pharmaceutical during coronary occlusion (2—7).Technetium-99m-sestamibi must therefore be rapidly availableto permit administration without any delay in reperfusiontherapy. Two major steps as part of the preparation instructions in the package insert of 99mTc@sestamibilimitthe availability of this agent on an emergency basis (8); asa result, multiple kits had to be prepared in advance eachday to permit its use in patients with acute myocardialinfarction in our previous clinical studies (3—5).First, thepreparation of99mTc@sestamibirequires 10—15 mm to bringthe water bath to a boiling state and another 10-mm boilingperiod for heating the vial contents. Second, unlike thetwo recently approved kits of Ceretec (9) and MAG3°(10), the package insert (8) for 99mTc..sestamibi does notrequire the verification of radiochemical purity (RCP)prior to administration of the radiopharmaceutical to apatient. However, it has been considered a part of goodnuclear pharmacy practice (1 1) to determine the RCP ofa radiopharmaceutical prior to patient administration toensure a dosage form of the highest safety, purity, andefficacy. As stated in the package insert (8), RCP for 99mTc@sestamibi ofat least 90% has been shown to provide safetyand effectiveness in the clinical trials. The recommendedradiochromatographic procedure for the determination ofRCP of 99mTc@sestamibiinvolves the use of an aluminumoxide-(A1203) coated thin-layer chromatography (TLC)plate (Baker-flex®,J.T. Baker Chemical Co., Phillipsburg,NJ) with absolute ethanol as developing solvent. In ourexperience, the entire chromatographic procedure, including the time to dry the sample spots and to run the TLCplate, takes approximately 30—40mm. These time-consuming labeling and quality control procedures need to besignificantly reduced in order to utilize @mTc@sestamibiforemergency purposes.

Gagnon et al. (12,13) have described a microwave ovenheating method for labeling sestamibi with 100 mCi (3,700MBq) @mTc@pertechnetatein 13 sec and have shown thatthe labeling efficiency determined by the TLC plate/ethanol system is adequate after microwave oven heating.Currently, U.S. federal government regulations (14) require all Nuclear Regulatory Commission (NRC) medicallicensees to prepare reagent kits in accordance with the

Technetium-99m-2-methoxy isobutyl isonitrile (@“Tc-sestamibi) is a radiopharmaceutical that can be useful in theevaluationof patientswith acute myocardialinfarction.Thecurrent method for preparation requires a lengthy boilingwater bath procedureand the recommendedqualitycontrolprocedureis cumbersomeand time-consuming.Usinga microwaveoven,the heatingtime necessaryto providea labeling efficiency (averaging 97% for sestamibWabeled with maximumallowable @Tcactivityandvolumehasbeenreducedto 10 sec. A new mini-paperchromatography (MPC)systemhas been developed to analyze the radiochemicalpurityof

@“Tc-sestamibiinvolving a 1:1 chloroform/tetrahydrofurandeveloping solvent. The recommended thin-layer chromatography (TLC) system involving the use of an Al203-coatedplaterequiresan averagetimefor dryingand developmentof 34.8±1.6 mm (n = 58) to complete, whereas the new MPCsystem has an average developing time of 2.3 ±0.1 mm (n= 26). For radiochemical purity values ranging from 71—99%

(n = 31), the MPC and TLC methods correlated closely (r =0.99) with a regression lineof MPC% = 1.05 TLC% —5.75.The combined use of the microwaveoven heating methodand our quick quality control system willfacilitate the rapid,emergency use of @‘Tc-sestamibiand eliminate the need foradvance preparation of multiplekits each day.

JNucIMed 1991;32:2162—2168

echnetium-99m-2-methoxy isobutyl isonitrile (@mTc@sestamibi) is a promising @mTc@labeledradiopharmaceutical for myocardial perfusion imaging (1,2). Myocardialperfusion imaging with 99mTcsestamibi can be utilized inpatients with acute myocardial infarction to quantify theamount of myocardium at risk and to assess final infarctsize and treatment benefit following acute reperfusiontherapy with either percutaneous transluminal coronaryangioplasty and/or thrombolytic therapy. The assessmentofmyocardium at risk requires administration ofthe radio

Received Feb. 6, 1991 ; revision accepted Jun. 4, 1991.For rep,ints contact: Joseph C. Hung, PhD, Diagnostic Nuclear Medicine,

Departmentof RadiOlOgy.Mayo Clinic,200 First St. SW, Rochester, MN55905.

2162 The Journal of Nuclear Medicine •Vol. 32 •No. 11 •November 1991

Rapid Preparation and Quality Control Methodfor Technetium-9 9m—2-MethoxyIsobutylIsonitrile (Technetium.-99m-Sestamibi)Joseph C. Hung, Mark E. Wilson, Manuel L. Brown, and Raymond J. Gibbons

Diagnostic Nuclear Medicine, Department ofRadiology, and Division ofCardiovascular Diseases, Mayo Clinic,Rochester, Minnesota, and Departmeni ofChemistry, Division ofScience and Mathematics, University of MinnesotaMorris, Morris, Minnesota

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manufacturer's instructions (i.e., package insert). Althoughthe microwave oven heating method is not mentioned inthe package insert, the boiling water bath method that isincluded is described as “recommended―(8). This language suggests that the microwave oven method can beadopted as an alternative way to prepare @Tc-sestamibi.On the other hand, the use of this method to prepare99mTcsestamibi on an emergency basis for patients withacute myocardial infarction would clearly “reducemedicalrisks to particular patients,―as any delay in the administration of the reperfusion therapy will increase the risk tothe patient. It will thereby satisfy condition three outlinedin the NRC's Interim Final Rule (15).

The purpose ofthis study is to confirm the feasibility ofusing a microwave oven heating method for labeling @mTc@sestamibi prepared with the maximum allowable activityand volume of@mTc@sodiumpertechnetate, and to developa more simple and rapid procedure for the quality controlof @mTc•sestamibiin routine and/or emergency uses.

MATERIALSAND METHODS

Preparation of ‘@‘“Tc-Sestamibiwith a Microwave OvenTo determine the optimal heating parameters (e.g., heating

time and output power of the microwave oven), a digital thermometer probe (Model 9800, Type K thermocouple, TaylorScientific Instruments, Arden, NC) was utilized to measure thetemperature of 3-ml 0.9% NaCI Injection, USP, contained in aCardiolite®(E. I. duPont de Nemours & Co., Billerica, MA) vial.After 10mm heatingin a boilingwater bath (96.9 ±1.2°C,n =17), the temperature of solution in the vial was measured to be

98.7±0.3°C(n= 6).It took8sectoreachthesametemperaturerange using a microwave oven (Kenmore, Model No.565.8962781,Sears,RoebuckandCo.,Chicago,IL) ata microwaveoutput powerof452.5 wafts.Wearbitrarilyaddedtwomoreseconds of healing time to optimize the microwave oven methodand the final temperatureof solution inside the vial after 10 secmicrowave heating was 106.8 ±3.8°C(n = 19). Technical specificationsofthe commercialmicrowaveovenweusedin our studyare listed in the note.

Technetium-99m-sestamibiwas prepared using a microwaveoven to heat five Cardiolite®kits. Each 5-mi Cardiolite®vialcontained 1.0 mg of tetrakis(2-methoxy isobutyl isonitrile) copper (I) tetrafluoroborate, 2.6 mg of sodium citrate dihydrate, 1.0mg ofL-cysteine hydrochloridemonohydrate,20 mg of mannital,and 0.075 mg of stannous chloride dihydrate, lyophilizedandstopperedunder nitrogen.Followingthe packageinsertdirections(8), the maximum activity (150 mCi; 5,550 MBq) of @mTc@sodium pertechnetatewasadded to the kit and the total volumewas adjusted to 3 ml using 0.9% NaCl Injection, USP.

Before placing the kit in the microwave oven, approximately10-15 ml of nitrogenwas withdrawnfrom the vial using a 20-misyringe until a vacuum was created. A styrofoam block (3 cmo.d.) was placed tightly over the metal cap on the vial to preventsparking.The vial was then placed in the microwave oven andheated for 10 sec at 452.5 watts. Labeling efficiency was evaluatedby TLC plates/ethanol radiochromotographysystem at 5 mm,30 mm, 1 hr, 3 hr, 6 hr, and 24 hr after reconstitution.

It is possible that microwave heating could cause molecularbreakdownof the cold or labeled sestamibi ligands. Radiochem

ical impurities generated by this hypothetical process may or maynot be detected by the TLC method. High-pressureliquid chromatography(HPLC)wouldbe a usefultool to assesssuchpossibleradiochemicalimpurities. Some @mTc@sestamibisolutions prepared with boiling water bath method or microwave oven heatingmethod were, therefore,analyzed with a HPLC system equippedwith a radioisotope detector. A 3.9 mm (i.d.) x 300 mm @Bond

apak C18i0-@smcolumn (Waters,Milford,MA)was used as theanalytical column. The mobile phase consisted of 45% methanol:35% 50 mM ammonium sulfate:20%acetonitrile. The flowrate was maintained at 2 mi/mm. Sampleswereanalyzedusinga 5-id injection, which corresponded to approximately 250 @zCi(9.25 MBq).

Radiochromatography of @°“Tc-SestamibiThe percentage of 99mTc..@mibi was measured using two

radiochromatographicmethods.Thin-Layer Chromatography (TLC) Method. This method is

described in the package insert (8). It involves the use of a predried ‘Baker-flex'®A1203lB-F TLC plasticplate (7.5 x 2.5 cm)as the stationary phase. Two drops of @mTc@sestamibisolutionwere applied side by side on top of a drop of pie-applied 95%ethanol wet spot. The sample spot was allowed to dry in adesiccator (typically takes about 15 mm) before the TLC platewasdevelopedwith ethanol in a 3.8 cm (O.D.) X 8 cm (L) glassbottle (All-Pak, Pittsburgh, PA). The glass bottle was capped witha screw cap to provide a solvent-saturated, even-vapor atmosphere. Only the @mTc@sestamibimigrated with ethanol to thesolvent front.

Mini-Paper Chromatography (MPC) Method. The MPC system involved the use of a precut paper strip (1 cm x 8.5 cm)from Solvent SaturationPads (Gelman Sciences, Ann Arbor,MI)as the stationaryphase with 1:1chloroform (CHC13)/tetrahydrofuran (THF) solution used as the mobile phase. Radiochromatogram scanner (Radiomatic VISTA Model 100, RadiomaticInstruments & Chemical Co., Inc., Meriden, CT) and autoradiographywere utilized initially to determine the R@(relativefront)values ofdifferent radiochemical species of@mTc@sestamibi. Afterthe TLC and MPC strips were scanned through the radiochromatogram scanner, the strips were exposed to an X-ray film(KodakEktascanBfilm, B-, EastmanKodakCompany,Rochester, NY). With the usual 150—200@Ci(5.6—7.4MBq) of@mTc@sestamibi sample applied to the TLC or MPC strip, the filmshould be exposed for approximately 10 mm. After the samplewas applied on the bottom ofthe strip,the paperstripwas placedin a Venoject®blood collection tube (Terumo Medical Corporation, Elkton, MD), which contained the mobile phase solvent. Aclosed solvent-saturated atmosphere was created by capping thetube with a rubber stopper. To test the feasibility of the MPCsystem in detecting hydrophilic @mTcspecies and hydrolyzedreduced 99mTc,samples from@ pertechnetate and99mTcsulfurcolloid solution were applied separately on MPCstrips and developed with 1:1 CHC13/THF.

Formulation of High, Low, and Intermediate RCPLevelsof @“Tc-Sestamibl

In order to determine the accuracy of the proposed paperchromatographyprocedure,it is necessaryto verifythe resultsofthe new MPC procedurewith those ofthe referenceTLC procedure. Technetium-99m-sestamibi solution with intermediateRCP values ranging from 83%-92% was created for the comparison study. This range is most Critical given the @90%RCP

Rapid Preparation and QC for @“Tc-Sestamibi•Hung et al 2163

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100-@$@—i-----‘=1@sz:=:=8iii-@@ao

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Ii:01 I I I I I I I I I i t@ I I I I0 3 6 9 12 15 18 2124lime

(hr)

@@owave

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Is0@6Is

@ BoilingwaterI I I I I I I

0 2 4 6 8 10Retention time (mm)

labeling specification stated in the package insert (8). Both quality

control procedures were compared in 99mTc@sestamibipreparations with RCP values in the low (70%—80%)(n = 5), intermediate (83%—92%)(n = 20), and high (95%—99%)(n = 6) rangeto evaluate the overallaccuracyofthe proposed RCP test methodat the lower and higherRCP levels.

The overall procedure was to prepare two kits: one of highRCP (normal preparation) and one of low RCP (as describedbelow). The individual RCP of each preparationwas measuredby the TLC procedure and then various volumes of each vialwere mixed to generate solutions of intermediate RCP. Thesolutions of intermediate RCP were analyzed by the referenceTLC procedure and the new MPC procedure simultaneously.

High RCP Preparation. Preparation was performed accordingto the package insert (8), using the maximum activity/volumeallowed, i.e., 150 mCi (5,550 MBq)/3 ml of @TcO@.The RCPwas determined by the referenceTLC procedure(RCP should beon the orderof 95% esmTc@sestamibi).

Low RCP Preparation. The vial was reconstituted with 150mCi (5,550 MBq)/3 ml of @mTc@sodiumpertechnetate. For thispreparation,the vial was allowed to sit at room temperature for1—3mm and then transferred to a precooled lead pig sifting inan ice bath. The RCP was measured with the reference TLCmethod. It is importantto keep the vial cold to minimize changesin the measured RCP. At room temperature, the RCP continuedto increase, thereby making it difficult to accurately preparesolutions of intermediate RCP. Under these conditions, the RCPshould be less than 50%.

Solutions with Intermediate RCP. The following equationswere used to calculate the volumes of both high and low RCPpreparationsneededto prepare solutionsof intermediate RCPs.The experimentally measured RCP values and the amount of99mTcactivity added to each vial during labeling were used in thefollowing equations:

aVol10=

l+a

Vol10 = volume (ml) ofstep 2 solution needed for intermediatestep 3 solution.

VOlh@ volume (ml) ofstep 1solution needed for intermediatestep 3 solution.

RCPh@ measured RCP of vial preparedin step 1.RCP1@,= desired RCP of intermediate solution (step 3).RCP10 = measured RCP of vial prepared in step 2 +1%.b = amount of 99mTcactivity (mCi) added to vial in step

c = amount of esmTc activity (mCi) added to vial in step

The volumes Volh,and Vol10calculated above were combinedto prepare solutions ofintermediate RCP. Because ofthe gradualchange in RCP in the low RCP kit, the actual RCP of theintermediateRCPsolutionwasdeterminedby the referenceTLCprocedure and the newly proposed MPC procedure at the sametime.

FIGURE1. Labelingefficiencycurvesof five @‘°‘Tc-sestamibikits preparedwith microwaveoven.The heavylinerepresentstheaverageRCPvaluesof fivekitsandthedottedlineindicatesthe minimumacceptanceRCPlevel(90%).

RESULTS

Preparationof @‘Tc-Sestamibiwith a MicrowaveOven

Five Cardiolite®kits were prepared in the microwaveoven with the addition of 3 ml of 99mTcactivity rangingfrom 142 mCi (5,254 MBq) to 159 mCi (5,883 MBq). Thelabeling efficiency (mean ±s.d.) determined by the TLCmethod at 5 mm, 30 mm, 1 hr, 3 hr, 6 hr, and 24 hr was96.9% ±1.4%, 96.8% ±1.6%, 97.0% ±1.4%, 96.8% ±1.5%,96.9% ±1.6%,and96.9% ±1.5%,respectively(Fig.1). The overall average RCP of these five kits was 96.9%±1.4% (n = 30) over the 24-hr period after reconstitution.No particulates or discoloration of the liquid were notedafter visual examination of the test vials.

HPLC analysis ofthe 99mTc@sestamibi samples preparedby boiling water bath and microwave oven methods produced the chromatographic patterns shown in Figure 2.Both HPLC chromatographs were almost identical. Thesame patterns were also observed on both samples analyzed at 1, 3, and 6 hr after preparation.

FIGURE2. HPLCchromatographofboilingwaterpreparationversus microwave oven preparation 24-hr post-reconstitution.Peaks 1 and 2: @“Tcimpurities,peak 3: @“Tc-sestamibi.Theretentiontime for peaks 1, 2, and 3 was approximately2 mm,3mm,and 5 mm,respectively.

VOlhI 1 —Voi10,

where—[RCPh (b/c)— [RCP1@,(b/c)]

a — RCP1@,—RCP10and

2.

1.

2164 The Journal of Nuclear Medicine •Vol.32 •No. 11 •November 1991

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us

@II

@@ y—1.OEx-5.18r=0.99n—31p—0.0001

@eo75@ ••70@

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TLCMPCDifferenceSample(%)(%)(%)*

I

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0

Origin

+

cm FIGURE5. OverallcompansonbetweenTLCandMPCmethods in the measurementof RCP(71%—99%)of @Tc-sestamibi.The RCPmeasuredby the MPCprocedurewas significantlylower than with the TLC procedure(p = 0.0001),but the magnitude of the differencewas verysmall(1.6% ±1.1%).

that the new MPC system slightly underestimatesthe RCPvalues determined by the TLC analytical system (Table 1)and thus a sample with acceptable RCP by MCP shouldalso be acceptable by TLC. The percent of primary 99mTc@sestamibi complex measured by the MPC procedure wasslightly but significantly lower than the TLC procedure (p= 0.0001), suggesting that the new procedure might reject

some kits with acceptable RCP by the old procedure.However, the difference was only 1.6% ±1.1% (Table 1).Only two kits with acceptable (90%) RCP by the TLC

TABLE IComparison Between TLC* and MPCt Analytical Systems

for IntermediateRCPKits

1 86.12 84.83 83.54 86.55 86.46 86.97 87.48 87.39 84.310 86.911 92.112 90.513 91.714 92.215 90.816 88.617 90.618 88.819 87.920 87.8

84.8 —1.384.2 —0.683.1 —0.485.8 —0.784.9 —1.582.8 —4.184.2 —3.285.7 —1.684.7 + 0.485.1 —1.890.6 —1.590.2 —0.391.3 —0.491.0 —1.289.5 —1.387.7 —0.988.9 —1.787.2 —1.686.2 —1.786.5 —1.3

Mean±s.d.1.6±1.1p@= 0.0001

I

C

0

Origin

cmcm* A1203 TLC with ethanol as mobile phase.

t Paper chromatography using 1 :1 CHCI3/THF as mobile phase.

t Difference (%) = MPC (%) —TLC (%).§Paired t-test.

FIGURE4. Autoradiographs(top) and radiochromatogramscans (bottom)for a bad @“Tc-sestamibipreparation(left)TLCmethod, RCP= 76.8%, (right)MPCmethod, RCP = 72.5%.

Rapid Preparation and QC for @“Tc-Sestamibi•Hung et al 2165

@?nt

U,@ ‘@@ , 8 10cm

FIGURE3. Autoradiographs(top) and radiochromatogramscans (bottom)fora good @Tc-sestamibipreparation(left)TLCmethod,RCP= 97.0%, (right)MPCmethod,RCP= 96.1%.

Comparison of Analytical MethodsThe distribution of 99mTcse@mibi on the MPC strip

was much broader in comparison with the Al203 TLCplate (Figs. 3 and 4). However, this considerable trailingpattern of the 99mTcsestamibj did not fall below the cutline at Rf 0.5 in either good @mTc@sestamibipreparations(Fig. 3) or bad 99mTcsestamibi preparations (Fig. 4).

The average time for drying and developing the A1203TLC plate was 34.8 ± 1.6 mm (n = 58), whereas theaverage time for developing the MPC strip was 2.3 ±0.1mm (n = 26). There was no pre-drying time for the MPCstrip to be considered since the strip was placed in the tubewhile the spot was still wet. Analysis of the samples of99mTc@jium pertechnetate (n = 5) and @mTc@sulfurcolbid (n = 5) by using the MPC system indicated that allradioactivity remained at the origin (Rf = 0.0).

The results from using the MPC procedure and thereference TLC analytical system were in good agreement(r = 0.99) for the measurement of overall RCP values inthe range of 71%-99% (Fig. 5). Individual measurementsof the intermediate RCP values, i.e., 83%—92%,are listedin Table 1. The RCP value of the new MPC systemexceeded that measured by the TLC analytical system inonly one case (Kit #9, difference = +0.4) which suggests

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procedure had unacceptable RCP by the MCP procedure(Kit #15, difference = —0.3%; Kit #17, difference =—l.7%)(Table 1).

DISCUSSION

Technetium-99m-sestamibi must be available on demand to assess myocardial perfusion in patients with chestpain or acute myocardial infarction (3-7). Without rapidmethods of formulation and quality control, four vials of99mTclabeled Cardiolite®would have to be prepared inadvance every day due to the 6-hr shelf life of 99mTc@sestamibi (3-5). This costly and impractical procedure isnecessitated by the lengthy labeling procedures with aboiling water bath and the time-consuming quality controlmethod using the recommended TLC procedure.

A microwave oven has been utilized to prepare 99mTc@sestamibi and shown to reduce the heating period considerably (12,13). In this study, we have confirmed that itonly takes 10 sec of heating time in a microwave oven tolabel 99mTcsestamibi and that excellent labeling efficiencycan be achieved with the addition ofthe maximum allowable activity and volume of@mTcO@.The RCP values aremaintained at an average of 97% with small variationsthroughout the entire 24-hr evaluation period which mdicates that the microwave oven heating method is a usefultechnique to prepare 99mTcse@mibi. The comparableresults from HPLC analysis of the microwave preparationversus standard boiling water preparation suggests that themicrowave oven method would be a reliable replacementfor the recommended boiling water bath method. Thelanguage in the package insert of Cardiolite®(8) indicatesthat the use of the boiling water bath method is only“recommended―to prepare @mTc@sestamibiand we believethat the fast labeling process of 99mTc@sestamibiusing themicrowave oven heating method would certainly reducemedical risks to patients with acute myocardial infarction.However, the legal considerations of utilizing this methodshould be judged and decided by each individual institution based upon their interpretation of the NRC regulations.

There are six technical precautions that must be considered in using the microwave oven for the preparation of99mTc@mibi First, the optimum heating time and wattage for the successful labeling of 99mTcsestamibi with aparticular microwave oven should be experimentally determined. Second, the metal cap of the vial needs to becovered with styrofoam to avoid electrical sparking. Third,a vacuum condition must be achieved before the labeledvial is heated with a microwave oven. Any residual gas leftin the head space ofthe vial could cause an ejection of therubber stopper due to the excess steam pressure built upin the vial. Fourth, the labeled vial must always be heatedin the same position inside the microwave oven. For thispurpose, we have designed a plastic vial holder that ispermanently mounted in the central area ofthe tray. Fifth,

microwave ovens with a digital control panel are moresuitable for setting short heating times (i.e., 10 sec) sincethey can be accurately set at the required heating period.Finally, based upon the preparation parameters of @mTc@sestamibi in our institution (e.g., 150 mCi; 5,550 MBciJkit, four kits/day, 10-sec microwave time, 0.5 m distanceto vial while heating), the daily radiation exposure fromthis process has been determined to be only 0.5 1 mR (5.1mSv) (this calculation assumes that the exposure rate for1 mCi (37 MBq) 99mTcat 0.5 m is 0.3 1 mR/hr (3. 1 mSv/hr) and does not consider any shielding which may beprovided by the microwave oven). The exposure rate maybe reduced further below the already low level by increasing the distance from the individual to the source. Thus,it may not be necessary to shield the microwave oven. TheALARA (as low as reasonably achievable) principle onlyrecommends taking “reasonable―approaches in order tomaximize protection from radiation exposure. The extraweight involved in placing lead sheets on a microwaveoven to provide shielding may interfere with microwaveoven performance. Moreover, using lead bricks to shieldaround the microwave oven may restrict access to themicrowave oven and therefore more time may be requiredin placing the unshielded vial inside the microwave oven.In our opinion, both radiation shielding approaches arecumbersome and impractical for reducing the already verylow radiation exposure. However, the ALARA conceptshould still apply during the entire preparation proceduresuch as using grip tongs to manipulate the labeled kit andkeeping a distance away from the microwave oven whileit is in use.

As stated earlier, the performance ofRCP determinationof 99mTcsestamibi has been regarded as part of goodnuclear pharmacy practice (11). There are several technical circumstances that would make it a necessity to verifythe RCP of 99mTc@tamibi before the clinical use of thisradiopharmaceutical in patients:

1. In this study, we only tested a 3-ml volume of 99mTc@sestamibi in the vial. This volume is ideal not onlyfor providing the desired specific concentration (i.e.,25—30mCi/ml; 925—1,110 MBgJml) for myocardialperfusion studies, but also suitable for dividing thevolume for multiple injections. The package insert(8) doesallowoneto add 1—3ml of 99mTc@sodiumpertechnetate injection to the vial. When any Cardiolite®kit is prepared with a lesser volume (i.e., <3 ml) in a microwave oven, the RCP of 99mTc@sestamibi should be determined before injectionsince different volumes will have different temperature responses in a microwave oven.

2. A more homogeneous temperature of liquid in thevial can be expected when it is heated in a boilingwater bath in comparison with a microwave oven.Inconsistent power output or variable microwavefrequency may furthermore cause uneven heat dis

2166 The Journal of Nuclear Medicine•Vol.32 •No. 11 •November 1991

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tribution in the liquid solution. Although our resultshave indicated that the microwave oven heatingmethod is quite reliable in preparing acceptable99mTc@tamibi the study is based upon only arelatively small scale of observations using a specifictype of commercial microwave oven. In addition,the loss or variation ofmicrowave power output andfrequency related to extended use of the microwaveoven should be evaluated on a long term basis.Consequently, the verification of RCP of 99mTcsestamibi as part ofthe microwave oven preparationwould be essential.

3. Any technical error in setting the microwave heatingtime below or beyond the predetermined time mayresult in the 99mTc@tamibi solution being renderedunsuitable for clinical use. Visual inspection andRCP measurement must, therefore, be performedbefore 99mTc@tamibi is acceptable for administration to patients. The A1203-coated plastic TLC platemethod is stated in the package insert (8) for thedetermination of RCP in 99mTcsestamibi However,this recommended TLC method for the measurement of 99mTc@tamibi would take at least 30 mmto complete. This time-consuming procedure defeatsthe purpose of using a microwave oven to expeditethe preparation of 99mTc@tamibi It is not onlyimpractical for the routine use of the agent but isunacceptable for any emergency clinical application.Although the MPC strip showed a relatively broaderdistribution of 99mTc@mibi radioactivity compared with a cleaner separation of 99mTc@sestamibispecies on the A1203TLC plate, our procedure doesprovide a much simpler and more rapid procedurefor routine and/or urgent quality control of @mTc@sestamibi.

Our proposed method for quality control provided radiochromatographic values that were closely correlatedwith the recommended TLC method. More importantly,the measurements by the two techniques were very closein the crucial intermediate range. Our proposed methodconsistently underestimated purity to a slight degree in theintermediate range; it gave a slightly higher value in only1 of 20 kits in this range. Thus, if the >90% standard wasused for each technique, our method might result in theoccasional rejection of a kit that would be acceptable bythe TLC method, but would be very unlikely to accept akit that was rejected by the TLC method.

In conclusion, we suggest that the combined use of themicrowave oven heating method along with an expedientone-strip RCP testing system can be performed in anynuclear medicine department or commercial nuclear pharmacy and provides a fast and reliable way to make 99mTcsestamibi available for either routine or emergency use.We believe that this approach reduces medical risk to thepatient by avoiding any delay in acute therapy for myocardial infarction.

RapidPreparationandQCfor @Tc-Sestamibi•Hungetal 2167

ACKNOWLEDGMENTS

The authorswould like to acknowledgethe technicalassistanceof Dr. Raymond Taillefer, Department of Nuclear Medicine,Hôtei-Dieu de Montréal, Montreal, Quebec, Canada, in this

project.The authors thank Dr. MarkW. Watson, E.I. duPont deNemours & Co., Inc., for his useful comments on this study, Mr.Gregory D. Smith, Radiation Safety Office, Mayo Clinic, for hishelp in evaluating the need for shielding of the microwave oven,and Dr. Wynn A. Volkert, Department of Radiology, Universityof Missouri-Columbia, for his critical review of the paper. Wealso thank Ms. Vicki S. Krage for her skillful assistance in themanuscriptpreparation.Cardiolite®kits suppliedby E. I. duPontde Nemours & Co., Inc. for this study are gratefully acknowiedged.

NOTE

Technical specifications of Kenmore microwave oven, ModelNo. 565.89627 (Sears, Roebuck and Co., Chicago, IL):

Power input: 120 volts, 12 ampersPower output:650 wattsMicrowavefrequency:2,450 MHzOuterdimensions: 10 l5/lóin.(H)x20 ll/i6in.(W)x 1513/16 in. (D)Cavity dimensions: 6 5/8 in. (H) x 14 in. (W) x 15 in. (D)Cavity volume: 0.8 ft3Weight: 36.5 lb

REFERENCES

1. Wackers FiT, Berman DS, Maddahi J, et al. Technetium-99m hexakis 2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety, andpreliminarycomparison to thallium-201 for myocardial perfusion imaging.JNucIMed 1989;30:301—311.

2. Kiat H, Maddahi J, Roy LT, et al. Comparison of technetium-99m-methoxy isobutyl isonitrile and thallium-201 for evaluation of coronaryartery disease by planar and tomographic methods. Am Heart J1989;l17:1—Il.

3. Gibbons Ri, Verani MS. Behrenbeck T, et al. Feasibility of tomographic99mTc..hexakj@..2.methoxy.2.methylpropy1..isenjmleimaging for the assessment of myocardial area at risk and the effect of treatment in acutemyocardial infarction. Circulation 1989;80:1277—1286.

4. Pellikka PA, Behrenbeck 1, Huber KC, Gibbons Ri. Measurement ofmyocardium at risk and salvage in myocardial infarction with ST-segmentdepression.Mayo ClinProc1990;65:1222—1226.

5. Pellikka PA, BehrenbeckT, Verani MS, Mahmarianii, Wackers FiT,Gibbons Ri. Serial changes in myocardialperfusion using tomographictechnetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile imagingfollowing reperfusion therapy of myocardial infarction. J Nuci Med1990;31:1269—l275.

6. Sinusas 1U, Trautman KA, Bergin 3D, et al. Quantification ofarea at riskduringcoronaryocclusionand degreeof myocardialsalvageafter reperfusion with technetium-99m methoxyisobutyl isonitrile. Circulation1990;82:1424—l437.

7. BeckerLC. Technetium-99m isonitriletomographyin patientswith acutemyocardial infarction: measurement of myocardial salvage by thrombolysis. JAm CoilCardiol 1990;15:315—317.

8. Cardiolite package insert. El. duPont de Nemours & Co., Inc., Billerica,MA. December 20, 1990.

9. Ceretec package inserL Amersham Corporation, Arlington Heights, ILJuly, 1990.

10. MAG3 package insert R 6/90. Mallinckrodt Medical, Inc., St. Louis, MO.11. NuclearPharmacy Practice Standards. Section ofNuclear Pharmacy, Acad

emy ofPharmacy Practice, American Pharmaceutical Association, 1986.12. Gagnon A, Taillefer R, Bavaria 0, LéveilléJ. Fast labeling of 99mTc..

methoxy isobutyl isonitrile(MIBI) with a microwave oven heating method

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[Abstracti. J NucI Med 1990;3 I:839.13. Gagnon A, Taillefer R, Bavaria 0, L@veilIéJ. Fast labeling of technetrium

99m-sestamibi with microwave oven heating. J NucI Med Technol1991:19:90—93.

14. Useof radiopharmaceuticals,generators,and reagentkits for imagingand

localization studies. Code of Federal Regulations—Energy,Title 10, Part35.200.

I5. Authorization to prepare radiopharmaceutical reagent kits and elute radiopharmaceuticalgenerators;Use of radiopharmaceuticalsfor therapy.Federal Register l990;55:34513—34518.

ages are sensitive but nonspecific.However, if the radionuciide dynamic images show displacement of

thecerebralvasculatureawayfromtheinnertableof theskull,theradionuclide study is not only sensitive but specific for an cxtracerebral collection, and a con

trast angiogram is unnecessary.

In the absence of this sign, abnormal static images usually indicatetheneedforcontrastangiographytoincreasediagnosticspecificity.if theradionuclide study is entirely normal, an extracerebralcollection isexceedingly unlikely. In a review ofthe literature on extradural hematoma, Cowan and Maynard foundthatonly 2 of 19patientswith proyen extradural hematomas hadnegative scans. In a large study byBrownet al. of5,835 dynamic, staticscintigrams, no patients with normal dynamic and static imagesweresubsequently found to have a subduralhematoma.

This issue contains three contributionsdealing with the appearance of epiduralhematomaoncerebralradionuclidestudies. Each paper makes its point clearly

and concisely,and at first glance this sub.-ject may seem a pedestriantopic for editorial comment. Nevertheless, a number ofpointsare worthyof discussion.

The vastmajorityofextraduralhematomas are indistinguishablefrom subduralhematomas by radionuclide imaging.Thesign ofseparation ofthe superior saggitalsinus from the skull, described by Buozaset al. andby Lin in this issue, appearstobe the only means of distinguishingthetwo types of lesions using radionuclidestudies. Despite its rarity, this sign istherefore an extremely useful one. Therim sign, unfortunately,provides no basisfor differentiation.

Lin drawsattentionto an interestingcharacteristic ofextradural hematomas atthevertex:theprimarilyvenousnatureof the hemorrhage.In this respect, cxtraduralhematomasat the vertexappearto constitutea distinct entity since, in sitesother than the vertex, they usually arecaused by arterial hemorrhage due tolacerationof a meningealartery.

ThepaperbyZilkha andIrwin raisesan important problem: the relative rolesofbrainscansandcontrastangiogramsin

extradural(orsubdural)hematomas.Thegross displacement of cerebralvasculature from the inner table of the

skull on the dynamic study in the case illustrated by Zilltha and Irwin is diagnostic

of a large extracerebralcollection. Theneed for a contrast angiogram in the face

ofsuch an unequallypositiveradionuclidestudy,togetherwith a fracture on the skullradiograph, must be questioned. It seemsappropriatethereforeto developa rationalpolicy concerning the roles of radionuclide and contrast studies in the diagnosis ofextradural and subdural hematomas. The following is such a rational approach (although it is not the only rationalapproach):

•Whentheclinicalproblemis acute,a contrastangiogram is more appropriatethana radionuclidestudy,and in emergency situations immediate surgery based solely onclinicaldiagnosismaybe necessary.The contrastangiogram is highlysensitive and highly specific.

•When the clinical problem is notacute, a radionuclide study is mdicated. The radionuclide static im

Accordingly,normal radionuclidestudies virtually exclude an extracerebralcollectionand patients should be followedclinicallywithout farther expensiveor invasive procedures. If the clinical picture

remains suspicious for an extracerebralcollection,a follow-upradionuclidescanis indicated. If the clinical picture becomes more acute, a contrast angiogramshould be performed. S

2168 TheJournalof NuclearMedicine•Vol.32 •No. 11 •November1991

EDITOR'S NOTE:Pleaseusecautionwhenrepeatingthisstudy.Duetothemanufacturer'smodificationofthethicknessoftheglassusedinthevials,themethodhereindescribedmayresultinanexplosionwhenthevialsareheatedinthemicrowaveasdirected.Dataonthisphenomenonhasjustbeenreceivedandwillbe publishedasa Letterto theEditorin an upcomingissueof the Journal.

@ @r@‘@ (T@ I @ti@'@

NOVEMBER 1976Epilogue on ExtraduralHematomaPeter M. Ronal, MD,PhD

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1991;32:2162-2168.J Nucl Med.   Joseph C. Hung, Mark E. Wilson, Manuel L. Brown and Raymond J. Gibbons  Isonitrile (Technetium-99m-Sestamibi)Rapid Preparation and Quality Control Method for Technetium-99m-2-Methoxy Isobutyl

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