Acute Acalculous Cholecystitis: A Complication of Hyperalimentation
Scott R. Petersen, MD,“*$ Salt Lake City, Utah George F. Sheldon, MD,+ San Francisco, California
Acute cholecystitis is an often unrecognized and potentially fatal complication in critically ill patients after surgery or trauma. The classic presentation of pain and tenderness in the right upper abdominal quadrant, fever, leukocytosis, and a palpable gallbladder is unusual in this setting, and diagnosis rests on clinical suspicion and ultrasonography. Gallstones will be absent in 22 to 53 per cent of patients in whom acute cholecystitis develops after an unrelated surgical procedure [I--4] and in 87 per cent of patients with this syndrome after major trauma . Many etiologic factors may be important in the development of acalculous cholecystitis. Fasting in the postoperative period [I$], anesthesia [I], narcotic analgesics [I], multiple transfusions [ 7,8], sepsis [8,9], hypotension [IO], and mechanical ventilation with positive end-expiratory pressure [II] have been suggested as potential causes. Recently, the prolonged use of total parenteral nutrition appears to predispose the patient to bile s&is and result in acute acalculous cholecystitis . Seriously ill postoperative or post-trauma patients are often treated with bowel rest and hyperalimentation because of hypermetabolism secondary to injury or infection and may be at increased risk of developing this complication. Over a 5 year period, eight patients in whom acalculous cholecystitis developed during therapy with intravenous hyperalimentation are reviewed with emphasis on factors contributing to pathogenesis and suggestions for possible prevention. From the Departments of Surgery, University of Utah College of Medicine,’ Salt Lake Citv. Utah and the Universitv of California Service.’ San Francisco General Ho&al, San Francisco, Cal&&. This work was &pport& in part by National Research Service Grant NIGMO 3072, Bethesda, Maryland. * NatioMl Research Service Fellow in Trauma and Burn Research NIGMO 7032. __-. Reprint requests should be addressed to Scott R. Petersen MD, Department of Swgery. Universityof Lltah College of Medicine, 50 N. Medical Drive, Salt Lake City, Utah 64132. Presented at the 31st Annual Meeting of the Southwestern Surgical Congress, Las Vegas, Nevada, April 23-26, 1979.
Material and Methods All cholecystectomies performed at the San Francisco General Hospital in the five year period from 1972 to 1977 were reviewed (Table I). Cases were accepted only if evidence of acute cholecystitis was present on intraoperative or pathologic examination and if the absence of gallstones was confirmed by examination of either the opened gallbladder in the operating room or the unopened specimen in the laboratory. Patients without gallbladder calculi but with intraoperative evidence of choledocholithiasis were excluded from the study. Of the 435 patients reviewed, 100 patients (23 per cent) had acute cholecystitis, and of these, 17 had no demonstrable calculi. Eight of the 17 patients received parenteral nutrition for 8 to 39 days (mean 21 days) before the diagnosis of acalculous cholecystitis. The parenteral solutions consisted of hypertonic glucose-crystalline amino acid infusions administered through central venous catheters. Intravenous fat emulsions were provided on a periodic basis (two to three times a week) to prevent essential fatty acid deficiency, and no patient received lipid as a primary caloric source. Clinical Features. There were six male and two female patients with acalculous cholecystitis who received hyperalimentation; their mean age was 53.8 years (range 28 to 76). All eight patients had had laparotomy or multiple trauma, or both. Three patients had blunt abdominal trauma after motor vehicle accidents, and one patient had a penetrating abdominal injury after a gunshot wound. Acute acalculous cholecystitis also occurred in four patients in the postoperative period (two after laparotomy for small bowel obstruction, one after an abdominal aortic aneurysmectomy, and one after excision of a retroperitoneal sarcoma). No patient in this series had a history of biliary tract disease. The typical findings of pain, tenderness, or a mass in the right upper abdominal quadrant were infre: quent, pain occurring in 62 per cent of the patients and a mass in 25 per cent. Fever (greater than 38’C) was present in all patients and leukocytosis (mean 20,400/mm3) in 71 per cent. In addition, 75 per cent had elevated bilirubjn values (mean 7.4 mg/dl, total) or increased alkaline phosphatase levels, or both. The mean duration of symptoms before abdominal exploration was 8 days (range 3 tq 17) The American Journal of Surgery
Figure 1. The frequency of acute acalculous cholecystitis contrasted with the use of totat parenteral nutrition. Hatched bars indicate &ents who redeived totalparenterat nutrition; open bars indicate patients who did not receive total parenteral nutrition. (Data ‘from:’ Sanders and Sheldon
[ w. 1
No. of Patients __.____
Chronic cholecystitis Gallstones present Gallstones absent Acute choiecystitis Gallstones present Gallstones absent Miscellaneous Trauma Carcinoma Cholecystoenteric fistulas
320 312 a 100 83 17 15 9 2 4
Excludes cholecystectomy for biliary bypass, pancreatic carcinoma right hepatectomy, and the like; includes chotecystectomy with associated choledocholithiasis. l
compared with 3.6 days in patients who presented at the hospital with symptoms of acute cholecystitis without associated trauma or surgery. The diagnosis of acute cholecystitis was made before laparotomy’in only 50 per cent of patients receiving hyperalimentation but in 89 per cept, of patients with acalculous cholecystitis who had no associated major illness, surgefy, or trauma, which emphasizes the difficulty of making an early, accurate diagnosis in these critically ill patients. The primary indication for operation in patients in whom the diagnosis of acalculous cholecystitis was not made until laparotomy was intraabdominal sepsis. Nine of the 17 patients with acute acalculous cholecystitis were seriously ill and required an extended period of intensive care. In these patients, prolonged fasting was universal and intravenous hyperalimentation was used in 89 per cent for an average of 3 weeks before laparotomy was performed. In no patient. in this series did symptoms of cholecystitis develop after oral intake was reinstituted, ,a phenomenon that has previously been stressed [~Jz]. In addition to intravenous hyperalimentation, sepsis, hypotension, multiple transfusions (more than 10 units of blood) and ventilator support were frequent common denominators (Table II).
Cholecyslectomy at San Francisco General Hospital From 1972 to 1977’
Factors Associated With Acalculous Cholecystitis” No. of Patients
Prolonged fasting Narcotic analgesics Total parenteral nutrition Sepsis Multiple transfusions (more than 10) Hypotension Ventilatory support
919 919 819 819 519
100 100 a9 a9 59
* Associated factors in nine patients in whom acute acatcutous cholecystitis developed after unrelated operation or trauma.
death was directly related to sepsis from acute cholecystitis in 80 per cent. During the period of this review, the frequency of acalculous cholecystitis increased and this increase ran parallel to a concomitant increase in the use of total parenteral nutrition at San Francisco General Hospital  (Figure 1). Comments
Cholecystectomy was performed in 13 sf the 17 patients (76 per cent) with acute acalculous cholecystitis: cholecystostomy was used in 4 (24 per cent). Twelve of the 17 patients (70.6 per cent) survived. However, in patients with multiple injuries or postoperative comp!ications requiring total parenteral nutrition, the survival rate decreased to 37.5 per cent, a finding not unexpected in this group of critically ill patients. Multiple organ system failure and sepsis were present in all of the patients who died, and Volume 139, December 1979
Intravenous hyperalimentation is a well established method of providing nutrition to seriously ill patients whose gastrointestinal tract cannot be used for alimentation. Complications of the use of total parenteral nutrition are well documented . Andersen  reported on a patient with Crohn’s disease in whom acute acalculous cholecystitis developed after a prolonged course of parenteral hyperalimentation. The patient’ had had a normal oral cholecystogram 6 months before parenteral feedings were instituted. When oral intake was resumed after 1 month of hyperalimentation, acalculous cholecys815
Petersen and Sheldon
surgery, possibly because of the lack of stimulation of cholecystokinin release during fasting. Because of our recent experience with acute acalculous cholecystitis, patients receiving hyperalimentation were studied prospectively with gallbladder ultrasonography. All of these patients had markedly distended gallbladders and one patient demonstrated the formation of “sludge” in the gallbladder on serial examinations. In addition to decreasing gallbladder emptying and concentration of bile, experimental and clinical evidence demonstrates that total parenteral nutrition also reduces gastrointestinal secretions including bile flow . Bile viscosity and bile salt concentration are further increased by water resorption and mucin secretion within the gallbladder, which results in bile inspissation [I]. This inspissated bile may not pass through the cystic duct readily and therefore may produce a functional obstruction. Experimentally, in the presence of obstruction, an increase in bile salt concentration within the gallbladder will produce the pathologic picture of acute cholecystitis . The pathophysiology of acute acalculous cholecystitis occurring in the postoperative or posttrauma period is characterized by a mosaic of contributing factors (Figure 2), any of which may be operative in a given patient. Failure of the gallbladder to empty is probably the most important predisposing factor, and parenteral hyperalimentation as well as many other factors probably further enhance biliary stasis. It is reasonable to assume that by periodically administering small amounts of fat (such as safflower oil) orally or cholecystokinin parenterally, both of which stimulate gallbladder contraction, this potentially serious complication may be prevented.
Acalculous Cholecystitis and Total Parenteral Nutrition
Author & Year
No. of Patients
Munster et al [ 91, 1971 Anderson [ 721, 1972 Miller , 1976 Long et al [ 7I], 1978
1 1 8
Crohn’s disease Postoperative Multiple trauma; postoperative; burns Multiple trauma: postoperative
0 0 35
Present series, 1979
titis developed. Andersen  postulated that parenteral alimentation promoted the bilary stasis that subseqtiently led to cholecystitis. Other investigators have also reported acalculous cholecystitis in patients receiving total parenteral nutrition [9,11,15] (Table III). Munster et al  reported 10 cases of acalculous cholecystitis in burn patients; 3 of the patients had received hyperalimentation before the onset of symptoms. Recently, Long et al [II] described their experience with acalculous cholecystitis in critically ill postoperative or posttrauma patients. Total parenteral nutrition was used in 47 per cent of the patients, and Long et al [II] believed that it was one of a number of significant contributing factors in the pathogenesis of acute acalculous cholecystitis. In 1956 Glenn and Wantz  outlined a proposed mechanism for the development of acute acalculous cholecystitis in the postoperative period. They emphasized the role of diminished gallbladder emptying due to the fasting state and stressed the developmental relation of acute cholecystitis to the resumption of oral feedings after a prolonged period of fasting. Gullick  also demonstrated radiographically that gallbladder evacuation is decreased after
In a 5 year period, eight patients in whom acute acalculous cholecystitis developed during intrave-
f BILE CONCENTRATION
Protongedfasting Ailal~aSiCs Dehydration Ventilator support
\ BILE INSPISSATION~
? Refeeding\ ACUTE
POST-TRAUMA/ POSTOPERATIVE STATE
Hypovoiamic shock Sepsis Vascalar accident
/ BACTERIAL/ FUNGAL INVASION
\ MUCOSAL INJURY
Figure 2. Proposed pathophysiology for the development of acute acaC culous cholecystitis and interaction with possible contributing factors. TPN = total parenteral nutrition.
Acute Acalculous Cholecystitis
nous hyperalimentation are reviewed with emphasis on fact.ors contributing to pathogenesis. Gallbladder distention, biliary stasis, and bile inspissation, thought. to be important in the pathogenesis of this disease, are enhanced with the use of hyperalimentation, and this potential complication is being seen w&h increasing frequency in seriously ill or injured patients who are being fed parenterally. In addition to hyperalimentation, sepsis, hypotension, multiple transfusions (more t.han 10 units), prolonged fasting, and venbilatory support were frequent common denominators. Typical findings of pain, tenderness, and a mass in the right upper abdominal quadrant are infrequent. and the diagnosis rests on a high index of suspicion and ultrasonography. This syndrome may be preventable by the stimulation of gallbladder emptying with intermittent fat ingestion or parenteral infusion of cholecystokinin. Acknowledgment: We thank Frank G. Moody, MD, for reviewing this manuscript and Rebecca Olson for helping in its preparal ion.
References 1. Glenn F. Wantz GE: Acute cholecystitis following the surgical treatment of unrelated disease. Surg Gynecol Obstet 102: 145. 1956. 2. Ottinger LW: Acute cholecystitis as a post-operative complication. Ann Surg 184: 162, 1976. 3. Schwegman CW, DeMuth WE Jr: Acute cholecystitis following operation for unrelated disease. Surg Gynecol Obstet 97: 167. 1953. 4. Thompson JW Ill. Ferris DO, Baggenstoss AH: Acute cholecystitis complicating operation for other disease. Ann Surg 155: 489, 1962. 5. DuPriest RW Jr, Khaneja SC, Cowley RA: Acute cholecystitis complicating trauma. Ann Surg 189: 84, 1979. 6. Knudson RJ, Zuber WF: Acute cholecystitis in the postoperative period. N Engl J Med 269: 289, 1963. 7. Weeder RS, Bashant GH, Muir RW: Acute noncalculous cholecystitis associated with severe injury. Am J Surg 19: 729, 1970. 8. Lindberg EF, Grinnan GL, Smith L: Acalculous cholecystitis in Vietnam casualties. Ann Surg 171: 152, 1970. 9. Munster AM, Goodwin MN, Pruitt BA: Acalculous cholecystitis in burned patients. Am JSurg 122: 591, 1971. 10. Golden GT, Sears HF II, Wangensteen SL: Posttraumatic cholecystitis. Am Surg 39: 275, 1973. 1 1. Long TN, l-leimbach DM, Carrico CJ: Acalculous cholecystitis in critically ill patients. Am J Surg 136: 31, 1978. 12. Anderson DL: Acalculous cholecystitis: a possible complication of parenteral hyperalimentation. Med Ann DC 41: 448, 1972. 13. Sanders RA. Sheldon GF: Septic complications of total parenteral nutrition: a five year experience. AmJ Surg 132: 214, 1976. 14. Dudrick SJ. Ruberg F$: Principles and practice of parenteral nutrition. Gasfroenterology 61: 901, 1971. 15. Miller DD: Postoperative acalculous cholecystitis due to Torulopsis glabrata. Arch Surg 111: 1404, 1976. 16. Gullick HD: Roentgenologic study of gallbladder evacuation following non-biliary tract surgery. Ann Surg 151: 403, 1960. 17. Hamilton RF, Davis WC, Stephenson DV, et al: Effects of parenteral hyperalimentation on upper gastrointestinal tract
secretions. Arch Surg 102: 348, 1971. 18. Thomas CG, Womach NA: Acute cholecystitis: its pathogenesis and repair. Arch Surg 64: 590, 1952.
Discussion A. James McAllister (Salt Lake City, 1TT): Gallbladder disease, with or without gallstones, is a common complication of other surgery. In treating these patients in our surgical, postsurgery. and surgical trauma unit, we have been aware of one or two cases of acalculous cholecystitis in the last year. We can use cholecystokinin or, if the patient’s alimentary tract allows, a couple of pats of butter, which is a lot cheaper than cholecystokinin. Maybe we should return to the use of biliary flush. Nitrites dilate the ampullary mechanism associated with fat feeding of these patients. Perhaps we should try deoxycholic acid in these patients to thin the bile and make it less viscid. I reviewed the cholecystectomies performed from 1964 to 1969 at our hospital and found that acute acalculous cholecystitis occurred in 29 per cent of the patients, the same figure Dr. Pet,ersen mentioned. We did not use total parenteral nutrition. Simple cholecgstostomy is not always a good treatment hecause this is a different type of disease. It is probably a blood-borne disease in many cases, and there is a liquefaction necrosis of the gallbladder. The devitalized portion must be excised and, if possible, a tube inserted into the cystic duct for that decompression. Carey Page (San Antonio, TX): Acute acalculous cholecystitis is a disease of critically ill patients who are unable to eat. Total parenteral nutrition is also used in critically ill patients who are unable to eat. Refore we blame the nutritional support technique for a complication that may occur without it, we need more substantiating data.
M. Matolo (Davis, CA): I have two questions
for Dr. Petersen. Since the mortality from acute acalculous cholecystit.is in your series of traumatized patients on prolonged hyperalimentation was very high, do you recommend incidental cholecystectomy during the initial laparotomy for multiple trauma, especially in those patients requiring total parenteral nutrition for more than 2 weeks postoperatively? Did you review your series to determine the incidence of acalculous cholecystitis in patients on hyperalimentation? Scott R. Petersen (closing): I agree that we have not proved that hyperalimentation causes acalculous cholecystitis. The most important factor is failure of the gallbladder to empty. Hyperalimentation has been shown in clinical and experimental studies to decrease gallbladder emptying and bile flow, and it may be one of a number of important factors in the pathogenesis of the disease. In answer to Dr. Matolo’s questions, we do not think that removal of the gallbladder during exploration for trauma is indicated because the incidence of this complication is low. As mentioned earlier, the major factor of importance is fasting in the postoperative or post-trauma period, leading to stasis of bile. This complication should be preventable by stimulating the gallbladder to contract with either oral fat or parenteral cholecystokinin.