Reprints available directly from the publisher Photocopying permitted by license only (C) Harwood Academic Publishers GmbH Printed in the United States of America REVIEW ARTICLE ACUTE CALCULOUS CHOLECYSTITIS What is new in diagnosis and therapy?

The management of patients with acute calculous cholecystitis has changed during recent years. The etiology of acute cholecystitis is still not fully understood. Infection of bile is relatively unimportant since bile and gallbladder wall cultures are sterile in many patients with acute cholecystitis. Ultrasonography is first choice for diagnosis of acute cholecystitis and cholescintigraphy is second best. Percutaneous puncture of the gallbladder that can be used for therapeutic drainage has also diagnostic qualities. Early cholecystectomy under antibiotic prophylaxis is the treatment of choice, and has been shown to be superior to delayed surgery in several prospective trials. Mortality can be as low as 0.5% in patients younger than 70–80 years of age, but a high mortality has been reported in octogenerians. Selective intraoperative cholangiography is now generally accepted and no advantage of routine cholangiography was shown in clinical trials. Percutaneous cholecystostomy can be successfully performed under ultrasound guidance and has a place in the treatment of severely ill patients with acute cholecystitis. Laparoscopic cholecystectomy can be done safely in patients with acute cholecystitis, but extensive experience with this technique is necessary. Endoscopic retrograde drainage of the gallbladder by introduction of a catheter in the cystic duct is feasible but data are still scarce.


ents with acu
e cholecystitis-.Some aspects of the management of these patients are controversial.The aim of this review is to analyse changes in the diagnostic and therapeutic procedures for acute cholecystitis.Etiology 2467 Acute cholecystitis is caused by gallstones in about 90-95% of patients'".The remaining 5-10% of patients suffer from acute acalculous cholecystitis, most frequently after surgery or during treatment in an intensive care unit.Acalculous disease of the gallbladder has been reviewed recently and will not be included in this review7'8.It is gener lly thought that gallstones cause obstruction of the cystic duct leading to changes of the bile flow giving rise to an inflammatory process within the gallbladder wall.Although the pathogenesis is not completely under- stood acute obstruction and stasis of bile are almost certainly both contributing factors.The infection of bile is relatively less important in this early stage since bile or gallbladder wall cultures are sterile in about 30-60% of the patients with acute cholecystitis9-11.

Other factors such as prostaglandins as a mediator lor inflammation or delayed gallbladder emptying in diabetic patients may also play a role in the development of acute cholecystitis but the mechanism is not yet fully understood12-14.


Signs and Symptoms

The clinical features of acute (calculous) cholecystitis have not changed over the years.Patients usually present with pain in the upper right quadrant of the abdomen.The pain is persistent and frequently radiates to the epigastrium or to the back and cannot easily be differentiated from biliary colic especially at the beginning of the disease.Kune describes: "the illness begins with an attack of biliary colic type of pain, but the pain does not settle down and remains unabated for one or more days''15.Nausea and vomiting are found as frequently as 86%.Mild fever (up to 38C) is present in about half of the patients16.

At physical examination right upper quadrant tenderness, localised peritonitis and a positive Murphy's sign are found in the majority of patients.Murphy's sign is elicited according to Bailey and Love's Short practice of surgery: by asking the patient to breathe in whilst gently palpating the gallbladder area.The patient will experience pain and 'catch her breath' just before the zenith of inspiration''17.

Generalised peritonitis is rare (in our series only 7%) and highly suspicious of perforation of the gallbladder16.A palpable mass is present in about one third of the patients.Laboratory examination is not specific for the diagnosis3'4'16.White blood cell count can be elevated up to 15 109/L and a mild elevation of liver function tests and serum bilirubin can be fou d, that is probably due to inflamma- tion around the gallbladder and Calot's Triangle.Also associated common bile duct stones that are present in approximately 20% of the patients and more frequently in the elderly can give rise to biliary obstruction and elevated liver function tests and serum bilirubin8-9.


Diagnostic Procedures

Although a plain abdominal roentgenogram will be used frequently in patients with acute abdominal pain, the study is of limited value for the diagnosis of acute cholecystitis21'22.Only calcified stones, that are present in about 20% of patients with cholelithiasis, can be visualised.The study is however highly sensitive when air bubbles in the

men or wall of the gal
bladder are seen, caused by gas forming organisms such as E. coli and Clostrida.

Ultrasonography is nowadays the most commonly used test for screening of patients with acute cholecystitis.It is relatively easy to perform, available at many locations (such as intensive care unit) and non-invasive.The sensitivity and specificity of the test for acute cholecystitis is respectively 90-95% and 70-98% depending whether so called major or minor criteria ar being used23-26.Major criteria are: gallstones and non-visualisation of the gallbladder.Minor criteria are" thickening of the gallbladder wall of more than 5 mm, tenderness of the gallbladder when palpated during the examination, gallbladder enlargement to more than 5 cm, a round gallbladder shape and pericholecystic fluid.Controversy exists over minor criteria: tenderness and pericholecystic fluid, since these can be considered major criteria because of the high specificity for acute cholecystitis.Ultrasonography is also useful in detecting other, non-gallbladder related causes of abdominal pain.

Cholescintigraphy is being used increasingly during the last 10 years, after the development of newer and better radioisotopic labelled substances23'25'27-3.These substances are excreted by the liver into the bile, thus visualising bile flow into the intestinal tract and also through the cystic duct into the gallbladder.For patients with acute cholecystitis non-visualisation f the gallbladder has to be related to visualisation of the intestinal tract.Non-visualisation of both gallbladder and intestinal tract implies delayed hepatic clearance or biliary obstruction.

Pericholecystic hepatic uptake has been described as a valuable secondary sign in the cholescintigraphic diagnosis of acute cholecystitis3.

Both the sensitivity and specificity of the tests (with different substances) vary between 90-97/o 23,25'27-3.Administration of low dose morphine especially in critically ill patients can reduce the number of false positive tests31 '32.Howe er the number of false positive tests is high in patients with hepatitis, pancreatitis, in patients receiving parenteral nutrition and in al oholics.

A percutaneous puncture of the gallbladder that can be used for therapeutic drainage has also important diagnostic qualities33'34.This feature will be dealt with later, when discussing percutaneous cholecystostomy, a technique used in critically ill patients35.Since the puncture can be performed under ultrasound guidance without moving the patient to another unit, it has advantag s above the more cumbersome cholescintigraphy.

Computer tomography (CT) has been reported to be successful in patients with acalculous cholecystitis but this modality is not used routinely for acute cholecystitis25.

Magnetic resonance imaging (MRI) is not yet fully evaluated but its role in acute cholecystitis so far seems limited.

Oral cholecystogram is not used because it will take 14-18 hours before optimal opacification t e gallbladder and because of the sensitivity for acute cholecystitis is 10w23, 36.

Intravenous cholangiography (IVC) has been used frequently in the past but visualisat on of the biliary tract was only limited.Therefore the method is seldomly used since the introduction of ultrasonograp y and cholescintigraphy.An IVC can sometimes be useful when the diagnosis is uncertain.Opacification of the gallbladder makes acute cholecystitis unlikely26.In summary ultrasonogr phy is first choice for diagnosis of acute cholecystitis and cholescintigraphy is second best.The last method is used less frequently nowadays in severely ill patients since percutaneous ultrasound-guided punctures are favoured for diagnostic and therapeutic purposes.


Treatment

After acute cholecystitis has been diagnosed, appropriate treatment and timing of this treatment has to be selected for the individual patient.Surgery is still the treatment of choice for acute cholecystitis.Use and type of antibiotics and timing and type of surgery will be discussed.


Use of antibiotics

Broad spectrum antibiotics are usually thought to be indicated as pro

ylaxis in
he perioperative period6.However, opinions on the specific antibiotic regimen may differ.Indeed acute cholecystitis is not an infectious disease, since in 30-60% of the patients no bacteria can be shown in the bile9-11.On the other hand acute cholecystitis is considered as one of the fac

rs (together with h
gh age, diabetes mellitus, common bile duct stones, previous biliary surgery) known to be associated with an increased risk of positive cultures13"19'37.The highest incidence of bactibilia is found within 24 hours after onset of acute cholecystitis1.Postoperative infections have been shown to occur in about 20% of patients with bactibilia and in 2.5% of the patients with sterile bile37.Unfortunately bile cultures can only be known after surgery, whereas the choice for antibiotics has to be made before operation.

Elevation of temperature (> 37.3C), serum bilirubin level (> 8.6 mol/L) and white blood cell count (> 14.109/L) have been shown to predict bactibilia in patients with acute cholecystitis38.It has been suggested that patients with 0-1 of these factors receive one single (preoperative) dose whereas in patients with 2-3 factors antibiotics are continued until the outcome of a bile culture is avail ble38.In one meta-analysis of antibiotic prophylaxis in biliary surgery the overall reduction of wound infection was 9% 39 The reduction was significantly greater (13% and 25 % respectively for early and late wound infection) for high risk patients including patients with acute cholecystitis.No difference between single and multiple dose regimens could be found, but in most trials studying different dosages different antibiotics were also used39.The choice of an antibiotic should be based on the organisms most commonly found in bile, such as E. coli, Klebsiella, Enterobacter, Proteus, Streptococcus and Staphylococcus faecalis.The antibiotic should be present in the tissue during the time of contamination.It is still not clear whether those antibiotics that reach a high concentration in the biliary tract should be chosen since the cystic duct is obstructed in acute cholecystitis39-41.Even in a prospective study in patients with acute cholangitis using Mezlocillin with a high biliary excretion no advantage over treatment with ampicillin and tobramycin having a lower biliary excretion was found42'43.Cephalosporins or a combination of penicillins with gentamycin or metronidazole is the most commonly used prophylactic regimen in the Netherlands44.

Generally patients with acute cholecystitis are not being treated with antibiotics for a 10ng period of time as primary treatment and surgery or biliary drainage is the treatment of choice43.However in those few patients not being operated on or treated by drainage, antibiotics can be used in order to prevent complications of the disease caused by bactibilia45.The choice of the antibiotics in these cir umstances will be the same as selected for prophylaxis and should be continued for 5-7 days39'44.The difference between acute cholecystitis and acute cholangitis can be 18 19 difficult especially in jaundiced patients For these patients treatment with antibiotics is mandatory although biliary drainage should be instituted without much delay.


Cholecystectomy and timing of surgery

There is agreement in the literature that cholecystectomy is the procedure of choice for most patients with acute cholecystitis1'4.It has been discussed for many years whether surgery should be performed early (within 24-48 hours after admission) or delayed (after 2-3 months).The results of randomized trials are strongly in favour of early cholecystectomy47-51, show

g no difference in post operative mort
lity (0-1%) and morbidity for the two strategies but a clear reduction in hospital stay47-51.In one paper the mean total hospital stay was 10.1 days in the early and 18.9 days in the delayed surgery group.When delayed surgery was chosen 10-20% of the patients had to be operated earlier than planned because of a downhill clinical course52.

Despite the outcome of these randomized trials many surgeons still favour delayed operation, especially when patients are admitted more than 48 hours after the onset of symptoms.This hesitation for cholecystectomy after a somewhat longer duration of symptoms probably reflects the philosophy that operating in severely edematous and inflamed tissue in Calot's Triangle carries an elevated operative risk.The infl ence of duration of the onset of symptoms and results of surgery was recently studied 16.No difference was found in mortality and morbidity with regards to duration of symptoms (<2 days vers.us 2-7days).The overall mortality was 1.6% (2 patients of 88 and 89 years died postoperatively).Early cholecystectomy is a safe procedure for patients with acute cholecystitis at least within 7 days after onset of symptoms6.Other studies of the last ten years have shown a gradual improvement of the results of surgery for acute cholecystitis, mortality being less than 0.5% in patients younger than 70-80 years of age6 '53-56.However the operative risk can be considerable in patients over 74 years of age 7 and a mortality as high as 11.6% has been reported after biliary surgery in octogenerians58.Perforation of the gallbladder because of acute cholecystitis still carries a high mortality.Especially in this group of patients early surgery is mandatory 59,6.


Intraoperative cholangiography

The efficacy of routine intraoperative cholangiography in patients that undergo elective surgery for symptomatic gallstone disease has frequently been challenged61-64.Selective cholangiography has been accepted generally in Europe now since no advantage of routine cholangiography was shown in clinical trials6-64.However especially in elderly patients with acute cholecystitis the incide

e of common bile duct stones is
as high as 50% and therefore routine cholangiography can be possibly recommended in this group.Cholangiography can also visualise the anatomy of the biliary tract and surgical trauma can so be prevented.On the other hand cholangiography is more difficult in patients when severe inflammation is present in Calot's Triangle and the obstruction of the cystic duct makes easy access for cholangiography impossible.Therefore we advise performing cholangiography selectively when it is possible without additional risk.When cholangiography cannot be performed safely ERCP and papillotomy may be necessary shortly after operation to provide adequate biliary drainage.But when the suspicion of common bile duct stones is very high (in elderly patients with jaundice or a dilated biliary tree on ultrasound) one should consider cholangitis as the main cause of the symptoms and ERCP and papillotomy should be performed as the first treatment and cholecystectomy can follow later if still indicated65-67.

Open or percutaneous cholecystostomy Cholecystostomy can be used in the treatment of acute cholecystitis for various indications some of which are obsolete, some still valid.Cholecystostomy can be a very prudent procedure" Firstly when morbidity and mortality of cholecystectomy under general anaesthesia is high.In these patients cholecystostomy could be performed under local anaesthesia35'68-71.Secondly, when technical diffi

lties are expected in operations in a
severely inflamed Calot's Triangle.And thirdly and more currently the percutaneous approach is favoured for critically ill patients in an intensive care unit for diagnosis and treatment of acute (acalculous) cholecystitis33'34.Cholecystostomy can be performed as a definitive procedure for calculous cholecystitis72-73.With ultrasound guidance an incision is made directly over the fundus of the gallbladder and after a purse string suture, bile is aspirated, stones are removed and a catheter is left behind.Tube cholangiography can be performed postoperatively in these patients and retained stones can so be removed or dissolved by MTBE and eventually "sclerosing" of the gallbladder mucosa can be performed72-76.Elective cholecystectomy can also be considered after improve- ment of the patients general condition.The risk of cholecystostomy mainly depends on the clinical condition of the patient.Frequently old studies are quoted.Mortality of open cholecystostomy for acute cholecystitis varies between 4 and 36% and morbidity between 10--60/o 72'71'74'77 About 50% of patients will develop symptomatic biliary tract disease two years after cholecystostomy.Others have reported that the need for a cholecystectomy at a later date is only exceptionally indicated and that more than 90% of the patients are asymptomatic after [1][2][3][4][5][6][7][8][9][10][11][12] years.The advantage of the open procedure over the percutaneous technique is that necrosis and perforation of the gallbladder that are more common in elderly, diabetic patients can be treated using the former technique71'72.The risk of peritoneal leak seems to be minimal although data about this complication after both methods are rather confusing.

A subtotal cholecystectomy as advocated by Terblanche can be considered as a minimal modification of the open cholecystostomyTM.

Percutaneous cholecystostomy under ultrasound guidance is relatively easy to perform in severely ill patients in an intensive care unit.The diagnostic accuracy of the method is high as is the success rate of puncture as therapy.Morbidity and mortality are reported respectively 25% and 10% being very much dependent on patient selection.The procedure can also be followed by cholangiography and cholecystoli hotomy or dissolution by MTBE75.The percutaneous approach to the gallbladder can be performed by a direct puncture or via the transhepatic route.The first technique is only possible in a limited number of patients because of the localisation of either liver or colon.The latter is nearly always possible but coagulation disorders should be corrected preoperatively.The possibility of not detecting necrosis and perforation of the gallbladder is already mentioned earlier.

Other Minimally Invasive Techniques Laparoscopic cholecystectomy has been largely restricted to patients with sympto- matic gallstone disease79-81.Acute cholecystitis is considered by most surgeons as a contraindication for this procedure.However when a large experience of this new technique has been obtained laparascopic cholecystectomy can be used in patients with acute cholecystitis.In the first consecutive eries of patients with acute cholecystitis treated by this technique a success rate of 66% (10/15) was reported without complications82.Five patients underwent laparotomy.The mean hospital stay was 2.7 days and the length of the operative procedure was 126 minutes as compared with around 90 minutes for laparoscopic cholecystectomy in non-acute cholecystitis.Cholangiography could be performed in 14/15 patients.These pre- liminary results suggest that laparoscopic cholecystectomy can be done safely in patients with acute cholecystitis.However, the authors have stressed that this procedure should only be attempted after extensive experience with laparoscopic biliary tract surgery has been obtained.A low threshold to perform laparotomy is advised.

Endoscopic Retrograde Cholecysto-endoprosthesis Recently endoscopic placement of an endoprosthesis into the cystic duct has been performed in 14 patients with (sub)acute cholecystitis83.This new technique was studied in patients with abdominal pain, leukocytosis, thickening of the gallbladder wall and fever.However patients "in need for surgery" were excluded, although the criteria were not clearly stated.Clinical i provement was found in two third of patients.These early results only show that successful introduction of a catheter in the cystic duct is possible but more data and comparison with surgical techniques have to be awaited.


Summary

Although acute calculous cholecystitis is a clear and unchanged clinical entity, the diagnostic and therapeutic procedures have been changed during the past years.Ultrasound is first choice for the diagnosis and cholescintigraphy is second best.However the percutaneous ultrasound guided puncture has become more popular having not only important diagnostic qualities but also therapeutic possibilities.The method

s easy t
perform in severely ill patients for instance in an intensive care unit and the diagnostic accuracy is high.

Preoperative antibiotics are mandatory in the treatment of acute cholecystitis (surgical as well as drainage).There is still debate on the choice of single or multi drug regimens, and type of antibiotics.Antibiotics are not a substitution for adequate drainage especially in jaundiced patients in which the differentiation between acute cholecystitis and cholangitis can sometimes be difficult.

Early cholecystectomy is the t eatment of choice at least within 7 days after onset of symptoms.During surgery selective cholangiography is favoured by ourselves, whereas others still recommend routine cholangiography.There is not much need for this in difficult circumstances (severe inflammation) when ERCP and papillo- tomy is widely available.

For patients with high operative risk and critically ill patients percutaneous holecystostomy is a good alternative treatment.The procedure can be followed by cholecystolithotomy or dissolution therapy.

Open cholecystostomy should probably be reserved when technical difficulties arise or are expected at cholecystectomy.Laparoscopic cholecystectomy for acute cholecystitis is possible in some patients but should only be perf rmed by surgeons with a large experience in laparoscopic surgery and a low threshold to convert into an open procedure is generally advised.Endoscopic cholecystic drainage is a new technique of which resul s should be awaited.
 
New trends in gallstone management. S Cheslyn-Curtis, R C G Russel, Br. J. Surg. 781991

Role of surgery in the management of gallstones. E Mack, Seminars in liver disease. 101990

Management of symptomatic gallstones in the elderly. T T Irvin, P M Arnstein, Br. J. Surg. 751988

Surgery for acute and chronic cholecystitis. R E Hermann, Surg. Clin. North Am. 701990

The management of acute cholecystitis in the elderly. L C J Van