Digestive Diseases and Sciences, l'ol. 40, No. 7 (July 1995), pp. 1547--1553

Intravenous Contrast Medium Does Not Increase the Severity of Acute Necrotizing Pancreatitis in the Opossum ANDREAS M. KAISER, MD, TERRANCE GRADY, PhD, DIRK GERDES, MD, MANJU SALUJA, PhD, and MICHAEL L. STEER, MD

Contrast-enhanced computed tomography provides diagnostic and prognostic information in patients with acute pancreatitis. To evaluate whether contrast medium may worsen the severity of acute pancreatitis, we have used a model of necrotizing pancreatitis induced by ligating the common bile-pancreatic duct in opossums. Animals were infused with either saline or an ionic contrast agent 48 and 96 hr after induction of pancreatitis. Hyperamylasemia, pancreatic edema, acinar cell fragility, and macroscopic evidence of pancreatitis were comparable in both experimental groups. The microscopic extent of inflammation was similar in both groups, whereas acinar cell injury/necrosis was less in the contrast group. We conclude that administration of this ionic contrast agent during early stages of necrotizing pancreatitis in the opossum does not worsen the disease severity. The concept that administration of contrast medium during early stages of pancreatitis is dangerous should not be accepted until additional experimental and clinical studies support its validity. KEY WORDS: pancreatitis: contrast media; severity; computed tomography: x-ray; animal.

Contrast-enhanced computed tomography (CT) is widely used during the early stages of acute pancreatitis to confirm the diagnosis and to predict the severity of an attack (1-3). However, a recent series of reports describing the results of studies employing an experimental model of acute pancreatitis in rats suggested that administration of contrast medium during the early stages of acute pancreatitis might worsen the severity of an attack (4-7). The authors of Manuscript received December 27, 1994; accepted March 27, 1995. From the Department of Surgery. Beth Israel Hospital, Harvard Medical School, Harvard Digestive Discases Center, Boston, Massachusetts 02215. Supported by NIH grant DK 31396. A. M. Kaiser is a Research Fellow of Harvard Medical School and is supported by Swiss National Science Foundation grant 81ZH-36652. D. Gerdes is supported by grant Ge778/1-1 of the Deutsche Forschungsgemeinschaft. Address for reprint requests: Dr. Michael L. Steer, Department of Surgery, Beth Israel Hospital, 330 Brookline Avenue, Boston. Massachusetts 02215.

those reports therefore, suggested that it might not be wise to perform contrast-enhanced CT during the early stages of clinical acute pancreatitis. In the current communication, we report the results of studies that have reevaluated this issue using a different model of experimental pancreatitis. The model we have employed involves induction of biliary pancreatitis by obstructing the common bilepancreatic duct (CBPD) of the American opossum. In earlier studies, we have noted that the severity of this form of experimental pancreatitis is closely related to the duration of duct obstruction and that that severity can be quantitated using relatively straight forward biochemical and morphological techniques (8-10). We now report that the severity of this form of experimental pancreatitis is not worsened by repeated administration of a clinically utilized ionic contrast agent, given in clinically utilized amounts, 48 and 96 hr after the induction of pancreatitis by duct

D(~estiw' Diseases and Sciences. VoL 40. No. 7 (July 199.5)

11163-2116/95/(170()-1547507.50/0t-~ 1995PlenumPublishingCorporation

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KAISER ET AL ligation. O u r observations lead us to question the belief that contrast m e d i u m can worsen the severity of clinical pancreatitis.

MATERIALS AND M E T H O D S Animal Preparation. Randomly trapped, apparently healthy opossums (Didelph& virginiana) of either sex weighing 2.3-3.6 kg were obtained from R-Zoo (Neshkoro, Wisconsin). Conditioned animals were housed in individual steel cages in a climate-controlled room with ambient temperature of 23 -+ 2~ with a 12-hr light-dark cycle. They were fed an opossum laboratory diet and given water ad libitum. Before starting the experiments, all animals were extensively dewormed (Ivemectin, 1% solution, 0.2 ml/kg intramuscularly, Merck-Agvet, Brassway, New Jersey) and, in order to prevent common streptococcus D skin infections as well as bacterial endocarditis (11), they were pretreated with a seven-day course of penicillin G (50,000 units/kg body weight intramuscularly on alternate days) with the last injection being given on the day of the operation. After approval by the Institutional Animal Care and Use Committee of Harvard Medical School and Beth Israel Hospital, the following experimental protocol was carried out. Eight opossums were randomly divided into two experimental groups, a saline group (N = 4) and a contrast agent group (N = 4). They were anesthetized with an intraperitoneal injection of pentobarbital (50 mg/kg body weight). Using sterile technique, an upper midline laparotomy was performed, and the common biliary and pancreatic duct (CBPD) was ligated at its point of entry into the duodenum. At the same time, an aliquot of blood from each animal was harvested from a mesenteric vein. The laparotomy incision was closed and the animals were allowed to awaken from anesthesia. Forty-eight and 96 hr after this procedure, all animals were again anesthetized. Temporary venous access was gained by placing a 20-gauge needle-catheter (FlashCath from Baxter, Deerfield, Illinois) into the jugular vein. After withdrawing blood for chemical analysis, 2 ml/kg body weight of either saline or diatrizoate meglumine (Renografin-60 from Squibb Diagnostics, New Brunswick, New Jersey) was administered as a rapid bolus. Fifteen minutes later, all animals were given 8 ml/kg body weight of saline to provide hydration. Five days after the initial operation, the animals were killed by intravenous administration of a lethal dose of pentobarbital, the abdomen was opened, and blood as well as portions of the pancreas were harvested for biochemical and morphological analysis. Two additional opossums, which had neither been operated on nor infused with either saline or renografin, were similarly killed and samples obtained to provide normal reference values. Morphology. Complete cross sections of the head, body, and tail of the pancreas were fixed in 10% neutral phosphate-buffered formalin. Paraffin-embedded 5-~m sections were stained with hematoxylin-eosin. They were examined in a blinded fashion by an experienced morphologist who was not aware of the identity of the sample. Acinar cell injury and necrosis were defined as destruction of the histoarchitecture with a loss of integrity of whole or parts of the acini in combination with an inflammatory reaction. After exclusion of nonacinar parts such as islets of Lang-

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erhans or perivascular and periductular adventitial tissue, the amount of acinar cell injury/necrosis and the extent of the interacinar space containing inflammatory cells and edema were each quantitated morphometrically using a computerized image analysis video unit (model CCD-72, Dage-MTI, Michigan City, Indiana) equipped with the NIH-1200 image analysis software. Previous studies from this laboratory (8-10) have indicated that the morphological changes characterizing this model of pancreatitis are relatively evenly distributed between the major segments (ie, in the head, body, and tail) of the gland, even though they are focally and nonhomogeneously present within the gland parenchyma. Thus, morphometric data from the various sections obtained from each animal were pooled for data analysis. Ten randomly chosen high-power microscope fields (125• were examined for each tissue sample and three tissue samples were evaluated for each animal. The results for acinar cell injury/necrosis were expressed as a percentage of the total acinar tissue. The mixed mesenchymal and inflammatory reaction was quantitated by measuring the area of the interacinar space containing cellular elements and edema and expressed as a percentage of the total exocrine tissue. Thus, the calculated value for injury/ necrosis reflects the fraction of total acinar tissue that appears either injured or necrotic, while the calculated value for the mesenchymal and inflammatory reaction reflects the fraction of total exocrine tissue that is occupied by interstitial fluid and mesenchymal and/or inflammatory cells. Assays. Blood was harvested from a vein or, at the time of sacrifice, from the right ventricle and serum prepared for measurement of amylase activity (see below), total bilirubin (12), and creatinine (13). Fragments of the pancreas were rapidly removed and weighed to determine pancreatic wet weight. These fragments were then desiccated by incubation at 160~ for 48 hr and reweighed to determine the dry weight. Pancreatic water content was calculated as the difference between wet and dry weight and expressed as a percentage of the pancreatic wet weight. Other pancreas samples were harvested for measurement of the tissue content of amylase activity, cathepsin B activity, total protein, and DNA content. Those samples were minced in ice-cold 50 mM phosphate buffer (pH 7.4) and subsequently homogenized using a Polytron homogenizer (Brinkman, Westbury, New York). Amylase activity was measured using 4,6-ethylidene (Gv)-p-nitrophenyl (G 0-~D-maltoheptaside (ET-GvPNP) (Sigma, St. Louis, Missouri) as substrate (1416). Cathepsin B activity was quantitated using CBZarginyl-arginine-/3-naphthylamide (Bachem, Philadelphia, Pennsylvania) as substrate (17). One unit of cathepsin B was defined as that activity which resulted in the generation of 1 mmol of naphthylamine in 1 min. Protein was determined according to Lowry et al (18), using bovine serum albumin as the standard. DNA was measured fluorometrically using Hoechst dye 33258 and calf thymus DNA as the standard (19). For determination of in vitro LDH release, pancreas fragments were prepared as previously described (10) and incubated in 8 ml of HEPES Ringer buffer (pH 7.4) at 37~ At selected time points, 100 ~1 of the medium was removed and centrifuged at 800g. LDH was measured in the supernatant (20) and expressed as percentage of total LDH content. The latter was determined by measuring Digestive Diseases and Sciences, Vol. 40, No. 7 (July 1995]

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TIME (DAYS) Unoperated Controls - - O ~ Contrast Group Saline Group Fig 1. Course of serum parameters during C B P D obstruction. Serum amylase (A) and creatinine (B) were measured on days 0, 2, 4, and 5 after ligation of the c o m m o n bile-pancreatic duct. Results shown are the mean _+ SEM for animals given saline (N = 4) or contrast medium (N = 4) 48 and 96 hr after duct ligation. C o l u m n s represent values obtained in unoperated control animals (N = 2).

LDH activity in the homogenized fragments at the end of the incubation period. Analysis of Data. Statistical analysis of the data was accomplished using one-way analysis of variance (ANOVA) and the Student-Newman-Keul's test as apost-hoc test. The data shown in figures represent means -- SEM values. The absence of error bars indicates that the SEMwas too small to illustrate. Differences in the observed results were considered significant when P -< 0.05. RESULTS All animals recovered quickly from anesthesia and displayed an appropriate behavior until the time of sacrifice. Food and water consumption was greater in the unoperated control animals, but was similar in each of the two study groups. Ligation of the CBPD resulted in hyperbilirubinemia, which increased in severity with time in both the saline and the contrastinfused groups. Serum bilirubin concentrations, five days after CBPD ligation, were comparable in both groups (5.0 + 0.9 mg/dl and 4.6 _+ 1.4 mg/dl, P > 0.05). Serum amylase activity increased, in a biphasic manner, after CBPD ligation (Figure 1A). The time course and the magnitude of hyperamylasemia were similar (P > 0.05) in the saline and the contrastinjected groups. Neither CBPD ligation alone (saline group) nor CBPD ligation combined with repeated Digestive Diseases and Sciences, Vol. 40, No. 7 (July 1995)

administration of contrast medium caused serum creatinine levels to rise above normal reference values (Figure 1B). Five days after CBPD ligation, macroscopic examination indicated that all of the study group animals had developed severe necrotizing pancreatitis. Fat necrosis, abscesses, and edema formation were noted, irrespective of whether they had been given saline or renografin. Pancreatic water content, which was 74 + 1.5% in the unoperated controls, was 80.9 _+ 0.3% and 79.9 +_ 0.7% in the saline and contrast-infused groups, respectively, five days after CBPD ligation (P > 0.05). Thus, the magnitude of pancreatic edema associated with duct ligation-induced pancreatitis was not altered by infusion of renografin. The in vitro release of L D H from pancreatic fragments was used as a measure of cell fragility (Figure 2). Fragments obtained from unoperated control animals released 6.6 + 1.8% of their L D H during in vitro incubation for 60 min. L D H release was increased in fragments obtained from animals five days after CBPD ligation, but the magnitude of that increase was similar (P > 0.05) in animals infused either saline or renografin. We have previously reported that CBPD ligation causes pancreatic amylase content to fall and pancreatic content of cathepsin B to rise (10). In unoperated

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KAISER ET AL

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control animals, pancreatic amylase content was found to be 6.2 _+ 0.2 units/mg, protein while cathepsin B content was 0.28 _+ 0.16 units/mg protein. Five days following CBPD ligation, pancreatic amylase content was 2.9 _+ 1.2 units/mg protein in the salineinfused group and 2.2 +_ 0.2 units/rag protein in the contrast infused group (P > 0.05). Cathepsin B content, five days after CBPD ligation, was 1.44 +_ 0.14 units/mg protein in the saline infused group and 1.78 + 0.46 units/mg protein in the group infused with renografin (P > 0.05). At the light microscope level of resolution, morphological changes of pancreatitis, including edema, inflammatory cell infiltration, acinar necrosis, and fat necrosis, were similar in the saline and the contrastinfused group five days after CBPD ligation. Morphometric analysis of samples was undertaken in order to quantitate these changes in an objective fashion. The intraanimal variation of the morphometry, expressed as the mean of the individual standard errors, was found to be negligible (1.5 + 0.1%). Injury/necrosis (Figure 3A) involved 36.4 _+ 0.8% of the acinar tissue five days after CBPD ligation in the group given only saline and 31.9 _+ 1.3% of the acinar tissue in the group infused with renografin (P < 0.05). Mesenchy1550

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mal tissue and inflammation, including edema fluid as well as the inflammatory cell infiltrate, occupied 47.7 _ 1.3% of the area incorporated by exocrine tissue in the saline-infused group and 47.6 _ 1.3% of the Digestive Diseases and Sciences, Vol. 40, No. 7 (July 1995)

CONTRAST MEDIUM IN SEVERE PANCREATITIS exocrine tissue area in the group given renografin (P > 0.05) as compared to 9.0 +-- 1.2% interstitial tissue in the unoperated control animals (Figure 3B). DISCUSSION Severe attacks of acute pancreatitis can be associated with considerable morbidity and a mortality rate that may approximate 40% (21). On the other hand, mild pancreatitis is usually a self-limited process associated with little morbidity and negligible mortality. Early identification of those individuals most likely to experience a severe attack of pancreatitis could allow selective application of potentially beneficial interventions such as peritoneal dialysis (22, 23), lesser sac lavage, surgical debridement (24-26), administration of dextran (27), and admission to an intensive care unit (28). Several approaches to the identification of such individuals have been developed, including the prognostic scoring systems described by groups such as those of Ranson and coworkers (29, 30, 31) and Imrie and coworkers (32, 33). Recently, there has been increasing appreciation of the value of CT in this setting, both to confirm the diagnosis and to predict the severity of an attack (34). Indeed, when rapid scans are obtained during bolus administration of contrast medium, CT can be used to estimate the extent of pancreatic necrosis (1-3, 35). Because the extent of pancreatic necrosis during the early stages of pancreatitis is closely related to the severity of an attack, this so-called dynamic contrast-enhanced CT, performed during the first several days after the onset of symptoms, has come to be regarded as the goldstandard test for predicting the likelihood of complications and/or death from pancreatitis (36). The results of a recent series of studies evaluating experimental pancreatitis have suggested that administration of radiographic contrast medium might worsen the severity of clinical pancreatitis (4-7). In those studies, either moderate or severe pancreatitis was induced in rats by the combined effects of supramaximal secretagogue stimulation and retrograde pancreatic ductal injection of bile salt. In animals with severe pancreatitis, but not in those with moderate pancreatitis, the mortality rate as well as the biochemical and morphological severity of pancreatitis were worsened by administration of either an ionic or a nonionic contrast agent. The authors concluded that the use of contrast-enhanced CT "early in acute pancreatitis should therefore be reconsidered and perhaps avoided." An accompanying editorial, by Balthazar and Freeny (37), rejected that conclusion, Digestive Diseases and Sciences, Vol. 40, No. 7 (Ju~, 1995)

pointing out several flaws in the experimental study as well as the fact that few, if any, clinical studies have documented a detrimental effect of contrast medium administration on the severity of pancreatitis. Surprisingly, however, the issues raised by Balthazar and Freeny have, to a great extent, been overlooked and, in many centers, clinicians have accepted the conclusion that administration of contrast agents during the early stages of acute pancreatitis is dangerous. We have chosen to reevaluate this issue using a different experimental model of acute necrotizing pancreatitis--one which we believe very closely resembles severe clinical biliary pancreatitis. In our studies, pancreatitis was induced by ligation of the CBPD in the American opossum. In previous studies, we (8-10) and others (38) have shown that ligation of the CBPD of the opossum causes hemorrhagic necrotizing pancreatitis and that the severity of that pancreatitis is dependent on the duration of ductal obstruction. In our studies, we have chosen to obstruct the common bile-pancreatic duct for five days because, at that time, roughly 60% of the acinar tissue appears viable on morphological examination and, thus, worsening of pancreatitis by necrosis of viable pancreatic tissue could be easily detected. We have elected to employ an ionic contrast agent (Renografin-60) that is frequently used clinically and to give the renografin at a dose (2 ml/kg body weight) used clinically. To unmask even mild detrimental effects of the renografin, we have administered it to each animal twice during the five-day period of duct obstruction. The results of our studies indicate that renografin, administered 48 and 96 hr after bile-pancreatic duct obstruction, does not worsen the severity of necrotizing pancreatitis in this model. The magnitude of hyperamylasemia, the increase in pancreatic water content (edema), the extent of in vitro LDH release from pancreas fragments (cell fragility), the decrease in pancreatic content of amylase, and the increase in pancreatic content of cathepsin B were all similar for animals given either renografin or saline after CBPD ligation. Macroscopic changes of pancreatitis were comparable in the two groups. At the microscopic level of resolution, the extent of inflammation was similar in the two groups and the extent of injury/ necrosis was actually greater in those animals given saline than in those given renografin. Thus, our studies indicate that administration of ionic contrast medium does not worsen the severity of experimental necrotizing biliary pancreatitis in this opossum model. Our findings are clearly at variance

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with those reported earlier by investigators who employed a rat model of pancreatitis for their studies. At a minimum, therefore, those observations indicate that the effects of contrast medium on experimental pancreatitis depend upon the model of experimental pancreatitis that is being used. Since administration of contrast medium does not worsen the severity of the opossum model of pancreatitis, we would argue that condemnation of the practice of performing contrast-enhanced CT during the early stages of pancreatitis is premature and that further studies, using other models as well as clinical material, will be needed before the potential detrimental effects of contrast medium on pancreatitis are fully elucidated. It should be emphasized, however, that contrast medium, both ionic and nonionic, may be harmful by mechanisms that do not involve worsening of pancreatic injury (39). In this regard, allergic reactions and renal injury are particularly noteworthy (40-42). Proper screening of patients for a history of dye or iodine allergy and appropriate hydration prior to administration of contrast medium may reduce the likelihood of those complications (43). REFERENCES I. Kivisaari L, Somer K, Standertskjold-Nardenstam CG, Schroder T, Kivilaakso E, Lempinen M: A new method for the diagnosis of acute hemorrhagic-necrotizing pancreatitis using contrast-enhanced CT. Gastrointest Radiol 9:27-30, 1984 2. London NJM, Leese T, Lavelle JM, Miles K, West KP, Watkin DFL, Fossard DP: Rapid-bolus contrast-enhanced dynamic computed tomography in acute pancrcatitis: A prospective study. Br J Surg 78:1452-1456, 1991 3. Johnson CD, Stephens DH, Sarr MG: CT of acute pancreatitis. Correlation between lack of contrast enhancement and pancreatic necrosis. AIR 156:93-95, 1991 4. Foitzik Tb, Bassi DG, Schmidt J, Lewandrowski KB, Fernandez-Del Castillo C, Ratmer DW, Warshaw AL: Intravenous contrast medium accentuates the severity of acute necrotizing pancreatitis in the rat. Gastroenterology 106:207-214, 1994 5. Foitzik T, Bassi DG, Lewandrowski K, Schmidt J, Fernandezdel Castillo C, Rattner DW, Warshaw AL: Intravenous contrast medium increases trypsinogen activation, cell necrosis and mortality in severe pancreatitis in the rat. Pancreas 7:737, 1992 6. Foitzik T, Bassi DG, Fernandez-del Castillo C, Rattner DW, Warshaw AL: Intravenous contrast medium impairs oxygen delivery to the pancreas in acute necrotizing pancreatitis in the rat. Gastroenterology 104:A124, 1993 7. Foitzik T, Bassi DG, Fernandez-del Castillo C, Warshaw AL: Intravenous contrast medium impairs oxygenation of the pancreas in acute necrotizing pancreatitis in the rat. Arch Surg 129:706-711, 1994 8. Lerch MM, Saluja AK, Dawra R, Ramarao P, Saluja M, Steer ML: Acute necrotizing pancreatitis in the opossum: Earliest morphological changes involve acinar cells. Gastroenterology 103:205-213, 1992

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9. Lerch MM, Saluja AK, Ri.inzi M, Dawra R, Saluja M, Steer ML: Pancreatic duct obstruction triggers acute nccrotizing pancreatitis in the opossum. Gastroenterology 104:853-861, 1993 10. R~nzi M, Saluja A, Lerch MM, Dawra R, Nishino H, Steer ML: Early ductal decompression prevents the progression of biliary pancreatitis: An experimental study in the opossum. Gastroenterology 105:157-164, 1993 1I. La Plante ES, Burrel RG: Bacterial endocarditits in opossums. Bull Wild Dis Assoc 2:10-12, 1966 12. Winsten S, Cchclyk B: A rapid micro diazo technique for measuring total bilirubin. Clin Chim Acta 25:441-446, 1969 13. Fabiny DL, Ertingshausen G: Automated reaction-rate method for determination of serum creatinine with the Centrifichem. Clin Chem 17:696-700, 1971 14. Pierre KJ. Tung KK, Nadj H: A new enzymatic kinetic method for the determination of alpha amylase. Clin Chem 22:1219, 1976 t5. Wallenfels K. Fo[di P, Niermann H, Bender H, Linder D: The enzyme synthesis by transglucosylation of a homologous series of glucosidically substituted maltooligosaccharides, and their use as amylase substrates. Carbohydr Res 61:359, 1978 16. Wallenfels K, Meltzer B, Laule G, Janatsche G: Chromogene and fluorogene Substrate ffir Nachweis und Bestimmung von alpha-Amylasen. Fresenius Z Anal Chem 301:169, 1980 17. McDonald JK, Ellis S: On the substrate specificity of cathepsin B1 and B2 including a new fluorogenic substrate for cathepsin B1. Life Sci 17:1269-1276, 1975 18. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265-275, 1951 19. Labarca C, Paigen K: A simple, rapid, and sensitive DNA assay procedure. Anal Biochem 102:344-352, 1980 20. Amador E, Dorfman LE, Wacker WEC: Serum lactic dehydrogenase: An analytical assessment of current assays. Clin Chem 9:391-399, 1963 21. Banks PA: Medical management of acute pancreatitis and complications, hi The Pancreas, Biology, Pathobiology and Disease, 2 ed. VLW Go, EP DiMagno, JD Gardner, H Reber, G Scheele (eds). New York, Raven Press, 1993, pp 593-611 22. Ranson JHC. Bermann RS: Long peritoneal lavage decreases pancreatic sepsis in acute pancreatitis. Ann Surg 211:708-716, 1990 23. Mayer AD, McMahon MJ, Corfield AP, Cooper M J, Williamson RCN, Dickson AP, Shearer MG, Imrie CW: Controlled clinical trial of peritoneal lavage for the treatment of severe acute pancreatitis. N Engl J Med 312:399-404, 1985 24. Ranson JHC: The role of surgery in the management of acute pancreatitis. Ann Surg 211:382-393, 1990 25. Sarr MG, Nagorney DM, Mucha P Jr, Farnell MB, Johnson CD: Acute necrotizing pancreatitis: management by planned, staged pancreatic necrosectomy/debridement and delayed primary wound closure over drains. Br J Surg 78:576-581, 1991 26. Wilson C, McArdle CS, Carter DC, Imrie CW: Surgical treatment of acute necrotizing pancreatitis. Br J Surg 75:1119-1123, 1988 27. Klar E, Herfarth C, Messmer K: Therapeutic effect of isovolemic hemodilution with dextran 60 on the impairment of pancreatic microcirculation in acute biliary pancreatitis. Ann Surg 211:346-353, 1990 28. Larvin M, McMahon MJ: APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet 2:201-204, 1989

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C O N T R A S T M E D I U M IN S E V E R E P A N C R E A T I T I S 29. Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC: Prognostic signs and the rolc of operative management in acute pancreatitis. Surg Gynecol Obstct 139:69-81, 1974 30. Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Localio SA: Objcctivc early identification of scvcre acute pancreatitis. Am J Gastroenterol 61:443-451, 1974 31. Ranson JHC, Pasternack BS: Statistical methods for quantifying the sevcrity of clinical acute pancrcatitis. J Surg Res 22:7991, 1977 32. Imric CW, Benjamin IS, Ferguson JC, McKay At, Mackenzie 1, O'Neill J, Blumgart LH: A single-center double-blind trial of Trasylol therapy in primary acute pancreatitis. Br J Surg 65:337-341, 1978 33. Wilson C, Heath DI, Imrie CW: Prediction of outcome in acute pancreatitis: A comparative study of APACHE II, clinical assessment and multiple factor scoring system. Br J Surg 77:126(1-1264, 1990 34. Balthazar E J, Ranson BM, Naidich DP, Megibow At, Caccavale R, Cooper MM: Acute pancreatitis: Prognostic valuc of CT. Radiology 156:767-772, 1985 35. Larvin M, Chalmers AG, McMahon M J: Dynamic contrast enhanced computed tomography: A precise technique for

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identifying and localising pancreatic necrosis. BMJ 300:14251428, 1990 Balthazar EJ, Robinson DL, Megibow AJ, Ranson JHC: Acute pancrcatitis: Value of CT in establishing prognosis. Radiology 174:331-336, 1990 Balthazar El, Freeny PC: Editorial: Contrast-enhanced computed tomography in acute pancreatitis: Is it beneficial or harmful. Gastroenterology 106:259-261, 1994 Scnninger N, Moody FG, Coelho JC, Van Buren DH: The role of biliary obstruction in the pathogenesis of acute pancreatitis in the opossum. Surgery 99:688-693, 1986 Cohan RH, Dunnick NR: lntravascular contrast media: Adverse rcactions. AJR 149:665-670, 1987 Bush WH, Swanson DP: Acute reactions to intravascular contrast media: Types, risk factors, recognition, and specific treatment. AJR 157:1153-1161, 1991 Berns AS: Nephrotoxicity of contrast media. Kidney lnt 36:730-740, 1989 Porter GA: Contrast-associated nephropathy. Am J Cardiol 64:22E-26E, 1989 Cohan RH, Dunnick NR, Bashorc TM: Treatment of reactions to radiographic contrast material. AIR 151:263-270, 1988

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