s.d. at rest, n = 7, p <0.01). By contrastthe changesof the basal clearances
were slight and unsignificant (1.46 ±0.71 % min1 s.d. compared with 1.40 ±0.82% min
s.d.). This increase of the apical lung clearance could be attributed primarilyto the increase of
apical blood flow induced by exercise and to the subsequent increase of the permeability surface
area product.
J NuclMed27:274—280, 1986
lasted 20 mm. As the twentieth frame was achieved, the exercise period started. Exercise was sustained for the next 7 mm at 50 W with a pedal speed of 60-70 cycles min@. The subjects had previously kept their shoulders carefully against the camera during pedaling for another experimental proce dure. The respiratory and heart rate were recorded immedi ately prior to and at the completion of exercise. One region of interest (ROl) was selected over each lung, on the first image of the resting phase, and subsequently divided at the level of the hilum by a horizontal line resulting in two other ROIs corresponding to upper and lower lung fields (later referred to as apex and base). These ROIs were applied to all the framed data of each study. Radioactivity was corrected for radionuclide decay and the data were sub mitted to a monoexponential regression analysis. An expo nential line of best fit was calculated for each ROI. The negative slope of this regression line was designated as the clearance rate “k―and was expressed in terms of percentage decrease of the radioactivity per mm (% min'). The clear ance rates of the right and left total lung fields, apices, and bases were computed on the data obtained during the 20-mm resting period. In order to make an adequate comparison with the data obtained during the 7-mm exercising period, the clearance rates were also computed on the first 7 mm of the resting period. However, to compute the clearance rates of apices and bases on these 7-mm intervals, the count rates from both apices or both bases were added for statistical reasons. Using this process, at the beginning of the resting period the initial count rate over the apical ROIs averaged 14,143 ± 6,567 per mm. The regression lines obtained corresponded closely at rest and at exercise to the data point: The correla tion coefficients (r) were always > 0.95 for the 20-mm clear ances and always >0.90 for the 7-mm clearances. No correc tion was done for radioactivity contained in pulmonary blood pool, or chest wall.
To check the possibilitythat the DTPA clearance during
the exercise could be influenced by the mucociliary transport, two roughly rectangular ROl chosen to represent 10%of the area of each lung image and centered around the hilus were drawn. The integrated count rates did not increase in these
ROIs betweenthe first and the seventhminuteofthe exercis
ing period. In contrast, a slight decrease was observed in both regions ( I,525 ±650 cpm compared with 1,380 ±820 for the right lung, n 7, N.S., 1,344 ±748 cpm compared with 880 ± 455 cpm for the left lung, n = 7, p <0.02). To assess the influence of the extrapulmonary thoracic background (stomach, renal, hepatosplenic activity) on the measurements of lower lung field activity, the count rate value in a rectangular ROI drawn between the lung bases and the kidneys was computed. This value did not change signifi cantly with time (768 ±41 2 cpm in the first minute compared with 965 ±552 cpm in the twenty-seventh mm). The mean count per pixel averaged 16.8 ±2.4% of the mean count pixel obtained in the basal ROI of the lung.
ControlStudies
In three subjects (1, 5, 7) the regional ventilation per unit volume was measured at rest and after 7 mm of exercise at
SOW using the washout curves of inhaled krypton-8Im
(slmKr) For each experimental condition, minute ventilation was measured with a classic spirometer and a posterior view
of 300,000 counts was recorded during steady state inhalation ofthe gas delivered through a face mask. Inhalation was then discontinued by removal of the mask. One-second frames were recorded during the washout phase. Radioactivity curves were obtained from the apices and the bases of the lungs. A line was fitted to the initial uncorrected exponential section of the washout curve to give the clearance (including both physical decay and biological clearance). Ventilation per unit alveolar volume (V/V) was then calculated by substract ing the decay constant of stmKr (3.2 min@) as previously described (1 1). The apicobasal ratios of ventilation per unit volume were expressed at rest and at exercise. In order to test the influence of the duration of the acquisi tion on the [99mTc]DTpA clearance values, a control study was performed in five other nonsmoking subjects ranging in age from 27 to 40 yr. After the inhalation, the lung radioactiv ity was followed during 27 mm, at rest. The clearance rates were computed as previously described during the first 7 mm and between the twentieth to the twenty-seventh minutes of the study.
Statistical Methods
Comparisons among the clearances ofthe total lung field at rest and at exercise were performed using a two-factor analy sis of variance within each group. Comparisons among the clearances of apices and bases at rest and at exercise were performed between the experimental and the control group using a three-factor variance analysis with repeated measure ments (12) followed by a two-factor analysis. Student's paired t-test was used for other comparisons. Values were expressed as the mean ±s.d., p value 0.05 was accepted as indicating statistic significance.
RESULTS
Rest
In the sevensubjectsthe mean tidal volumeduring inhala
tion was 460 ml ±259 and the deposition of the aerosol was homogeneous (Fig. I ). Their mean respiratory rate before @ exercise was 12.7 ±3 min. Their mean heart rate was 94 ± 10 min@ which can be explained by some initial anxiety before starting to pedal (Table I). The clearance rates of their total lung field measured at rest were not significantly differ ent whether computed in the first 7 mm (Table 2) or during the 20 mm ofthe resting period: 1.56 ±1.1 1% min@ for the right lung and 1.46 ±0.55% min@ for the left lung com pared with 1.45 ±0.87% min@ and 1.23 ±0.58% min1, respectively. The clearance rates computed during the entire resting period in each apex and base showed that the apical clear ances were significantly higher than the basal clearances I. ±0.95% mint compared with I .30 ±0.76% min@ (p <0.05, n 7) for the right lung and I .59 ±0.58% min@ compared with 1.1 I ±0.55% min1 (p <0.02, n 7) for the left lung (Fig. 2). No difference was found between the right and left lung by the variance analysis. At rest, the apical V/V computed with 8ImKr was lower than the basal V/V (0.7 ±0.2 min@ compared with 1.26 ± 0.2 min'). The distribution of V/V between the apex and basewas I: 1.6.
Volume 27 •Number 2 •February 1986 275
rateSubject Heart rate Respiratory (min1)no. Age (min1)
II1 (yr) Sex 1 lIt I
262 36 M 80 120 14
143 32 M 88 91 9
444 29 F 90 120 12
225 26 M 90 116 10
306 34 F 94 118 13
407 25 F 108 156 18
26Mean±s.d. 35 F 110 120 13
29±10p* 94±10 120±19 12± <0.01* <0.
exercise.t I Rest immediately before the II =Exercise.p II.following Value obtained comparing values obtained from Iand
ispulmonary the inhalation of the aerosol (4). The extra- increased significantly at exercise. This constancy
blood(largebackground is obviously nonhomogenous easily explained since DTPA is cleared from the
blooduate.airways, stomach, kidneys) and difficult to eval- by the kidneys ten times faster than it enters the
ratecontrolNevertheless, the data reported here show that, in from the lungs (15). Since the background count
lungbetweensubjects, there was nonsystematic difference never exceeded 15% of the count rate of the lower
significantlycomputed the values computed immediately and those field and remained constant, it does not
inexperimental 20 mm after the inhalation. Moreover, in the modify the general trend of the phenomena observed
toROI, group, the count rate in a background the lungs. Therefore we decided, as have others,
(16).the reflecting the extrathoracic background under overlook it
lung bases, remained quite constant at rest and For statistical reasons, the quality of the monoexpo
2[9@Tc] TABLE
DTPAClearance Rates(k)(%
min1)Subject Basesno. Age Left lung Rightlung Apices
(yr) Sex l lIt I II I II I II
. I First 7 mm of resting period. t II = Exercise for experimental group and interval between twentieth and twenty-seventh mm of resting period for control group. t p Value obtained comparing values obtained from I and II.
TABLE 1
Heart Rates and Respiratory Rates at Rest and Exercise
Experimental136M0.781.79232M1.202.53329F1.511.81426M2.513.58534F1.761.89625F1.053.05735F1.462.18Mean
0.69Pt<0.05Control827F0.850.67940F1.681.891029F0.761.101128M0.820.751234F0.940.94Mean ±s.d.1.46 ±0.562.4 ±
0.48ptN.S. ±s.d.1.01 ±0.381.07 ±
±1.12.52 ±1.
±0.753.4 ±0.
±0.821.46 ±0.
N.S.
0.97 ±0.39 0.92 ±0.34 1.89 ±0.85 1.56 ±0.82 0.89 ±0.63 1.34 ±0.
N.S. N.S. N.S.
Volume 27 •Number 2 •February 1986 277
LEFT LUNG.^ RIGHT^ LUNG^ I^ APICES BASES
-I
I
I
I
rest exercise rest exercise
3-
E
@ I
-@ I (
1@@
I
••;-@@;@base apex base FIGURE 2
Comparison of clearance rate (k) of [99@Tc]DTPAin apex
and base of each lung.(D)Means; (J..)s.d. Meanclearance
is significantly higher in apices than in bases (p < 0.05)
I
I
I
I
I
:
FIGURE
Comparison of apical and basal clearance rates (k) of
[99@'Tc]DTPAat rest and exercise in seven subjects. (0) Means; (1.) s.d. In apIces, mean clearance rate is signifi nential fit depends on the count nate in every ROl and, cantly different at exercise from mean at rest (p < 0.01)
therefore, we added the count rate of both apices and
bases together; no significant difference occurred be
tween left and right lung. With this procedure the
correlation coefficients for the best fit monoexponential
regression analysis averaged 0.94 ±0.06.
The results obtained at exercise in this study provide
a new finding. Exercise at 50 W, in upright position,
causes a doubling of the apical clearance of the
[99mTc]DTPA with insignificant changes of the basal
clearance. This increase appeared immediately after
the onset of exercise; it is probably slightly underesti
mated since no attempt was made to correct the results
from accumulation of radioactivity in chest wall or in
pulmonary blood volume which increases in upright
exercise (1 7). These results could be explained by three
different factors: regional changes in mucociliary clear
ances, ventilation or perfusion.
The effect of mucociliary clearance on the upper
respiratory tract, which may be to increase the clear
ance of [99mTc]DTPA, can easily be excluded. This
mechanism would have resulted in an hilar accumula
tion of radioactivity which was not observed after the 7-
mm exercising period.
The effect of the hyperventilation induced by exer
cisc on the alveolar distension must also be discussed.
The regional differences of DTPA clearances through
out the lungs have, indeed, been attributed primarily to
the regional differences of the degree ofalveolar disten
sion (4). Experiments on normal subjects or animals
placed under positive end-expiratory pressure have sup
ported this explanation (18). In addition, we found as
reported by others that at rest there is an uneven distni
bution of the [99mTc]DTPA clearance in normal lungs.
The clearance is higher in the apices than in the bases in
upright posture, which can be explained in terms of
alveolar distension. In the seated subject, there is a
gravity-dependent gradient of alveolar volume. Due to
regional differences in static transpulmonary pressure,
the upper lung regions appear to be relatively more
expanded than the lower ones and consequently have a
higher clearance.
At exercise we observed some redistribution of the
ventilation towards the upper zones of the lungs. The
apical ventilation value ratio increased 50% more than
the basal one, but this lead to an homogenization of
regional ventilation volume ratios throughout the
lungs. This is in keeping with the previous reported data
from Bryan et al. (8). Thus, ifalveolar distension was a
278 Meignan,Rosso,Leveauetal (^) The Journal of Nuclear Medicine
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