designed to stress this function. For example, liquid mealsdo not show a lag phase, since triturationis unnecessary.

Similarly, labeled liver pate meals, mechanically groundto a fine particle size, reveal a short lag phase and probablydo not constitute an adequatetest of gastricmilling(6). Weused a scrambled egg and toast sandwich meal because it isreadily prepared, palatable and meets other criteria for avalid test meal (7); it necessitates considerable gastric milling before emptying can occur and thus allows assessmentof both the lag phase and the linear emptying phase.

The purpose of this study is to describe, define andcharacterize both the lag and emptying phases with anacceptable standard meal in a group of normal adults. Weattempted to fit the emptying data to power exponentialfunctions, as has been proposed (3,4,8). We found that thiswas not possible unless data were ignored because a significant fraction of the normal subjects (and also our patientpopulation)demonstrateda transientincrease in count rateover the first 30 mm or more; simpler descriptors of lagphase and emptying rate were more useful. We theorizedthat the count rate increase was due to attenuation ofradiation by the test meal and, therefore, in addition to ourmain purpose, we supplemented our clinical studies withmathematical and in vitro experiments to test this hypothesis.

The lag phaseof gastricemptyingreflects,in largemeasure,theclinically important milling function of the stomach, but there islittleagreementon the bestwayto acquire,analyzeandcharactenze lag phase dataof gastricemptyingstudies.Methods:Twentynormalvolunteerswerefeda standard°@Tc-suffurcolbid scrambledeggandtoastbreakfastandimagingdatawereacquiredat 15-mmintervatsin bothanteriorandposteriorprojectionswiththe subjectseated.Results: In a significantpercentageof thesubjects,thestomachcountrateroseabovetheinitiatcountrate,evenwithgeometricmeancorrection.We attributedthe count rate rise to meal self-absorptionand conducted mathematical and in vitro experiments, the results ofwhichsupportedthisthesis.Attemptsat modelingthedatawithpower exponentiat fits were unsuccessful in many cases andwerecomplex,nonintuitiveandof limitedclinicalutility.Accordingly,gastricemptyingratesweredeterminedby simplelinearregressionfromgeometricmean data.The startingindex(thetimeatwhichtheregressionlineequalled100%)wascalculatedto reflectthelagphase.Normatrangesweredeterminedformenand women. Conclusion: Our method of test performance issimple,eliminatesconfoundingvariablesand providesresultswith intuitivemeaning and with direct clinical relevance.

KeyWords:gastricemptying;solidmeatlagphase;stomach

J NuciMed1994;35:1023-1027

he stomach has at least two mechanical functions in thedigestive process: it serves as a mill, triturating food intoparticles small enough (less than 1—2mm) to pass throughthe pyloric valve (1,2); and it servesasa pump, propellinggastric contents into the intestine. Studies with radiolabeledsolidmealshaveshowna lagphase(periodof minimal or absent emptying) representative of the milling function, followed by linear emptying of gastric contents, therate of which depends on a variety of factors such as mealsizeandcomposition.The durationandcharacterizationofthe lag phase is also dependent on a number of factors,such as type of meal, ingested particle size and samplinginterval (3—5).In order for the lag phase to be a validrepresentation of gastric milling, test parameters must be

ReceivedApr.28,1993;revisionacceptedJan.20,1994.ForcorrespondencecontactMarthL Nusynowftz,MD,Dept.ofRedk@Ogy,

UniversityofTexasMedicalBranch,Galveston,TX77555-07930.Reprintswillnotbeavailable.

1023Gastric EmptyingLag Phase •Nusynowitzand Benedetto

The Lag Phase of Gastric Emptying: Clinical,Mathematical and In Vitro StudiesMartin L. Nusynowitz and Anthony R. Benedetto

Division ofNuclear Medicine, Department ofRadiolo@j', University of Texas Medical Branch, Galveston, Texas

METhODS

Clinical StudiesStudies were performedon 10 normal males (ages 26—32yr.

68—129kg,1.68—1.90m)and10normalpre-menopausalfemales(ages 20—47yr, 52—98kg, 1.58—1.73m) using a standard 300-g(350kcal) meal consisting of two large scrambled eggs on two thinslices ofwhite toast, 5 g ofmargarine and 150ml ofwater; 37 MBqof @Tc-sulfurcolloid was added duringpreparationof the eggs.Themealwas eatenwithin10mm,andour subjectswere imaged,siftinguptight, at 15-mmintervalsduringa L5—3-hrobservationperiod, with elapsed time commencing at completion of the meal.

Images were collected with a parallel-hole collimator for 1 miseach, first in the anterior projection and then in the posteriorprojection;total elapsed timewas less then 3 mis. Stomachregionof interest (ROI)datawere decay-correctedand used to generategraphs of the fraction of the meal remaining in the stomach as afunction of time for the anterior, posterior and derived geometric

mean data. Geometric mean was calculated as the square root ofthe productof the anteriorand posteriordata at each time point.The graphsexhibited excellent linearity, usually between 30 and105mis.Thedatawereenteredintoa linearleast-squaresfit

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Using various values of the linear attenuation coefficient, j@,torepresent the range of gamma-ray energies employed in combinedliquid-solid meals, the attenuation of a gamma ray emitted fromthe center of each slice was calculated along the path from theslice to the gamma camera. The fraction of gamma rays emittedfrom each slice was summed for all slices within the solid cylinderand then multiplied by the surface area of the slice to obtain thetotal number of gamma rays reaching the gamma camera.

In Vftro StudiesSolutions of sodium pertechnetate (@mTc;37 MBq/ml) and

sodiumiodide(1311;7 MBq/ml)were prepared.For each radionuclide alone, 300-mi “meals―were prepared by adding 1-ml aliquots of each solution and 299 ml of distilled water to glasscontainers having varying diameters to simulate a spreading meal.

A gammacamerawas positionedabovethetallestcontainerandkept at that height for all measurements. A nuclear medicine computer was used to extract data from ROl drawn around each meal.

RESULTS

Clinical StudiesFigure 2 contains curves of grouped normal subject geo

metric mean data, and Table 1 shows the values for thestarting indices and emptying rates for the anterior, posterior and geometric mean data. Note that the slopes for allthree data groups (“projections―)are not signfficantlydiiferent from one another for either the males or the females,but that the slopes for the females are smaller than those ofthe males for each of the three projections. This reflects aslower rate of gastric emptying for estrogenized women ascompared to men, confirming a previously described finding (9). Note also that the starting indices for each of thethree projections are significantly different for both themen and the women.

The 15—30-minand 30—45-miscolumns in Table 2 showthe numbers of normal volunteers whose gastric count raterose above 100%(Fig. 3). Note that count rates for 35%ofthe subjects rose to over 100% of the initial count rate forthe geometric mean data and that all 20 were below 100%by 45 min. The SI values for all normals were also less than45 min except for one male whose SI was 49 min.

FiGURE 2. Geomethcmean gastiic emptyingdata for normalvolunteerwomen(closedcirdes)andmen(opencircles).Errorbarsrepresent1s.e.and0 denotenumberof indMdualsateachtime.

A

I

0FiGURE1. Anteriorimagesof thestomach.(A—C)Normalvolunteerat0, 15and30 mmpostingestionshowingmildclumpingandrapidspreadingofthemeal.(D-F)D@be1icpatientat0,30and45mmpostingestionshowingsevereclumpingandminimalspreading.

routine that calculated the slope of the emptying portion of thecurve in units of percentage initial value per minute, the Y-intercept of the line of best fit, and the correlation coefficient, r.

Ananalysisofcovariancewasperformedtodeterminewhetherthe slopes between curves were significantly different. The datafrom males and females were analyzed separatelybecause of theknown effect of estrogenization (9). We compared the three pro

jections for each individual, then grouped all of the individualvalues at a given time to obtainan averageemptyingcurve graphfor each projectionfor each gender. A 95%confIdencelevel wasused for testing statistical significance of differences.

In addition,the startingindex, SI, was calculatedfor eachsubject (10—11). The SI is the time at which the backprojected lineofbest fit of the linear portion of the emptying curve intersects the100%value and is a measureof the lagphase.

Mathematical StudiesEfforts to fit power exponential equations to the patient data

(3,4,8) were unsuccessful in many cases because the curve roseabove the zero-time value of 100% even in the geometric meancount ratecurves. Power exponentialformulationscannotaccommodate values greater than 100%.A rise above 100%can occur incurves obtained from an anterior projection because the meal ismoving anteriorlyas it progresses throughthe stomach, but thiseffect cannot explain the count-rate rise with geometric mean datasince they are depth-independent.

To explaingeometricmeanvaluesgreaterthan100%,we postulated that attenuation of gamma rays by the meal itself may beresponsible for the increase in count rate and for the lengtheningof the period of time before linearemptying is evident. The mealis compact during the time immediately after ingestion and gradually spreadsas timeprogresses (Fig. 1). Thus, the surfaceareaofthe meal becomes larger while the volume remains relativelyconstant, so that the area-to-volume ratio increases with time.Sample self-attenuationdecreases as the area-to-volumeratio increases (and as the meal thickness decreases). Thus, the countrate observed by a gamma camera would increase with time.

To test this,a mathematicalmodelof thestomachwas developed. A 300-g meal was assumed to take the shape of a rightcircular cylinder of constant 300-cm3volume and varying height,creating varying degrees of self-attenuation. Calculations weremade of the gamma-ray flux that would impinge on a gammacamera with a parallel-hole collimator for the various source geometries. The cylinders were divided into slices 0.01 mm thick,each containingequal concentrationsof activity.

a?CC

E0

I) 15 30 45 60 75 90 105 120 135 1 50 165 180

TIme after Ingestion (mm)

1024 The Journal of Nuclear Medicine•Vol. 35 •No. 6 •June 1994

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Males(n= 10) Females(n= 10)

0—1515-3030-45mmmmmmTotal

7 2 1 10

1311 (p = 0.07 @_1)also increased as the projected area of

the column increased,but to a lesserdegree,as expectedwith the higher-energygamma ray.

DISCUSSION

Datz (7) pointed out the need for standardization andscrupulous attention to methodology to minimize variability for valid gastric emptying data, and our methods address each of these issues (Table 3). Whereas our dataindicatethatslope determination(i.e., emptyingrate) is notdependent on projection for a 300-g meal (Table 1), there isno doubt that measurement of the lag phase is highly dependent on projection. We strongly support the position ofDatz to usethe geometricmeanto eliminatethe confounding effect of variable patient attenuation resulting from theposterior-to-anterior transit of the labeled meal as it proceeds from the fundus to the antrum.

As our experiments demonstrate, another important reason for using the geometric mean is that the lag-phasecurve is confounded by the diminishing self-attenuation ofradiation by the food as it spreads and moves toward theantrum. This spreading effect is operative even before significant emptying has occurred, frequently resulting in arise in the apparent percentage of food remaining in thestomach as compared to the value obtained immediatelyafter meal ingestion. Our thesis that this phenomenon is thecause of the increase, even when using geometric meancorrections, is supportedby both our mathematicalanalysis andour in vitro experiments.

Despite the constraint that measurement of the lag phasecannot exactly reflect the milling process because of theeffect of uncontrollable variables such as mastication andfluidsecretion by the stomach, the lag phase has clinicallysignificant implications, and its accurate determination isimportant(6,12). However, there is no consensus on thebest method of either obtaining the data or quantitativelycharacterizing the lag phase.

A power-exponential or modified power-exponential fithas been proposed and extensively employed (3,8,13), but

TABLE IStar@ngIndex and Gastric EmptyingRate Values for Normal

MatesandFemales

Startingindex(min)*tAnterior30.5±26.332.7 ±38.3Posterior—2.0±16.8—13.1 ±24.5Geometric

mean10.8 ±18.44.5 ±32.5Gastricempt@ngrate(%

min@)**Anterior—0.80±0.25—0.54 ±0.07Posterior—0.73±0.17—0.50 ±0.08Geometric

mean—0.74 ±0.19—0.52 ±0.05

*,@Jlvaluesexpressedas mean±1 s.d.tp@j@frjnsare allsignificantlydifferent(mates,p < .01;females,p

< 0.05); no difference between males andfemalesfora ghien projection.

*Formalesandfemales,prc@ectionsarenotsignificantlyditferentfora givenprojection,valuesfor malesdifferfromthoseof women(p <0.01).

As expected, the number of curves above 100% at eachof the time periods in Table 2 was greater for the anteriorprojection and lower for the posterior projection, as compared to the geometric mean data, since the meal proceedsanteriorly as it passes down the stomach.

Mathematical ModelsFigure4 demonstrates the dramaticincrease in the gam

ma-ray flux striking the gamma camera as the projectedarea of the 300-cm3cylindrical meal increased. An area of41.4 cm2, where the height of the meal equals its diameter,corresponds to the geometry assumed to exist immediatelyfollowing ingestion of the meal. The fraction ofgamma raysescaping from the cylinder and recorded by the gammacamera at this configuration ranged from about 78% for@= 0.07 cm' (1311) to about 60% for p. 0.15 cm' (@Tc).

The effect of self-attenuation was thus somewhat smallerfor the smaller attenuation coefficients (higher energygamma rays), but not small enough to ignore.

In Vitro DataThe results, using glass containers of radioactive solu

tions, demonstrated increasingly higher count rates for@Tc(j@= 0.15 cm1) as the projected area of the @Tc

column increased (Fig. 5). The measured count rates for

TABLE 2Onset of LinearGast,ic EmptyingPhase In Normal

Volunteers*

FiGURE3. Normalandabnormalstar@ngindicesinsubjectswithnormalgast@cempt@ngrates.(U)Normalfemalew@irapidonsetofemptying(notenegativeSI);(•)NormalmalefromFigure1 withnormalonset of empt@ng;(A) D@bebcmale from Fmgure1 withmarkedlydelayed,abnormalonsetof emptying.

MalesEstrogenized 6 2 2 10

females

*Numborin whomgastricemptyingcurvedroppedbelow100% inindicatedinterval.

1025Gastric EmptyingLag Phase •Nusynowitzand Benedetto

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Desirable*ActualGastric

emptyingmarkerFoodTypeof food SolidphaseeggmealParticle

size Large (> 5mm)Mealcaloriecontent 350kcalMealweight 300gStability

oftagExcellentRadiOpharmaCeUtlcal@Tc-suffurcolloidPatient

positionandmovement Sitting;nowalkingImaginginterval 15-mmimagesto120—180mmPatient

motionduringacquisitionNoneDecaycorrectionUsedDual-radioisotope

crosstalkcorrectionSingleradioisotopeAttenuation/geometriceffects GeometricmeanTime

ofdayMomingSex/sexhormoneeffects SeparatenormalvaluesStress

effects Quietroom*F@@

thiscolumnfromDatz(7).

TABLE 3Desirableand ActuatTechnical Parametersfor Radionuclide

Gastric EmptyingStudies

I

I100120140160180200

Pro@tedarea(cm')

FiGURE4. Theore@caleffectofseff-attenuafonofgammaraysbythe meal as a fonc@onof projectedarea of the meal. Curvesarenormalizedto 40 cm@,the presumedgeometryimmed@talypostingestion,and are plottedfor linearattenuationcoefficientsof 0.07cm@1(0)@ 0.15cm@ (•).

this empirical fitting procedure is neither necessary nordesirable. First, the power exponential procedure results inthe derivationof three variables, two to describe the equation of fit and a third to describe the lag phase, none ofwhich represents a readily recognizable physiological parameter (3). Second, most authorities agree that the emptying phase for a solid meal is linear, but the power-exponential fit models the data exponentially. Third, because ofour observations that in about one-third of normals, andeven more commonly in abnormalpatients, the emptyingcurve rises above 100% due to the self-attenuation phenomenon (Figs. 3—5),power exponential fits are impossibleto calculate unless values greaterthan 100%are truncated.Instead, we advocate fitting the linearly-emptying portionof the data with a least-squares regression line and calculating the SI as a measure of lag phase from the slope andY-intercept.

Describing reproduciblyand exactly where gastric emptying starts is impossible from inspection of the curve, butthe starting index addresses this problem nicely. Simply

FiGURE5. Experimentallymeasuredeffectofself-attenuafonofgammaraysas a fonc@onof projectedarea.Curvesarenormalizedto 40 cm2@ are presentedfor @rc(A) andfor 131I(Li).

put, the SI is the time at which the backprojected regression line of emptying equals 100% (Fig. 3). The techniquedescribed herein relates the starting index to the concept oftime elapsed before linear emptying is established. Notethat if the lag phase is short, the backprojected line of fitmay result in a negative starting index (Fig. 3). Since allnormal curves dropped below the 100%point by 45 min,normal and abnormal lag phase may be defined in thisalternative, less mathematical manner.

Elashoff et al. (8) outlined a set of characteristicsfor themathematical analysis of gastric emptying data, includingthat: “Thecurve should provide a good fit to the datapoints observed . . .“over a wide rangeof conditions. Theindividualregression coefficients for our 20 normalvolunteers were all greater than 0.96, demonstrating a superb fitfor a linear model. Similar linearity was observed in ourpatient population. This technique not only has the advantage of simplicity, but it also relates the slope of emptyingto the readily comprehensible physiologic parameters ofconstant linear emptying rate or of grams per minute leaving the stomach. For example, our geometric mean emptying rate for males of 0.74% min' corresponds to 2.2 gmin1 (0.74% min' x 300 g-meal), which is similar inmagnitude to values reported by Moore et al. (14).

CONCLUSION

If the emptying rate was sufficient to distinguish normalfrom abnormalgastric function, data obtained from eitherthe anterior or posterior projections would suffice, sincethe slopes of the emptyingcurves are essentially identical.However, because the lag phase is an important parameterof gastric function that largely reflects milling, its accuratecharacterization is essential, and the use of geometric meandata is mandatory. We have found an initial rise in gastriccount rate following the zero-time (100%) value in a large

Projected arsa (cm2)

1026 TheJoumatof NuclearMedicine•Vol.35 •No. 6 •June 1994

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percentage of both normal subjects and in our patients.This elevation may persist for up to 45 min in normalsubjects, after which time the linear emptying phase supervenes. Power exponential fits have been proposed to characterize the gastric emptying curve, but they suffer fromdrawbackscompared to a straightline fit. A straightline fitto the emptying phase data is both readily performed andunderstandable, has high correlation coefficients and iseasily translatableinto physiologic meaning:percentageofmeal or mass of food emptied per minute. In addition, itallows for calculation of the starting index (a measure ofthe lag phase), the time at which the fitted regression line ofemptyingcrosses the 100%count rateline. A startingindexgreater than 45 min is considered abnormally prolongedand thus indicative of a milling-phase disorder.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the generous assistance ofJohn R. Mathias,MD, Division of Gastroenterology,Departmentof Internal Medicine, in the recruitment of the normal volunteers.Partial funding for imagingofthe normal volunteers was furnishedby Glaxo Pharmaceuticals.

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from the human stomach. Gastroenterolog,, 1981;80:1489—1496.

2. Minami H, McCallum RW. The physiolo@jrand pathophysiology of gastricemptyingin humans.Gastmentemlogy1984;86:1592-1610.

3. SiegeIJA, Urbain J-L, Adler LP, et al. Biphasic nature ofgastric emptying.Gut 198829:85-89.

4. Urbain J-LC, Siegel JA, Charkes ND, MaurerAR, Malmud LS, Fisher RS.The two-component stomach: effects of meal particle size on fundal andantral emptying. EuriNuciMed 1989;15:254-259.

5. Christian PE, Datz FL, Moore JO. Confirmation of short solid food lagphase by continuousmonitoringof gastricemptying.I NuciMed 1991;32:1349—1352.

6. MaurerMI, KnightLC,KrevskyB. Properdefinitionsforlagphaseingastric emptying of solid foods [Letter]. I Nuci Med 1992;33:466-467.

7. Datz FL. Considerations for accurately measuring gastric emptying [Editonail. JNucl Med 1991;32:881-884.

8. Elashoff JD, Reedy Ti, Meyer JH. Analysis of gastric emptying data.Gastroentemlogy 1982;83:1306—1312.

9. DataFL, ChristianPE,MooreJ. Gender-relateddifferencesin gastricemptying. INuci Med 1987;2&1204-1207.

10.HuntJN,SpurrellWR.Thepatternofemptyingof thehumanstomach.IPhysic@I1951;113:157—168.

11.SoergelKH, PalmerDP,LooFD,WoodCM.Abnormalgastricemptyingindiabetics and the effects of metoclopramide [Abstract]. GastroenteroIo@j1980;78:1265.

12.HorwitzM, HardingPE,ChattertonBE,CollinsPi, ShearmanDJC.Acuteandchroniceffectsof domperiodoneongastricemptyingindiabeticautonomic neuropathy. Dig DLsSci 1985;30:1-9.

13.YungBCK,SostreS. Lagphaseinsolidgastricemptying:comparisonofquantificationby physiologicaland mathematicaldefinitions.I Nuci Med1993;34:1701—1705.

14. Moore JG, Christian PE, Coleman RE. Gastric emptying of varying mealweight and composition in man: evaluation by dual liquid- and solid-phaseisotopic method. Ag Dis Sci 1981;26:16-22.

Gastric Emptying Lag Phase •Nusynowitzand Benedetto 1027

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1994;35:1023-1027.J Nucl Med.   Martin L. Nusynowitz and Anthony R. Benedetto  The Lag Phase of Gastric Emptying: Clinical, Mathematical and In Vitro Studies

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