REVIEW 
Annals of Nuclear Medicine Vol.11, No.2, 67-73, 1997 
Topics in Pulmonary Nuclear Medicine 
Kenji KAWAKAMI 
Department of Rediology, The Jikei University School of Medicine 
Key words: pulmonary ventilation, pulmonary perfusion, nuclear pulmonology, mucocilliary measurement, epithelial permeability 
INTRODUCTION 
REVIEWING THE PUBLICATIONS of past few years on nuclear pulmonology, we notice that many of them are about lung tumors and pulmonary circulation abnormality, followed by COPD and infectious diseases (Fig. 1). Ventilation-perfusion studies are predominant as to methods as shown in Fig. 2. An increase in PET studies has also been noticed over the past few years. Considering the global trend of these publications, this article reviews ventilation-perfusion scintigraphy and the evaluation of mucocilliary movement, lung epithelial permeability and the distribution of therapeutic agents inhaled by means of aerosols. 
VENTILATION AND PERFUSION 
The most recent topic in 133Xe studies is dynamic SPECT with the three head camera. Figure 31 shows a case of emphysema. The delay in the washout of 133Xe gas in the peripheral area is clearly seen. A better resolution of the abnormalities, whether they are central or peripheral, has become possible with SPECT, and it can be useful for the early detection of ventilatory disturbances and the diagnosis of diseases. 
Other useful aspects of xenon studies include follow-up of the therapy and deciding on the withdrawal time for the drug. Abnormalities cannot be detected in pulmonary function tests, since the lesion is focal, especially in infectious diseases or chronic bronchitis. Even after the X-ray and CT have shown normal results, focal abnormalities remain in the xenon tests. Consequently, we believe that the treatment should be continued as long as abnormalities remain in the xenon tests, particularly in cases of diffuse panbronchiolitis. 
81mKr gas is also available for use in routine clinical examinations. The characteristics of 81mKr are indicated in Table 1. It is possible to quantitatively evaluate changes in the ventilatory volume by maintaining a constant 81mKr-gas concentration during continuous inhalation. It is also possible to obtain various items of physiological information, especially related to respiratory impedance and compliance, by having the subject inhale a small amount of gas as a bolus. Thirdly, this makes various challenge tests possible. 
We keep the 81mKr gas concentration constant by attaching a fan to the mouthpiece during continuous inhalation. By this method, a linear relationship is obtained between the 81mKr concentration and the ventilatory volume. Figure 42 shows regional changes in ventilation after MDI (metered dose inhaler) therapy in a patient with asthma, and there are the sites where ventilation was improved by MDI inhalation therapy, and those where it had deteriorated. These deterioration sites explain the temporary decrease in PaO2 in blood gas following MDI inhalation. 
Next, the results of a bolus inhalation of 81mKr in an asthmatic patient are shown in Fig. 5 (a).2 When the bolus gas was inhaled quickly, a defect appeared in the right lung, as shown by the arrow, but when it was slowly inhaled, it disappeared. This is because, as shown in the lower schema, a turbulent flow occurs in the stenosis of the central airway when the inhalation speed has been increased. This occurs due to the impedance changes caused by the turbulent flow, and it occurs in the stenosis of the central airway. Figure 5(b) shows the inhalation ratio of the 13N2 gas detected by PET and the ratio of respiratory impedance in the left and right lungs, when stenosis occurs at 0%, 50% and 70%, found by inflating a balloon catheter inserted into the left main bronchus. And when the gas was inhaled slowly ( I Hz), the left to right (L/R) ratio was 1.0, but when it was inhaled quickly (10 Hz), the L/R ratio for inhaled 13N2 gas decreased whereas that of the respiratory impedance increased, as the stenosis becomes noticeable.3 This experimental study supports our clinical results. In the obstruction of the peripheral airway, the defect gets bigger with slow inhalation. 
We next observe the compliance by changing the gas inhalation lung volume. Figure 62 indicates an asthma patient. When the gas is inhaled from the functional residual capacity (FRC) level, it does not enter the left lung, but when the lung volume is increased to tidal volume (TV) and total lung capacity (TLC), the gas is inhaled in both sides of the lung. This is due to the decrease in compliance in the left lung. The penetration of the drug in the left lung can be obtained by increasing the lung volume at inhalation, and this is useful in evaluating the distribution of the pharmaceuticals in the inhalation therapy method. 
The usefulness of technegas studies is highly enhanced with SPECT imaging. In recent years, pertechnegas with low radiation has been produced by using the technegas generator, and it is used in ventilatory studies. Since this tracer is cleared from the alveolar wall, it is also used to evaluate lung epithelial permeability. Information related to the hemodynamics of the lung, obtained by nuclear medicine, is listed in Table 2. Pulmonary embolism is a most useful indication of perfusion scintigraphy. Several diagnosis criteria (PIOPED, Biello, & Mc Neil) are used. On ROC curve analysis of these three criteria, the accuracy of the criteria of Biello was highest. In addition to these criteria, some other signs that can be useful, such as the peripheral stripe sign, the enhanced V/Q mismatch sign, and the segmental contour pattern, should be considered. 
The stripe sign consisted of the presence, on the perfusion images, of a stripe of perfused lung tissue between a perfusion defect and the adjacent pleural surface.4 The presence of the stripe sign accurately predicted the absence of pulmonary embolism. 
The enhanced V/Q mismatch is a regional area of increased ventilation radioactivity in the embolized region of the lung that is more than the normal ventilation radioactivity in the adjacent or contralateral normally perfused lung.5 The stripe sign contour pattern is a finding of V/Q mismatch, which demonstrates bilateral, patchy, non-segmental defects. This finding is seen in pulmonary veno-occlusive disease, primary pulmonary hypertension and microthromboembolic disease.6 
The evaluation obtained by combining these findings leads to a decrease in cases belonging to low probability of the PIOPED criteria, and this is useful for the improvement of specificity. 
MUCOCILLIARY MEASUREMENT 
1) Probe for the Inhalation Therapy 
The accurate evaluation of the distribution of the inhaled drugs is a decisive factor for the therapy effect. The distribution of inhaled particles, the particle size, the inhalation speed, the lung volume level for inhalation and the application of a spacer are considered to be other influential factors. Figure 77 shows the distribution of the methacholine labeled with 99mTc, and it shows the different patterns of aerosol distribution in its changed particle size. Aerosol with a particle size of 9 ,t is used in the upper figure and most of it is deposited in the central airways. On the other hand, aerosol with a particle size of 1u is used in the lower figure, and it is evenly distributed in the lung field. 
What effect the deposit pattern of these two cases has on pulmonary function is indicated in Fig. 8. The left side of the figure shows the changes in the conductance (sGaw) as an index of the response in the large airways. The conductance had significantly decreased with the 9/u aerosol five minutes later, suggesting stenosis in the central airways. On the other hand, the right side indicates the unevenness of perfusion (Log SDQ), as an index of changes in the peripheral airways. Both of them had changed in the same way. Perfusion changes occurred slowly, compared to the conductance, because the tracer, which had been deposited in the central airways, was absorbed from the bronchial mucosa and had moved to the capillaries of the peripheral airways. This suggests the necessity of choosing the aerosol size in asthma therapy, according to whether the asthma are of the central airway obstruction type or of the peripheral type.8 
Various types of spacers are used to avoid the influence of lung volume at inhalation. Figure 9^9 shows the distribution of the inhaled Salbutamol labeled with Tc, and since it has been inhaled by using a spacer, it is evenly distributed within the lung, but the deposition rate within the lung is low, about 2% of the inhaled volume, and more than 90% was left within the spacer. It is therefore necessary to perform deep breathing in this case. This result suggests that the drug should be inhaled from a higher lung volume level in this case. 
The distribution of inhaled drug is influenced by the lung volume level from which the drug is inhaled. Inhalation from the FRC level does not result in penetration of the drug in the left lung as shown in Fig. 6, but the gas is evenly inhaled in the (FRC + TV) whole lung, when it is inhaled from the higher level, as shown in the middle and right (TLC) images. 
Steroid inhalation therapy has been used in asthma for the treatment of inflammatory processes. Figure 1010 indicates 18FDG PET after injecting Allergen in the left upper lung field in a patient' with asthma. 18 FDG, which results in glycolysis in the inflammatory cells, is clearly accumulated in the area of allergic reaction. This suggests the suitability of the steroid therapy. 
2) The Mucocilliary Movement 
The evaluation of mucocilliary movement, as indicated on Table 3,11 is used for the evaluation of non-respiratory function, for the effects of pharmacological agents, for physical therapy and so on. The method includes the follow up of MAA droplets deposited under bronchoscopy on the trachea, the cinescintigraphy which evaluates the dynamic trace of the movement of the aerosols which have been deposited in the large bronchi with aerosol inhalation, and the methods for measuring the velocity of the aerosols deposited in the lung fields. Each of these methods has advantages. 
Figure 11 indicates the changes in the mucocilliary velocity before and after therapy in a patient with asthma. The ordinate shows the distance that covered and the abscissa indicates the time. The mucocilliary velocity is clearly improved after therapy. We have evaluated the regional mucocilliary velocity in diffuse pan-bronchiolitis (DPB). The velocity decreases in the lower lung field in DPB . 
3) Epithelial Permeability 
Lung epithelial permeability is the only in vivo method used in studying the damage to alveolar-capillary integrity. Measurements of lung epithelial permeability are listed in Table 4. It is accelerated with various pathophysiological conditions. The left side of Fig. 12 shows the changes in capillary wedge pressure in the cases in which IL-2 therapy was performed for metastatic cancer. The wedge pressure increases gradually following the administration of IL-2, and it decreases with the withdrawal of the drug after 5 days of administration. 
The right side of the Fig. 12 shows the DTPA clearance. The clearance is accelerated by the IL-2 administration, while it is improved with the cessation of the agent. It is therefore useful to detect the side effects of the drug on alveolar-capillary integrity in an early stage and to evaluate the therapeutic results for various interstitial pulmonary diseases,12 
Compared with the results of BAL, there is a significant correlation between the lymphocytes and the DTPA clearance, while there is no correlation with the neutrophils, which correlate with 67Ga uptake. 
Recently, pertechnegas has also been used instead of DTPA. Figure 1 3 shows the clearance of DTPA and that of pertechnegas in pulmonary embolism. The clearance of DTPA in the middle column and that of pertechnegas in the lower column are both accelerated in the defect in the right upper lung field which is shown in the lung per-fusion scintigraphy of the upper column. The results of our study indicate that the clearance of pertechnegas is accelerated in pulmonary embolism, and a correlation with DTPA is also observed. There are some reports about the application of pertechnegas for the measurement of epithelial permeability in interstitial lung diseases. Be-cause pertechnegas particles are smaller than those of DTPA, it penetrates into the alveoli, even in COPD. The setting of ROI in the lung fields is therefore easily and accurately, done without the effect of hot spots. We think that pertechnegas is a radioactive tracer which should be studied further. 
I have reported here on the ventilation-perfusion scintigraphy, the mucocilliary movement, and the evaluation of the lung epithelial permeability, including some recent topics. 
CONCLUSION 
Recent advances in nuclear pulmonology involve the evaluation of non-respiratory function by radionuclide medicine and tumor imaging in the lungs, but ventilation-perfusion studies are ever more important now that CT and MR are being widely used. 
In this article, recent trends in ventilation-perfusion scintigraphy were reviewed, and the clinical importance of the measurement of mucocilliary movement and epithelial permeability have been stressed for the management of chronic obstructive lung diseases. 
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