1996;37:267-269.J Nucl Med.   Elizabeth Oates, Donna-Lee G. Selland, Cynthia T. Chin and Dwight M. Achong  Optimizes Diagnosis of Acute CholecystitisGallbladder Nonvisualization with Pericholecystic Rim Sign: Morphine-Augmentation

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diagnostic success based on the pattern of gallbladder nonvisualization with a pericholecystic rim sign before morphine togallbladder nonvisualization after morphine in a group ofpatients undergoing morphine-augmented cholescintigraphy.

MATERIALS AND METhODSTwo experienced nuclear physicians blinded to the final diag

noses reviewed 170 consecutive morphine-augmented cholescintigrams completed over a 6-yr period (April 1988—June1994). Eachstudy was displayed on the computer and analyzed for a pericholecystic rim sign before morphine (all had gallbladder nonvisualization at about 1 hr as the reason for morphine augmentation). Apericholecystic rim sign was deemed present when it was notedindependently by both observers; in six cases, a consensus wasreached after initial disagreement. When present, each pericholecystic rim sign was graded as marked or mild. Marked referred topericholecystic uptake much more intense than adjacent liver,while mild corresponded to less pronounced but definite pericholecystic uptake that was slightly greater than adjacent liver.

Forty-three patients (28 women, 15 men, age range: 28—88yr.average = 56 yr) had a pericholecystic rim sign. This group wasfurther evaluated for persistent gallbladder nonvisualization versusgallbladder visualization after morphine.

All patients were fasting for at least 4 hr prior to cholescintigraphy. Nine were pretreated with intravenous sincalide (0.02mcg/kg/3 mm) (Kinevac, Squibb, Princeton, NJ) because of prolonged fasting (>48 Kr) or hyperalimentation.

Following intravenous injection of4.0 mCi (148 MBq) of@Tcmebrofenin, dynamic images were acquired for 30 mm on a large fieldof view gamma camera equipped with a low-energy, all-purposecollimator and peaked at 140 keV with a symmetric 20% window.Serial sets of static 5-mm views in the anterior, left anterior obliqueand right lateral projections followed at 30, 45 and 60 mm.

At approximately 1 hr (actual range: 40—150mm), intravenousmorphine sulfate (0.04 mg/kg) was administered if gallbladdernonvisualization and small bowel activity were observed. Sets of5-mm static images were repeated at 20 and 40 mm after morphineadministration. Nine patients whose gallbladders failed to visualizepromptly after morphine underwent delayed imaging between 2and 24 hr (average = 7 hr). Five patients with minimal residualhepatic activity received a booster dose of @°@Tc-mebrofenin(2mCi, 74 MBq) 10—15mm before morphine augmentation (4).

Persistent gallbladder nonvisualization after morphine confirmed acute cholecystitis while gallbladder visualization indicatedchronic cholecystitis. Cholescintigraphic diagnoses were correlatedwith surgical pathology in 33 patients (77%), 27 of whom wereoperated on within 1—3days; in 6, surgery followed 7—43dayslater. In I0 nonsurgical patients, correlation was made with clinicalcourse and included ultrasonography in six.

Real-time ultrasonographic criteria for cholecystitis included:

This study investigated the value of morphine-augmentation inpatients who demonstrated gallbladdernonvisualizationwfth a pencholecystic nm sign at 1 hr, a cholescintigraphicpattern consideredhighly predictive of acute cholecystitis. Methods Retrospectively,170 consecutive morphine-augmentedcholescintigramswere anatyzedfor the presenceof a perioholecysticnm sign, marked or mild,associated wfth gallbladder nonvisualizationat 1 hr (before morphine);thosewithapericholecysticnmsignwerefurtherevaluatedfor Persistentgallbladdernon@sualizationversusgallbladder @ñsualizationafter morphine. Scintigraphic interpretationswere correlatedwith surgical pathology or clinical diagnosis. Results Before morphine, 43/170 (25%) patients demonstrated gallbladder nonvisualizalion with a pericholecystic nm sign. Since only 31 had acutecholecystitis, a diagnosis based solely on that scintigraphic patternwould have resulted in 12 false-positives. After morphine, gailbiadder visual@ationcorrectly excluded acute cholecystitis in seven; asingle false-negative was encountered; five false-positives remamned.Morphine-augmentation improved the posith,e predictivevalue from 72% (gallbladder nonvisualizationwith pericholecysticnm sign before morphine)to 86% (gallbladdernonvleual@ationaftermorphine).Of 24 patients with marked pencholecysticrim signs, 21had acute cholecystitis.Of 31 with acute cholecystitis, however, 10(32%) had a mild penicholecysticnm sign. Conclusion: Morphineaugmented cholescintigraphy optimizes the diagnosis of acutecholecystitis in patientswith the suggestive,but not pathognomonic,cholescintigraphicpatternat 1 hr of gallbladdernonvisual@ationwitha penicholecysticrim sign, regardlessof its intensity.Key Words radionuclide imaging; gallbledder cholecystitis; morphine sulfate

J NuciMed1996;37267—269

Comparedtoconventionalcholescintigraphy,morphine-augmentation improves specificity and shortens the imaging timefor the diagnosis of acute cholecystitis (1—4).Described as awell-defined, sometimes broad, curvilinear or crescentic bandof increased hepatic activity adjacent to the gallbladder fossa, apericholecystic rim sign has been observed in 20%—60% ofpatients with gallbladder nonvisualization (5—8).As reported,the cholescintigraphic pattern of gallbladder nonvisualizationwith a pericholecystic rim sign at 1 hr predicts acute cholecystitis (positive predictive value >90%) and is strongly associatedwith advanced or complicated acute cholecystitis (perforation,gangrene, necrosis, abscess, ulceration, hemorrhage, fibrousexudate) (5—9).

Is gallbladder nonvisualization with a pericholecystic rimsign at 1 hr an appropriate and sufficient endpoint for diagnosisof acute cholecystitis, as advocated by many authors (3,5—7,9),or, should morphine augmentation be pursued regardless, assuggested by others (10)? To address this issue, we compared

ReceivedDec.30,1994;revisionacceptedJun.7, 1995.Forcorrespondencecontact 8@theth Oates, MD,New England Medioal Center, 750

Was@ngton St., Boston, MA02111.

MORPHINE-AUGMENTATIONWITHRIM SIGN •Gates et al. 267

Gallbladder Nonvi sualization with PericholecysticRim Sign: Morphine-Augmentation OptimizesDiagnosis of Acute CholecystitisElizabeth Oates, Donna-Lee G. Selland, Cynthia T. Chin and Dwight M. AchongDivision ofNuclear Medicine, Department ofRadiology, New England Medical Center, and Tufts University School ofMedicine, Boston, Massachusetts

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Acutechoiocysb@s(n=31)Chronic

cholec@(n=11)Surgical

(n =33*)257Complicated(n=11)110Acalculous(n=5)32Nonsurgical

(n =10)64•Tabio

excludes1 surgicallyabsentgallbladder.

TABLE IClinicopathologic Profile A B

FIGURE1.Twe-posith,eacutecalculouscholecystffis.Markedperk@hoiocystic rimsign(arrow)at1hr(A)withpersistentgallbladdernonvisuaiizationat40mm after morphine administration (B). Spontaneous enterogastnicrefiux(curvedarrow).

cholelithiasis, sludge, gallbladder wall thickening, pericholecysticfluid and direct tenderness.

Histopathologic criteria for acute cholecystitis were polymorphonuclear cellular infiltration and mural edema. Advanced (cornplicated) acute cholecystitis was defined as perforation, gangrene,necrosis, abscess, ulceration, hemorrhage or fibrin deposition.Chronic cholecystitis showed a predominant lyrnphocytic infiltration, fibrosis, glandular changes and, usually, gallstones.

RESULTSBefore morphine administration, gallbladder nonvisualiza

tion with a pericholecystic rim sign was observed in 43/170(25%) patients. Acute cholecystitis was diagnosed in 31 (72%)and chronic cholecystitis in 11; one patient had a surgicallyabsent gallbladder on reoperation for suspected acute cholecystitis (Table 1). Gallstones were present in all but five. Almostone-half(l 1/25) had complicated acute cholecystitis at surgery.

Gallbladder nonvisualization with a pericholecystic rim signat 1 hr correctly predicted acute cholecystitis in 3 1/43 (72%), 30of whom showed persistent gallbladder nonvisualization aftermorphine (Table 2) (Figs. 1, 2). Gallbladder visualization aftermorphine correctly identified seven patients without acutecholecystitis (Figs. 3, 4). There were five false-positives (Fig. 5)and a single false-negative after morphine (Table 2).

Pericholecystic rim signs were graded as marked in 24(56%)and mild in 18 (Table 3). A marked pericholecystic rim signcorrelated with acute cholecystitis in 21/24 (6 complicated); amild pericholecystic rim sign correlated with acute cholecystitisin 10/1 8 (5 complicated). Of 3 1 patients with acute cholecystitis, 32% demonstrated mild pericholecystic rim signs.

TABLE 2Correlation of Scintigraphic Patterns before and after Morphine

with Diagnosisof Acute Cholecystitis

1? FP PR/ TN FN NPV

31 12 72% —

*Frvesincalidepretreatment;five mebroteninbooster doses; seven delayedimaging.

1ThreeSInCaIKJepretreatment;twodelayedimaging.*OneSinCalidepretreatment.1? = true-positive;FP= false-positive;PPV= positivepredictivevalue;

TN = tnie-negabve FN = false-negative NPV = negative pred@tive value.

DISCUSSIONOn conventional cholescintigraphy with delayed imaging,

gallbladder nonvisualization suggests cystic duct obstructiondue to acute cholecystitis. False-positives due to chronic cholecystitis and other conditions, such as prolonged or inadequatefasting, hyperalimentation and acute pancreatitis, may confoundthat diagnosis. Morphine augmentation is clearly superior todelayed imaging up to 24 hr (11 ). Patients, however, withsevere intercurrent illness and hepatocellular dysfunction have ahigh incidence (60%) of false-positive morphine-augmentedcholescintigraphy (12). In this study, an unequivocal pericholecystic rim sign was observed in a patient without a gallbladder.

Gallbladder nonvisualization with a pericholecystic rim signat 1 hr has been considered virtually diagnostic of acutecholecystitis (5—9).This cholescintigraphic pattern is not pathognomonic and may be encountered in chronic cholecystitis(7). A pericholecystic rim sign has also been described withdelayed gallbladder visualization in chronic cholecystitis (10)and with gallbladder visualization in acute cholecystitis(13,14).

Although pericholecystic rim signs are subjective, two experienced observers agreed on the presence and grading of

BA

PremorphinePencholecystic

rimsignPostmorphine

Gallbladdernonvisual@ation

Gallbladdervisualization

- - A

30* 5t 99%

- - - 7n@ 88%

FIGURE2. Twa-positive complicatedacute choiscystffis.Marked pericholecysticrimsign(arrow)at30mm(a@4andgallbladderncnvioualizationat40mm after morphine administration (B). Enterogastric refiux after morphine(curved @.

B

FIGURE 3. True-negativethrontc calculous cholecystftis.Marked, broadpericholecysticrim sign (arrow)at 30 mm (A)with gallbladdervisualization(openarrow)at 20 mmaftermorphine.Enterogastricrefiuxaftermorphineadministration(curvedarrow).

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

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AcuteGrade cholecystitisChroniccholecystffisMarked(n=24)

21*3Mild(n=18)lot8*6/19

(32%)compicatedatsurgery.t5/6(88%) complk@atedat surgery.

TABLE 3Correlationof PencholecysticRim Sign Grade with Final Diagnosis

A B

FiGURE 4. True-negath,echronic calculous cholecystitis.At 1 hr (i@4,gallbladdernonvisualizationwith mild pencholecysticrim sign (arrow);at 20 mmafter morphine (B), gallbladder visualization (open arrow) excluding acutecholecystiti@

A

tion, two serious intercurrent illness) that could have led tofalse-positive studies. Except for one patient with chroniccalculous cholecystitis, all had mild pericholecystic rim signs.

The single false-negative was encountered in a patient withacute calculous cholecystitis in whom surgery occurred 25 dayslater (such that morphine-augmented scintigraphy may havebeen true-negative when performed). False-negative morphineaugmentedcholescintigraphy is a recognizedbut unusualphenomenon; morphine may raise biliary pressure sufficiently to overcomean incomplete cystic duct occlusion (15—18).

CONCLUSIONMorphine-augmentation should be considered in any patient

with the cholescintigraphic pattern of gallbladder nonvisualization with a pericholecystic rim sign. Safe and readily accomplished, this pharmacologic maneuver optimizes the diagnosisof acute cholecystitis and is of particular value in those with amild pericholecystic rim sign.

REFERENCESI. ChoyD,ShiEC,McLeanRG,HoschlR,MurrayIPC,HamJM.Cholescintigraphyin

acute cholecystitis:use of intravenousmorphine.Radiology 1984;l51:203—207.2. Kim EE, Pjura G, Lowry P. Nguyen M, Pollack M. Morphine-augmented cholescin

tigraphy in the diagnosis of acute cholecystitis. AJR l986;l47: I 177—I179.3. Keslar Pi, Turbiner EH. Hepatobiliary imaging and the use of intravenous morphine.

C/inNuc/Med 1987;l2:592—596.4. Fink-BennettD,BalonH,Robbins1, TsaiD.Morphine-augmentedcholescintigraphy:

its efficacy in detectingacute cholecystitis.J NucIMed 1991;32:123l—1233.5. Bushnell DL, Penman SB, Wilson MA, Polcyn RE. The rim sign: association with

acute cholecystitis. J Nuc/ Med l986;27:353—356.6. Meekin GK, Ziessman HA, Klappenbach RS. Prognostic value and pathophysio

logic significance of the rim sign in cholescintigraphy. J Nuc/ Med l987;28: 1679—1682.

7. Swayne LC, Ginsberg HN. Diagnosis of acute cholecystitis by cholescintigraphy:significance of pericholecystic hepatic uptake. AiR 1989; 152: 1211—12 I3.

8. Bohdiewicz Pi. The diagnostic value of grading hyperperfusion and the rim sign incholescintigraphy. C/in Nuc/ Med 1993;18:867—87l.

9. Brachman MB, Goodman MD, Waxman AD. The tim sign in acute cholecystitis.Comparison of radionuclide, surgical and pathologic findings. C/in Nuc/ Med 1993;18:863—866.

10. LowryPA,Tran HD. Delayedvisualizationof the gallbladderwitha rim sign.Anunusual finding in chronic cholecystitis. C/in Nuc/ Med 199l;16:l—3.

I 1. Kim CK, Juweid M, Woda A, Rothstein RD. Alavi A. Hepatobiliary scintigraphy:morphine-augmented versus delayed imaging in patients with suspected acute cholecystitis. J Nuc/ Med l993;34:506—509.

12. Fig LM, WahI RL, Stewart RE, Shapiro B. Morphine-augmented hepatobiliaryscintigraphy in the severely ill: caution is in order. Radio/ogy 1990:175:467—473.

13. Thorstad BL, Sakow N, Dubovsky EV. The pericholecystic hepatic activity sign in anormal DISIDA study. Case report. C/in Nuc/ Med 1987:12:721—722.

14. Morrison JC, Ramos-Gabatin A, Gelormini RG, Brown JW, Pius NL. Promptvisualization ofthe gallbladder with a rim sign—acuteor subacute cholecystitis. J Nuc/Med l993;34:1169—ll7l.

15. Mack JM, Slavin JD, Spencer RP. Two false-negative results using morphine sulfatein hepatobiliary imaging. C/in Nuc/ Med 1989:14:87—88.

16. Conrad MR. Goldfarb AL, Weaver AA. False-negative morphine-augmented biliaryimage. C/in Nuci Med 1989;I4:625.

17. Yen EE, Low JC, Azizi F. False-negative morphine-augmented cholescintigraphy in apatient with gangrenous cholecystitis. C/in Nuc/ Med 1992; 17:929 —930.

18. Achong DM, Newman iS, Oates E. False-negative morphine-augmented cholescintigraphy: a case ofsubacute gallbladder perforation. J Nuc/ Med 1991;33:256—257.

B

FiGURE5. False-positivechroniccalculouscholecysthis.Mild perk@holecystic rim sign (arrow)at 1 hr@ with gallbladdernonvisualizationat 40 mmaftermorphine(B).Enterogastnicrefiuxaftermorphine(curvedarrow).

pericholecystic rim signs in almost all patients. In this morphine-augmented population, 25% demonstrated a pericholecystic rim sign. Obvious (marked) pericholecystic rim signsmay predict more severe (complicated) gallbladder disease (8).Similarly, in this study, marked pericholecystic rim signs moreoften signaled acute cholecystitis (positive predictive value =88%) than did mild pericholecystic rim signs (positive predictive value = 56%) (Table 3). One-third ( 10/3 1) ofpatients withacute cholecystitis demonstrated mild pericholecystic rim signs.Unexpectedly, only 32% of marked pericholecystic rim signswere associated with complicated acute cholecystitis in contradistinction to 83% of mild pericholecystic rim signs.

In this study, terminating cholescintigraphy at 1 hr basedsolely on gallbladder nonvisualization with a pericholecysticrim sign—without morphine augmentation—would have resulted in 12 (28%) misinterpretations (Table 2). Morphineaugmentation sharply reduced the number of false-positivesfrom 12 to 5 and improved the positive predictive value foracute cholecystitis from 72% to 86% without adding significantly to time or effort.

For five patients with false-positive results (gallbladdernonvisualization after morphine), chronic calculous cholecystitis was diagnosed surgically 3—10days later in four; each had amild pericholecystic rim sign. Concomitant patient conditions,such as liver disease, intercurrent illness, or hyperalimentationdid not contribute to these false-positive studies. There was asurgically absent gallbladder in one patient with a markedpericholecystic rim sign.

Of seven patients with true-negative results (gallbladdervisualization after morphine) for chronic cholecystitis, fivewere calculous and two acalculous. In three of these patients,surgery was performed 1 day, 7 days and 43 days later.Interestingly, three had conditions (one hepatocellular dysfunc

MORPHINE-AUGMENTATION WITH RIM SIGN •Oates et al. 269

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