images could be obtained in ventilator-dependent patients, butthey did not measure ventilation with a radioactive gas.

The purpose of this study was to practically assess 99m1cDTPA aerosol as a tool to define ventilated lung regions inpatients maintained on mechanical ventilation. As a prelude toclinical studies, we studied commercially available nebulizingsystems on the bench to measure their efficiency and particledistribution of the generated aerosol. Then, utilizing techniquesdeveloped in spontaneously breathing and mechanically ventilated patients, we simultaneously measured regional ventilationwith 99mTd@DTPAaerosol and 5lm}(@gas in five patients.

MATERIALSAND METhODSIn Vitro Bench Testing

In previous studies, we reported that mass-produced disposableplastic nebulizers, generally marketed for single use, do not exhibituniform behavior between units from the same lot (9). Furthermore, it is not certain how many times a single unit can be seriallystudied without failure. Therefore, before performing bench studiesof nebulizer output, particle size measurements and patient deposition, we pretested all nebulizers. After pretesting, each accepteddevice was only used once.

Nebulizer PretestingThree commercially available radioaerosol delivery systems

(AeroTech I, CIS-US, Inc., Bedford, MA; Biodex Venti-Scan II,Shirley, NY; and Mallinckrodt UltraVent, St. Louis, MO) used byour hospital's nuclear medicine section were evaluated. Six units ofeach type were tested with a bench method previously described byMcPeck et al. (10) to determine comparability. To standardize thevolume fill of each nebulizer, every DTPA kit (Squibb, NewBrunswick, NJ) was reconstituted with 150 mCi 99mTc in 2 mlsaline. Then 15 mCi 99mTcDTPA were withdrawn from the kit andreconstituted to 3 ml saline and placed in the nebulizer to be tested.The nebulizerwas connected to a flow meter and operated at a flowrate of 10 liter/mm until nebulization ceased. The outlet of eachnebulizer was connected to a low-resistance absolute filter uponwhich the radioaerosol was collected (Fig. 1). After nebulizationwas complete, the filter medium was removed from its housing andplaced in a radioisotope calibrator (Capintec CRC-bR, Montvale,NJ) to determine its radioactivity. After correction for decay, theradioactivity deposited on the filter was expressed as a percentageof the initial nebulizer activity.

After these tests, the mean and s.d. for each group wasdetermined. Any nebulizer whose function lay outside of two s.d.

of the mean was not used. The remaining nebulizers of each brandwere set aside for approximately24 hr to allow the radioisotope todecay and then rinsed with distilled water and flushed with dry air.Thereafter, by random selection, two of each brand were assignedto output studies, two were assigned to particle distributionmeasurementsand any remaining units were not used. Based uponthese results, a specific brand of nebulizer was selected and asecond set of nebulizers was similarly pretested for the patientdeposition studies.

The goal of this study was to determine the usefulnessof radiolabeled aerosols in the assessmentof regionalventilation in tracheotomized patients maintained on mechanical ventilation. MethodsThree commercially availableradioaerosolnebulizerkits were studied on the bench to determine nebulizer efficiency and particledistribution of 99@'Tc-DTPAaerosols.We studied ventilated tracheotomized human subjects with a gamma camera and simultaneously measured regional ventilation with 81m@.ges and °@TcDTPA aerosol. Images were compared by ana@ialsof radioactivitydisttibutions in computer-generated regions of interest. ResuttsThe UltraVentnebulizingsystemproducedthe smallestparticleswith a mass median aerodynamicdiameter of 0.9 @mcompared tothe AeroTechI and Venti-ScanII systems,which both producedaerosols of 1.3 @m.Despite relatively small particle sizes, @TcDTPAdeposition imageswith the UltraVentnebulizerdid not accurately represent regional ventilation as measured by 81m@equilibnum. Visual inspection of images revealed significant amounts ofparticledeposition in the regionofthe tracheawhich was diminishedbut not eliminated following replacement of the tracheotomy tubeinner cannula. Based on regional analysis, correlation betweenradioactivitydistributions of both isotopes was poor (r = 0.262, p =0.162)with segmentalanalysissuggestingthat the upperand middlelung regions were significantlyaffected by residualtracheal activity.Conclusion: The lungs of patients marntainedon mechanicalyentilation can be imaged after the inhaletion of @‘Tc-DTPAfromcommercially available delivery kits, but the correlation betweenaerosol deposition and regionalventilation is poor. Better definitionof ventilated lung segments is obtained when using a gas such as8lmy@@.because tracheal activity with the radiolabeled gas is mini

mized.Key Words radiolabeled aerosols; krypton-81m; particle depoaltion; technetium-99m-DTPA

J NucI Med 1996;37:239-244

Themostcommonclinicalindicationforpulmonaryscintigraphy is the evaluation of patients suspected of having pulmonary embolism (I ). Perfusion lung imaging is highly sensitivebut not specific in making the diagnosis (2,3). Its specificity,however, is enhanced when combined with ventilation measurements (3,4). Theoretically, ventilation is best measuredusing radioactive gases such as I33Xe or 81m@., but they havesignificant practical disadvantages (5). In the last decade, it hasbeen recognized that the deposition of radiolabeled aerosols inthe lungs can be used as an index of regional ventilation and, inspontaneously breathing patients, nebulized 9@Tc-diethylenetriamine penta-acetate (DTPA) aerosols have been useful indiagnosing embolism (6).

Patients supported by mechanical ventilation can have all ofthe usual risk factors for embolic disease plus the addedtechnical complication of the ventilator-airway apparatus. Butler et al. (7) and Vezina et al. (8) showed how deposition

Received Dec. 9, 1994; revision accepted Jun. 20, 1995.For correspondence or re@s contact: Gerald C. Sm@done, MD, PhD, Pulmonary/

Critical Care DMsion, State Universityof NewYorkat StonyBrook, HSCT17-040, StonyBrook,NY,11794-8172.

AEROSOLSAS INDICESOF VENTILATION•Cabahug et al. 239

Utility of Technetium-99m-DTPA in DeterminingRegional VentilationCorazon J. Cabahug, Michael McPeck, Lucy B. Palmer, Ann Cuccia, Harold L. Atkins and Gerald C. Smaldone

Departments ofRadiology, Respiratory Care and Medicine, State University ofNew York at Stony Brook,Stony Brook, New York

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v@t@ ToT.T.

AIR FLOWMETER utilize the integral filter to isolate the nebulizer and valve systemfrom the ventilator circuit (Fig. 2). For each test run, a randomlychosen nebulizer from the group previously tested for comparability was filled with 2 ml @Tc-DTPA in saline (nebulizer charge).

Theentirenebulizerwas thenplacedin the radioisotopecalibratorto measure its radioactivity. Aerosol delivery to the test lung

(inhaled mass) was captured on the inhaled mass filter placed at thedistal end of a Shiley (Irvine, CA) #8 disposable tracheotomy tubeinner cannula(11). Filters were changedat 5-mm intervals and thefilter medium was removed from its housing and placed in theradioisotope calibrator to determine its radioactivity. This sequence

was repeateduntil no furtherradioactivitywas measuredon theinhaled mass filter. In this manner, measurements on serial filtersdefmed nebulizer function over time. Radioactivity at each intervalwas corrected for decay and expressedas a percentageofthe initialnebulizer charge (inhaled mass %, the percentage of the nebulizer

charge delivered to the filter). This quantity of radioactivityrepresents the mass of a tracer placed in the nebulizer that wouldhave been inhaled by the patient (11 ) and represents the output ofthe nebulizer at that point in time.

Measurement of Partide D@bibutionTwo additional nebulizers from the group previously tested for

comparability were charged with 2 ml @“TcDTPA in saline

(approximately 15 mCi). The test bench setup incorporating theventilator, the nebulizer system, the #8 inner cannula and the testlung were all the same. A 1-piece, however, was inserted into thecircuit immediately proximal to the #8 inner cannula and its freelimb was connected to a 10-stage cascade impactor (CaliforniaMeasurements,GS-l, Sierra Madre, CA) sampling at a rate of 1.0liter/mm for 2 mm. The ventilator powered the nebulizer onlyduring its inspiratory cycle. The particle distribution was determined by measuring the cumulative radioactivity on successivecascade impactor stages and plotting the values on probability

paper. The resulting data were approximated by a straight linerepresenting a log-normal distribution. The mass median aerody

namic diameter (MMAD) was read from the ordinate at the pointwhere the straight line intersected the 50% value on the abcissa.

InVivo Patient StudiesFive ventilator-dependent patients were recruited from our

long-term ventilator care unit. They were free of signs of acutedisease, e.g., bronchospasm and acute tracheobronchitis. Eachpatient's airway was maintained by tracheotomy and they were

FIGURE2. Schematic of the test benchsetup for three brandsof radioaerosolnebulizersystems(nottoscale):MalllnckrodtUltraVent(top),CISAerOTechI (middIe),and BiodexVerdi-ScanII (bottom).To measureaerosoldelivety(Inhaledmass%),theventllatorwasconnectedtothe high-efficiencyparticulatean'(HEPI@fitter(VentIn)that representsthe Inletofeachnebulizersystem.The HEPAfittertraps radioaerosoland preventsit fromcontaminatingtheventilatorandamblentenvironment.The patientconnectorofeachnebulizersystemwasconnectedtoa#8tracheotomytube(fl) innercannula.A low-resistanceabsolutefitterOnhaledmassfiftet)wasInterposedbetweenthedistalendof theIT andthe mechanicaltestlung. Thenebulizerdrivelinefrom theventilatorwas connectedto the Nab Infithngoneachnebulizer.SamplIngof theaerosolfor particlesizestudiesby cascedeImpactorwasCOndUCtedthroughaconnectorlocatedat pointA.

1OL/minOUTPUTFILTER

NEBULIZERUNDERTEST

NEBULIZERDRIVELINE

FIGURE1. Preliminarytesting of nebukzerfunction.E@h nebubzerundertesting was powered with air from a 50-psig backpressure compensatedflowmeteratlOliters/min,andtheoutputofradioactivftywascOllectedonanabsolutefilter.

Technetium-99m-DTPA Aerosol OutputOutput studies simulating standardized ventilator-patient condi

tions were conducted in vitro using a Puritan-Bennett (Carlsbad,CA) model 7200ae ventilatorthathad previouslybeen characterized in this laboratory with respect to its nebulizer drive function(10). The ventilator with the nebulizer system under investigationwas connected to a Bio-Tek (Winooski, VT) VT-l single compartment test lung with compliance set at 0.025 1/cmH2and resistanceset at 5 cm H20/liter/sec (Fig. 2). These test lung settings weremaintained for all experiments. The ventilator was set in the controlmode at breathing rate = 15/mm, tidal volume = 1000 ml, squarewave inspiratory flow pattern and inspiratory flow rate 45liter/mm in order to yield a 1:2 I:E ratio with a 33% inspiratorytime fraction (duty cycle). The FIO2 of each ventilator was set at0.2 1 for all experiments. Because the presence of a heated,molecular-type of humidifier has been previously shown to diminish aerosol delivery to the output filter by a mean (±s.d.) of41% ±3.5% (11 ), we bypassed the humidifier during both thebench and the subsequent clinical studies.

None of the package inserts provided with the nebulizerscontained instructions concerning the use of the system with aventilator, but, upon inspection of each device, the method ofconnection to the ventilator circuit appeared obvious. The systemswere attached to the Y-piece of the circuit in such a way as to

NEBULIZERDRIVELINE

To TI.08T.T.

IiIMALEDW@SSFILTER

Nsbln

To TI.

240 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 2 . February1996

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PatientEtiologyof

resr@ratoryLOSvBreathingrate*Tidalvolume*no.Age Sex fallure(days)(breaths/mm)(ml)

NebubzerActivitynebuhzed

(% Charge)Run

timeuntildry

(mm)Randomlyselected

dispositionUltraVentAl43.812.5PartiCle

sizestudyA235.513.0Outher@notusedA346.113.0ParticlesizestudyA443.910.0InhaledmassstudyAS45.312.9Not

usedA642.016.3InhaledmassstudyMean

(s.d.)44.2 (1.4)13.0 (2.0)n = 5;outlierdiscardedVenti-Scan

IIBi46.06.0OutIiet@notusedB252.37.8ParticlesizestudyB351.17.7Not

usedB459.47.8ParticlesizestudyB557.18.8InhaledmassstudyB656.88.0InhaledmassstudyMean

(s.d.)55.4 (3.1)8.0 (0.4)n = 5;outherdiscardedAerolech

ICl50.46.0InhaledmassstudyC248.47.7ParticlesizestudyC349.67.8InhaledmassstudyC447.28.0Not

usedC537.99.5Oudier@notusedC652.49.3ParticlesizestudyMean

(s.d.)49.6 (1.8)7.8 (1.1)n = 5;outlierdiscardedUltraVentDl44.114.1Patient

1D239.514.6Patient20341

.514.0Patient3D441.812.7Patient4D540.014.7Patient

5Mean(s.d.)41 .4(1.8)14.0 (0.8)n = 5

*@êJ@ing rate and tidal volume are the Principle ventilator settings.

LOSv = length of stay on ventilatoras of the day of testing. CVA=cerebralvascularacadent;CABG= coronaryarte.ybypassgraft MVA=motorvehicleaccident

mechanically ventilated with either a Bear 2 or Bear 3 ventilator(Bear Medical, Riverside, CA) in the assist/control or SIMV modewithout PEEP. Informed consent was obtained and the protocolwas approved by the Human Studies Committee of UniversityHospital. Each patient was studied on the ventilator that he/she hadbeen using and at the ventilator settings that were in effect at thetime of the study. Their clinical data and ventilator settings arelisted in Table 1. An UltraVent nebulizer, selected randomly froma second set of nebulizers that had been bench tested to assurecomparability, was connected to the ventilator circuit as shown inFigure 2. All studies were conducted in the patient's room using aportable gamma camera (GE Starcam, Milwaukee, WI) and theportable lead shielding supplied by the manufacturer for thenebulizer.

For the aerosol ventilation studies, the nebulizer was chargedwith 30 mCi @“Tc-DTPAto a volume of 2 ml. The same protocolutilized for the in vitro studies described previously was followed;namely, the humidifier was bypassed and the nebulizer waspowered only during inspiration by the nebulizer driving system ofthe ventilator. At the start of nebulization, 8Imj@was simultaneously introduced into the inspiratoryline ofthe ventilator circuit.The patient's pulmonary radioactivity was monitored by thegamma camera (initially set for 8l@j@)@As activity in the lungsincreased, the camera was positioned for an anterior image. Afterseveral minutes, 8Im}(@@equilibrium was verified (less than 5%change in count rate over 15 sec serial test counts) and a kryptonequilibrium scan was obtained and stored in the computer. Immediately after krypton imaging, the camera was switched to the9@Tc window and a count rate of approximately 100,000 cpm wasverified (usually after 3—5min of nebulization).The nebulizer wasswitched off and a @“Tc-DTPAdeposition image obtained. Then,the inner cannula of the tracheotomy tube was changed (to reducetracheotomy tube activity on the image) and a repeat depositionimage acquired.

Image MalysisThe images were analyzed two ways: visual assessment in a

manner similar to that used clinically (i.e., presence of a wellventilated segment for Slmj(j@versus @“Tc-DTPA)and quantitativeanalysis. In previous studies, Köhn(12) demonstrated a goodcorrelation between regional krypton and technetium activity insimilarly performed experiments in spontaneously breathing patients. Using the 8lmj(j@image as a template, a lung outline wasdrawn. Then, the lungs were divided into six regions as suggestedby Köhn(12). The 8lmj@ regions were superimposed on thedeposition images and regional radioactivity for each isotope was

TABLE 2Pretestingof Nebulizersfor Comparability P@orto Bench Testing

TABLE IPatient Characteristicsand VentilatorSethngs

and Clinical Studies

119MQuadriplegia71210660270MCVA,s/pCABG201422900375FCVA,s/p

@my13817700474Ms/pCABG,

paralysisof Lhemidiaphragm17620850569MMVA,CVA3318740

converted into a regional percentage by defining 100% as the totalactivity within the lung regions on a given image. Correlationbetween 8lm@çj@and @Tcactivities were determined by linearregression.

RESULTSResults of the preliminary nebulizer comparability experi

ments are listed in Table 2. After deletion of any outlier, themean quantity of aerosol produced by the different nebulizersvaried from 41.4% to 55.4% of the nebulizer charge. For eachdevice, however, the variation between the remaining exampleswas relatively small (s.d. ±I .4 to 3.1). Table 2 also lists the fateof each nebulizer in subsequent experiments (i.e., nebulizeroutput, particle distribution studies or not used). The first set ofUltraVent nebulizers (Al to A6) were used in preliminarybench testing only; the second set (Dl to D5) were used in thepatient deposition studies.

Figure 3 shows the inhaled mass data for each of the threebrands. While the different nebulizers seemed to functionrelatively similarly in pretesting (Table 2), the performance ofthe nebulizer/tubing/ventilator combinations was significantlymore variable. Duplicate experiments revealed that the AeroTech I was nearly twice as efficient as the UltraVent andVenti-Scan II systems with between 30 and 35% ofthe originalamount of @Tc-DTPA placed in the nebulizer (nebulizercharge) reaching the filter at the distal tip of the tracheotomy

AEROSOLS AS INDICES OF VENTILATION •Cabahug et al. 241

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20 40 60 80

40nificant deposition in the tracheotomy area that, in general, isreduced but not eliminated upon removal of the tracheotomytube's inner cannula. With the availability ofthe 81}(j@data, it iseasier to assess the 9@Tc-DTPA scans. Patient 1 does notventilate the right lung and each region of the left lung is seenwith both the radioactive gas and aerosol images. Similarconcordance of ventilation and particle deposition is seen forPatient 2. On the other hand, the images for Patients 3, 4 and 5do not reveal the lung periphery because ofenhanced activity inthe trachea as well as central deposition of particles. The effectoftracheal deposition on image assessment is further illustratedby the observation that the lung periphery is better seen in allpatients when the tracheal activity is reduced by changing theinner cannula. This maneuver does not remove all of thetracheal activity. Some activity remains as a likely consequenceof turbulent deposition in the trachea.

Image analysis was quantified by analyzing regional activityfrom the 8lmj@ images and the corresponding 9@Tc-DTPAimages acquired after the tracheotomy tube was changed tominimize the effect of tube deposition. On a percentage basis, thedistribution ofdeposited @Tc-DTPAdoes not correlate well withthe equilibrium distribution of 8lm}(@@•With each patient's lungdivided into six regions, the overall correlation coefficient isonly 0.262, p = 0.162. The influence of the tracheal depositionis apparent when the regional analysis is correlated for theupper, middle and lower lung zones separately. Under thoseconditions, the distribution of krypton and technetium in lungregions abutting the tracheotomy do not correlate significantly(r = 0.274, p = 0.444 and r = 0.456, p = 0. 186 for the upperand middle zones, respectively), while there is a significantcorrelation in the lower lung regions between both isotopes (r =0.742, p = 0.0141).

DISCUSSIONThis study demonstrates that regional ventilation cannot be

well approximated with 9@Tc-DTPA aerosols in mechanicallyventilated patients. Our findings differ from those reported byButler et al. (7), whose group performed a retrospective studycomparing ventilationlperfusion scans in mechanically ventilated as well as spontaneously breathing patients suspected ofhaving pulmonary embolism. They concluded that 9@TcDTPA aerosol scans in mechanically ventilated patients areassociated with good peripheral penetration of activity. Thefrequency, however, of a reverse mismatch was significantlyhigher in the mechanically ventilated group.

Whereas there can be multiple causes for reverse mismatch,it can be expected if the measure of ventilation does notpenetrate to the lung periphery. This was the case in ourpatients, as well as the case reported Butler et al. (7). Our studysuggests that reverse mismatch can be reduced if ventilation isquantified with a gas (Fig. 4).

Our findings also differ from those reported by Köhn(12)who studied spontaneously breathing patients. Köhnperformeda comparative analysis of krypton and aerosol depositionimages in patients with varying degrees of obstructive disease.Using the same analytical approach (linear regression, six lungregions), he found a good correlation between 8Im}(@@and9@Tc-DTPA (r = 0.94, p < 0.001). The particles used by Köhnwere smaller than those of our study (0.37 @.tmversus 0.9 pm).Furthermore, in a more recent study, a similar correlation to thatof Köhnwas reported by O'Riordan and Smaldone (13) inspontaneously breathing patients using particle distributionsthat ranged as large as 2.5 @m.Therefore, the failure of our99mTcDTpA data to correlate with regional ventilation asassessed by 8lmj@jis likely related to deposition in the trache

AeroTechI

30

(1)Cl)

•0

UltraVent20

10

00

Duration of Nebulization (mm)

FiGURE3. Percentageof inhaledmass (percentageof initialnebulizercharge)overtime,measuredatthedistalendofa#8tracheotomytubeinnercannula.Measurementsof radioactivityweremadeat 5-mmintervalsuntilthe nebulizerrandry.Nebulizationto drynessis indicatedby thedevalopmontof a plateau.

tube. Furthermore, the slope of the AeroTech I curve is abouttwice as steep as the other brands, indicating more rapiddelivery of aerosol with a plateau in approximately 20 mm.

The mass median aerodynamic diameters were similar for theAeroTech I and Venti-Scan II at 1.3 p@m,o@= 1.92. TheUltraVent produced the smallest particles at 0.9 @m,a = 1.67.

Decision Regarding Choice of Delivery SystemFrom the bench data, the AeroTech I was the most efficient

delivery system. The UltraVent produced the smallest particlesproximal to the tracheotomy tube. In spontaneously breathingpatients, the major factor affecting interpretation of 99mTc..DTPA aerosol ventilation scans is the central deposition ofparticles (6, 17). Therefore, the UltraVent system, with itssmaller particles, was chosen for the patient studies in anattempt to minimize central deposition. To compensate for therelative inefficiency of that nebulizer, we used 30 mCi of99mTcDTpA as the nebulizer charge in the human studies. Thisallowed completion of the deposition/ventilation measurementsin the shortest time possible (usually within 5 min) to reducepossible artifacts from 9@Tc-DTPA clearance.

Human Ventilation StudiesGamma camera images for the simultaneously performed

ventilation and deposition studies are shown for the five patientsin Figure 4. The regions of interest drawn over the 8lmj(j@equilibrium image and superimposed on the 9@Tc-DTPA scansare also shown. Pulmonary ventilation appears to be welldefined for all patients with separation of 8I@j(@activity in thetubing from the lung images. Obvious nonuniformities weredetected. For example, the entire right lung of Patient 1 was notventilated. Inspection of the 99mTc@DTPAimages reveals sig

242 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 2 •February1996

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Patient Blmkr equilibrium

1

2

3

99m Tc-DTPA 99m TC@DTPA*

,.. -

4

5

FIGURE 4. Krypton equilibrium and technetiumdepositionimagesobtainedinfiveventilator-dependent patients.Actualpatientorientationis shown.Thelungoutlinewasdeterminedby an81m@equilibtiumimage(leftcolumn)andsubsequentlysuperimposedoverthe °°“Tc-DTPAdepositionimages.(Middlecolumn)Depositionimagesobtainedat approximately100,000cpm afterapproximately3-5mmof nebulization.(Rightcolumn)Depositionimagesobtainedimmediatelyafter the tracheotomytube innercannulawas replaced.The right lungouthnefor Patient1 wasestimatedfromthe chestradiograph.

otomy tube and trachea and not to particle size distribution perse and its effects on lung parenchymal deposition. This conclusion is supported by the improved relationship found for thelower lung regions which are not strongly affected by trachealactivity and the lack of significant upper airway depositionreported in spontaneously breathing patients inhaling similaraerosols (13,14).

The bench studies indicate that use ofthe other commerciallyavailable aerosol delivery systems that we studied will notimprove the results because both the AeroTech I and VentiScan II produce larger particles; therefore, it is unlikely thattracheal deposition will be reduced. Furthermore, we do notexpect significant differences in the pattern of depositionbetween patients intubated with endotracheal tubes and ourtracheotomized patients. Other investigators have reported similar degrees of tracheal deposition in intubated patients following aerosol inhalation (15).

*after replacement of inner cannula

AEROSOLSAS INDICESOF VENTILATION•Cabahug et al. 243

Different factors determine regional ventilation and regional particle deposition. Regional ventilation is dependenton local pulmonary compliance and airway resistance (16).The factors influencing particle deposition are more complex. Regional ventilation is required to deliver a particle butthe tendency of a region to retain that particle is determinedby three processes: gravitational sedimentation, inertial impaction, and to a lesser extent, diffusion. The relative importance ofeach process is in turn determined by the density, diameter anddiffusion coefficient ofthe inhaled particle, its residence time in theairway, local airway anatomy and the rate of airflow (1 7). In arecent editorial, O'Riordan and Smaldone (14) assessed the predictive value of aerosol studies in measuring regional ventilation.They evaluated studies in normal subjects and patients withobstructive and restrictive lung disease and concluded that quantitative measurement of regional ventilation is best accomplishedwith radioactive gases rather than radiolabeled aerosols. They did,

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however, show that the findingsofKöhn(12) were consistentwiththe clinical studies of Alderson et al. (2), which indicated thataerosol studies were adequate to assess whether a lung segment isventilated or not in the context of a diagnostic evaluation ofpulmonary emboli. Aerosol studies, however, were not sufficientlyaccurate to quantitate local ventilation (e.g., prior to resectionalsurgery). Finally, our results indicate that, because of turbulenttracheal deposition, @Tc-DTPAstudies may be inadequate forthe assessment of pulmonary emboli in mechanically ventilatedpatients.

CONCLUSIONThe lungs of patients maintained on mechanical ventilation

can be imaged after inhalation of 9@Tc-DTPA from commercially available delivery kits, but the correlation betweenaerosol deposition and regional ventilation is poor. Betterdefinition of ventilated lung segments is obtained when using agas such as

ACKNOWLEDGMENTSWe thank Gail Fox and April Plank, nurse practitioners in the

Respiratory Care Unit, and Janet Bingales, Nuclear MedicineDepartment, for technical assistance and Gael Valentine of theRespiratoryCare Department for illustrations. Supported in partbyUniversity Hospital operational grant 371318.

REFERENCESI. Neuman RD, Sostman HD, Gottschalk A. Current status of ventilation-perfusion

imaging. Semin Nuci Med 1980;lO:I98—217.

2. AldersonP0, BielloDR. K.hanAR, et al. Comparisonof ‘33Xesinglebreathandwashout imaging in the scintigraphic diagnosis of pulmonary embolism. Radiology1980;137:48I—486.

3. McNeil BJ. A diagnostic strategy using ventilation-perfusion studies in patientssuspected of having pulmonary embolism. J Nucl Med 1976;17:6I3—616.

4. CheelyR, McCartneyWH, DelaneyDi, et a). The roleof noninvasivetestsversuspulmonary angiography in the diagnosis of pulmonary embolism. Am J Med 198 l;70:17—22.

5. MettlerFA, GuiberteauMi. Essentialsofnuclearmedicineimaging.Philadelphia:WBSaunders; 1991:147—148.

6. Alderson P0, Biello DR. Gottschalk A, et al. Technetium-99m aerosol and radioactivegases compared as adjuncts to perfusion scintigraphy in patients with suspectedpulmonary embolism. Radiology l984;I53:515—521.

7. Butler SP, Alderson P0, Greenspan RL, et al. The utility of technetium-99m-DTPAinhalational scans in artificially ventilated patients. J Nucl Med 1990;31:46—51.

8. Vezina W, Chamberlain M, Vinitski 5, et al. Radioaerosol ventilation imaging inventilator-dependent patients. Clin NucI Med 1985;1O:759—766.

9. SmaldoneGC,FuhrerJ, SteigbigelRT,McPeckM.Factorsdeterminingpulmonarydeposition ofaerosolized pentamidine in patients with human immunodeficiency virusinfection. Am Rev Respir Dis 1991;I43:727—737.

10. McPeckM,O'RiordanTO,SmaldoneGC.Choiceofmechanicalventilator:influenceon nebulizer performance. Respir Care 1993;38:887—895.

11. O'RiordanTO, Greco Mi, SmaldoneOC. Nebulizerfunctionduring mechanicalventilation. Am Rev Respir Dis 1992;145:l117—I122.

12. KöhnH. The use of radioactive aerosols to assess pulmonary ventilation. J AerosolMed 1992;5:189—199.

13. O'Riordan TO, Smaldone OC. Regional ventilation and regional deposition duringinhalation of pentamidine. Chest I994;I05:395—401.

14. O'RiordanTO, SmaldoneOC, ed. Aerosolsas indicesof regionalventilation.JAerosolMed I994;7:111—117.

15. Maclntyre N, Silver R, Miller C, et al. Aerosol delivery to intubated, mechanicallyventilated patients. Crit Care Med 1985;I3:81—84.

16. Milic-Emili J, Henderson J, Dolovich M, et al. Regional distribution ofinspired gas inthe lung. J AppI Physiol I966;2 I:749—759.

17. Agnew J. Physical properties and mechanisms of deposition of aerosols. In: ClarkeSW,PaviaD,eds.Aerosolsand thelung:clinicalandexperimentalaspects.London:Butterworth; 1984:49—70.

which could not be predicted adequately by the administeredactivity.Changesof alkalinephosphataselevelssuggest anti-tumoreffects of leaRe@HEDP.Key Words breast cancer@bone metastases;rhenium-i 86-HEDP;dosage escalation;bone marrow toxicity

J NucI Med I996 37244-249

Boneisthemostcommonsiteofmetastaticdiseaseinbreastcancer patients. The majority of patients with advanced breastcancer have evidence of bone metastases by time of death (1).The most prominent symptom associated with bone metastasesis pain, which characteristically develops gradually over weeksor months and becomes progressively more severe (2).

Bone metastases require treatment in order to palliate pain.Localized external-beam radiotherapy is an effective modalityin the treatment of bone pain and offers partial or completerelief in 73%—96%of patients treated (3,4). The probability ofrelief appears slightly better with bone metastases from breastcancer as compared with the instance of carcinoma of thekidney or prostate (2). A common problem in this group of

Rhenium-i 86-i ,i -hydroxyethylidene diphosphonate CasRe@HEDP)has beenusedfor the palliativetreatmentof metastaticbone pain.APhasei dosageeSCalatknstudy was performedusing IseRe@HEDPinpatientswithmetastaticbreastcancer.Methods Twelvepatientswith metastatic breast cancer were studied. Each patient had atleast four bone metastasesand adequate hematologicalfunction.Groupsof threeconsecutivepatientsweretreatedw@,dosagesstartingat 1295MBq (35mCi)and increasingto 2960 MBq(80 mC@(escalatedin incrementsof 555 MBa). Results A translent increasein pain(“flare―reaction)wasobservedinsixpatients.Twopatientswho received2960 MBq lasRe@HEDPshowed Grades 3 (platelets25-50 x 109/l)and 4 (platelets< 25 x i 0@/l)platelettoxicity, whichwas defined as unaccejStable. Prior to treatment, alkaline phosphataselevelswereelevatedinsevencases.Thesepatientsshoweda transientdeclinein alkalinephosphataselevelsduringthe first4wk. Conclusion: The maximum tolerated administered activity ofleaRe@HEDPin patients with metastatic breast cancer is 2405 MBq(65mC@.Thrombocytopeniaproved to be the dose-limitingtoxicity,

ReceivedNov.14,1994;revisionacceptedJun.6, 1995.ForcorrespondenceorreprintscontactJ.M.H.deIQerIcMD,DepartmentofNudear

Med@ne,UniversityHospItalUtrecht,RoomE02.222,P.O.Box 85500,3508GAUtrech@TheNetherisnds.

244 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 2 •February1996

Phase 1 Study of Rhenium- 186-HEDP in Patientswith Bone Metastases Originating from Breast CancerJohn M.H. de Klerk, Alfred D. van het Schip, Bernard A. Zonnenberg, Aalt van Dijk, Jac M.S.P. Quirijnen, Geert H. BlijhamandPeterP.vanRijkDepartment ofNuclear Medicine, Oncology Section, Department ofinternal Medicine and Centerfor Hospital Pharmacy,University Hospital Utrecht, Utrecht, The Netherlands

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1996;37:239-244.J Nucl Med.   Corazon J. Cabahug, Michael McPeck, Lucy B. Palmer, Ann Cuccia, Harold L. Atkins and Gerald C. Smaldone  Utility of Technetium-99m-DTPA in Determining Regional Ventilation

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