Merle K. Loken and Hugh D. Westgate

University of Minnesota Hospitals, Minneapolis, Minnesota

During the past several years considerable atten monary-function laboratory (6—9). Thus because of tion has been given to evaluating pulmonary disease their universal availability, the noble are being using radioisotopic techniques. The majority of the used more extensively, and, of these gases, ‘33Xehas radioactive preparations used for these studies can the best physical characteristics (5, 10—13). be divided into two general categories : colloidal In this paper we report our preliminary experience aggregates of albumin and radioactive gases. Macro using an Anger scintillation camera to record pul aggregates labeled with 1311or [email protected]'Tchave been used monary uptake and clearance of ‘33Xein patients extensivelyfor determining regional pulmonary per referred to our service for pulmonary-function evalu fusion and, as such, are useful for evaluating patients ation. The radioactive xenon was administered either with suspected pulmonary emboli (1—5). The dis by inhalation or intravenous injection. tribution of these macroaggregates in the is usually determined by conventional rectilinear scan MATERIALS AND METHODS ning although the scintillation camera has also been We obtain 133Xe in 1-curie ampules at approxi used effectively (4,5). mately biweekly intervals from Ridge National To obtain information on ventilation and Laboratory. The is contained in a volume of one of the radioactive gases—oxygen, dioxide, about 5 cc at a of about 10 mmHg (Fig. 1). or xenon—must be used. The half- of For most of our work we need the xenon in gamma-emitting oxygen and carbon radioisotopes with saline, and we have devised a special technique are extremely short so that the cyclotron used for for making this transfer (Fig. 2). After unpackaging their production must be very close to the pul Received Nov. 10, 1966; accepted March 8, 1967.



@ tt 4 [email protected]‘@7 @‘Q' 1.0 11 22 13 2.4 1 1― ___ 22 212 HG. 1. XenonampulefromOakRidgeNationalLoboratory,shownwith FIG.2. Apparatusassembledfortrans. rubber connector, adaptor and long plunger needle. ferring xenon into saline solution.

Volume 9, Number 2 45 LOKEN AND WESTGATE

the xenon ampule and assaying it for radioactive dose of about 10 millirads which is only a small per content, we sterilize it in zepharin solution and then centage of the gonadal dose from a conventional immobilize it in a hollow cylinder with plaster radiograph of the pelvis and is considered safe for of Paris. A 2-in. length of rubber tubing with routine diagnostic radioisotope work (14) . Admin a ¼-in. inner diameter is then fitted over the ampule istration of this amount of 133Xeresults in counting and clamped. After clamping, a specially designed rates over the which are considerably higher metal adapter is inserted on the other end of the than can be recorded optimally by any gamma cam rubber tube and secured with a clamp (Fig. 1) . A era available at this time. Therefore we conclude rubber cap is placed over the open end of this metal that in practice the upper limit for [email protected] activity used adapter, and a 50-cc glass with two stop for pulmonary-function studies is governed more by cocks is attached to its side arm. All components of the resolving characteristics of the instruments used this system are sterilized before use. The assembly to detect the than by the radiation dose to procedure is then carried out aseptically. The entire patients. system is fixed in place as shown, and sterile saline Of the many radioactive gases that exist, 133Xe is added to replace all the air in the system. Because is the most promising for pulmonary-function studies the solubiity of xenon in saline is much less than in today. The isotope has a half- of 5.27 days, and air, it is of utmost importance to remove all air from its gamma ray of 81 key is suitable for localization the system to obtain an acceptable of studies with the instruments now available. This is xenon in saline. particularly true with our scintillation camera which A 100-cc syringe ifiled with sterile saline is fitted has recently been installed with bi-alkali cathode with two stop cocks and a long needle. The needle is photomultiplier tubes. The low work function for inserted through the rubber cap and advanced care electron release in these photomultiplier tubes im fully through the glass seal on the xenon ampule. proves the resolution in studies using radioactive The plunger of the syringe is advanced slowly so such as 133Xe which emit relatively low that sterile saline is flushed through the ampule. The gamma . xenon then enters into saline solution which is flushed Because one obtains high counting rates with 5— through the system daily for three or four days until 10 mc of ‘33Xe,the “deadtime―of the recording essentially all the xenon has been removed from the instruments must be maintained at an absolute mini ampule. mum. Recent circuitry modifications have decreased The extremely short biological half-life of inert the dead time of our scintillation camera to about gases such as ‘33Xemakes it possible to administer 4 @secwhich appears to be about the shortest dead rather large quantities of radioactivity to patients time possible for an instrument with this design. without significant radiation . Calculations However, it is sufficiently good to let us obtain show that an intravenous or intra-arterial injection scintiphotograms of isotope distribution at about of 40 mc ‘33Xedissolved in saline results in a gonadal 1-sec intervals.

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FIG.3. Pulmonaryuptakeandclearancecurvesfollowingin halation or intravenous administration of lmXe.

HG. 4. Semilogplotforanalyzingclearancetimesof xenon administered by intravenous injection or inhalation (normal subject).


A third modification made on our scintillation a consolidation in the right upper lung field which camera was the addition of a second ratemeter so that was biopsied during bronchoscopy and found to be counts collected from half the crystal are fed to one a bronchogenic carcinoma. The scintiphotogram ratemeter and recorder and those from the other half shows a decreased of the right upper lung go to a second ratemeter and recorder.* With this field in the region of the tumor. The remainder of system data on xenon uptake and clearance can be both lung fields visible on the scintiphotogram ap obtained simultaneously with serial scintiphotograms pears to be quite well perfused with . of the radioactive xenon distribution in both hemi lungs.

RESULTS Figure 3 shows typical patterns of xenon uptake and clearance from lungs of two patients taken at random. Curve A was obtained during administration of xenon by inhalation for 4 mm. The subject then breathed room air and a xenon clearance was recorded. Curve B shows clearance of xenon from a normal lung after intravenous administration of 5 mc of xenon in saline. FIG.6. “@Xeand @‘111Tcpulmonaryscintiphotogramsof patient (AK.) with ‘farmer'slung.― Figure 4 gives a logarithmic analysis of data from curves such as those in Fig. 3. Each curve is made up of more than one clearance component as the dis Figure 6 shows one scintiphotogram made after tinct changes in slope indicate. The initial or fast administering xenon in saline to a patient (A.K.) components of each curve are quite similar, as is clear with a clinical diagnosis of “farmer's lung.― The from the fact that the T1, 2clearance times are nearly conventional scan in the figure was made after ad the same (27 and 30 sec for injection and inhalation ministering 3 mc @9―Tclabeled to macroaggregates of studies, respectively) . As time progresses, more albumin. Both these studies show marked irregu residual activity is recorded for the xenon-inhalation larity in the perfusion of the lung fields, particularly procedures than for the xenon-injection ones. in the peripheral portion of the right lobe. Figure 5 shows the initial scintiphotogram oh Figure 7 contains three selected posterior-view tamed after injecting 5 mc ‘33Xeto a patient (M.B.) scintiphotograms and a chest x-ray of a patient with carcinoma of the lung. The chest x-ray reveals (C.D. ) with a right scoliosis. The initial picture (No. 1) , made during inhalation of xenon from the

C Since this manuscript was written, a new console has spirometer, shows reasonably uniform ventilation of been installed for the scintillation camera which permits both lung fields. The second scintiphotogram was quadrant field splitting so that data can be collected on upper and lower lung fields bilaterally. An analog-to-digital converter, 1,600-channel memory system and high-speed magnetic-tape unit are on order. This equipment will let us divide the lungs into as many as 1,600 segments for regional evaluation of pulmonary function. Computer analyses of these data are planned.


FIG.5. Initialscintiphotogramof lungobtainedafterxenon FIG.7. Chestx-rayandthreeselectedpulmonaryscintiphoto injectionis compared with chest x-ray of patient(M.B.)who has grams obtained after ‘@Xeinhalation on a patient (C.D.) with bronchogenic carcinoma. rotoscoliosis. Pictures are posterior views.

Volume 9, Number 2 47 LOKEN AND WESTGATE

. @\ The next three patients in Table 1 are those shown in Figs. 4—6.Patient A.K. with “farmer'slung―has abnormally long xenon-clearance times after both @ i,,. - . @\&, inhalation and injection of xenon. Patient C.D. with :ea'@ ., ;@‘@ a scoliosis shows moderate depression of pulmonary function by conventional tests. The xenon-clearance half time on the left side appears to be normal while on the right side there is an indication of a delay that correlates well with the persistence of xenon activity in the right lower lung field (Fig. 5 ) . Pu! monary-function data and xenon-clearance meas FiG. 8. Two lung scintiphotogramson a patient with dis urements on patient M.E. with rheumatic heart ease. Initial scintiphoto (left) was made immediately after @Xe injection. Scintiphoto (right) was made about 10 sec later. Both disease are nearly normal. are posterior views. The last three patients in Table 1 were diagnosed to have multiple A-V fistulae, and made immediately after disconnecting the spirometer chronic bronchitis, respectively. All these patients from the patient and shows some delay in xenon particularly the two with cystic fibrosis and chronic clearance in the right lower lung field. This delay bronchitis—have some abnormalities in conventional is even clearer in scintiphotogram No. 3 which was pulmonary-function tests. In addition, the xenon made 2 mm later. clearance values are abnormal in the patients, par Figure 8 shows two selected posterior-view scinti ticularly the values obtained after xenon inhalation photograms of a patient with emphysema (ME.). by the last two patients in Table 1. The initial scintiphotogram (No. 1) was obtained immediately after intravenous injection of 5 mc of DISCUSSiON xenon. The other scintiphotogram is the third in the There are two gas systems which are now used to series and was obtained about 40 sec after xenon evaluate pulmonary function. Each gas has different injection. This picture shows •that the xenon has physical characteristics that give it certain advan cleared from the majority of the lung fields bilaterally tages for certain tests. The noble gases, of which except for three localized areas at the apices bilat ‘38Xeis the most widely used, made up the first sys erally and in the right midlung field. These findings tern. Because xenon does not diffuse readily into pul suggest that there are localized areas which are well monary tissue fluids, it is an excellent gas for meas perfused but poorly ventilated, as one would expect uring ventilatory function of the lungs. The second in bullous emphysema. system—the oxygen system—is used in studies with In addition to the xenon studies, we recorded oxygen,carbonmonoxideandcarbondioxide.Oxy spirograms for the majority of our patients using a gen in its molecular form is somewhat more soluble Godart Pulmotest. Direct recordings were made of than xenon; however, it is the least soluble of the tidal volume, respiratory rate, minute volume, vital three gases in the oxygen system, and its peak activity capacity and its subdivisions, timed vital capacity, in the lungs after a single inhalation is representative forced expiratory volume, maximum flow rates and of pulmonary ventilation. is the most maximum capacity. These values, all re soluble of these gases and is used for measuring corded with patients in a sitting position, were made pulmonary blood flow because the gas diffuses very the same day as the ‘33Xestudy. Before recordingthe rapidly. spirogram, a single arterial blood sample was taken The pulmonary administration of these radioiso from all patients in a supine position to obtain arterial topes can be made by two routes: inhalation or oxygen tension (Pa02). intravenous injection. Both noble gases and radio Data from these studies and a xenon clearance on isotopes from the oxygen system are administered by selected patients are summarized in Table 1. The inhalation; noble gases in saline solution can also be first patient listed in the table (M.B.) is the one in administered by intravenous injection. We have used Fig 3. All pulmonary-function tests on this patient both administration routes in our studies with 133Xe. were abnormal, particularly the forced expiratory We chose xenon for our studies because it is volume and maximum breathing capacity which are readily available. Its 5.27-day physical half-life and about 50% of normal. Xenon clearance times 8 1-key gamma-ray make it more desirable are abnormally long, particularly on the right side than 85Kr which is also chemically inert but has a where the half time of xenon clearance following half-life longer than 10 years and emits a gamma inhalation was 56 sec—about twice normal. photon in less than 1% of its disintegrations.


To measurepulmonaryperfusion,we inject 5—10lems when there are poorly ventilated spaces because mc of xenon in saline into an antecubital . As the isotope has a low , making rebreathing the injection is made, the patient is instructed to maneuvers possible. These rebreathing maneuvers inhale slowly to avoid a Val Salva maneuver. The let one study the time required for equilibrium to peak counting rate obtained is proportional to pul be reached. If equilibrium is delayed, there is good monary blood flow, and the subsequent exponential evidence of poor ventilation throughout the lungs clearance is a measure of combined alveolar as is the case in , emphysema, bullous disease diffusion and pulmonary ventilation. If xenon is of the lung and bronchial stenosis. available only as an air-gas , it is possible to Perfusion problems of the lung can be visualized measure perfusion by observing the clearance curve clearly by conventional scanning techniques after after inhalation of a ‘33Xeair mixture. For best administration of macroaggregates. However, be results inhalation should be a single tidal volume cause the administration of these “micro-emboli―is containing 1—5mc of xenon. In this case the ex unphysiological, the use of radioactive xenon is ponential clearance one observes is a measure of preferable. A regional analysis of perfusion is im : alveolarcapillarydiffusionandarterialperfusion.portant for evaluating possible pulmonary emboli With the xenon system there is no adequate way and for studying patients with mitral stenosis in to measurealveolar capillary diffusion directly. When whom there may be a marked alteration in distribu xenon is administered by inhalation, the clearance is tion of pulmonary blood flow, particularly when the a measure of diffusion and perfusion. When it is patient is placed upright. administered by injection, the clearance is a meas We have made pulmonary-function studies on 51 ure of diffusion and ventilation. At no time is diffu patients using either or both the inhalation and intra sion isolated independently for measurement. The venous technique for ‘33Xeadministration. Clearance best method of measuring pulmonary ventilation is curves have been recorded for both techniques. to have the patient inhale a xenon-air mixture from Studies of normals show that the curves obtained a spirometer system for several minutes until an after inhalation are quite similar to those obtained equilibrium state is reached. In such a system oxygen after xenon injection. Calculations show that clear is added to replace the carbon dioxide that is con ance curves are normally made up of a fast corn tinuously removed. The rebreathing technique lets ponent and one or more slower components. The one examine the “wash-in―of xenon into poorly slower components are more evident after xenon ventilated areas of the lungs until equilibrium is inhalation than after xenon injection. The slow reached (Fig. 3). After this procedure, the patient clearance components probably relate to the pro begins to breathe room air, and a “wash—out―curve longed clearance time of xenon from body tissues of xenonis obtained.Witha scintillationcameraone as well as to the small amount of xenon that is can obtain serial scintiphotograms during these recirculated through the lungs. Occasionally we find wash-in and wash-out phases to determine the re that the initial half time clearance for inhalation is gional ventilatory capacity of the lung. Xenon is shorter than for injection and probably represents a particularly valuable for evaluating ventilatory pro!>. tracing on patients who are hyperventilating. In


time for Xe clearance (sec) pulmonary-function Right lung Left lung PulmonaryPa03Conventional tests (% of normal)Half injec- inhala injec- inholo Patient pathology(mmHg)VCFEVt [email protected] tiontion tion

M. B. Carcinoma right lung 55 89 51 48 35 56 26 35 A. K. Farmer's lung — — — — 150 220 120 130 C. D. Scoliosis 98 64 83 77 45 48 27 30 M. E. Rheumatic heart disease 82 93 70 93 28 47 23 36 A. L. Multiple A-V flstulae 78 118 63 58 42 42 35 36 R. H. Cystic @brosis 59 71 46 24 — 236 — 118 C. J. Chronic bronchitis 50 33 69 37 82 140 92 275 Normal (average) 90 100 100 100 28 28 28 28

* Vital capacity (% of normal). t Initial 1 @secforcedexpiratoryvolume(% of normal). * Maximumvoluntaryventilation(% of normal).

Volume 9, Number 2 49 LOKEN AND WESTOATE patients with normal pulmonary function we find photoscanning liver, spleen, lung, and other organs. I. Nuc!. that there is usually excellentcorrelation between the Med. 5:259, 1964. initial half-time clearance measurements (Table 1). 2. WAGNER,H. N., SABISTON,C. D., MCAFEE, J. 0., Tow, D. ANDSTERN,H. S.: Diagnosisof massivepulmonary We have also used ‘83Xeto study patients with a embolism in man by radioisotope scanning. New England variety of pulmonary disorders including scoliosis, J. Med. 271:377, 1964. asthma, emphysema, lung carcinoma, cystic fibrosis, 3. QUINN, J. L., III, AND WHITLEY, J. E.: Lung scinti hemosiderosis, farmer's lung and various forms of scanning. Radiology 83:937, 1964. cardiac disease. Conventional pulmonary-function 4. LOKEN, M. K., TELANDER,0. T. ANDSALMON,R. J.: 99m compounds for visualization of body or studies have also been performed on these patients. gans. JAMA 194:152, 1965. A detailedcomparisonof these data with those of 5. LOKEN,M. K. ANDBUOBY,R. D. : Visualization of the xenon clearance is considered elsewhere (15). lung by methods of scintiphotography. Am. I. Roenigenol., Preliminary correlative analyses of data have shown Rad. Ther. and Nuci. Med. 97:850, I 966. good agreement among these methods for evaluating 6. KNIPPING, H. W., BOLT, W., VALENTIN, H., VEN RATh, H., AND ENDLER, P. : Regionale Funktionsanalyse in pulmonary function. der Kreislaufund Lungen Klinik mit Hilfe der Isotopenthora The vital capacity is an indication of the pul kographie und der selektiven Angiographie der Lungenge monary volume and should relate to the peak luXe fass. Munch. Med. Wschr. 991, 1957. concentration prior to the fast component of the 7. DOLLERY,C. T. ANDWEST,J. B.: Regional uptake of ‘38Xewashout curve. The vital capacity is therefore radioactive oxygen, and carbon dioxide in the lungs of patients with mitral stenosis. Circulation Re.c. an indication of the amount of restrictive lung dis 8:765, 1960. ease. The forced expiratory volume per sec (FEV, 8. DYSON, N. A., HUGH-JONES,P., NEWBERY,0. R., 1 see) and maximum voluntary ventilation (MVV) SINCLAIR, J. D. AND WEST, J. B. : Studies of regional lung indicate the degree of obstructive lung disease be function using radioactive oxygen. Brit. Med. I. 1:231, 1960. cause to a large degree they measure resistance to 9. WEST,J. B. ANDDOLLERY,C. T. : Distribution of blood flow and ventilation-perfusion ratio in the lung, measured air flow (expiratory) . These two values should relate with radioactive CO2. I. App!. Physiol. 15:405, 1961. closelyto the half time of 133Xeclearance. Decreases Jo. BALL,W. C.,STEWART,P. [email protected],L. 0. 5. in arterial oxygen tension should relate to a lower AND BATES, D. V. : Regional pulmonary function studied than-normal total-lung ‘83Xecontent after the patient with xenon-l33. I. Clin. Invest. 41:519, 1962. breathes to equilibrium in a closed system compared I 1. MALLETT, B. L. AND VEALL, N. : The measurement of regional cerebral clearance rates in man using xenon-i 33 with total-lung ‘33Xeafter injection of an intravenous inhalation and extracranial recording. Clin. Sci. 29:179, bolus of 183Xe. 1965. 12. MCHENRY,L. C.: Cerebralblood flow. New England I. Med. 274:82, 1966. . ACKNOWLEDGMENT 13. LOKEN, M. K. ANDWESTGATE,H. D. : Evaluation of The authors acknowledgewith thanks the technical as pulmonary function using 133-xenon and the scintillation sistance of Stephen Bostrom. This work was supported by camera. Am. I. Roentgenol., Rad. Ther. and Nuclear Med. grants from the Public Health Service (NB-03364, 5R01- 100:835, 1967. HE09204 and l-T01-CAO5 190) and the Minnesota Division 14. LASSEN, N. A.: Assessment of tissue radiation dose of the American Cancer Society. in clinical use of inert gases with examples of absorbed doses from 3-H, 85-Kr, I 33-Xe. Minerva NucI. 8:211, i964. 15. WESTOATE,H. AND LOKEN, M. K. : Comparison of REFERENCES conventional tests and 133-xenon clearance techniques for 1. TAPLIN, 0. V., JOHNSON, D. E., DORE, E. K. @‘&nevaluation of pulmonary function. Amer. Rev. Resp. Dis KAPLAN,H. S.: Suspensions of radioalbumin aggregates for eases. Submitted for publication.