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  • Acute Cholecystitis: *

    An Experimental Stuidy

    SA-m E. STEPHENSON, JR., M.D., CARL B. NAGEL, M.D.

    From the Department of Surgery and the S. R. Light Laboratory for SuirgicalResearch, Vanderbilt University School of AMedicinie, Nashiville 5 Tennessee

    "THE PATHOLOGICAL problems presentedby that profitable stone quarry, the gall-bladder, are numerous and varied. . . Inthe past far too much stress has been laidupon the presence of calculi. Calculi areincidental, not essential, to gallbladder dis-ease." 8 This statement by William Boyd in1923 summarizes much of our inadequateknowledge covering the pathogenesis ofexperimental and clinical acute cholecysti-itis from the time of John Hunter to thepresent.The problem of priority between stones

    and an inflammatory response is still un-settled. It seems reasonable to assume, how-ever, that with the exception of certainmetabolic diseases, most cases of acutecholecystitis with or without cholelithiasishave the primary defect of an inflammatoryreaction predisposing to stone formation ata later date.Many factors have been implicated in

    the past as being the major cause of acutecholecystitis. This group of experiments isdesigned to evaluate a number of factorswhich may or may not be of importance inthe development of this disease in the ex-perimental animal.

    Procedure

    Randomly selected adult mongrel dogswere anesthetized with pentobarbital so-dium, 15 mg./kg. body weight. A standard-

    *Presented before the Southern Surgical As-sociation Boca Raton, Florida, December 4-6,1962.

    ized operative procedure was then carriedout on each of 60 animals. The abdomenwas opened through an upper midline in-cision and the gallbladder and cystic ductexposed. Care was taken to isolate thecystic duct from the surrounding arteryand veins. If vascular injury occurred, theanimal was excluded from the study.The gallbladder in most groups was then

    cannulated through the cystic duct withthe withdrawal of 8.0 to 10 cc. of bile forpH determination and quantitative bac-teriologic cultures. An equal amount ofmaterial to be evaluated was injectedthrough the same needle. In most cases thecystic duct was then ligated. The woundswere closed. No antibiotics were given andall animals were sacrificed at 48 hours. Thegallbladders were removed intact, and bilewas aspirated under sterile conditions forrepeat pH and bacteriological studies.

    Eleven different combinations of stresswere employed:

    I. Ligation of the cystic duct after injection ofautogenous pancreatic juice;

    II. Ligation of the cystic duct after injectionof autogenous gastric juice (two of these animalshad a previous vagotomy and showed no essentialchange from the unvagotomized gastric juice);

    III. Ligation of the cystic duct after injectionof normal saline;

    IV. Ligation of the cystic duct followed by afatty meal;

    V. Ligation of the cystic duct following the in-jection of 0.1 N hydrochloric acid;

    VI. Ligation of the cystic duct following theinjection of 1.0 per cent phenol;

    687

  • 688TABLE 1. Percentage of Grad

    the Gallbladder Wall

    Group SE

    Gastric secretionw-ith ligation

    Panicreatic secretionwvith ligationi

    Pancreatic enzvineswvith ligation

    Saliniewitlh ligation

    CGastric secretionwkvithout ligation

    Pancreatic secretionwithout ligationi

    VII. Ligation of the c!injection of 25,000 units o

    VIII. Ligation of the cinjection of 90 mg. of tryp

    IX. Ligation of the cyinjection of 25,000 units of

    X. Injection of gastricof the cystic duct;

    XI. Injection of pancr(tion of the cystic duct.

    Resu

    The desire to haveamong the various agnecessitated the exclus

    STEPHENSON AND NAGEL Annals of SurgeryMlay 1963

    'ed Microscopic Changes in expired before the scheduled time of sacri-of Selected Groups fice. Although an occasional animal inIPercentage of Animals various groptps expired, the onlv death

    wvith Patlhological r *Cliange rates of significance vere in the grouipse Mereloderate Nonie with ligation and gastric juiice (46 c' ) or

    71 29 0 trypsinogen (50c).Perforation of the gallbladder occurred84 16 0 only twice, on both occasions following the

    instillation of gastric jtuice combined with83 17 ligation of the cystic duct.16 66 16S The determination of bile pH had no

    definite correlation between the degree of28 57 15 inflammatory reaction and varied little

    from the preoperative measurement irre-25 75 0 spective of the material injected. The aver-

    age pre-injection pH was 7.3, with a rangeof 5.8 to 7.7. The average pH at sacrifice

    ystic duct following the was 7.1, with a range of 5.3 to 7.9. The re-f chymotrypsinogen; sults were not consistent in any groupystic duct following the though the groups receiving gastric juice)sinogen; and hydrohlori cended to showzstic duct following the and hydrochloric acid tended to showtrypsin; slightly lower pH values. These figuresjuice without ligation were not statistically significant.

    eatic juiee without liga- Bacteriological studies were also unre-wvarding. Three of 32 animals had positivecultures initially, and 72 per cent of the

    [lts animals had a positive culture at sacrifice.a comparative study Again there was no correlation between;ents and maneuvers the severity of the reaction in the gall-sion of animals who bladder -wall and the presence of a positive

    FIG. 1. Three examples of the gross changesproduced by ligation of the cystic duct and injec-tion of pancreatic juice (829), pancreatic juicewithout ligation (830) and gastric juice withoutligation (831).

    67 .... , ..

    FIG. 2. Two illustrative gross specimens demon-strating the changes at 48 hours with a ligatedcystic duct following the injection of gastric juice(678) and pancreatic juice (679).

  • Volume 157Number 5 ACUTE CHOLECYSTITIS 689

    FIG. 3. A composite of photomicrographs demonstrating the microscopic changes produced in theexperimental study. A. Normal gallbladder wall. B. Changes with the injection of trypsinogen demon-strating mucosal and submucosal edema and intramural hemorrhage. C. Gastric juice with normalmucosa and marked edema and congestion of the wall. D. Typical changes following the injection ofpancreatic juices demonstrating normal mucosa in disruption of the normal submucosal architecture.

    bacteriological culture. The most frequentorganisms recovered were streptococcusfecalis and staphylococci.

    In each of the 11 groups of animals therewere pathological changes of acute chole-cystitis developing in varying degree in thegallbladder wall as seen by both gross andmicroscopic examination. The gross re-sponse varied from edema and injection tofrank gangrene (Fig. 1, 2). Microscopicallyall sections were graded as to the degree ofinvolvement present. Table 1 represents thepercentage of change present in selectedgroups with comparative grading as tosevere, moderately severe, or normal frommicroscopic evaluation. For this evaluationsevere change represents involvement of alllayers of the gallbladder wall with associ-ated intramural hemorrhage; moderatelysevere changes indicate the lack of involve-

    ment of the mucosa; and normal refers tono abnormality or minor amounts of peri-toneal reaction believed to be secondary tothe operative procedure (Fig. 3).

    Severe changes in the cystic wall werenoted in at least one animal of each group.Groups I, II, and VIII, receiving pan-creatic juice, gastric juice, and trypsinogenrespectively, demonstrated the most severemucosal involvement. Each of these threegroups had ligation of the cystic duct as-sociated with the injection.Of particular interest in the study are

    Groups X and XI in which gastric or pan-creatic juice were injected without manipu-lation or ligation of the cystic duct. All ofthe animals receiving pancreatic juice and85 per cent of animals receiving gastricjuice in this manner developed severe ormoderately severe gross and microscopic

  • 690 STEPHENSON AND NAGEL

    changes. Most previous reports 13, 15, 24, 31have noted the necessity of cystic duct ob-struction for the development of experi-mental actute cholecystitis. Exceptions tothis are the reports of Mann '9 and Aron-sohn 5 referred to in the discussion. Inanalyzing these two groups of animals, oneconcludes that the reflux of pancreatic juiceor gastric juice up the unobstructed chole-dochus or cystic duct could precipitate in-flammatory changes in the gallbladder wallmicroscopically identical with acute chole-cystitis. This occurs with or without thepresence of bacteria, with or without aperihilar inflammatory response, or with orwithout vascular insufficiency either fromthe arterial or venous aspects.The results of this group of experiments

    demonstrate that a number of both physio-logical and extraneous agents are capableof producing the gross and microscopicchanges associated with acute cholecystitisin the dog. It seems fair to assume that,especially concerning the physiologicalagents, the same progression of changesoccur in the human. The high incidence ofsevere and moderately severe reactions inthe wall of the gallbladder following theinjection of whole pancreatic juice, as wellas purified pancreatic enzymes (trypsin,chymotrypsinogen, and trypsinogen), sup-ports the data suggesting that a commonpancreatico-choledochal channel not onlyincreases the incidence of pancreatitis frombile reflux, but also increases the incidenceof acute cholecystitis from pancreatic re-flux and may then in part predispose tocholelithiasis. The factor of greater interestto the authors, however, is that of gastricjuice. In the majority of patients no func-tional common channel exists. In all pa-tients the amount of gastric juice propelledinto the duodenum far exceeds the amountof pancreatic juice present. When ref