State of the Art The Use of Radioisotope Techniques for the Evaluation of Patients with Pulmonary Disease! HENRY N. WAGNER, JR.
Contents
Introduction Cardiopulmonary Nuclear Medicine Nuclear Instrumentation Measurement of Regional Lung Function Pulmonary Embolism How Perfusion Lung Scans Are Interpreted Parenchymal Lung Disease Radioactive Tracers in Preoperative Assessment of Regional Lung Function Early Detection of Obstructive Lung Disease Pulmonary Venous Hypertension Cor Pulmonale Differential Diagnosis of Cyanosis Inhalation of Aerosols Summary Introduction
Radioactive tracer studies of the lung began in 1955 when Knipping and associates (l) first used xenon-133 as a possible aid in the early diagnosis of carcinoma of the lung. They were not successful, but their work is of historic interest. Subsequently, West and co-workers (2) at Hammersmith Hospital in London began to use cyclotron-produced radioactive gases, including oxygen-15 and radioactive carbon dioxide in physiologic studies of the lungs. These studies 1 From the Divisions of Nuclear Medicine and Radiation Health, The Johns Hopkins Medical Institutions, Baltimore, Md. 21205.
provided important information about the effects of gravity and other factors on the distribution of ventilation and perfusion and documented the regional character of involvement in many patients with obstructive lung disease. It was not until 1963, however, that a radioactive tracer procedure began to achieve widespread clinical usefulness in studies of the lungs (3). Cassen and associates (4) invented the rectilinear scanner in 1951, and shortly thereafter this device began to be used in hospitals throughout the world in the diagnosis of thyroid and brain disorders, setting the stage for its use in the study of the distribution of pulmonary arterial blood flow. The impetus to the development of lung scanning was the emphasis in the 1960s on the emergency surgical treatment of acute massive pulmonary embolism. Lung scanning and pulmonary arteriography developed hand in hand in the late 1960s and were given momentum by the Urokinase Pulmonary Embolism Trial (5), which increased our understanding of the role of these procedures and the natural history of pulmonary embolic disease. Today, lung scanning is widely used in medical practice, and research studies of the use of radioactive tracers in diseases of the heart as well as the lungs are proceeding at a rapid pace. It is beyond the scope of this article to describe the use of radioactive tracers in cardiovascular disease in detail (6-10), but the advances being made in nuclear medicine procedures in coronary and valvular heart disease are being extended to the diagnosis of cor pulmonale (11). In cardiovascular nuclear medicine, the distinction between the pulmonary and the cardio-
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 113, 1976
203
204
HENRY N. WAGNER. JR.
vascular systems is becoming less emphasized and it is useful to consider them together. Cardiopulmonary Nuclear Medicine
A half century ago, Blumgart and Weiss (11) conceived the idea that radioactive tracers would be useful for the study of the circulation. They measured the velocity of the circulation by injecting solutions of radium salts intravenously and monitoring the time of arrival of the tracer at the opposite antecubital fossa in a group of normal persons and patients with cardiac diseases. The instrument they used was a cloud chamber, one of the earliest radiation detection devices. Their concepts became a reality with the advent of safe, efficient radioactive tracers, the invention of sensitive detection instruments, and application of modern data processing. The latter has made possible the achievement of a quantitative capability not previously present. Although still in the process of evolution, such quantitative studies are rapidly achieving widespread use in the study of the heart and lungs. As Pierson and Van Dyke (8) stated recently, "One of the important developments of instrumentation which enables nuclear medicine to become quantitative is the development of the digital computer to the stage where it is fast enough, small enough, cheap enough and responsive enough for ordinary mortals to deal with on a friendly basis." They proposed further that "the seventies should be the decade of calibration and validation of these techniques, to the satisfaction of the critical scientist." As with radiographs, the great value of radioactive tracer studies lies in their capability for nondestructive, simple measurements. But whereas radiographs provide information primarily about body structures, radioactive tracers make their greatest contribution in permitting measurement of regional function. Although it is true that contrast angiography and other radiographic techniques also provide functional information, the ability to employ hundreds of safe and potentially useful radioactive tracers in nuclear medicine makes it theoretically possible to study nearly every function of the body. Let us consider first the measurement of regional pulmonary arterial blood flow. There are 300 million pulmonary arterioles of diameter 15 to 30 !LID and 280 billion capillaries of diameter 5 to 7 !LID in the lungs. Because pulmonary blood vessels are temporarily occluded by particles of a larger size, lung perfusion imaging is based on the intravenous injection of radioactive particles
or microspheres of human serum albumin of diameter 15 to 30 /LID. Because the density of the microspheres is comparable to that of red blood cells, their distribution throughout the lungs is determined by the distribution of pulmonary arterial blood flow. During injection the patient is in the supine position and breathing normally; forced inspiration or expiration changes the distribution of particles in the lungs. Patients suspected of having pulmonary venous hypertension are often injected while in an erect position. The perfusion of the apices, normally less than to the bases in this position, is increased in patients with this problem because the pulmonary vascular resistance is increased in the lower regions of the lung with diversion of blood flow to the upper regions. In a patient with right-toleft shunt some of the microspheres will reach the systemic arterial circulation; therefore, care must be taken not to inject more than 50,000 microspheres. Regional ventilation is determined by imaging with a scintillation camera the initial distribution and washout of the inhaled radioactive gas, 133Xe. The patient lies in a supine position with the detector beneath him and inhales the 133Xe, which is mixed with air. Regional ventilation is determined after an initial single breath, after 5 min of equilibration of rebreathing 133Xe from a closed system, and during the clearance of the gas from the lungs. Regional ventilation is estimated from the image by visual assessment of the retention of the gas or by quantification of regional clearance rates with a computer. Bronchoconstriction, bronchial obstruction, or tissue destruction cause decreased regional concentrations of the radioactive gas. The supine position is selected to facilitate correlation of ventilation and perfusion. It is essential that the patient be in the same position during both types of examination. Nuclear Instrumentation
In looking at a problem in medical diagnosis, the physiologically oriented physician asks himself or herself what functions should be measured to help solve the patient's problems and what degree of spatial and temporal resolution is required in the measurements. Will it be necessary to measure only pulmonary perfusion, or must both perfusion and ventilation be measured? Will it suffice to measure the function of the lungs as a whole, or will it be necessary to compare the functions of one region with another? Will it suffice to measure the distribution
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
of blood flow with intravenously injected microspheres, or will it be necessary to make rapid measurements of the distribution of a radioactive gas throughout the lungs or of the changes in the volumes of the cardiac chambers as they fill and empty? Individual counting intervals of as little as one-fiftieth of a second must be examined for certain studies such as the ejection fraction of the ventricles (8, 12). These factors determine the types of radiation detection instruments that can be used and the types of measurements that can be made. The most widely used instrument in nuclear medicine today for measurement of the distribution of activity in vivo is the 'Y scintillation camera, invented by Anger (13) and subsequently greatly improved by the addition of data processing equipment (14). When we consider that the 'Y camera can create images with 10,000 or more image cells (picture elements), each ol which may be made up of 256 or even more counts per min, we can appreciate the large amount of data generated and the impossibility of quantification without the use of a computer. Although video instrumentation has been used by some for analysis of 'Y camera data, most prefer the use of digital computer systems (15). The maximal spatial resolution of the scintillation camera using the highest resolution collimator is about one centimeter at the face of the detector with considerable falloff at greater depths. Usually a computer matrix of 64 X 64 is used, although a 128 X 128 picture element matrix is better. The temporal resolution requirement depends on the type of study being performed. For studies such as the washout of 133Xe from the lungs, cardiac output, intracardiac shunt measurement, and transit time analyses from one cardiac chamber to another, 0.5 or 1.0 sec frames will suffice. If the time activity curve of the right or left ventricle is to be obtained, 48 or more frames per sec are desirable. With high degrees of temporal or spatial resolution, there are statistical limitations imposed by the limitation in the amount of radioactive tracer that is administered. In such cases, a compromise must be made between temporal and spatial resolution. The addition of a digital computer greatly expands the usefulness of the scintillation camera, particularly in quantification of the results. Special purpose (hardwired) devices are also being developed and applied at a rapid rate and help increase the value of the studies, although with less flexibility than the digital systems.
205
Measurement of Regional Lung Function
The application of physiologic principles to the study of lung function has greatly improved both our understanding of the pathophysiology of lung disease and the care of the patients. Pulmonary functional evaluation includes measurement of vital capacity, inspiratory and expiratory reserve volumes, inspiratory capacity, functional residual capacity, residual volume, and total lung capacity. These measure the function of the lungs as a whole and are performed with a spirometer or a body plethysmograph. Radioactive tracers are most widely used to measure regional function. Even in normal persons, all parts of the lung are not uniformly ventilated and perfused. In certain lung diseases, the hallmark is the abnormal distribution of function. Tracer studies supplement the information obtained in procedures such as maximal voluntary ventilation, peak flow rates, lung compliance, airway resistance, and dead space/ volume measurements. Let us next consider specific diseases. Pulmonary Embolism
The most widely used radioactive tracer procedure in the study of the lungs is the perfusion lung scan. Although not a specific test for pulmonary embolism, it is a sensitive test because it gives an accurate depiction of the distribution of regional pulmonary arterial blood flow (1618). The physician is often faced with the problem of a patient who has pain in the calf or pleuritic chest pain. It is likely that in more than 80 per cent of patients who are previously healthy and ambulatory, pain in the calf or pleuritic-type chest pain is not caused by deep vein thrombosis or pulmonary embolism. Often leg pain is nothing more serious than a pulled muscle, inflammation of varicose veins, mild trauma, or cramp. Less commonly, a ruptured Baker's cyst may simulate the pain and swelling of venous thrombosis. Of course, marked swelling of the calf and thigh with unequivocal signs should lead to hospitalization of the patient and heparinization, but because this can cause bleeding in up to 20 per cent of patients, the decision to anticoagulate the patient should not be made without adequate evidence (19). A normal 4-view lung scan makes it exceedingly unlikely that pulmonary embolism is present. One of the reasons for the popularity of lung scanning is that it provides information useful in making important decisions concerning anticoagulation of the patient. In the pres-
206
HENRY
R
p
ANT.
R.LAT.
L
~-
WAGNER. JR.
L
POST.
R
A ----~A~~L~.LAT ~·--~ · P_
A
-5secs
Equil.
5
''···::-.
......
:... :
.. '.. .... : ~ .
,-·
. . .. .··
·..··
--~1~5~----------~2~5 =-----------~40.__~ B
Fig. I. A. (Top) Bilateral perfusion defects are noted on this 4-view scan of a patient with pulmonary emboli. R = right, L = left, A = anterior, P = posterior, Ant. = anterior, Post. = posterior, L. Lat. = left lateral, R. Lat. =right lateral. B. (Bottom) A normal xenon-133 ventilation study of the same patient. Both lungs are well ventilated and there is no d elay noted in the washout phase. Equil. =equilibration view.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
ence of a negative lung scan, no further pursuit of the diagnosis of pulmonary embolism is necessary. In pulmonary embolism there are usually one or more segmental perfusion defects noted in the lung, the regional ventilation study is normal, and an accompanying chest radiograph is often normal (figure JA, B). Most emboli occur in the lower lobes of the lungs and involve the superior and posterior segments. A lobar defect or lack of perfusion to one entire lung may be noted if a large vessel is occluded. It is often helpful to repeat a positive lung scan in 4 to 5 days to observe the characteristic changing pattern or perfusion defects in pulmonary embolism. This is due to partial resolution of original emboli, new emboli, or fragmentation of a large embolus into smaller emboli. The probability of acute pulmonary emboli is increased when on a repeat scan new perfusion defects appear, whereas some defects clear. Usually the perfusion defects resolve significantly within the first 2 weeks and then to a Jesser extent during the next 3 months. In 1967 Tow and Wagner (20) examined the rate of recovery of pulmonary arterial blood flow in a series of patients with pulmonary embolism. Of the patients with small lesions (less than 15 per cent), 4 per cent recovered completely, the lung scan being interpreted as normal within 2 weeks. After 4 months 67 per cent had recovered and an additional 8 per cent had improved. Thirty per cent of the patients with moderate-sized lesions (15 to 30 per cent) recovered within 3 weeks, whereas 38 per cent recovered after 4 months and another 13 per cent improved. Twenty per cent of the patients with
R . ANT
p
R.LAT.
L
A
L
A
207
severe lesions (greater than 30 per cent) recovered within 4 weeks, 20 per cent recovered after 4 months, and an additional 50 per cent improved. Thirty-three per cent of the patients with major emboli had persistent perfusion defects on the lung scan for more than a year. The resolution of pulmonary emboli was slower in the presence of cardiovascular disease and with increasing age of the patient. New emboli occurred in less than 10 per cent of cases of pulmonary embolism and in such patients new segmental defects were noted on the scan. How Perfusion Lungs Scans Are Interpreted
The characteristics of perfusion defects help increase the diagnostic specificity as follows (21): (J) The interpretation of "no evidence of pulmonary embolism" may be made if a 4-view lung scan (anterior, posterior, and both laterals) is normal. (2) If the blood flow to the apices is greater than to the bases of the lungs and there is no evidence of focal perfusion defects, the interpretation should be "probable pulmonary venous hypertension without evidence of pulmonary embolism." (3) Pulmonary congestion or pleural effusion is suggested if there is no evidence of segmental perfusion defects and if the regions of decreased perfusion correspond to one or more fissures, often with increased blood flow to the upper portions of the lungs. (4) If on the posterior but not the anterior view one lung has a decrease in perfusion, there is a high probability of pleural effusion (figure 2). (5) Symmetric perfusion defects at the apices
POST R
L.LAT.
p
Fig. 2. A marked decrease in perfusion is noted in the posterior and right lateral views of this 4-view lung scan. This patient has a left-sided pleural effusion, as noted on the chest radiography. For definition of abbreviations, see figure I.
208
HENRY N. WAGNER, JR.
indicate parenchymal lung disease rather than pulmonary embolism. (6) A high probability of pulmonary embolism is suggested when one or more perfusion defects correspond with segmental arteries. An accompanying radiograph may be normal. In the presence of chronic obstructive pulmonary disease, arteriography will determine superimposed pulmonary embolism. (7) It is frequently noted in young adults with tetralogy of Fallot or other causes of right-toleft shunts that there is an increased concentration of radioactivity in the kidneys, denoting a right-to-left shunt (figure 3). Regional perfusion defects are observed in patients with congenitally hypoplastic pulmonary arteries. An extreme example is shown in figure 4. (8) Pulmonary infection is indicated when the perfusion defects correspond to areas of consolidation on the radiograph. (9) There is a high probability of neoplasm
when an entire lung lacks perfusion. Hilar bronchogenic carcinoma is more likely to produce this effect than pulmonary embolism. (10) Pulmonary edema is indicated when there are nonsegmental perfusion defects noted on the scan together with decreased perfusion of the medial aspects of the lung and along the fissures. Increased perfusion may be observed in the apices of the lungs in such patients. Parenchymal Lung Disease One of the important contributions of radioactive tracer studies of the lungs has been to document that all lung diseases have decreased pulmonary arterial blood flow to the involved regions. This does not mean that they are totally ischemic, because the blood flow is provided in most cases by the bronchial circulation. It does mean that intravenously injected particles fail to accumulate in these regions in the absence of a right-to-left intracardiac shunt. These findings
Fig. 3. There are multiple subsegmental perfusion defects noted bilaterally in this patient with Eisenmenger's disease. The activity noted in the kidneys indicates a right-to-left shunt, which is associated with this disease. For definition of abbreviations, see figure I.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
L
R
p
A
R
L
A
p
Fig. 4. This patient with a hypoplastic left pulmonary artery has minimal perfusion to the left, as noted in the lung scan. For definition of abbreviations, see figure I. complicate the interpretation of perfusion lung scans, but are at times valuable in the assessment of the degree of regional involvement by disease processes. Combined measurement of both regional ventilation and perfusion greatly improves the diagnostic specificity. It is now common practice to perform 133Xe ventilation studies together with anterior, posterior, and both lateral views of the distribution of perfusion. The use of multiple views permits characterization of lesions according to their size, shape, and position. The technique of radiospirometry with 133Xe requires the use of either the scintillation camera or multiple radiation detectors (14). The latter permit the use of smaller administered doses of 133Xe, but one does not obtain the spatial resolution that can be obtained with the scintillation camera. The use of the scintillation camera permits closer correlation of perfusion and ventilation defects. With the scintillation camera, the first step is to have the patient inhale radioactive 133Xe from a spirometer. The patient takes a deep breath, and the initial distribution of the activity is determined in the form of a single image. The second step consists of having the patient rebreathe the 133Xe for a period of 3 to 5 min. An image is obtained at the time that reveals the 133Xe space or alveolar air space. This image is particularly suitable for comparison with the single breath inhalation study, so that
209
the relationship between ventilation and lung volume can be ascertained. After the equilibration image, the patient is allowed to breathe into a collection system and the rate of clearance of the xenon from the various zones of the lung is measured. In most cases, this is done by serial images at 5-sec intervals, but in many laboratories the data are recorded in some storage system so that the clearance rate constants can be measured mathematically. In patients with parenchymal lung disease, such as infections (22) or chronic obstructive pulmonary disease (23, 24), the perfusion defects are accompanied by regional ventilation defects. The chest radiograph of a patient with sarcoidosis is shown in figure 5A; in 5B is the distribution of perfusion defects in the same patient. Lobar perfusion defects are noted in the perfusion lung scans of patients with lobar pneumonia with consolidation. Patchy nonsegmental perfusion defects are noted in the case of bronchopneumonia. Because there is reduced ventilation to the affected area, there is absence of 133Xe noted on the ventilation study. Either diminished ventilation or lack of ventilation, which corresponds to discrete perfusion defects, are noted in patients with bullae (figure 6A, B).
R L Fig. 5. A. This anterior view of the lung scan reveals a nonhomogeneous distribution of radioactivity throughout both lungs. The diagnosis of this patient was sarcoidosis.
Fig. 5. B. A chest radiograph shows diffuse involvement of the disease bilaterally. R ::: right; L ::: left. A lung scan performed in patients during an asthmatic attack often reveals large, irregular, segmental and nonsegmental defects (25). A changing pattern is noted on repeated studies during several days. A normal lung scan may be obtained between attacks (figures 7A-C).
Diminished ventilation corresponding to the perfusion defects is noted in the ventilation study. In patients with carcinoma of the lung the perfusion defect is often massive, often involving the entire lung. This may result from extrinsic obstruction of the main pulmonary artery. Regional ventilation is diminished when there is bronchial obstruction (figure 8). Radioactive Tracers in Preoperative Assessment Of Regional Lung Function
L
R
Fig. 6 A. This anterior view of the lung scan of a patient with bullous emphysema shows marked de· crease in perfusion to the right lung and upper lobes of the left lung. R ::: right; L ::: left.
The classic method for examination of differential lung function before pulmonary resection has been bronchospirometry (26, 27). More recently radioactive tracer techniques have provided a useful, noninvasive alternative (28-31). Both regional perfusion and ventilation have proved useful. Such studies have been found useful in the localization of roentgenologically occult cancer (30, 32), in providing information about the extent of involvement of the lungs (31), and in predicting the pulmonary functional loss after resection. A number of radioactive tracers that concentrate in neoplasms have been evaluated in patients with lung cancer. About 80 per cent of patients with bronchial neoplasms accumulated gallium·67 (33). Mercury-197 has also been used for this purpose. Lesions smaller than 2 em in diameter could not be visualized with the use of
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
211
Fig. 6. B. The chest radiograph reveals a massive bulla in the right lung and bullae in the upper and middle lobes of the left lung.
197Hg scintigraphy. Arborelius and associates (34) combined the use of 197Hg scintigraphy in radiospirometry and found an accuracy of 80 per cent. Tracer studies have been used preoperatively in patients with tuberculosis (22) and bullous emphysema as well as in carcinoma of the lung.
It is well accepted that the chest radiograph is an
insensitive mea ns of detecting early obstructive lung diseases as well as pulmonary embolism. This has led to the increasing interest in techniques such as closing volume measurements and regional measurements with radioactive tracers to provide more sensitive tests. After the pioneering physiologic investigations of Dollery and co-workers (35), Ball and associates (36) in 1962 used 133Xe a nd observed regional ventilation abnormalities in patients with
Fig. 7. A. This patient's lung scan was performed during an acute asthmatic attack. The posterior view shows bila teral perfusion defects more marked in the right upper lobe.
Fig. 7. B. A scan performed the following day revealed perfusion to the originally poorly perfused regions. R == right; L = left.
Early Detection of Obstructive Lung Disease
212
HENRY N. WAGNER. JR.
chronic obstructive lung disease. Since then, regional abnormalities have been found in asthma, chronic bronchitis, and emphysema. Perfusion and ventilation images in a patient with emphysema are shown in figures 9A and B. For comparison, figure 10 is an example of a 133Xe ventilation study with the scintillation camera in a person with normal ventilation. Of particular interest is the finding of Anthonisen and associates (23) that symptomatic patients with chronic obstructive pulmonary disease and nearly normal spirometric pulmonary function tests have clear-cut regional abnormalities. Two subsequent reports suggest that regional lung function measurements can detect abnormalities in asymptomatic subjects at a time when measurement of whole lung function including closing volumes is still within the variation observed among healthy persons. In the first study (37), radioisotopic regional lung function measurements using both albumin microspheres labeled with technetium-99m and inhaled 133Xe were compared to measurement of total lung function in a population of 30 participants in an epidemiologic study of the causative factors of obstructive pulmonary disease. Five of the 8 asymptomatic subjects who had no evidence of obstructive lung disease by the tests of total function had abnormal regional function measurements. The closing volume was ab-
normal in 3 of these 5, suggesting the presence of peripheral airways disease. Regional lung function was abnormal in all subjects who were symptomatic, who had a forced expiratory volume in 1 secj forced vital capacity ratio < 75 per cent, or who had an elevated closing volume or residual volume. The data suggested that measurement of regional lung function may be a highly sensitive test for the early diagnosis of chronic obstructive lung disease. A long-term prospective study would be required to determine the significance of these regional abnormalities. A second study (38) suggesting the sensitivity of regional function measurements was a study of 18 narcotics addicts without any symptoms of respiratory disease. Thirteen had regional abnormalities of perfusion of the lungs; 5 had abnormal zones of ventilation as well. Only time will tell the ultimate usefulness of regional pulmonary function measurements in the early diagnosis of obstructive airways disease. Pulmonary Venous Hypertension
Left ventricular failure and disease of the mitral valve frequently cause pulmonary venous hypertension. Redistribution of pulmonary arterial blood flow can be demonstrated in patients with congestive cardiac failure when tracers are injected in the supine position, resulting in increased perfusion to the upper lung fields. A
Fig. 7. C. A chest radiograph of the same patient.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
R
p
ANT.
L
A L. LA._T _ _
L
A
POST.
R.LAT
213
R
p
Fig. 8. The 4·view lung scan -and chest radiograph reveal extensive involvement of carcinoma of the right lung. There is a marked decrease in perfusion to the middle and lower lobes of the right lung. For definition of abbreviations, see figure I.
perfusion defect may be noted in the right middle lung field as a result of an enlarged atrium. In patients with cardiac failure the ventilation study is usually normal. A decrease in volume will be noted on the equilibration study with a normal washout if the patient has edematous lungs. Cor Pulmonale A recent use of radioactive tracers in patients with lung disease is in the study of the heart. Although these techniques are used today primarily in patients with coronary heart disease, they are beginning to be used in patients with lung disease. There are 3 types of procedures: (1) Distribution of regional myocardial blood flow can be depicted with the use of potassium analogues, such as ionic thallium-201 or rubidium-81. (2) Radionuclide angiocardiography is based on imaging the passage of an intravenously injected dose of [99mTc) albumin as it passes through the heart, lungs, and great vessels. The size of the intracardiac chambers, transit times from one region of the circulation to another, and the presence of left-to-right intracardiac chambers can be detected. (3) Regional and gen-
eral contractility of both ventricles can be determined after the [99mTc) albumin has become distributed in the vascular compartment. This is accomplished by "gating" or activating the scintillation camera by means of the patient's electrocardiogram. Several hundred beats can be examined during the end of systole and diastole. Comparison of the scintillation camera images of the heart can reveal the end-systolic and enddiastolic volumes, stroke volume, and ejection fraction. Validation studies to date have been limited to the study of the left ventricle, but initial results indicate that important information can be obtained about the right ventricle as well. The position of the patient that is most useful is the left anterior oblique position in which the right and left ventricles can be viewed separately. The intraventricular septum can be viewed to permit proper positioning of the patient. The types of information that can be obtained in these studies are dilatation and hypertrophy of the right and left ventricles and the relative performance of these 2 structures. In many patients to date, the differential diagnosis of cor pulmonale and the latter condition complicated
214
HENRY N. WAGNER, JR.
R
p
ANT
R.L T
L
L
A
A
POST
p
L.LAT
A
B
Fig. 9 A. (Top) In this patient with emphysema, the 4-view lung scan reveals nonsegmental perfusion defects bilaterally. There is decreased perfusion to both apices, more marked on the right. B. (Bottom) Decreased ventilation of both apices is noted in the single breath (S. Br.) view of the xenon-133 ventilation study. Delayed washout of the 133Xe from both lungs is noted bilaterally. Equil. =equilibration view; for definition of other abbreviations, see figure 1.
RADIOISOTOPE TECHNIQUES
S.Br.
I~
215
PUUIONARY DISEASE
Equil.
- Ssecs.
R
L
.....
.. (•
'.
5
20
10
Fig. 10. This normal ventilation study shows a uniform distribution of the xenon-133 gas in both lungs, in the single breath (S. Br.) and equilibration (Equil.) views. The 133Xe is expelled rapidly and uniformly as noted in the washout phase of the study (bottom row). R right; L left.
=
by coronary heart disease and left ventricular dysfunction have been aided by these procedures. Only time will tell their eventual role, but initial results have been encouraging. Differential Diagnosis of Cyanosis
Another area of usefulness of radioactive tracers is the study of patients with suspected respiratory problems is the diagnosis of r ight-to-left intracardiac shunts. In 1970 Hurley and associates (39) reported the use of radionuclide angiocardiography in the differential diagnosis of patients with congenital cyanotic heart disease. In all 30 patients with congenital cyanotic heart disease, the radionuclide angiocardiogram indicated an intracardiac right-to-left shunt. There were 3 fa lse positives among the 46 other pa· tients, none of whom had shunts. The principal indication was the appearance of the tracer in the left heart or abdominal aorta before the lungs were fully perfused. These results were confirmed and extended by Wesselhoeft and associates (40) in 43 children 3 years of age or less,
=
26 of whom had congenital heart disease. The criteria were improved and all 26 patients were correctly diagnosed as having congenital heart disease. There were no false positives. In many patients, the type of abnormality, such as transposition of the great arteries and truncus arteriosus, was correctly diagnosed before cardiac cath· eterization. Further validation and improvements were made by Kriss (7), and b y others. In normal subjects the pulmonary mean transit time, which can be measured or estimated subjectively by inspection of the serial images of the radionuclide angiocardiogram, averaged 6.5 ± l.O sec. Interpretation of transit times involves estimation of cardiac chamber sizes, because the reciprocal of the mean transit time in a given region is the ratio of blood flow through the region to the volume of the region the tracer is crossing. Inhalation of Aerosols
For almost a decade, aerosolized droplets incorporating a radioactive tracer, such as 99mTc or
216
HENRY N. WAGNER, JR.
indium-113m, have been used in experimental and clinical studies of the lungs (41, 42). The goal has been to facilitate measurement of the relative perfusion and ventilation to regional lesions as an aid in the differential diagnosis of pulmonary thromboembolism. In this method, the patient is connected to a nebulizer, the nostrils are occluded by means of a clip, and the patient breathes normally with a mouthpiece connected to a nebulizer. About 1.5 mCi of (99mTc] albumin or 3.0 mCi of 113min solution are retained by the lung parenchyma. The droplet size must be optimized so that the particles are small enough to reach the alveoli. Lung imaging is begun immediately and 4 views are obtained. Characteristic patterns have been observed in patients with chronic obstructive pulmonary disease, including bullous emphysema and chronic bronchitis. The distribution of the aerosol is related both to bronchial mucous deposits and other obstructions as well as to the distribution of ventilation. The measurement is not purely regional ventilation but is determined to a large degree by deposition of the aerosol by impaction. An important advantage of the use of inhaled aerosols rather than tssxe is that multiple views can be obtained. In the case of tssxe, only one view can be obtained unless the tssxe is administered several times. On the other hand, the advantage of tssxe is that ventilation rather than ventilation plus impaction is measured. An advantage of the use of 113min is that the aerosol inhalation study can be performed immediately after the perfusion study with 99mTc microspheres. The higher energy photon emission (390 kev) from 113min can be easily distinguished from the lower photon energy (140 kev) of 99mTc. An advantage of the inhaled aerosol technique is that mucociliary activity can be investigated, although only preliminary studies of this type have been performed to date. It is likely that inhaled particle studies will become more prevalent in the future. Most laboratories still use 133Xe for measurement of regional ventilation and 99mTc microspheres or particles for regional perfusion. Summary Although it is true that pulmonary perfusion scanning is generally accepted primarily in the differential diagnosis of pulmonary embolism, the introduction of regional ventilation studies with radioactive 133Xe, the use of the computer to provide quantitative data, and the advances
being made in cardiovascular nuclear medicine indicate that nuclear medicine procedures will be used more and more in the evaluation of patients with a variety of lung and heart diseases. They have already proved of value in the following circumstances: (I) differential diagnosis of pulmonary embolism; (2) assessment of regional involvement in pulmonary parenchymal disease, including degenerative, neoplastic, and infectious diseases; (3) detection of bullous disease and the determination of the possible effectiveness of surgery; (4) assessment of the response to radiation therapy in patients with carcinoma of the lung; (5) detection of pulmonary venous hypertension in patients with mitral valve or left ventricular disease; (6) detection of cor pulmonale; (7) differential diagnosis of cyanosis in newborn infants. References I. Knipping, H. W., Bolt, W., Vernath H., Valentin,
2.
3.
4.
5. 6.
7.
8.
H., Ludes, H., and Endler, P.: Ein neue methode zur prufung der herz und lungen funktion. Die regionale funktion analyse in der lungen und herzklinik mit hilfe der radioactiven endelgases xenon-13!1, Dtsch Med Wochenschr, 1955, 80, 1146. West, J. B., Dollery, C. T., and Hugh-Jones, P.: The use of radioactive carbon dioxide to measure regional blood flow in the lungs of patients with pulmonary disease, J Clin Invest, 1961, 40, 1. Wagner, H. N., Sabiston, D. C., McAfee, J. G., Tow, D., and Stern, H. S.: Diagnosis of massive pulmonary embolism in man by radioisotope scanning, N Engl J Med, 1964,271, !177. Cassen, B., Curtis, L., Reed, C., and Libby, R.: Instrumentation of 1-131 used in medical studies, Nucleonics, 1951, 9, 46. Urokinase pulmonary embolism trial, A national cooperative study, Circulation, 1973, Supplement II; AHA Monograph 39. Jones, R. H., and Anderson, P. A. W.: Congenital heart disease: Imaging and analytic methods, in Quantitative Nuclear Medicine Cardiography, R. N. Pierson, Jr., J. P. Kriss, R. H. Jones, and W. J. Macintyre, ed., John Wiley and SOns, New York, 1975, p. 32. Kriss, J. P.: Acquired cardiovascular disease, in Quantitative Nuclear Medicine Cardiography, R. N. Pierson, Jr., J. P. Kriss, R. H. Jones, and W. J. Macintyre, ed., John Wiley and Sons, New York, 1975, p. 66. Pierson, R.N., Jr., and Van Dyke, D. C.: Analysis of left ventricular function, in Quantitative Nuclear Medicine Cardiography, R. N. Pierson, Jr., J.P. Kriss, R. H. Jones, and W. J. Macintyre, ed., John Wiley and SOns, New York, 1975, p.l23.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
9. Wagner, H. N., Jr.: The heart and circulation, in Nuclear Medicine, H. N. Wagner, Jr., ed., Hospital Practice Publishing Co., New York, 1975, p. 112. 10. Wagner, H. N., Jr., and Rhodes, B. A.: Radioactive tracers in diagnosis of cardiovascular disease, Prog Cardiovasc Dis, 1972, 15, !. II. Blumgart, H. L., and Weiss, S.: Studies on the velocity of blood flow. VII. The pulmonary circulation time in normal resting individuals, J Clin Invest, 1927,4, 399. 12. Zaret, B. L., Strauss, H. W., Hurley, P. J., Natarajan, T. K., and Pitt, B.: A noninvasive scintiphotographic method for detecting regional ventricular dysfunction in man, N Eng! J Med, 1971, 284, 1165. 13. Anger, H. 0.: Instruments: Specific devices, in Nuclear Medicine, H. N. Wagner, Jr., ed., Hospital Practice Publishing Co., Inc., New York, 1975, p. 29. 14. Natarajan, T. K., and Wagner, H. N., Jr.: Functional Images of the Lungs in Dynamic Studies with Radioisotopes in Medicine, International Atomic Energy Agency, Vienna, SM-185fl5, vol. II, 1974. 15. Wagner, H. N., Jr., and Natarajan, T. K.: Computers, in Nuclear Medicine, H. N. Wagner, Jr., ed., Hospital Practice Publishing Co., Inc., New York, 1975, p. 41. 16. Gilday, D. L., Poulose, K. P., and Deland, F. H.: Accuracy of detection of pulmonary embolism by lung scanning correlated with pulmonary angiography, Am J Roentgenol Radium Ther Nucl Med, 1972, 115,732. 17. Greenspan, R. H.: Does a normal isotope perfusion scan exclude pulmonary embolism?, Invest Radial, 1974, 9, 44. 18. Tow, D. E., and Simon, A. L.: Comparison of lung scanning and pulmonary angiography in the detection and follow-up of pulmonary embolism. The urokinase pulmonary embolism trial experience, Prog Cardiovasc Dis, 1975, 17, 239. 19. Sasahara, A. A., Mcintyre, K., Criss, A. J., and Belko, J. S.: Aggressive approach to the management of pulmonary embolism, Cardiovasc Clin, 1969, 1' 261. 20. Tow, D. E., and Wagner, H. N., Jr.: Recovery of pulmonary arterial blood flow in patients with pulmonary embolism, N Engl J Med, 1967, 276, 1063. 21. Wagner, H. N., Jr., and Strauss, H. W.: Radioactive tracers in the differential diagnosis of pulmonary embolism, in Cardiovascular Nuclear Medicine, H. W. Strauss, B. Pitt, and A. E. James, ed., C. V. Mosby Co., St. Louis, 1974, p. 278. 22. Lopez-Majano, V., Wagner, H. N., Jr., Tow, D. E., and Chernick, V.: Radioisotope scanning of the lungs in pulmonary tuberculosis, JAMA, 1965,194, 1053.
217
23. Anthonisen, N. R., Bass, H., Oriol, A., Place, R. E. G., and Bates, D. V.: Regional lung function in patients with chronic bronchitis, Clin Sci, 1968,35,495. 24. Bentivoglio, L. G., Beerel, F., Stewart, P. B., Bryan, A. C., Ball, W. C., Jr., and Bates, D. V.: Studies of regional ventilation and perfusion in pulmonary emphysema using xenon 133, Am Rev Respir Dis, 1963, 88, 315. 25. Heckscher, T., Bass, H., Oriol, A.: Regional lung function in patients with bronchial asthma, J Clin Invest, 1968,47, 1063. 26. Gaensler, E. A., Patton, W. E., and Frank, N. R.: Bronchospirometry. VII. Indications, .J Lab Clin Med, 1953,41,456. 27. Snider, G. L.: A critical evaluation of bronchospirometric measurement in predicting loss of ventilatory function due to thoracic surgery, J Lab Clin Med, 1964,64, 321. 28. Maynard, C. D.: Role of the scan in bronchogenic carcinoma, Semin Nucl Med, 1971,1, 195. 29. Tauxe, W. N., Carr, D. J., and Thorsen, H. C.: Perfusion lung scans in patients with inoperable primary lung cancer, Mayo Clin Proc, 1970, 45, 337. 30. Wagner, H. N., Jr., Lopez-Majano, V., Tow, D. E., and Langan, J. K.: Radioisotope scanning of lungs in early diagnosis of bronchogenic carcinoma, Lancet, 1965, 1, 344. 31. Arborelius, M., Jr., Kristersson, S., Lindell, S. E., Miorner, G., and Svanberg, L.: Xenon-133 radiospirometry and extension of lung cancer, Scand J Respir Dis, 1971,52, 145. 32. Lindell, L., Lindell, S. E., and Svanberg, L.: Regional lung function in roentgenologically occult lung cancer, Scand J Respir Dis, 1972, 53, 109. 33. Larson, S. M., Milder, M. S., and Johnston, G. S.: Tumor-seeking radiopharmaceuticals: Gallium67, in Radiopharmaceuticals, G. Subramanian, ed., Society of Nuclear Medicine, Inc., New York, 1975, p. 413. 34. Arborelius, M., Nosslin, B., and Lindell, S. E.: 197Hg-scintigraphy and 133Xe-radiospirometry in the diagnosis of pulmonary tumor, Scand J Respir Dis, 1974, 85 (Supplement, p. 119). 35. Dollery, C. T., Hugh-Jones, P., and Matthews, C. M. E.: Use of radioactive xenon for studies of regional lung function, Br Med J, 1962, 2, 1006. 36. Ball, W. C., Jr., Stewart, P. B., Newsham, L. G., and Bates, D. V.: Regional pulmonary function studied with xenon 133, .J Clin Invest, 1962, 41, 519. 37. McKusick, K., Wagner, H. N., Jr., Soin, J. S., Benjamin, J. J., Cooper, M., and Ball, W. C.: Measurement of regional lung function in the early detection of chronic obstructive pulmonary disease, Scand .J Respir Dis, 1974, 85 (Supplement, p. 51). 38. Soin, S. S., McKusick, K. A., and Wagner, H. N., Jr.: Regional lung function in narcotic addicts,
218
HENRY N. WAGNER, JR.
JAMA, 1973,224, 1717. 39. Hurley, P. J., Strauss, H. W., and Wagner, H. N., Jr.: Radionuclide angiocardiography in the diagnosis of congenital heart disease in infants, Circulation, 1972,45, 77. 40. Wesselhoeft, H., Hurley, P. J., Wagner, H. N., Jr., and Rose, R. D.: Nuclear angiocardiography in the diagnosis of congenital heart disease in infants, Circulation, 1972, 45, 77.
41. Taplin, G. V., Poe, N.D., Dore, E. K., and Greenberg, A.: Bronchial patency and aerated space assessment by scintiscanning, LCFB, 1967, 16, 297. 42. Taplin, G. V., Poe, N. D., Dore, E. K., Greenberg, A., and Isawa, T.: Radioaerosol inhalation scanning, in Pulmonary Investigation with Radionuclides, A. J. Gilson and W. M. Smoak, ed., Charles C Thomas, Springfield, Ill., p. 296.
Contents
Introduction Cardiopulmonary Nuclear Medicine Nuclear Instrumentation Measurement of Regional Lung Function Pulmonary Embolism How Perfusion Lung Scans Are Interpreted Parenchymal Lung Disease Radioactive Tracers in Preoperative Assessment of Regional Lung Function Early Detection of Obstructive Lung Disease Pulmonary Venous Hypertension Cor Pulmonale Differential Diagnosis of Cyanosis Inhalation of Aerosols Summary Introduction
Radioactive tracer studies of the lung began in 1955 when Knipping and associates (l) first used xenon-133 as a possible aid in the early diagnosis of carcinoma of the lung. They were not successful, but their work is of historic interest. Subsequently, West and co-workers (2) at Hammersmith Hospital in London began to use cyclotron-produced radioactive gases, including oxygen-15 and radioactive carbon dioxide in physiologic studies of the lungs. These studies 1 From the Divisions of Nuclear Medicine and Radiation Health, The Johns Hopkins Medical Institutions, Baltimore, Md. 21205.
provided important information about the effects of gravity and other factors on the distribution of ventilation and perfusion and documented the regional character of involvement in many patients with obstructive lung disease. It was not until 1963, however, that a radioactive tracer procedure began to achieve widespread clinical usefulness in studies of the lungs (3). Cassen and associates (4) invented the rectilinear scanner in 1951, and shortly thereafter this device began to be used in hospitals throughout the world in the diagnosis of thyroid and brain disorders, setting the stage for its use in the study of the distribution of pulmonary arterial blood flow. The impetus to the development of lung scanning was the emphasis in the 1960s on the emergency surgical treatment of acute massive pulmonary embolism. Lung scanning and pulmonary arteriography developed hand in hand in the late 1960s and were given momentum by the Urokinase Pulmonary Embolism Trial (5), which increased our understanding of the role of these procedures and the natural history of pulmonary embolic disease. Today, lung scanning is widely used in medical practice, and research studies of the use of radioactive tracers in diseases of the heart as well as the lungs are proceeding at a rapid pace. It is beyond the scope of this article to describe the use of radioactive tracers in cardiovascular disease in detail (6-10), but the advances being made in nuclear medicine procedures in coronary and valvular heart disease are being extended to the diagnosis of cor pulmonale (11). In cardiovascular nuclear medicine, the distinction between the pulmonary and the cardio-
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 113, 1976
203
204
HENRY N. WAGNER. JR.
vascular systems is becoming less emphasized and it is useful to consider them together. Cardiopulmonary Nuclear Medicine
A half century ago, Blumgart and Weiss (11) conceived the idea that radioactive tracers would be useful for the study of the circulation. They measured the velocity of the circulation by injecting solutions of radium salts intravenously and monitoring the time of arrival of the tracer at the opposite antecubital fossa in a group of normal persons and patients with cardiac diseases. The instrument they used was a cloud chamber, one of the earliest radiation detection devices. Their concepts became a reality with the advent of safe, efficient radioactive tracers, the invention of sensitive detection instruments, and application of modern data processing. The latter has made possible the achievement of a quantitative capability not previously present. Although still in the process of evolution, such quantitative studies are rapidly achieving widespread use in the study of the heart and lungs. As Pierson and Van Dyke (8) stated recently, "One of the important developments of instrumentation which enables nuclear medicine to become quantitative is the development of the digital computer to the stage where it is fast enough, small enough, cheap enough and responsive enough for ordinary mortals to deal with on a friendly basis." They proposed further that "the seventies should be the decade of calibration and validation of these techniques, to the satisfaction of the critical scientist." As with radiographs, the great value of radioactive tracer studies lies in their capability for nondestructive, simple measurements. But whereas radiographs provide information primarily about body structures, radioactive tracers make their greatest contribution in permitting measurement of regional function. Although it is true that contrast angiography and other radiographic techniques also provide functional information, the ability to employ hundreds of safe and potentially useful radioactive tracers in nuclear medicine makes it theoretically possible to study nearly every function of the body. Let us consider first the measurement of regional pulmonary arterial blood flow. There are 300 million pulmonary arterioles of diameter 15 to 30 !LID and 280 billion capillaries of diameter 5 to 7 !LID in the lungs. Because pulmonary blood vessels are temporarily occluded by particles of a larger size, lung perfusion imaging is based on the intravenous injection of radioactive particles
or microspheres of human serum albumin of diameter 15 to 30 /LID. Because the density of the microspheres is comparable to that of red blood cells, their distribution throughout the lungs is determined by the distribution of pulmonary arterial blood flow. During injection the patient is in the supine position and breathing normally; forced inspiration or expiration changes the distribution of particles in the lungs. Patients suspected of having pulmonary venous hypertension are often injected while in an erect position. The perfusion of the apices, normally less than to the bases in this position, is increased in patients with this problem because the pulmonary vascular resistance is increased in the lower regions of the lung with diversion of blood flow to the upper regions. In a patient with right-toleft shunt some of the microspheres will reach the systemic arterial circulation; therefore, care must be taken not to inject more than 50,000 microspheres. Regional ventilation is determined by imaging with a scintillation camera the initial distribution and washout of the inhaled radioactive gas, 133Xe. The patient lies in a supine position with the detector beneath him and inhales the 133Xe, which is mixed with air. Regional ventilation is determined after an initial single breath, after 5 min of equilibration of rebreathing 133Xe from a closed system, and during the clearance of the gas from the lungs. Regional ventilation is estimated from the image by visual assessment of the retention of the gas or by quantification of regional clearance rates with a computer. Bronchoconstriction, bronchial obstruction, or tissue destruction cause decreased regional concentrations of the radioactive gas. The supine position is selected to facilitate correlation of ventilation and perfusion. It is essential that the patient be in the same position during both types of examination. Nuclear Instrumentation
In looking at a problem in medical diagnosis, the physiologically oriented physician asks himself or herself what functions should be measured to help solve the patient's problems and what degree of spatial and temporal resolution is required in the measurements. Will it be necessary to measure only pulmonary perfusion, or must both perfusion and ventilation be measured? Will it suffice to measure the function of the lungs as a whole, or will it be necessary to compare the functions of one region with another? Will it suffice to measure the distribution
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
of blood flow with intravenously injected microspheres, or will it be necessary to make rapid measurements of the distribution of a radioactive gas throughout the lungs or of the changes in the volumes of the cardiac chambers as they fill and empty? Individual counting intervals of as little as one-fiftieth of a second must be examined for certain studies such as the ejection fraction of the ventricles (8, 12). These factors determine the types of radiation detection instruments that can be used and the types of measurements that can be made. The most widely used instrument in nuclear medicine today for measurement of the distribution of activity in vivo is the 'Y scintillation camera, invented by Anger (13) and subsequently greatly improved by the addition of data processing equipment (14). When we consider that the 'Y camera can create images with 10,000 or more image cells (picture elements), each ol which may be made up of 256 or even more counts per min, we can appreciate the large amount of data generated and the impossibility of quantification without the use of a computer. Although video instrumentation has been used by some for analysis of 'Y camera data, most prefer the use of digital computer systems (15). The maximal spatial resolution of the scintillation camera using the highest resolution collimator is about one centimeter at the face of the detector with considerable falloff at greater depths. Usually a computer matrix of 64 X 64 is used, although a 128 X 128 picture element matrix is better. The temporal resolution requirement depends on the type of study being performed. For studies such as the washout of 133Xe from the lungs, cardiac output, intracardiac shunt measurement, and transit time analyses from one cardiac chamber to another, 0.5 or 1.0 sec frames will suffice. If the time activity curve of the right or left ventricle is to be obtained, 48 or more frames per sec are desirable. With high degrees of temporal or spatial resolution, there are statistical limitations imposed by the limitation in the amount of radioactive tracer that is administered. In such cases, a compromise must be made between temporal and spatial resolution. The addition of a digital computer greatly expands the usefulness of the scintillation camera, particularly in quantification of the results. Special purpose (hardwired) devices are also being developed and applied at a rapid rate and help increase the value of the studies, although with less flexibility than the digital systems.
205
Measurement of Regional Lung Function
The application of physiologic principles to the study of lung function has greatly improved both our understanding of the pathophysiology of lung disease and the care of the patients. Pulmonary functional evaluation includes measurement of vital capacity, inspiratory and expiratory reserve volumes, inspiratory capacity, functional residual capacity, residual volume, and total lung capacity. These measure the function of the lungs as a whole and are performed with a spirometer or a body plethysmograph. Radioactive tracers are most widely used to measure regional function. Even in normal persons, all parts of the lung are not uniformly ventilated and perfused. In certain lung diseases, the hallmark is the abnormal distribution of function. Tracer studies supplement the information obtained in procedures such as maximal voluntary ventilation, peak flow rates, lung compliance, airway resistance, and dead space/ volume measurements. Let us next consider specific diseases. Pulmonary Embolism
The most widely used radioactive tracer procedure in the study of the lungs is the perfusion lung scan. Although not a specific test for pulmonary embolism, it is a sensitive test because it gives an accurate depiction of the distribution of regional pulmonary arterial blood flow (1618). The physician is often faced with the problem of a patient who has pain in the calf or pleuritic chest pain. It is likely that in more than 80 per cent of patients who are previously healthy and ambulatory, pain in the calf or pleuritic-type chest pain is not caused by deep vein thrombosis or pulmonary embolism. Often leg pain is nothing more serious than a pulled muscle, inflammation of varicose veins, mild trauma, or cramp. Less commonly, a ruptured Baker's cyst may simulate the pain and swelling of venous thrombosis. Of course, marked swelling of the calf and thigh with unequivocal signs should lead to hospitalization of the patient and heparinization, but because this can cause bleeding in up to 20 per cent of patients, the decision to anticoagulate the patient should not be made without adequate evidence (19). A normal 4-view lung scan makes it exceedingly unlikely that pulmonary embolism is present. One of the reasons for the popularity of lung scanning is that it provides information useful in making important decisions concerning anticoagulation of the patient. In the pres-
206
HENRY
R
p
ANT.
R.LAT.
L
~-
WAGNER. JR.
L
POST.
R
A ----~A~~L~.LAT ~·--~ · P_
A
-5secs
Equil.
5
''···::-.
......
:... :
.. '.. .... : ~ .
,-·
. . .. .··
·..··
--~1~5~----------~2~5 =-----------~40.__~ B
Fig. I. A. (Top) Bilateral perfusion defects are noted on this 4-view scan of a patient with pulmonary emboli. R = right, L = left, A = anterior, P = posterior, Ant. = anterior, Post. = posterior, L. Lat. = left lateral, R. Lat. =right lateral. B. (Bottom) A normal xenon-133 ventilation study of the same patient. Both lungs are well ventilated and there is no d elay noted in the washout phase. Equil. =equilibration view.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
ence of a negative lung scan, no further pursuit of the diagnosis of pulmonary embolism is necessary. In pulmonary embolism there are usually one or more segmental perfusion defects noted in the lung, the regional ventilation study is normal, and an accompanying chest radiograph is often normal (figure JA, B). Most emboli occur in the lower lobes of the lungs and involve the superior and posterior segments. A lobar defect or lack of perfusion to one entire lung may be noted if a large vessel is occluded. It is often helpful to repeat a positive lung scan in 4 to 5 days to observe the characteristic changing pattern or perfusion defects in pulmonary embolism. This is due to partial resolution of original emboli, new emboli, or fragmentation of a large embolus into smaller emboli. The probability of acute pulmonary emboli is increased when on a repeat scan new perfusion defects appear, whereas some defects clear. Usually the perfusion defects resolve significantly within the first 2 weeks and then to a Jesser extent during the next 3 months. In 1967 Tow and Wagner (20) examined the rate of recovery of pulmonary arterial blood flow in a series of patients with pulmonary embolism. Of the patients with small lesions (less than 15 per cent), 4 per cent recovered completely, the lung scan being interpreted as normal within 2 weeks. After 4 months 67 per cent had recovered and an additional 8 per cent had improved. Thirty per cent of the patients with moderate-sized lesions (15 to 30 per cent) recovered within 3 weeks, whereas 38 per cent recovered after 4 months and another 13 per cent improved. Twenty per cent of the patients with
R . ANT
p
R.LAT.
L
A
L
A
207
severe lesions (greater than 30 per cent) recovered within 4 weeks, 20 per cent recovered after 4 months, and an additional 50 per cent improved. Thirty-three per cent of the patients with major emboli had persistent perfusion defects on the lung scan for more than a year. The resolution of pulmonary emboli was slower in the presence of cardiovascular disease and with increasing age of the patient. New emboli occurred in less than 10 per cent of cases of pulmonary embolism and in such patients new segmental defects were noted on the scan. How Perfusion Lungs Scans Are Interpreted
The characteristics of perfusion defects help increase the diagnostic specificity as follows (21): (J) The interpretation of "no evidence of pulmonary embolism" may be made if a 4-view lung scan (anterior, posterior, and both laterals) is normal. (2) If the blood flow to the apices is greater than to the bases of the lungs and there is no evidence of focal perfusion defects, the interpretation should be "probable pulmonary venous hypertension without evidence of pulmonary embolism." (3) Pulmonary congestion or pleural effusion is suggested if there is no evidence of segmental perfusion defects and if the regions of decreased perfusion correspond to one or more fissures, often with increased blood flow to the upper portions of the lungs. (4) If on the posterior but not the anterior view one lung has a decrease in perfusion, there is a high probability of pleural effusion (figure 2). (5) Symmetric perfusion defects at the apices
POST R
L.LAT.
p
Fig. 2. A marked decrease in perfusion is noted in the posterior and right lateral views of this 4-view lung scan. This patient has a left-sided pleural effusion, as noted on the chest radiography. For definition of abbreviations, see figure I.
208
HENRY N. WAGNER, JR.
indicate parenchymal lung disease rather than pulmonary embolism. (6) A high probability of pulmonary embolism is suggested when one or more perfusion defects correspond with segmental arteries. An accompanying radiograph may be normal. In the presence of chronic obstructive pulmonary disease, arteriography will determine superimposed pulmonary embolism. (7) It is frequently noted in young adults with tetralogy of Fallot or other causes of right-toleft shunts that there is an increased concentration of radioactivity in the kidneys, denoting a right-to-left shunt (figure 3). Regional perfusion defects are observed in patients with congenitally hypoplastic pulmonary arteries. An extreme example is shown in figure 4. (8) Pulmonary infection is indicated when the perfusion defects correspond to areas of consolidation on the radiograph. (9) There is a high probability of neoplasm
when an entire lung lacks perfusion. Hilar bronchogenic carcinoma is more likely to produce this effect than pulmonary embolism. (10) Pulmonary edema is indicated when there are nonsegmental perfusion defects noted on the scan together with decreased perfusion of the medial aspects of the lung and along the fissures. Increased perfusion may be observed in the apices of the lungs in such patients. Parenchymal Lung Disease One of the important contributions of radioactive tracer studies of the lungs has been to document that all lung diseases have decreased pulmonary arterial blood flow to the involved regions. This does not mean that they are totally ischemic, because the blood flow is provided in most cases by the bronchial circulation. It does mean that intravenously injected particles fail to accumulate in these regions in the absence of a right-to-left intracardiac shunt. These findings
Fig. 3. There are multiple subsegmental perfusion defects noted bilaterally in this patient with Eisenmenger's disease. The activity noted in the kidneys indicates a right-to-left shunt, which is associated with this disease. For definition of abbreviations, see figure I.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
L
R
p
A
R
L
A
p
Fig. 4. This patient with a hypoplastic left pulmonary artery has minimal perfusion to the left, as noted in the lung scan. For definition of abbreviations, see figure I. complicate the interpretation of perfusion lung scans, but are at times valuable in the assessment of the degree of regional involvement by disease processes. Combined measurement of both regional ventilation and perfusion greatly improves the diagnostic specificity. It is now common practice to perform 133Xe ventilation studies together with anterior, posterior, and both lateral views of the distribution of perfusion. The use of multiple views permits characterization of lesions according to their size, shape, and position. The technique of radiospirometry with 133Xe requires the use of either the scintillation camera or multiple radiation detectors (14). The latter permit the use of smaller administered doses of 133Xe, but one does not obtain the spatial resolution that can be obtained with the scintillation camera. The use of the scintillation camera permits closer correlation of perfusion and ventilation defects. With the scintillation camera, the first step is to have the patient inhale radioactive 133Xe from a spirometer. The patient takes a deep breath, and the initial distribution of the activity is determined in the form of a single image. The second step consists of having the patient rebreathe the 133Xe for a period of 3 to 5 min. An image is obtained at the time that reveals the 133Xe space or alveolar air space. This image is particularly suitable for comparison with the single breath inhalation study, so that
209
the relationship between ventilation and lung volume can be ascertained. After the equilibration image, the patient is allowed to breathe into a collection system and the rate of clearance of the xenon from the various zones of the lung is measured. In most cases, this is done by serial images at 5-sec intervals, but in many laboratories the data are recorded in some storage system so that the clearance rate constants can be measured mathematically. In patients with parenchymal lung disease, such as infections (22) or chronic obstructive pulmonary disease (23, 24), the perfusion defects are accompanied by regional ventilation defects. The chest radiograph of a patient with sarcoidosis is shown in figure 5A; in 5B is the distribution of perfusion defects in the same patient. Lobar perfusion defects are noted in the perfusion lung scans of patients with lobar pneumonia with consolidation. Patchy nonsegmental perfusion defects are noted in the case of bronchopneumonia. Because there is reduced ventilation to the affected area, there is absence of 133Xe noted on the ventilation study. Either diminished ventilation or lack of ventilation, which corresponds to discrete perfusion defects, are noted in patients with bullae (figure 6A, B).
R L Fig. 5. A. This anterior view of the lung scan reveals a nonhomogeneous distribution of radioactivity throughout both lungs. The diagnosis of this patient was sarcoidosis.
Fig. 5. B. A chest radiograph shows diffuse involvement of the disease bilaterally. R ::: right; L ::: left. A lung scan performed in patients during an asthmatic attack often reveals large, irregular, segmental and nonsegmental defects (25). A changing pattern is noted on repeated studies during several days. A normal lung scan may be obtained between attacks (figures 7A-C).
Diminished ventilation corresponding to the perfusion defects is noted in the ventilation study. In patients with carcinoma of the lung the perfusion defect is often massive, often involving the entire lung. This may result from extrinsic obstruction of the main pulmonary artery. Regional ventilation is diminished when there is bronchial obstruction (figure 8). Radioactive Tracers in Preoperative Assessment Of Regional Lung Function
L
R
Fig. 6 A. This anterior view of the lung scan of a patient with bullous emphysema shows marked de· crease in perfusion to the right lung and upper lobes of the left lung. R ::: right; L ::: left.
The classic method for examination of differential lung function before pulmonary resection has been bronchospirometry (26, 27). More recently radioactive tracer techniques have provided a useful, noninvasive alternative (28-31). Both regional perfusion and ventilation have proved useful. Such studies have been found useful in the localization of roentgenologically occult cancer (30, 32), in providing information about the extent of involvement of the lungs (31), and in predicting the pulmonary functional loss after resection. A number of radioactive tracers that concentrate in neoplasms have been evaluated in patients with lung cancer. About 80 per cent of patients with bronchial neoplasms accumulated gallium·67 (33). Mercury-197 has also been used for this purpose. Lesions smaller than 2 em in diameter could not be visualized with the use of
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
211
Fig. 6. B. The chest radiograph reveals a massive bulla in the right lung and bullae in the upper and middle lobes of the left lung.
197Hg scintigraphy. Arborelius and associates (34) combined the use of 197Hg scintigraphy in radiospirometry and found an accuracy of 80 per cent. Tracer studies have been used preoperatively in patients with tuberculosis (22) and bullous emphysema as well as in carcinoma of the lung.
It is well accepted that the chest radiograph is an
insensitive mea ns of detecting early obstructive lung diseases as well as pulmonary embolism. This has led to the increasing interest in techniques such as closing volume measurements and regional measurements with radioactive tracers to provide more sensitive tests. After the pioneering physiologic investigations of Dollery and co-workers (35), Ball and associates (36) in 1962 used 133Xe a nd observed regional ventilation abnormalities in patients with
Fig. 7. A. This patient's lung scan was performed during an acute asthmatic attack. The posterior view shows bila teral perfusion defects more marked in the right upper lobe.
Fig. 7. B. A scan performed the following day revealed perfusion to the originally poorly perfused regions. R == right; L = left.
Early Detection of Obstructive Lung Disease
212
HENRY N. WAGNER. JR.
chronic obstructive lung disease. Since then, regional abnormalities have been found in asthma, chronic bronchitis, and emphysema. Perfusion and ventilation images in a patient with emphysema are shown in figures 9A and B. For comparison, figure 10 is an example of a 133Xe ventilation study with the scintillation camera in a person with normal ventilation. Of particular interest is the finding of Anthonisen and associates (23) that symptomatic patients with chronic obstructive pulmonary disease and nearly normal spirometric pulmonary function tests have clear-cut regional abnormalities. Two subsequent reports suggest that regional lung function measurements can detect abnormalities in asymptomatic subjects at a time when measurement of whole lung function including closing volumes is still within the variation observed among healthy persons. In the first study (37), radioisotopic regional lung function measurements using both albumin microspheres labeled with technetium-99m and inhaled 133Xe were compared to measurement of total lung function in a population of 30 participants in an epidemiologic study of the causative factors of obstructive pulmonary disease. Five of the 8 asymptomatic subjects who had no evidence of obstructive lung disease by the tests of total function had abnormal regional function measurements. The closing volume was ab-
normal in 3 of these 5, suggesting the presence of peripheral airways disease. Regional lung function was abnormal in all subjects who were symptomatic, who had a forced expiratory volume in 1 secj forced vital capacity ratio < 75 per cent, or who had an elevated closing volume or residual volume. The data suggested that measurement of regional lung function may be a highly sensitive test for the early diagnosis of chronic obstructive lung disease. A long-term prospective study would be required to determine the significance of these regional abnormalities. A second study (38) suggesting the sensitivity of regional function measurements was a study of 18 narcotics addicts without any symptoms of respiratory disease. Thirteen had regional abnormalities of perfusion of the lungs; 5 had abnormal zones of ventilation as well. Only time will tell the ultimate usefulness of regional pulmonary function measurements in the early diagnosis of obstructive airways disease. Pulmonary Venous Hypertension
Left ventricular failure and disease of the mitral valve frequently cause pulmonary venous hypertension. Redistribution of pulmonary arterial blood flow can be demonstrated in patients with congestive cardiac failure when tracers are injected in the supine position, resulting in increased perfusion to the upper lung fields. A
Fig. 7. C. A chest radiograph of the same patient.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
R
p
ANT.
L
A L. LA._T _ _
L
A
POST.
R.LAT
213
R
p
Fig. 8. The 4·view lung scan -and chest radiograph reveal extensive involvement of carcinoma of the right lung. There is a marked decrease in perfusion to the middle and lower lobes of the right lung. For definition of abbreviations, see figure I.
perfusion defect may be noted in the right middle lung field as a result of an enlarged atrium. In patients with cardiac failure the ventilation study is usually normal. A decrease in volume will be noted on the equilibration study with a normal washout if the patient has edematous lungs. Cor Pulmonale A recent use of radioactive tracers in patients with lung disease is in the study of the heart. Although these techniques are used today primarily in patients with coronary heart disease, they are beginning to be used in patients with lung disease. There are 3 types of procedures: (1) Distribution of regional myocardial blood flow can be depicted with the use of potassium analogues, such as ionic thallium-201 or rubidium-81. (2) Radionuclide angiocardiography is based on imaging the passage of an intravenously injected dose of [99mTc) albumin as it passes through the heart, lungs, and great vessels. The size of the intracardiac chambers, transit times from one region of the circulation to another, and the presence of left-to-right intracardiac chambers can be detected. (3) Regional and gen-
eral contractility of both ventricles can be determined after the [99mTc) albumin has become distributed in the vascular compartment. This is accomplished by "gating" or activating the scintillation camera by means of the patient's electrocardiogram. Several hundred beats can be examined during the end of systole and diastole. Comparison of the scintillation camera images of the heart can reveal the end-systolic and enddiastolic volumes, stroke volume, and ejection fraction. Validation studies to date have been limited to the study of the left ventricle, but initial results indicate that important information can be obtained about the right ventricle as well. The position of the patient that is most useful is the left anterior oblique position in which the right and left ventricles can be viewed separately. The intraventricular septum can be viewed to permit proper positioning of the patient. The types of information that can be obtained in these studies are dilatation and hypertrophy of the right and left ventricles and the relative performance of these 2 structures. In many patients to date, the differential diagnosis of cor pulmonale and the latter condition complicated
214
HENRY N. WAGNER, JR.
R
p
ANT
R.L T
L
L
A
A
POST
p
L.LAT
A
B
Fig. 9 A. (Top) In this patient with emphysema, the 4-view lung scan reveals nonsegmental perfusion defects bilaterally. There is decreased perfusion to both apices, more marked on the right. B. (Bottom) Decreased ventilation of both apices is noted in the single breath (S. Br.) view of the xenon-133 ventilation study. Delayed washout of the 133Xe from both lungs is noted bilaterally. Equil. =equilibration view; for definition of other abbreviations, see figure 1.
RADIOISOTOPE TECHNIQUES
S.Br.
I~
215
PUUIONARY DISEASE
Equil.
- Ssecs.
R
L
.....
.. (•
'.
5
20
10
Fig. 10. This normal ventilation study shows a uniform distribution of the xenon-133 gas in both lungs, in the single breath (S. Br.) and equilibration (Equil.) views. The 133Xe is expelled rapidly and uniformly as noted in the washout phase of the study (bottom row). R right; L left.
=
by coronary heart disease and left ventricular dysfunction have been aided by these procedures. Only time will tell their eventual role, but initial results have been encouraging. Differential Diagnosis of Cyanosis
Another area of usefulness of radioactive tracers is the study of patients with suspected respiratory problems is the diagnosis of r ight-to-left intracardiac shunts. In 1970 Hurley and associates (39) reported the use of radionuclide angiocardiography in the differential diagnosis of patients with congenital cyanotic heart disease. In all 30 patients with congenital cyanotic heart disease, the radionuclide angiocardiogram indicated an intracardiac right-to-left shunt. There were 3 fa lse positives among the 46 other pa· tients, none of whom had shunts. The principal indication was the appearance of the tracer in the left heart or abdominal aorta before the lungs were fully perfused. These results were confirmed and extended by Wesselhoeft and associates (40) in 43 children 3 years of age or less,
=
26 of whom had congenital heart disease. The criteria were improved and all 26 patients were correctly diagnosed as having congenital heart disease. There were no false positives. In many patients, the type of abnormality, such as transposition of the great arteries and truncus arteriosus, was correctly diagnosed before cardiac cath· eterization. Further validation and improvements were made by Kriss (7), and b y others. In normal subjects the pulmonary mean transit time, which can be measured or estimated subjectively by inspection of the serial images of the radionuclide angiocardiogram, averaged 6.5 ± l.O sec. Interpretation of transit times involves estimation of cardiac chamber sizes, because the reciprocal of the mean transit time in a given region is the ratio of blood flow through the region to the volume of the region the tracer is crossing. Inhalation of Aerosols
For almost a decade, aerosolized droplets incorporating a radioactive tracer, such as 99mTc or
216
HENRY N. WAGNER, JR.
indium-113m, have been used in experimental and clinical studies of the lungs (41, 42). The goal has been to facilitate measurement of the relative perfusion and ventilation to regional lesions as an aid in the differential diagnosis of pulmonary thromboembolism. In this method, the patient is connected to a nebulizer, the nostrils are occluded by means of a clip, and the patient breathes normally with a mouthpiece connected to a nebulizer. About 1.5 mCi of (99mTc] albumin or 3.0 mCi of 113min solution are retained by the lung parenchyma. The droplet size must be optimized so that the particles are small enough to reach the alveoli. Lung imaging is begun immediately and 4 views are obtained. Characteristic patterns have been observed in patients with chronic obstructive pulmonary disease, including bullous emphysema and chronic bronchitis. The distribution of the aerosol is related both to bronchial mucous deposits and other obstructions as well as to the distribution of ventilation. The measurement is not purely regional ventilation but is determined to a large degree by deposition of the aerosol by impaction. An important advantage of the use of inhaled aerosols rather than tssxe is that multiple views can be obtained. In the case of tssxe, only one view can be obtained unless the tssxe is administered several times. On the other hand, the advantage of tssxe is that ventilation rather than ventilation plus impaction is measured. An advantage of the use of 113min is that the aerosol inhalation study can be performed immediately after the perfusion study with 99mTc microspheres. The higher energy photon emission (390 kev) from 113min can be easily distinguished from the lower photon energy (140 kev) of 99mTc. An advantage of the inhaled aerosol technique is that mucociliary activity can be investigated, although only preliminary studies of this type have been performed to date. It is likely that inhaled particle studies will become more prevalent in the future. Most laboratories still use 133Xe for measurement of regional ventilation and 99mTc microspheres or particles for regional perfusion. Summary Although it is true that pulmonary perfusion scanning is generally accepted primarily in the differential diagnosis of pulmonary embolism, the introduction of regional ventilation studies with radioactive 133Xe, the use of the computer to provide quantitative data, and the advances
being made in cardiovascular nuclear medicine indicate that nuclear medicine procedures will be used more and more in the evaluation of patients with a variety of lung and heart diseases. They have already proved of value in the following circumstances: (I) differential diagnosis of pulmonary embolism; (2) assessment of regional involvement in pulmonary parenchymal disease, including degenerative, neoplastic, and infectious diseases; (3) detection of bullous disease and the determination of the possible effectiveness of surgery; (4) assessment of the response to radiation therapy in patients with carcinoma of the lung; (5) detection of pulmonary venous hypertension in patients with mitral valve or left ventricular disease; (6) detection of cor pulmonale; (7) differential diagnosis of cyanosis in newborn infants. References I. Knipping, H. W., Bolt, W., Vernath H., Valentin,
2.
3.
4.
5. 6.
7.
8.
H., Ludes, H., and Endler, P.: Ein neue methode zur prufung der herz und lungen funktion. Die regionale funktion analyse in der lungen und herzklinik mit hilfe der radioactiven endelgases xenon-13!1, Dtsch Med Wochenschr, 1955, 80, 1146. West, J. B., Dollery, C. T., and Hugh-Jones, P.: The use of radioactive carbon dioxide to measure regional blood flow in the lungs of patients with pulmonary disease, J Clin Invest, 1961, 40, 1. Wagner, H. N., Sabiston, D. C., McAfee, J. G., Tow, D., and Stern, H. S.: Diagnosis of massive pulmonary embolism in man by radioisotope scanning, N Engl J Med, 1964,271, !177. Cassen, B., Curtis, L., Reed, C., and Libby, R.: Instrumentation of 1-131 used in medical studies, Nucleonics, 1951, 9, 46. Urokinase pulmonary embolism trial, A national cooperative study, Circulation, 1973, Supplement II; AHA Monograph 39. Jones, R. H., and Anderson, P. A. W.: Congenital heart disease: Imaging and analytic methods, in Quantitative Nuclear Medicine Cardiography, R. N. Pierson, Jr., J. P. Kriss, R. H. Jones, and W. J. Macintyre, ed., John Wiley and SOns, New York, 1975, p. 32. Kriss, J. P.: Acquired cardiovascular disease, in Quantitative Nuclear Medicine Cardiography, R. N. Pierson, Jr., J. P. Kriss, R. H. Jones, and W. J. Macintyre, ed., John Wiley and Sons, New York, 1975, p. 66. Pierson, R.N., Jr., and Van Dyke, D. C.: Analysis of left ventricular function, in Quantitative Nuclear Medicine Cardiography, R. N. Pierson, Jr., J.P. Kriss, R. H. Jones, and W. J. Macintyre, ed., John Wiley and SOns, New York, 1975, p.l23.
RADIOISOTOPE TECHNIQUES IN PULMONARY DISEASE
9. Wagner, H. N., Jr.: The heart and circulation, in Nuclear Medicine, H. N. Wagner, Jr., ed., Hospital Practice Publishing Co., New York, 1975, p. 112. 10. Wagner, H. N., Jr., and Rhodes, B. A.: Radioactive tracers in diagnosis of cardiovascular disease, Prog Cardiovasc Dis, 1972, 15, !. II. Blumgart, H. L., and Weiss, S.: Studies on the velocity of blood flow. VII. The pulmonary circulation time in normal resting individuals, J Clin Invest, 1927,4, 399. 12. Zaret, B. L., Strauss, H. W., Hurley, P. J., Natarajan, T. K., and Pitt, B.: A noninvasive scintiphotographic method for detecting regional ventricular dysfunction in man, N Eng! J Med, 1971, 284, 1165. 13. Anger, H. 0.: Instruments: Specific devices, in Nuclear Medicine, H. N. Wagner, Jr., ed., Hospital Practice Publishing Co., Inc., New York, 1975, p. 29. 14. Natarajan, T. K., and Wagner, H. N., Jr.: Functional Images of the Lungs in Dynamic Studies with Radioisotopes in Medicine, International Atomic Energy Agency, Vienna, SM-185fl5, vol. II, 1974. 15. Wagner, H. N., Jr., and Natarajan, T. K.: Computers, in Nuclear Medicine, H. N. Wagner, Jr., ed., Hospital Practice Publishing Co., Inc., New York, 1975, p. 41. 16. Gilday, D. L., Poulose, K. P., and Deland, F. H.: Accuracy of detection of pulmonary embolism by lung scanning correlated with pulmonary angiography, Am J Roentgenol Radium Ther Nucl Med, 1972, 115,732. 17. Greenspan, R. H.: Does a normal isotope perfusion scan exclude pulmonary embolism?, Invest Radial, 1974, 9, 44. 18. Tow, D. E., and Simon, A. L.: Comparison of lung scanning and pulmonary angiography in the detection and follow-up of pulmonary embolism. The urokinase pulmonary embolism trial experience, Prog Cardiovasc Dis, 1975, 17, 239. 19. Sasahara, A. A., Mcintyre, K., Criss, A. J., and Belko, J. S.: Aggressive approach to the management of pulmonary embolism, Cardiovasc Clin, 1969, 1' 261. 20. Tow, D. E., and Wagner, H. N., Jr.: Recovery of pulmonary arterial blood flow in patients with pulmonary embolism, N Engl J Med, 1967, 276, 1063. 21. Wagner, H. N., Jr., and Strauss, H. W.: Radioactive tracers in the differential diagnosis of pulmonary embolism, in Cardiovascular Nuclear Medicine, H. W. Strauss, B. Pitt, and A. E. James, ed., C. V. Mosby Co., St. Louis, 1974, p. 278. 22. Lopez-Majano, V., Wagner, H. N., Jr., Tow, D. E., and Chernick, V.: Radioisotope scanning of the lungs in pulmonary tuberculosis, JAMA, 1965,194, 1053.
217
23. Anthonisen, N. R., Bass, H., Oriol, A., Place, R. E. G., and Bates, D. V.: Regional lung function in patients with chronic bronchitis, Clin Sci, 1968,35,495. 24. Bentivoglio, L. G., Beerel, F., Stewart, P. B., Bryan, A. C., Ball, W. C., Jr., and Bates, D. V.: Studies of regional ventilation and perfusion in pulmonary emphysema using xenon 133, Am Rev Respir Dis, 1963, 88, 315. 25. Heckscher, T., Bass, H., Oriol, A.: Regional lung function in patients with bronchial asthma, J Clin Invest, 1968,47, 1063. 26. Gaensler, E. A., Patton, W. E., and Frank, N. R.: Bronchospirometry. VII. Indications, .J Lab Clin Med, 1953,41,456. 27. Snider, G. L.: A critical evaluation of bronchospirometric measurement in predicting loss of ventilatory function due to thoracic surgery, J Lab Clin Med, 1964,64, 321. 28. Maynard, C. D.: Role of the scan in bronchogenic carcinoma, Semin Nucl Med, 1971,1, 195. 29. Tauxe, W. N., Carr, D. J., and Thorsen, H. C.: Perfusion lung scans in patients with inoperable primary lung cancer, Mayo Clin Proc, 1970, 45, 337. 30. Wagner, H. N., Jr., Lopez-Majano, V., Tow, D. E., and Langan, J. K.: Radioisotope scanning of lungs in early diagnosis of bronchogenic carcinoma, Lancet, 1965, 1, 344. 31. Arborelius, M., Jr., Kristersson, S., Lindell, S. E., Miorner, G., and Svanberg, L.: Xenon-133 radiospirometry and extension of lung cancer, Scand J Respir Dis, 1971,52, 145. 32. Lindell, L., Lindell, S. E., and Svanberg, L.: Regional lung function in roentgenologically occult lung cancer, Scand J Respir Dis, 1972, 53, 109. 33. Larson, S. M., Milder, M. S., and Johnston, G. S.: Tumor-seeking radiopharmaceuticals: Gallium67, in Radiopharmaceuticals, G. Subramanian, ed., Society of Nuclear Medicine, Inc., New York, 1975, p. 413. 34. Arborelius, M., Nosslin, B., and Lindell, S. E.: 197Hg-scintigraphy and 133Xe-radiospirometry in the diagnosis of pulmonary tumor, Scand J Respir Dis, 1974, 85 (Supplement, p. 119). 35. Dollery, C. T., Hugh-Jones, P., and Matthews, C. M. E.: Use of radioactive xenon for studies of regional lung function, Br Med J, 1962, 2, 1006. 36. Ball, W. C., Jr., Stewart, P. B., Newsham, L. G., and Bates, D. V.: Regional pulmonary function studied with xenon 133, .J Clin Invest, 1962, 41, 519. 37. McKusick, K., Wagner, H. N., Jr., Soin, J. S., Benjamin, J. J., Cooper, M., and Ball, W. C.: Measurement of regional lung function in the early detection of chronic obstructive pulmonary disease, Scand .J Respir Dis, 1974, 85 (Supplement, p. 51). 38. Soin, S. S., McKusick, K. A., and Wagner, H. N., Jr.: Regional lung function in narcotic addicts,
218
HENRY N. WAGNER, JR.
JAMA, 1973,224, 1717. 39. Hurley, P. J., Strauss, H. W., and Wagner, H. N., Jr.: Radionuclide angiocardiography in the diagnosis of congenital heart disease in infants, Circulation, 1972,45, 77. 40. Wesselhoeft, H., Hurley, P. J., Wagner, H. N., Jr., and Rose, R. D.: Nuclear angiocardiography in the diagnosis of congenital heart disease in infants, Circulation, 1972, 45, 77.
41. Taplin, G. V., Poe, N.D., Dore, E. K., and Greenberg, A.: Bronchial patency and aerated space assessment by scintiscanning, LCFB, 1967, 16, 297. 42. Taplin, G. V., Poe, N. D., Dore, E. K., Greenberg, A., and Isawa, T.: Radioaerosol inhalation scanning, in Pulmonary Investigation with Radionuclides, A. J. Gilson and W. M. Smoak, ed., Charles C Thomas, Springfield, Ill., p. 296.
