The history of lung imaging with radionuclides

The History of Lung Imaging with Radionuclides George V. Taplin

TYPES of lung imaging test agents and T WO procedures for their administration were developed at the UCLA Laboratory of Nuclear Medicine and Radiation Biology between 1963 and 1965./-4 The first of these was devised to image the blood flow pattern in the lungs by rectilinear scanning, after the i.v. injection of macroaggregates of human serum albumin (HSA) labeled with 131I, size range, 10-50pm? The macroaggregates were first produced in January 1963, but this agent stemmed from the development of a simplified method of preparing colloidal-size (10-20nm) 131l albumin suspensions by pH adjustment and heating in a water bath at 90-95~ for 8-10 min under gentle agitation? Albumin colloid labeled with 131I is useful in visualizing the liver, spleen, and bone marrow by scanning./In such studies, however, if the size of the particles exceeds 5-10#m, lung entrapment is easily demonstrable. Therefore, an extensive study was made to determine the optimal size for lung visualization by temporary capillary and arteriolar blockade. The size was adjusted so that pulmonary entrapment lasted no longer than a half-life of 4-8 hr. In the first animal trials, extremely low specific activity (approximately 50~tCi/mg of HSA) was used. Even so, the scan dose (300pCi in 6 mg HSA) was 50100 times below the minimum toxic dose level (20-30mg of HSA/kg). This work was first reported in a scientific exhibit at the Tenth Annual Meeting of the Society of Nuclear Medicine in Montreal, Canada, in June 1963. 6 Lung scanning in man was initiated in November 1963 From the Laboratory of Nuclear Medicine and Radiation Biology, University of California, Los Angeles, Calif. George V. Taplin, M.D.: Professor of Nuclear Medicine and Radiological Sciences, Associate Director, Laboratory of Nuclear Medicine and Radiation, Biology, and Director, Nuclear Medicine, Research Laboratory, University of California at Los Angeles. Address reprint requests to George V. Taplin, M.D., Laboratory of Nuclear Medicine and Radiation Biology, University of California, 900 Veteran Ave., Los Angeles, Calif. 90024. Received for publication May 3, 1974. 9 1979 by Grune & Stratton, Inc. 0001-2998/7 9/0901~900950 200/0 178

at UCLA ~'2 after Wagner's Human Studies, using much higher specific activity HSA suspensions (1000pCi/mg of HSA). The second development was made in 1964 and first reported in 1965. 3 Radioaerosols were administered to anesthetized dogs via tracheal intubation. They were produced by a positive pressure nebulizer. Subsequently, similar procedures, radioaerosols, and nebulizer equipment were studied in man. 4 In 1966 colloidal radioactive gold, 198Au, was replaced by 99mTc-HSA and sulfur colloid 99mTC as test agents, to decrease radiation exposure to the lungs. 7 This communication describes in detail lung perfusion and airway patency inhalation procedures, along with an evaluation of their current value in the differential diagnosis of pulmonary embolism, and in the detection of obstructive airways disease. TM The relationship of both procedures to the findings from plain chest radiography and pulmonary angiography is compared in a variety of pulmonary and obstructive airways disorders. PRINCIPLES OF LUNG IMAGING

Perfusion Imaging The lungs may be visualized by radionuclide imaging whenever gamma-emitting radionuclides are delivered to the lungs in concentrations exceeding those in the heart and overlying tissues. Suspensions of albumin 1311macroaggregates or macroaggregated albumin 99mTC in the size range of 10-50~tm were found to be remarkably safe, 12 and satisfactory test agents for lung perfusion imaging in man (Fig. 1). After injec-

The author demonstrating perfusion lung images and chest film in major pulmonary embolism of the right upper

lobe (August 1974). Seminars in Nuclear Medicine, Vol. IX, No. 3 (July), 1979

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Hemocytometer View :Jl~"

Fig. 1. Hemocytometer view (• comparing the size of human red blood cells with a sample of the very early albumin 1311aggregates (5-50p.m). The squares are 50 • 50/~m for size estimation,

tion, aggregates larger than 10~m are immediately trapped in the pulmonary arteriolar-capillary bed, with 90%-95% efficiency. On the assumption that complete mixing occurs in the heart, the amount of radioactivity retained in any given region of the lung is proportional to blood flow at the time of the i.v. injection. These fragile, soft, and malleable aggregates then become eroded and fragmented into smaller particles. These smaller aggregates (1-5urn) can then traverse the alveolar capillary network and reenter the general circulation. After entrapment in the reticulo endothelial system, they are metabolized and the ~3'I label is mainly excreted in the urine, but only when the thyroid is blocked. The normal removal rate from the lung ranges from half-life values of between 4 and 8 hr.

Inhalation Lung Imaging

droplets are distributed evenly throughout the lower respiratory tract in normal persons. Relatively little is retained in the throat, trachea, or large bronchi. The aerosol is produced with an ultrasonic nebulizer,* and this inhalation procedure is conducted in a closed system to prevent contamination of room air. With aerosols of this small-size distribution, approximately 2%-10% of the administered dose is retained in the lower respiratory tract. Approximately 10%-15% is exhaled, whereas 50% of the aerosol remains in the medication chamber of the nebulizer, and approximately 25% adheres to the tubing that channels the inhaled aerosol to the mouthpiece. With the latest ultrasonic nebulizers, approximately 2 ml of radioactive solution can be converted to a dense aerosol each minute. A sufficient amount (20-30 mCi of albumin 99mTC or neutral ll3mln) deposits 0.5-1.0 mCi of the aerosol in the upper and lower respiratory

After normal tidal volume inhalation of radioactive aerosols composed of particles ranging in size from 0.1 to 2.0~zm, the radioactive

*Mistogen Ultrasonic Nebulizer, Mistogen Company, Oakland, California

180

GEORGE V. TAPLIN

passages and alveoli. In the average subject, this requires an inhalation period of 5-10 min. Lung imaging may be started immediately after completion of the inhalation procedure. The rate of lung removal of nonabsorbable radioactive aerosols in normal subjects is slow (half-life, 15-20 days). 13 Clearance from the trachea and major bronchi is much faster: 30-90 min. In individuals with obstructive airway disease, however, excessive aerosol deposition occurs in the major bronchi. The lung removal rate curves from such individuals have a distinct two-phase pattern, indicating that approximately one-half of the total quantity of aerosol initially deposited is removed from the upper airways quite rapidly (4-6 hr), but thereafter, the removal rate is relatively slow. Imaging during the first hour displays the initial distribution pattern. In normal persons, the lung images after radioaerosol inhalation and macroaggregate injection are nearly identical but have an entirely different physiologic significance (Fig.

2). The inhalation scan delineates the volume of aerated lung, and the amount of inhaled radioactivity deposited in a given region varies in proportion to ventilation, but only in normal persons. In individuals with excessive deposition in the upper airways, as in obstructive bronchopulmonary disease, the aerosol inhalation lung pattern is not a good indicator of regional ventilatory performance. In such cases, however, the lung images indicate the degree and site(s) of partial or complete obstructive airways disease and/or of airflow interference (Fig. 3). LUNG I M A G I N G E Q U I P M E N T , AND

PAST

PRESENT

In the early studies (1963-1967), conventional rectilinear scanners with either 3- or 5-in. sodium iodide crystals and coarse collimators were employed (7 and 19 holes, respectively). Since 1967, a ten-probe rectilinear scanner and/or scintillation cameras were employed. With either of these instruments, lung images of

NORMAL S . D . , o~ , 57

AEROSOL INHALATION

PERFUSION

PULMONARY FUNCTION FINDINGS

ANTERIOR

ANTERIOR

OBSERVED

% OF PREDICTED

FEV1

4,397

124

MEFR

5,256

167

P02 02 SINGLE BREATH

98 0.67

>I00

NON SMOKER IMPRESSION: NORMAL L POSTERIOR

POSTERIOR

Fig. 2. Normal perfusion and radioaerosol lung images in a normal subject, tmmTc macroaggregates (3 mCi) were injected for the perfusion study, followed by the inhalation of 20 mCi. 1'3raincolloid with 1.0 mCi was retained in the lungs. Results of some standard pulmonary function tests are shown to be normal in this 57-yr-old man.

181

LUNG IMAGING WITH RADIONUCLIDES

SEVERE

PERFUSION

OBSTRUCTIVE AIRWAY DISEASE R . V . , d , 58

AEROSOL INHALATION PULMONARYFUNCTIONFINDINGS OBSERVED

ANTERIOR

FEVl

1.20

MEFR

0.801

3.17 02 SINGLE BREATH

ANTERIOR

pO2

64.00

% OF PREDICTED 33.8

9.79 GREATLY+

MOD. LOW

SMOKER IMPRESSION: SEVEREAIRWAY DISEASE

RIGHT LATERAL

RIGHT LATERAL

Fig. 3. Composite of abnormal perfusion and aerosol lung images, together with the results of pertinent pulmonary function tests. All three studies are grossly abnormal.

high resolution and information density (100300 K) are obtained in 1.0-3.0 rain per view. CLINICAL APPLICATIONS

Lung perfusion and inhalation imaging give the physician valuable tools in the diagnosis and management of major pulmonary disorders. These include pulmonary embolism, tuberculosis, hronchogenic carcinoma, and chronic obstructive bronchopulmonary disease. These two radionuclide lung imaging procedures are unique among tests of pulmonary function in their capacity to reveal regional alterations in pulmonary arterial blood flow, ventilation, and airway patency. They aid the radiologist in the interpretation of chest films and angiograms, and serve as screening procedures for routine or selective pulmonary angiography and bronchography. 14 They supplement tests of integrated pulmonary function by localizing areas of normal and malfunctioning lungs, and thereby

help the thoracic surgeon in planning his operative procedures/5 Their diagnostic value is best exemplified in pulmonary embolism, the most common lethal form of pulmonary disease in hospital practice, ~6 which is estimated to cause approximately 47,000 deaths annually in this country. Lung perfusion imaging discloses the primary physiologic disturbance in this disease--regional pulmonary ischemia--and either excludes or leads to an early diagnosis far more frequently than any other single procedure. ~v Inhalation lung imaging provides further evidence for the diagnosis of acute pulmonary embolism (Fig. 4) and is especially helpful in patients with underlying obstructive bronchopulmonary disease (Fig. 5) in its capacity to demonstrate either airway patency to, and ventilation of the ischemic segment or lobe of the lung involved (pulmonary embolism), or by showing matching perfusion and airway patency defects ~'js'~9 (obstructive emphysema), or by

182

GEORGE V. TAPLIN

PERFUSION

INHALATION

POSTERIOR VIEWS

LEFT LATERAL VIEWS

I. P., ,37 Fig. 4. Composite of chest films compared with perfusion and aerosol inhalation lung images in a 37-yr-old w o m a n w i t h suspected pulmonary embolism (PE). The perfusion images, together w i t h normal chest films, are strongly indicative of a diagnosis of PE. The demonstration t h a t the ischemic lesions in the left lung are well ventilated increases the probability of pulmonary embolism to nearly 100%.

providing evidence for the existence of both disorders, simultaneously. RECENT ADVANCES IN LUNG IMAGING (AFTER INHALING MISTS OR DUSTS)

Two important advances were made in 1974 in the inhalation of wet and dry aerosols for lung imaging? j The wet aerosol procedure was made 3-5 times more efficient by replacing the air blower with a demand valve (Fig. 6) on the nebulizer. This improvement has converted wet aerosol inhalation from a tedious, excessively time-consuming experimental procedure into a rapid, reliable, routine test in the clinical practice of Nuclear Medicine2~(Fig. 7). Dry radioaerosoi inhalation, employing micro-

pulverized (mean size,
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183

UNDERLYING COPD PERFUSION

INHALATION

r84 i

J L

ANTERIOR VIEWS

1=

LEFT LATERAL VIEWS

O.J.,(f, 52 Fig. 5. Composite of chest films, perfusion, and inhalation scans of a 52-year-old mate patient w i t h suspected PE. The perfusion scan shows several subsegmantal defects and tall lungs. The aerosol study shows a grossly abnormal pattern typical of chronic obstructive airway and lung disease, indicating t h a t a diagnosis of PE is most unlikely, and the abnormal perfusion scans can be readily explained on the scan findings indicative of underlying obstructive airways disease.

Fig. 6. Comparison of t h e ultrasonic nebulizer model 143 w i t h t h e latest model 145, which is approximately 2.5 times more efficient in converting a solution to a fine aerosol. A more important feature is t h e replacement of the air blower line, by a o n e - w a y demand valve. This modification adds another factor of 3 - 5 to the amount of aerosol deposited in the patients" lungs.

NEBULIZER M O D E L

145

GEORGE V. TAPLIN

184

99mTc-S COLLOID WET AEROSOL

ANT

ANTERIOR

RIGHT LATERAL

NEBULIZER 145 (DEMAND VALVE IN PLACE OF BLOWER) N . M . , ~ , 45 Fig. 7. Anterior and right lateral lung images in a normal woman, age 45 yr, made immediately after inhaling 20 mCi of colloid ~ T c - S using the modified nebulizer 145. 30OK images were obtained in 111 sec, indicating that approximately 2.0 mCi of ~"Tc had been deposited in the lungs after a 5-min inhalation period.

r

7

Top with Puncturing Device - -

RT LATI

G.D,R.,(~, 30- Volunteer Fig. 9 Lung images made after inhaling, in a single breath, 3mCi of tin-lactose Se'TC powder (<5#m in size} using the Syntex powder inhaler. Approximately 0.5 mCi was deposited evenly throughout the lung fields, with little or no deposition in the posterior pharynx and trachea. A small amount of tracer appears in the stomach. The 100K camera lung images required a 2.0-min exposure.

house" p r e p a r a t i o n or for m a n u f a c t u r i n g by the r a d i o p h a r m a c e u t i c a l industry. It is e s t i m a t e d that the test m a t e r i a l in kit form m a y not be m a d e generally available for a few years. PREDICTED IMPROVEMENTS IN THE NEAR FUTURE

Two methods of p r o d u c i n g d r y - p o w d e r e d aerosols of 99mTc-tin-lactose or 113mln a r e being devised. One can be p r e p a r e d c o m m e r c i a l l y in the near future by the method devised in our l a b o r a t o r y by G e r a l d D. Robinson. 23 This proced u r e is suitable for p r o d u c t i o n by c e r t a i n c o m p a n i e s h a v i n g the c a p a b i l i t y o f r a p i d delivery in ready-to-use form, as is being done with ~SF for bone scanning. T h e second "inhouse" kit-type p r e p a r a t i o n is likely to t a k e m o r e time to develop. ACKNOWLEDGMENTS Spinning Wheel and Powder Copsule

Bose- to hold Functional Components--

Fig. 8 Photographic breakdown of the essential components of a commercially available powder inhaler (Syntex). The powder capsule and spinning wheel are shown separately. The top of the apparatus with the device to puncture the capsule is shown above the base, which holds all the essential parts.

The author wishes to express his appreciation and gratitude for the assistance of his many colleagues, who generated most of the data herein reported. These include Drs. Norman D. Poe, Delores E. Johnson, Leonard Swanson, Earl K. Dore, Michael Hayes, Toyoharu Isawa, Michael Uszler, and Lalitha Ramanna. 1 am equally grateful to Mary Lee Griswold for her important part in the development of colloidal size and macroaggregated, radioiodinated albumin suspensions, and to Ethel Plummer and Dennis Elam for their excellent technical assistance. The author is especially grateful to the following individuals and companies: Gordon Lindenblad, Ph.D., Director of Research of the Radiopharmaceutical Division of the Mallinckrodt Chemical Works; H. Maroon, M.D., and G. Bruno, Ph.D., of E. R. Squibb & Sons Radiopharmaceutical Division; L. Robert Cameto, President

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of the Mist-O-Gen Equipment Company, for supplying the nebulizer equipment during the past 10 yr and for assistance in improving existing equipment, particularly during the past several months; Hector Pimentel of the UCLA Laboratory of Nuclear Medicine and Radiation Biology for photographic

assistance. Finally, the author wishes to acknowledge the major support of this and preceding work of this type done during the past 10 yr by the GEN-12 contract between the U.S. Atomic Energy Commission and the University of California.

REFERENCES

I. Taplin GV, Johnson DE, Dore EK, et al: Suspensions of radioalbumin aggregates for photoscanning the liver, spleen, lung, and other organs. J Nucl Med 5:259, 1964 2. Taplin GV, Johnson DE, Dore EK, et al: Lung photoscans with macroaggregates of human serum radioalbumin. Experimental basis and initial clinical trials. Health Phys 10:1219, 1964 3. Taplin GV, Poe ND: A dual lung-scanning technic for evaluation of pulmonary function. Radiology 85:365, 1965 4. Taplin GV, Poe ND, Greenberg A: Lung scanning following radioaerosol inhalation. J Nucl Med 7:77, 1966 5. Taplin GV, Griswold ML, Dore EK: Preparations of colloidal suspensions of human serum albumin I TM for estimating liver blood flow and reticuloendothelial system functions in man. USAEC Rep UCLA-481, June t961 6. Taplin GV, Dore EK, Johnson DE, et al: Colloidal radioalbumin aggregates for organ scanning. Scientific exhibit, Tenth Annual Meeting of the Society of Nuclear Medicine, Montreal, Canada, 1963 7. Taplin GV, Johnson DE, Kennady JC, et al: Aggregated albumin labeled with various radioisotopes. Radioactive Pharmaceuticals, USAEC, T1D, 1966 8. Dore EK, Poe ND, Ellestad MH, et al: Lung perfusion and inhalation scanning in pulmonary emphysema. Am J Roentgenol Radium Ther Nucl Med 104:770, 1968 9. Poe ND, Dore EK, Swanson LA, et al: Fatal pulmonary embolism. J Nucl Med 10:28, 1969 10. lsawa T, Wasserman K, Taplin GV: Lung scintigraphy and pulmonary function studies in obstructive airway disease. Am Rev Resp Dis 102:161, 1970 11. McNeil B, Holman L, Adelstein JA: The scintigraphic definition of pulmonary embolism. JAMA 227:753, 1974 12. Poe ND, Taplin GV: Pulmonary scanning, in Blahd WH (ed): Nuclear Medicine (ed 2). McGraw-Hill, 1971

13. Poe ND: Lung scanning with radioactive particles, aerosols, and gases. Int Anesthesiol Clin 8:655, 1970 14. Poulose KP, Reba RC, Gilday DL, et al: Diagnosis of pulmonary embolism. A correlative study of the clinical scan, and angiographic findings. Br Med J 3:67, 1970 15. Ueda H, lio M, Kaihara S: Determination of regional pulmonary blood flow in various cardiopulmonary disorders, study and application of macroaggregated albumin (MAA) labeled with 13q. Jpn Heart J 5:431, 1964 16. Freiman DG, Suyemoto J, Wessler S: Frequency of pulmonary thromboembolism in man. N Engl J Med 272:1278, 1965 17. Taplin GV: Scintiscanning in the assessment of regional pulmonary function, in Gordon BL (ed): Clinical Cardiopulmonary Physiology. New York, Grune & Stratton, 1969 18. Isawa T, Hayes M, Taplin GV: Radioaerosol inhalation lung scanning: its role in suspected pulmonary embolism. J Nucl Med 12:606, 1971 19. Taplin GV, Poe ND, lsawa T, et al: Radioaerosol and xenon gas inhalation and lung perfusion scintigraphy. Scand J Resp Dis [Suppl] 85:144, 1974 20. Taplin GV, Elam D, Griswold ML, et al: Aerosol inhalation in lung imaging (work in progress). Radiology 112:431, 1974 21. Taplin GV, Bryan FA: Administration of micronized therapeutic agents by inhalation or topical application. Science 105:502, 1947 22. Taplin GV, Cohen SH, Mahoney EB: Prevention of postoperative pulmonary infections. Inhalation of micropowdered penicillin and streptomycin. JAMA 138:4, 1948 23. Taplin GV, Robinson GD, Elam DA: Potential value and high efficiency of dry aerosols for lung imaging. J Nucl Med 15:537, 1974 (abs)