a history of the dissolution of retained choledocholithiasis

A History of the Dissolution of RetainedCholedocholithiasis

Edward Kelly, MD, Jane D. Williams, MD, Claude H. Organ, Jr., MD, Oakland, California

BACKGROUND: Common duct calculi retained aftergallbladder surgery continue to present a clinicalchallenge especially in the era of minimally inva-sive surgery. This review examines the strategyof dissolution therapy used throughout the his-tory of biliary tract surgery and its use to themodern surgeon.

DATA SOURCES: Original journal articles and re-views were identified using standard surgicaltextbooks and MEDLINE. Keywords for search-ing included choledocholithiasis, dissolution,mono-octanoin, common duct stones, MTBE,cholic acid, and gallstones.

CONCLUSIONS: Dissolution therapy used initially asan alternative to open surgery is now used moreeffectively as an adjunct to laparoscopic or en-doscopic biliary tract surgery. The current reviewdemonstrates a majority of patients with retainedcholedocholithiasis respond to dissolution andcan be safely managed without choledochotomy.Am J Surg. 2000;180:86–98. © 2000 by ExcerptaMedica, Inc.

The problem of biliary stones extends far back intoantiquity. It is estimated that 20 million people inthe United States have gallstones, and approxi-

mately 500,000 cholecystectomies, laparoscopic or open,are performed annually.1 Common duct stones are found inapproximately 2% to 6% of patients who have undergonecholecystectomy and choledochotomy and still pose a ma-jor therapeutic problem. Stones that are multiple or largerthan 7 mm are unlikely to disappear or pass spontaneously,and the surgeon must make a choice between reoperation,endoscopic sphincterotomy, or basket extraction via T-tube tract.2 In 1972 Burhenne3 described a steerable cath-eter to extract residual bile duct stones. Endoscopic sphinc-terotomy and stone extraction is recognized as thetreatment of choice for retained bile duct stones in post-cholecystectomy patients or in persons who are poor sur-gical risks. Even in recent series, the complication rates forendoscopic stone extraction are variable, based on the skilland experience of the endoscopist. A large multicenterprospective trial has reported an overall complication rate

of 8.1% in 1,600 patients undergoing endoscopic stoneremoval.4 The failure rate for postoperative endoscopicsphincterotomy and stone extraction in modern series is3% to 23%5; the most commonly cited reason for failure ofthis approach is a large size stone that cannot be removedthrough sphincterotomy.

A wide variety of methods for dissolving biliary stoneshave been described since Vollisnieri first described thesolubility of gallstones in alcohol and turpentine in 1722.6

Endoscopic techniques and interventional radiology havetransformed the management of duct stones, but dissolvingstones with solvents is still a useful means under certainconditions. As common duct stones larger than 5 mm areunlikely to disappear spontaneously and surgical reexplora-tion carries significant morbidity, many efforts have beendirected at noninvasive therapeutic options.3,7–9 Duringthe past 2 decades, our understanding of gallstone forma-tion and dissolution has improved. Attempts were made todissolve gallstones as long as 300 years ago, many of whichwere successful. Interestingly, the first attempts to dissolveretained stones were made by surgeons.10 Techniques av-idly advocated in one decade were discarded in the next.Improved bile duct exploration, cholangiography, chole-dochoscopy, endoscopic retrieval, endoscopic retrogradecholangiopancreatography (ERCP), and papillotomy havevirtually eliminated the need for this treatment modalitytoday.11

TYPES OF STONESMost gallstones in the Western world are largely choles-

terol and therefore soluble with conventional dissolutionagents. Pigment stones, both black and brown, are mostlycalcium bilirubinate, with limited amounts of cholesterol.Black stones predominate in hemolytic disorders, andbrown stones are most common in Asian patients. Brownstones are thought to be related to biliary tract infections,bacterial and parasitic.10,12–14 The chemical compositionof bile duct stones has not been studied as extensively asgallstones have been. Calcium bilirubinate is the dominantcomponent of de novo primary biliary duct stones second-ary to the deconjugation of bilirubin diglucuronide.15

However, the stones may be mostly cholesterol if theyoccur in patients with gallbladder stones.

Comprehension of pathogenic factors in the developmentof various stones is crucial in addressing dissolution ther-apy; these are summarized in Table I.

TURPENTINE, ETHER AND OTHEREARLY METHODS

The concept of dissolving gallstones was introduced in1722, when Vollisnieri described the use of turpentine forin vitro dissolution.6 The discovery of ether as a solvent for

From the Department of Surgery, University of California,Davis—East Bay, Oakland, California.

Requests for reprints should be addressed to Edward Kelly,MD, Department of Surgery, 1411 East 31st Street, Oakland,California 94602.

Manuscript submitted December 7, 1999, and accepted in re-vised form June 25, 2000.

REVIEW

86 © 2000 by Excerpta Medica, Inc. 0002-9610/00/$–see front matterAll rights reserved. PII S0002-9610(00)00428-1

gallstones is credited to Walker,16 who dissolved an im-pacted cystic duct stone by injecting diethyl ether througha cholecystectomy sinus tract in 1891; and in 1892, Nau-nyn demonstrated in vivo dissolution in 1 to 2 months afterplacing human gallstones in dog gallbladders.17 In 1897,Hawker dissolved bile duct stones with an infusion ofglycerin and ether through a biliary fistula. In 1908,Wright18 reported using turpentine intraoperatively on apatient who had a cystic duct impacted with stones. Dis-solution of human gallstones has been subsequentlyachieved in the gallbladders of sheep, pigs, goats, dogs andmonkeys, all of which have bile that is less saturated withcholesterol than that of humans.19–21

In 1935, Pribram22 reported instilling ether into the com-mon duct via T-tube catheter. He reported success withthis technique in all of 51 cases. Pribram’s treatment rou-tine for retained common duct stones consisted of cathetercholangiograms obtained on the fifth postoperative dayfollowing common duct exploration, followed by etherinstillation if residual stones were observed. The patientfasted a few hours prior to this treatment to reduce hepaticbile flow, which dilutes the ether. The duct was aspirateduntil empty, and ether was injected drop by drop until thepatient felt discomfort; usually no more than 3 mL wasrequired. Ether was aspirated and the process repeatedseveral times. At this point, 5 to 10 mL of warm olive oilor paraffin was then instilled to lubricate the duct and thetube clamped. These treatments were carried out severaltimes a day for a week before a repeat cholangiogram wasobtained. If common duct stones remained, the patientcould then carry out these treatments at home, returningperiodically for cholangiograms until the stones disap-peared. Best3 later (in 1944) advocated a 3-day regimen oforal choleretics and cream for all patients prior to surgeryto flush “liver” stones down into the common duct, wherethey could be removed at surgery.

Pribram reported the dissolving time to vary between 1and 6 weeks, depending on stone composition. He intro-duced a double-barreled catheter for this purpose, whichtheoretically allowed for decompression of the ether vaporas it flows in through one port and out the other. Pribrammodified this technique with agents such as procaine hy-drochloride (novocaine), atropine, amyl nitrate, and otherdrugs to relax the sphincter of Oddi but he was not fullyconvinced that they were beneficial.24,25 Interestingly, Pri-bram felt the gallbladder played a “hormonal” role inregulating taste and appetite and concluded that its re-moval should be avoided. Further, he believed that chole-cystectomy contributed to hepatitis, and described an op-eration, cholecystocholedochostomy, in which a wideanastomosis was created between the gallbladder and thecommon duct, so that stones could easily pass and thegallbladder remain intact.

In addition to the role of hormonal regulation of thegallbladder, other early investigators linked cirrhosis andhepatitis to cholecystitis in the presence of common ductstones. Evarts Graham,26 in 1917, reported that the occur-rence of hepatitis has been accepted as a “constant accom-paniment of cholecystitis.” He noted a frequency of en-larged livers associated with biliary tract inflammation, anda paucity of information on the subject in the literature atthe time. Graham cites 8 cases with microscopically evi-dent “interlobular hepatitis.” He advocated the operationdevised by Kehr, consisting of excision of the gallbladderand cystic duct, and passing a small tube into the hepaticduct for external drainage. These early common ductdrainage procedures were limited by the high mortalityrates, as antimicrobial therapy was not yet available.26

Another pioneer of common bile duct exploration, FrankLahey,27 not only advocated cholecystectomy but alsocommon duct exploration in at least 50% of cases. Hepoints out in particular the frequency with which small

TABLE ITypes of Bile Duct Stones

Cholesterol Brown Black

Origin Gallbladder(secondary stones)

Ducts 6 gallbladder(Primary stones)

Gallbladder 6 ducts(Primary or secondary stones)

Components 40%–70% cholesterol 15% cholesterol60% calcium bilirubinate15% calcium phosphate

2% cholesterol6% calcium carbonate40% calcium bilirubinate9% calcium phosphate

Predisposing factors Obesity2 Bile salt pool1 Cholesterol synthesis1 Progesterone

Diet: low protein, highcarbohydrate

CholangitisBiliary strictureBiliary infections:● Parasitic● BacterialBiliary stasis:● Total parenteral nutrition● Vagotomy

CirrhosisChronic hemolysisSickle cell anemiaHeart valve replacement

Shape, size, number Multiple: smooth facetedSingle: $2.5 cm,

smooth, round

Smooth, round1–3 cm

Multiple, irregular or smoothUsually ,0.5 cm.

Physical characteristics Hard, laminated Hard Soft, friable

DISSOLUTION OF RETAINED CHOLEDOCHOLITHIASIS/KELLY ET AL

THE AMERICAN JOURNAL OF SURGERY® VOLUME 180 AUGUST 2000 87

stones, low in the duct, are overlooked at operation. Sincethe treatment of common duct stones was difficult, at best,in the early part of this century, his stance was one ofprevention.

In 1937 Walters and Wesson28 used amyl nitrate alongwith ether instillation in a similar case report. Fragmenta-tion of the stone with ether, and expulsion of the fragmentsinto the duodenum, were accomplished by raising intra-ductal pressure with ether and dilating the sphincter ofOddi with amyl nitrate. At around this time, Probstein andEckert,29 using a dog model, investigated the effects ofether on the obstructed common bile duct, as well as invivo solubility of stones in ether. They found this lipidsolvent to be a hepatotoxin. They also linked a calciumcomponent in the stones with an inability to dissolvethem. Best and Hicken,30 in 1938, outlined a regimeninvolving systemic magnesium sulfate, amyl nitrate, andatropine, and olive oil or heavy cream via T-tube to helpdecrease sphincter spasm and lubricate the duct, allowingthe passage of retained biliary stones. In 1939 Pribram andBerlin24 added liquid paraffin to their ether regimen tofacilitate their passage into the duodenum.

Part of the reason ether was useful for this purpose wasnot only that it dissolved common duct stones, but it alsomounted a head of pressure behind the foreign body andexpelled it into the duodenum, as shown by Walters.28

Following this rationale, Best et al,31 in 1939, incorporatedthe use of dehydrocholic acid, a choleretic, into the non-operative treatment of retained biliary stones. Increasingbile flow resulted in increased pressure, also expelling thestones forward into the duodenum. The advantage in thismethod was that a T-tube was not necessary.

Burgess and Honolulu,32 in a case report, used ether withnitroglycerine in 1940. Raffl,33 in 1941, reported success inboth of two cases when he injected ether into a T-tubefollowed by saline irrigation to partially flush out dissolvedstones. Amsterdam and Sterling34 reported mixing etherwith novocaine to successfully dissolve a common ductstone in 1948. Stricker and Adkins35 reviewed this litera-ture in 1954 and concurred with this approach. The lastpublished work regarding intracholedochal instillation ofether, by Sasson36 in 1969, recorded the use of a combi-nation of ether and olive oil in retained common ductstones in 3 cases, with success.

Diethyl ether is currently considered an obsolete anes-thetic agent owing to the explosive concentrations neces-sary for general anesthesia. This thin, colorless, highlyvolatile liquid is still used today in organic chemistry forextractions and in the preparation of certain reagents.With its vaporization pressure of 224 mL vapor/cc liquid(and boiling point of 35°C), an increased pressure gradientis built up as it is instilled into a normothermic humanbeing.37 Pribram felt that the pressure generated by etherdid not expel stones, as proposed by others. He reasonedthat causing sphincter spasm makes expulsion of stones lesslikely and dissolution more likely. He added ethanol toether to reduce its boiling point; however, in vitro studiesdemonstrates that this also decreases ether’s dissolvingcapabilities.33 Walters and Wesson28 and others26,33,34

postulated that part of the efficacy in ether treatment lay inthe fact that it blew the stones out of the duct into the

duodenum. The side effects of ether instillation describedin these early papers were nausea, vomiting, abdominalpain, and anesthesia.36,37 Ether as a gallstone solvent waspopularized in the pre-antibiotic era, when the mortality ofreoperation on a patient with retained common duct stonesapproached 50% in some series.

Currently, there is new enthusiasm for ether in the formof methyl-tert-butyl-ether as a dissolving agent for retainedcommon duct stones.38,39

CHLOROFORMThe use of chloroform to dissolve common duct stones

was an outgrowth of a search for a better solution thanether for the retained common duct stone. Ether treat-ments were painful, and the substance is dangerous andhepatotoxic. An attractive feature of chloroform is that ofits boiling point of 61°C, which is much higher than thatof ether. It is a much more powerful stone solvent thanether, and this can be intensified by heating.40 Reports onthe use of chloroform to dissolve stones were publishedduring the 1940s and 1950s. Best et al17 evaluated 113agents in vitro but found only chloroform and ether to beeffective solvents for gallstones. Narate and Cipolla,41

working with dogs, found chloroform to be an excellentstone solvent. Autopsy reports revealed no hepatotoxicityin the dogs. It is now known that chloroform has severeside effects, including centrilobular hepatic necrosis, duo-denal hemorrhage with ulceration, and death. Torreysap42

reports a case of successful dissolution of residual commonduct stones using chloroform T-tube installations, but theprocedure also completely anesthetized the patient for sev-eral minutes. Ether and chloroform fell into disfavor as aresult of improved biliary tract surgery, and the introduc-tion of antimicrobial therapy and a better understanding ofthe pathogenesis of gallstones occurred.

SALINE FLUSH, HEPARIN, AND LOCALANESTHETICS

The use of heparinized saline to dissolve gallstones byirrigation was popularized around 1970 by Gardner andothers.43–45 This concept was based on increasing thesuspension stability of bile by the addition of heparin, asubstance that is highly negatively charged. The polargroups on the surface of the stone are positively chargedand oriented toward the solution. Dispersion supposedlyoccurs in the presence of negatively charged ions whichcan lead to gallstone dissolution. Electrophoretic studies byGardner and associates46 determined that bile tends topromote agglomeration of positively charged suspendedparticles. If agglomeration were a step in the formation ofgallstones, any material that would increase the negativesurface charge would promote dispersion of particles inbile, and therefore prevent gallstones. The zeta potential,to which Gardner makes frequent reference in his work,43

is a reflection of the net surface charge of a particle and thedielectric constant and ionic composition of the suspend-ing solution. This is influenced by adding divalent ionelectrolytes and changing the temperature and pH of thesolution. Lowering the zeta potential promotes agglomera-tion. One can conceptualize these two opposing forces asfollows:


88 THE AMERICAN JOURNAL OF SURGERY® VOLUME 180 AUGUST 2000

Zeta potential 2 tends to disperse

1 2

Van der Waal’s forces 2 tend to agglomerate

Gardner and coworkers46 reported successful dissolutionin 31 of 43 cases of retained common duct stones. Gard-ner’s method is to infuse, as a continuous drip, 5,000 unitsof heparin in 750 mL saline every 24 hours via T-tube.There were no complications. The anecdotal report byChary44 of 5 patients was in agreement. While Gardnermaintained that he did not fully understand the mecha-nism of action of heparin on gallstones, in vitro testsindicated a tendency for stones not to dissolve but tofragment, presumably as a result of heparin’s effect on thesuspension stability of particles. Lahana et al47 in 1973reported that some quaternary amines such as heparin weresuccessful in fragmenting gallstones. In vitro studiesshowed that a combination of sodium cholate and heparinwas better than either agent alone in reducing gallstonesize. One may argue that the irrigation itself was the agentof stone removal, as much of the work does not includecontrol patients, with saline drip alone. Romero and But-terfield,45 in 1974, incubated various types of gallstones insolutions of bile with heparinized saline, to assess dissolu-tion by changing the zeta potential. These investigatorsand others noted no reductions in weight of the stones, norfragmentation, and concluded that the stones vanishingduring treatment with a drip of heparinized saline was dueto irrigation alone.45 Methods claiming a successful disso-lution of bile duct stones when reduction of stone size isnot documented by serial cholangiography must not beconsidered proof of dissolution. This method is consideredobsolete today and reports on its use have ceased.

Flushing saline via the T-tube can result in the stonesbeing carried into the duodenum by the irrigant. Severalauthors from the late 1940s through the early 1970s reportanecdotal successes with flushing large volumes of salinethrough the T-tube, with and without addition of localanesthetic to relax the sphincter of Oddi, facilitating thepassage of stones.13,48–52

Ten patients with retained stones confirmed by cholan-giograms postoperatively were treated by Catt and associ-ates51 in 1974 by simply flushing the common duct throughthe T-tube. Probanthine was administered intramuscularlyto relieve sphincter of Oddi spasm one half hour prior tobile duct flushing with 1 L of sterile saline solution con-taining 40 cc of 1% lignocaine. The patient’s position waschanged to facilitate distribution of the solution to all partsof the biliary tree. The T-tube was clamped after eachtreatment, but released if the patient became symptomatic.This technique was successful in 6 of 10 patients withoutcomplication. In 1 patient, complete removal took 53 daysand 13 flushing procedures. Bile duct cultures were positivein 9 of 10 patients, and fevers were associated with theflushing in 8 of 10 patients. The authors believe thatcholangio-venous reflux induced by the washout procedureresulted in a transient bacteremia.51 Castleden52 reported asuccess rate of 50% with this method as late at 1976.

In 1988, Tritapepe et al53 reported a combination treat-ment of intravenous ceruletide-induced relaxation of thesphincter of Oddi followed by intraductal saline flushing for

the treatment of residual common duct stones. Interest-ingly, this was proposed as a “novel procedure for thetreatment of residual common bile duct stones.”53

BILE ACIDSExperimentation on bile was initiated with the evolution

of modern chemistry. In 1833, Demarcay separated threecomponents from bile that were likely to have been bileacids. In 1843, Strecker separated taurocholic acid andglycocholic acid and demonstrated their relationship tocholic acid.54 In 1873, Maurice Schiff, while a politicalexile in Florence, described the enterohepatic circulationand proposed oral bile salt therapy.55 In 1928, Green,Aldrich, and Rountree demonstrated the enterohepaticcirculation by demonstrating the presence of bile acids inportal blood after oral administration.56 Wakefield andassociates,54 in 1929, published their observations of pa-tients given the sodium salt of dehydrocholic acid (decho-lin) intravenously, and found it to be nontoxic in the dosesgiven. The quality of the bile was noted to be diluted andlarger in quantity. In 1928, Viihland was awarded theNobel Prize for work elucidating the structure of cholicacid.54

Investigators began to experimentally administer thesevarious bile acids, some of which were toxic to animals, andnoted that some of these substances increased bile flow.Wright, Whipple, and Andrews illustrated the importanceof the relationship of bile acids to cholesterol metabolism.Andrews, Schoenheimer, and Hrdina demonstrated thathuman bile contains cholesterol in the form of unstablewater-soluble complexes with bile salts. When these com-plexes were dialyzed, the cholesterol precipitated. Thisearly work suggested that conditions which alter the ratioof bile salts to cholesterol would be conducive to gallstoneformation.56 In 1937, Rewbridge56 studied 5 patients withgallstones demonstrated on cholecystogram. These patientswere fed bile salts and olive oil for 9 months. All of thepatients reported subjective improvement with digestionand relief of constipation, with disappearance on x-ray ofstones in 2 patients.56 However, Rewbridge was unable toreproduce these results again.17

In 1968, Admirand and Small57 characterized the bile ofpatients with gallstones as supersaturated with cholesteroland outlined the physicochemical relationships betweencholesterol, bile salts, and phospholipids as a triangularcoordinate. This is an elegant way to express relativeproportion of lipids in bile and predicting the physical stateof the mixture. This triangular coordinate diagram reflectsthe molar concentration of one component expressed as apercentage of the total amount in the mixture. The com-position of any component mixture is plotted as a uniquepoint. They delineated a boundary zone, which indicatesthe limit of cholesterol solubility, and points falling belowthis line represented the composition of bile. Samples werecomposed of mixed micelles, which were less saturatedthan cholesterol.

In the late 1960s, Hofmann55 and Thistle et al,58 fromthe Mayo Clinic, studied the effects of administering bileacids on bile saturation in patients with gallstones. Bileacids stimulate hepatic synthesis of phospholipid as well assecretion of phospholipid into bile. Biliary cholesterol out-put increases with administration of bile salts, but not to



the extent that phospholipid does. When bile acid outputdecreases below 10 mmoles/kg per hour in humans, itbecomes saturated with cholesterol.59 An excess of choles-terol in relation to phospholipids and bile salts results ineither cholesterol crystal formation or the liquid crystallinephase. Normal molar ratios of bile salts to phospholipids tocholesterol are 74:20:6, respectively. Potential for crystal-lization exists when cholesterol accounts for more than10% of the total biliary lipid concentration.57

In 1971, Thistle and Schoenfield et al reported thatchenodeoxycholic acid (CDCA), given orally to gallstonepatients decreased cholesterol saturation of bile, allowingthe potential for gallstone dissolution. CDCA, a naturally-occurring bile acid, accounts for 20% to 30% of the totalbile acid pool. CDCA expands the bile acid pool by inhib-iting hydroxymethylglutaryl coenzyme A (HMG-CoA) re-ductase activity (the rate-limiting step in hepatic choles-terol synthesis), decreasing biliary cholesterol secretionand reducing the duration of secretion of saturated bile. Itexpands the total bile salt pool, but does not improvecholesterol solubility, nor does it cause gallstone dissolu-tion directly.11,59 Current evidence suggests the mecha-nism of action is reduction in biliary cholesterol secretionsecondary to inability to synthesize endogenous cholesterolin the liver. It decreases cholesterol absorption; free cho-lesterol and CDCA compete for incorporation into mi-celles (CDCA solubilizes cholesterol in micelles). It alsodecreases intestinal transport time, which further decreasesabsorption. The net result is a decrease in the absolute andrelative amounts of biliary lipid secretion and the produc-tion of a bile unsaturated with cholesterol.58,60 The actualmechanics of stone dissolution with CDCA involves thesingle passage of molecules from the crystalline state to theunsaturated mixed micelle.55 In 1972 Danziger et al61

treated gallstone patients with 0.74 to 4.5 g per day ofCDCA orally, from 6 to 22 months, and 4 of 7 patientsshowed partial or complete gallstone dissolution.

The use of CDCA was limited by the side effects ofdiarrhea, liver function abnormalities, and minor increasesin serum low-density lipoprotein cholesterol levels. CDCAis metabolized by enteric flora into lithocholate, a knownhepatotoxin. In humans, lithocholate is rapidly eliminatedby a sulfating mechanism.55

The National Cooperative Gallstone Study (NCGS),involving 916 patients, was a comprehensive double-blindmulticenter prospective trial assigning patients to groups ofCDCA, in a high or low dose, or placebo.58 The publishedresults were disappointingly low (complete dissolution of19% after 2 years)—lower than other nonrandomized stud-ies previously published. Interestingly, there has also beena noticeable lack of interest, on the part of major pharma-ceutical companies, in this drug. The reasons include noperceived market, too little profit margin, and lack ofpatent protection.55 Additionally, the documented recur-rence rate after cessation of therapy was 25% to50%.13,62,63 Side effects such as diarrhea occurred in 50%of the patients. Hypertransaminasemia, probably due to theaccumulation of lithocholic acid, was reported. The par-ticipants in the study had a high dropout rate, partiallyattributable to continuing abdominal symptoms. Analysisof the NCGS data on lipid metabolism suggests that there

may be potential carcinogenic effects of CDCA.13 Also,there is a body of conflicting information concerning thelinks between bile acids and colon cancer, but there is noevidence to date that the increased exposure of the colonto bile acids in dissolution increases the risk. Gallstonereformation is the major drawback of this form of treatmentfor cholelithiasis, especially in those patients with multiplegallstones.64

In 1972 Way and colleagues65 reported successful disso-lution of bile duct stones in 12 of 22 patients (54%) usinga sodium cholate solution infused via T-tube into thecommon duct. Sodium cholate, 100 mM, was giventhrough continuous infusion. The duration of this treat-ment was 14 days, and the high intestinal load of bile saltcaused diarrhea.65 Solutions of higher concentrations areknown (from animal experimentation) to cause severe ductinflammation. Some other bile salt solutions, includingdeoxycholate, dissolve cholesterol gallstones both in vivoand in vitro. In vitro studies show the mechanism to be thesimple passage of cholesterol molecules from the surface ofthe stone to micelles of bile salts. There has been a de-creased level of enthusiasm for common duct stone disso-lution with bile acids due to its side effects, limited success,cost, and prolonged treatment times. Other authors re-ported similar results around this time. Lansford et al66

infused sodium cholate, at a concentration of 100 mM, viathe T-tube into the common bile duct, successfully in 5 of6 patients. They placed a small catheter within the T-tubeand infused the solvent directly. The presence of the T-tube allowed continuous infusion and drainage.66 Cholan-giograms were used to follow the presence or absence ofstones, but no comment was made regarding whether ornot the stone decreased in size or was simply flushed out.Complications included back pain when the stone wasimpacted in the duct in 3 patients and pancreatitis in 2.Toouli et al67 used a 200 mM solution in 16 patients, 14via T-tube and 2 via cholecystostomy tubes. They admin-istered cholestyramine orally along with this treatment toabsorb the bile salts and decrease diarrhea. In this studydissolution occurred in 13 of 16 subjects. The complica-tions listed are diarrhea, pain, and fever.67

Ursodeoxycholate (UDCA) is the 7-b-hydroxy epimer ofchenedeocycholate and is present normally in only traceamounts in humans.55,68 UDCA was first isolated frompolar bear liver in 1907 and has been an over-the-countertonic in Japan for 25 years.55 In 1974, reports of gallstonedissolution in patients who were treating themselves withlarge doses of this tonic prompted several therapeutic trials,which demonstrated successful gallstone dissolution with-out the transaminase elevation or diarrhea observed withCDCA.69 It is marketed in many European countries,where UCDA is preferred over CDCA. In 1977, UDCAwas approved by several third-party payors for reimburse-ment and was then approved for marketing, but lack ofperception of an agent that could be patented and devel-oped cheaply has prevented its growth.55

Like CDCA, the net effect of UDCA is to induce theproduction of bile unsaturated in cholesterol. This isbrought about by (1) an increase in the total bile salt poolsize, (2) a decrease in biliary cholesterol secretion, and (3)a probable decrease in HMG-CoA reductase activity. Dis-



solution is more complex with UDCA than with CDCA.UDCA-rich bile forms a liquid crystalline mesophase at thegallstone surface, composed mainly of cholesterol andphospholipids, that is less dense than bile and may permitUDCA to induce cholesterol solubilization above its equi-librium solubility. Clinical trials, such as the Franco-Bel-gian Cooperative Study, which compared UDCA withCDCA, have consistently demonstrated lower rates of di-arrhea and hepatotoxicity than comparable trials withCDCA.69 This prospective randomized controlled studycomparing CDCA with UDCA found that UDCA wasequally effective, and produced fewer side effects at a lowerdose than CDCA.69 It had no consistent effect on serumaminotransferase activities, suggesting that UDCA is not apotential hepatotoxin. However, no histologic studies havebeen done to confirm this hypothesis. There were noeffects noted on the serum triglyceride or cholesterol con-centration. UDCA is noted to result in reduced concen-tration of lithocholate, possibly due to resistance of the7-b-hydroxy group to bacterial transformation. Salvioli etal,15 in 1983, published a prospective controlled trial todetermine the effects of UDCA administration to patientswith bile duct stones.15 All of the 28 patients had radiolu-cent stones, without cholangitis or jaundice. This trialrandomized patients to receive UDCA versus placebo in 3daily doses for 2 years. In 50% of the patients receivingUDCA, stones disappeared completely; placebo had noeffect on stone size.

Both CDCA and UDCA are effective agents in certaincircumstances for the dissolution of cholesterol gallstones.UDCA is effective at about half the CDCA dosage, whichresults in more rapid dissolution, less hepatotoxicity, andfewer side effects. The main application of these agents inthe treatment of common duct stones has been in conjunc-tion with biliary lithotripsy. These agents are not recom-mended to treat patients with common bile duct or intra-hepatic stones by oral dissolution, as the success rates arelow and in many of these patients complications develop,requiring surgery.69 Additionally, the cost of prolongedtherapy is prohibitive, with lithotripsy adding increased cost.

TOPICAL AGENTSTopical agents or contact solvents may be the dissolution

strategy of choice for patients with retained common ductstones, if access to the biliary tree is available through acommon duct catheter or endoscopically. Solvents can beintroduced via nasobiliary tube through sphincterotomyand thus reduce the size of the stone.3 In some patients,endoscopic extraction may be impossible, as in patients inwhom endoscopic sphincterotomy has failed owing to thelarge size of the retained stone. Stones high in the biliarytree or above a stricture may not be accessible to eitherendoscopic techniques or solvents. A safe method of infu-sion is by gravity drip or low-pressure pump. It is importantthat the solution be given under low pressure, so as not toinfuse agents into liver parenchyma or gain access to thevenous system. Also, no leak should occur into the perito-neal cavity, such as from a choledochostomy site.13

MONO-OCTANOINMono-octanoin (MO) was approved as a direct contact

solvent for biliary stones in 1985. This medium-chain

diglyceride with excellent cholesterol solubility is a thick,viscous bacteriostatic oil that is liquid above 18.5°C.70

Adding a small amount of water decreases viscosity andtherefore increases dissolution.12 Mono-octanoin is hydro-lyzed by pancreatic lipase into octanoic acid (which iscompletely hydrolyzed to carbon dioxide), and glycer-ol.12,71 The advantage of mono-octanoin over bile salts isthe rapidity of dissolution, with success rates (of cholesterolstones) ranging initially from 50% to 75%. In an in vitrostudy of composition of gallstones, Sharp and Gadacz72

reported that a cholesterol content of 40% or greatercorrelates with a 91% dissolution rate. Smith73 studied andidentified structural features of gallstones that affect disso-lution in mono-octanoin. Stones were dissolved in mono-octanoin and ethanol or mono-octanoin and a thiol-reduc-ing agent, which had been shown previously to dissolvegallstone matrix elements. These data indicate that thematrix content of gallstones inhibits stone dissolution inmono-octanoin.

In 1978, Thistle and colleagues71 reported infusion ofmono-octanoin into the bile ducts of 8 patients with re-tained stones and found it to be safe and effective. In 1982,Gadacz2 popularized a method for MO administration us-ing an infusion pump with an in-line manometer to limitintrabiliary pressure to 12 to 15 cm of water. It is infusedinto the common bile duct at 3 to 7 cc/hour; the averagetime to dissolution is 5 days. Mono-octanoin is nontoxic tothe liver but when introduced under pressure has causednoncardiac pulmonary edema in about 0.1% of patients.74

It is contraindicated in patients with jaundice or recentduodenal ulcer, as it can cause duodenitis. Mono-octanoincan also be infused via a transhepatically placed catheter,as Mack et al10 reported in 1981 in an uncontrolled study.

In 1981, Hofmann et al70 reported data on 118 patientsusing mono-octanoin for dissolution of stones in the com-mon or hepatic duct. This was accomplished by infusion ofthe solute via T-tube or endoscopically placed retrogradecatheter. Side effects were pain, nausea and vomiting, mildamylase elevation, and duodenal erosion. Infusion lasted 1to 21 days. Their results reflect that 48.5% of the stonestotally disappeared, 20% decreased in size or number, and34% didn’t change. They concluded that their data supportthe efficacy of mono-octanoin for dissolving retainedstones. They felt mono-octanoin to be the solvent ofchoice for dissolution of retained stones when other meth-ods of extraction are not possible.

In 1986, Palmer and Hofmann62 collected data involving343 patients between 1977 and 1983 reported by 222physicians. They reported complete dissolution in 26% andpartial dissolution in 29%, allowing other techniques, suchas basket retrieval, for removal. The average stone diameterand treatment time were 11 mm and 7.2 days, respectively.However, in 36% there was little or no response, andtreatment was discontinued because of side effects in 9%.They concluded that mono-octanoin is moderately effec-tive as a second line, but occasionally first line, treatmentfor retained common duct stones.

The only controlled trial with MO, performed by Velascoet al,75 compared MO with washout (saline and heparin).MO was two to three times more successful. Side effects,including abdominal pain, nausea, vomiting, duodenitis,



acute cholangitis, pancreatitis, and septicemia have beenreported, but these are complications observed with anytechnique involving manipulation of the biliary tract in-volving stones obstructing the biliary tract. Symptoms usu-ally subside when the infusion is stopped. Limitations ofclinical success may be related to the difficulty of attainingpure solvent in constant contact with the stone, the com-position of the stone, or the location of the stone. Theideal situation would be one of constant convective mixingaround a nearly pure cholesterol stone using a catheterwith a pump and withdrawal cycle.12 Crummy and Mackengineered a system wherein a polyethylene catheter isplaced into the common duct next to the T-tube withinthe T-tube tract, so the MO can be constantly infusedwhile the T-tube provides constant drainage. Stones highin the biliary tree may be inaccessible by this technique. Ithas the advantage that it can be administered by thepatient at home.72

METHYL-TERT-BUTYL ETHERMethyl-tert-butyl ether (MTBE) is a stable aliphatic

ether with a specific gravity of 0.74 and pharmacokineticslike that of di-ethyl ether in that it is an excellent choles-terol solvent, is narcotic in large quantities, and is flam-mable. However, with a boiling point of 55.2°C, it remainsliquid at body temperature, making it suitable for use inthe biliary tree. In vitro, cholesterol gallstones dissolve50 times more rapidly in MTBE than with mono-oc-tanoin.12,70 Dissolution is improved by close contact of thesolution with the stone, and absence of bile. MTBE isalmost equally effective in dissolving stones containing40% to 90% cholesterol in in vitro experi-ments.12,13,62,63,67,75 However, this effect is limited invivo, as the low specific gravity of MTBE cause it to floaton top of bile and stones.

MTBE should be infused cautiously into the bile ductbecause of toxic effects. When MTBE was infused into thebile ducts of dogs under 30 cm of pressure, reflux intosystemic circulation occurred, resulting in hemolysis, pneu-monitis, and death.38 Complications of conventionalMTBE therapy include nausea, upper abdominal pain, du-odenitis, hemolysis, and mild anesthesia.70 Most (90%) ofthe substance is excreted on the breath, and a portion ofMTBE is metabolized to methanol and formate.38 Tran-sient minor elevations of transaminases are occasionallynoted.76

After preliminary in vitro experiments with gallstones ofdiffering cholesterol composition and in vivo experimentswith dogs, Allen et al39 used MTBE in human subjects. In1985, they reported cases of dissolving cholesterol stones.Multiple gallstones were dissolved via percutaneous place-ment of a transhepatic cholangiographic needle or vianasobiliary catheter. The gallbladder provides an enclosedchamber for continuous infusion and aspiration of MTBE,while minimizing systemic absorption.38

In 1988, Brandon and Teplick77 described MTBE infu-sion in 10 patients with 113 retained biliary stones. Theyused a percutaneous transhepatic approach in which twocatheters were employed (an 8-Fr pigtail catheter, alongwith a 7-Fr balloon catheter) to occlude the distal CBDand prevent systemic absorption of the ether, and promotemaximum stone contact. Alternatively, in some cases they

used an accessory biliary drainage catheter. From 5 to 20 ccamounts of MTBE were instilled into the patients andwithdrawn in a short time, to promote thorough mixing.The average total perfusion time was just over 2 hours perpatient. The average time for completion of this therapywas 8 days, with some patients having complete dissolutionwhile others required basket extraction of stone remnants.There was little morbidity in this study, mainly upperabdominal burning, odor of ether on the breath, and mildsedation. Although their success rate was 90%, these au-thors concluded that there were some disadvantages to thistreatment. The procedure had to be performed in theradiology department with continuous physician monitor-ing, and often for several hours a day. The unpleasant odoralso seeped into surrounding rooms, causing headaches,irritation of the eyes, and nasal congestion of exposedpersonnel.71

Murray and Laferia,76 in 1988, achieved successful disso-lution in 8 of 10 elderly patients with retained calculi whohad failed the endoscopic approach. In 6 patients thestones were greater than 1.5 cm. A nasobiliary approachwas used, and 5 mL of MTBE was installed and thenaspirated four times. This was repeated every 4 hours untileither the stones disappeared, shrinkage of the stones al-lowed endoscopic removal, or stone dissolution ceased.Three patients of 10 had complete stone dissolution, and 5had partial dissolution after 3 to 5 sessions. The remaining2 had insignificant responses and required operative ther-apy.76 Kaye et al77 report successful clearance of commonduct stones in 10 of 12 patients treated with MTBE usingnasobiliary access to shrink the stones, and allow endo-scopic retrieval.

CALCIUM CHELATORS ANDMUCOLYTIC AGENTS

As most topical agents are cholesterol solvents, brown orblack pigment stones may not be affected, and a largefraction of patients with ductal or intrahepatic stones are ofthe pigment variety. Insoluble debris may remain after useof a cholesterol solvent.78 Calcium-chelating agents suchas EDTA, citrate, UDCA, polysorbate-20 (a non-ionicdetergent food additive), and limolene, have been intro-duced for dissolution of stones containing calcium biliru-binate and calcium carbonate. Also, insoluble debris may

TABLE IIWho Used It First (In Vivo)

Substance Date Author(s) Country

Ether 1891 Walker EnglandTurpentine 1908 Wright EnglandChloroform 1945 Narat and Cipolla USATopical anesthetics 1946 Harris and Marcus USAHeparin saline (flush) 1971 Bern and Gardner USANa Cholate 1972 Admirand, Dunphy,

and WayUSA

Chenodeoxydrolic acid 1972 Danziger USAUrsodeoxycholate 1975 Makino and

ShinozakiJapan

Mono-octanoin 1981 GadaczMethyl-tert-butyl ether 1985 Allen, Borody, and

ThistleUSA



remain after dissolution of the cholesterol component withcholesterol solvents. In vitro experiments show improveddissolution of stones with noncholesterol components atcarefully controlled pH and concentration.12,78,79 Surfaceactive agents such as glycerol octanoate and bile salts act todisrupt the organic matrix of stones. Papain and trypsinhave been used with calcium chelators in some Japanesestudies to degrade mucoid substances present in some pig-ment stones.12

In 1972, Igimi and associates80 reported that naturallimolene had excellent dissolution properties with choles-terol stones in vitro, and observed complete dissolution ofcommon duct stones in 13 of 15 patients. D-limolene(p-metha 1, 8 diene) is a monoterpine obtained from thepeel of citrus fruits. D-limolene has a low toxicity exceptwhen given intravenously. Complications include abdom-inal pain, nausea, vomiting, and diarrhea. D-limolene re-quires administration through a special rubber catheterthat is chemically resistant to this substance. In vitrostudies show synergism when it is mixed in with MO in a3:2 ratio to dissolve cholesterol stones in a small number ofpatients.12

In 1986, Nelson et al78 harvested gallstones from 20subjects and used spectroscopy to divide them into calciumbilirubinate or calcium carbonate groups. Solvents such asEDTA, citrate, DMSO, cholate, and polysorbate-20 werestudied alone and in combination and at varying pH. Thedissolution of calcium and pigment from these stones was

most effective using EDTA 1% with polysorbate-20 1% atpH of 9.5. In addition, these experiments showed thatcomposition stones could be dissolved more rapidly byusing mono-octanoin alternated with EDTA than mono-octanoin alone. Because calcium bilirubinate stones maycontain up to 20% to 60% of an organic matrix, theaddition of papain was used to disaggregate the structure ofthe stone by enzymes and surfactants.

Clinical work in this area includes 17 patients with bileduct calculi treated alternately with a modified mono-octanoin, glycerol octanoate, and a bile salt EDTA solu-tion via nasobiliary tube. Fifty-seven percent of patientshad complete dissolution, 24% required immediate opera-tion, and 18% required operation within 1 month. Of note,in the patients who were operated upon, mild acute andchronic inflammation was found in gallbladder and com-mon duct walls.78 Nausea and diarrhea occurred in approx-imately 50% of these patients.12,78

Black pigment stones have an extensively cross-linkednetwork, rendering them difficult prospects for dissolution.EDTA was found to be helpful in in vitro dissolutionprobably by disrupting the calcium, but the black pigmentswere noted to remain behind as fine sand. Therefore,disaggregation rather than dissolution more accurately de-scribes this process.12 The combination of EDTA and lipidsolvent per nasobiliary catheter has been used as an adjunctto endoscopic retrieval of common bile duct stones.81

Gallbladder mucin may be important in nucleation of

TABLE IIIEther

Author/YearNumberof Cases

NumberSuccessful Comment

DissolutionTime

AdverseReactions

Walker, 1891 1 1 Injected into cholecystectomy sinustract.

2 Days None

Pribram, 1937, 1939, 1947 51 51 Administered via T-tube. Also usedolive oil and paraffin as adjuncts.Used double-barreled catheter.

1–6 Weeks States ether is welltolerated #3 cc

Probstein, Eckert, 1937 11 N/A Used dogs to assess effects of etherinjections. Observed that calciumfound around stones decreased ethersolubility. Unsuccessful attempts todissolve mixed stones in rubbertubing. All dogs said to have“objected strenuously.”

N/A Nausea, vomiting,jaundice, andanesthesia

Walters, Wesson, 1937 1 1 Ether and ETOH instilled into T-tubewith amyl nitrate.

9 Days Biliary colic

Burgess, Honolulu, 1940 1 1 5–10 cc ether into biliary fistula daily 35 with inhalations of amyl nitrate.

1 Week None

Raffl, 1941 2 2 3 cc ether into T-tube, then normalsaline irrigation.

6 Weeks and2 weeks

Amsterdam, Sterling, 1948 2 2 Two case reports. Both 3–4 ccdailyinstillation of ether. One with inhalingamyl nitrate; one with daily infusion ofNupercaine with ether.

3 Months and11 months

Colic

Strickler, Adkins, 1954 4 3 Nupercaine 10 cc, ether 5 ETOH 5 cc,mineral oil 5 cc via T-tube twice daily.

1–14 Weeks 1 Case, colic

Sasson, 1969 3 3 Ether and olive oil via T-tube. 3 Days–2 weeks

Nausea, vomiting,abdominal pain

N/A 5 not applicable.



cholesterol crystals in supersaturated bile, and reducingagents may enhance dissolution by solubilizing layers ofstone matrix in between layers of crystalline cholesterol,thereby increasing the contact of solvent with cholesterol.

Smith and Lamont82 identified a macromolecular biliru-bin-mucin complex in the matrix and tested the ability oftwo thiol reducing agents, 2-mercaptoethanol and N-ace-tylcysteine, to solubilize this matrix. These agents en-hanced matrix dissolution and released high molecularweight mucin-bilirubin complex as well as pigment, com-pared with aqueous buffer alone. The investigators foundthat 2-mercaptoethanol and N-acetylcysteine accelerated

gallstone dissolution in mono-octanoin versus mono-oc-tanoin alone.80 Guitaoui et al83 have shown that in vitrodissolution of brown stones by organic solvents is acceler-ated by the mucolytic agents dithiorythritol and N-acetyl-cysteine.

Since bile from patients with cholesterol gallstones nu-cleates cholesterol faster than patients without gallstones,Gallinger et al84 investigated whether differences in gall-bladder proteins might account for the difference in bilenucleation time. Higher gallbladder protein concentrationcorrelated with increased occurrence of cholesterol stonesand with in vitro nucleation time, and it has been sug-

TABLE IVOther Solvents



DissolutionTime

AdverseReactions

Wright, 1908 1 1 Described the use of turpentineintraoperatively in a patient withimpacted common duct stones.

10 Minutes None

Best, Hicken, 1938 2 2 Nitroglycerin sublingually, atropine andolive oil orally, T-tube irrigated withnormal saline and olive oil.

1 Month None

Narat, Cipola, 1945 11 (dogs) Not stated Erroneously concluded chloroform did notproduce any change in liver, gallbladder,or ducts

5 Days Pain with ether,no pain withchloroform

Best, Rasmussen,Wilson, 1953

10 8 113 solutions or combinationsinvestigated.

3 Days–2 weeks

Nausea

Torreysap, 1958 1 1 Chloroform through polyethylene tubethreaded into T-tube.

5 Days Generalanesthesia

Harris, Marcus, 1946 1 1 Nupercaine and saline instilled into T-tube.First to use intraductal anesthetics.

30 Minutes None

Glenn, Hill, 1948 1 1 Intraductal anesthetics and saline viaT-tube.

5 Days None

Smith, 1963 4 4 Saline irrigation through T-tube. None NoneLamis, Letton,

Wilson, 19693 2 Warm saline irrigation.

Gardner, 1973, 1975 44 32 Heparinized saline drip. 3–8 Days Colicky painCatt, Hogg, 1973 10 6 Intramuscular propelanthine bromide; flush

with saline with lignocaine.1–53 Days 90% had pyrexia

Castleden, 1976 8 4 Probanthine IM, lignocaine via T-tube,followed by normal saline.

16 Days Right upperquadrant pain

Chary, 1977 5 5 Heparinized saline flush. 3–8 Weeks Not stated

TABLE VBile Acids/Salts



DissolutionTime Adverse Reactions

Best/Hicken, 1939 2 2 Used oral dehydrocholic acid (decholin),along with nitroglycerin, T-tubeinstallations of olive oil, or lipoiodine viaT-tubes.

Not stated

Way et al, 1977 22 12 Infusion of Na cholate via T-tube and oral. 3–14 Days Nausea, diarrhea,pancreatitis,cholangitis, ductinflammation

Salvioli et al, 1983 28 8 Compared ursodeoxycholate withplacebo. Concluded stones don’tdissolve spontaneously.

24 Months



gested that patients with cholesterol gallstones have lost anormal mechanism for reduction of protein concentrationin the gallbladder.74

SUMMARYSince the beginning of this century, the complicated

problem of retained choledocholithiasis has fueled thesearch for the ideal solvent and has prompted surgeons andgastroenterologists (Table II) to investigate a number ofpromising solutions. All clinical series reported suffer fromlow numbers of patients, as this problem is thankfullyuncommon. In addition, it is difficult to determine whichpatients had a significant dissolution effect or merely passedtheir stones due to the mechanical effects of irrigation.Also, as the following tables demonstrate, every dissolutiontherapy is associated with a spectrum of adverse reactionsand a cumbersome array of tubes for patients to strugglewith for the duration of therapy, which can last for severalweeks.

The earliest solvent used clinically was simple ethyl ether

(Table III). As shown, all series using ether showed sig-nificant side effects such as depression of consciousness,nausea, vomiting, and jaundice. While this therapy wassuccessful in these small series, it proved unwieldy due tothese reactions as well as the hazards of handling flammableether.

Less toxic agents including chloroform and saline werethen used (Table IV). Patients still suffered adverse reac-tions, either from systemic absorption of the solvent orfrom irrigation of the common duct with high volumes ofaqueous solvent. When bile acids became readily availablefor oral use, these were also tried as solvents for commonduct stones (Table V). Unfortunately, these proved to bepoor solvents, taking a long time to dissolve only a minor-ity of stones and still producing a number of adverse effects.

Aliphatic solvents still held the best hope of rapid disso-lution, but were also associated with the most toxicity. Twonewer agents were studied in the 1960s: mono-octanoin(MO) and methyl-tert-butyl-ether (MTBE). MO has the

TABLE VIMono-Octanoin



DissolutionTime

AdverseReactions

Thistle et al, 1980 12 10 Infused via T-tube. 4–21 Days Mild anorexia,nausea

Jarrett, Bell, 1981 24 15 complete,5 partial

Mechanical extraction used on some ofthe patients with remaining stones.Used mono-octanoin 1 weekpostoperatively.

5–112 Days Diarrhea, biliarycolic

Hofmann et al, 1981 118 54 complete,24 partial

Infusion via T-tube or nasobiliary catheter. 1–21 Days Nausea, vomiting,diarrhea, painDuodenal erosionin one patient

Mack, Crummy,1981

4 Percutaneous transhepatic approach. 4–8 Days

Witzel et al, 1981 16 12 Nasobiliary. 6–25 Days Fever, leukocytosisSmith, Lamont,

1985In vitro study Adding sulfhydryl bond-breaking agents,

2-mercaptoethanol and N-acetylcysteineto mono-octanoin increases thedissolution speed.

Not applicable

Palmer, Hofmann,1986

343 88 complete,70 partial

Collated case reports 1977–1983. Mono-octanoin ineffective in 36%. Treatmentstopped in 9% due to side effects.

Not stated Abdominal pain,nausea, vomiting,diarrhea

TABLE VIIMethyl-Tert-Butyl Ether (MTBE)

Author/YearNumber of

CasesNumber

Successful CommentDissolution

TimeAdverse

Reactions

Thistle et al, 1986 19 18 Percutaneous approach. Cycles ofinstillation/aspiration of MTBE.

4–12 Hours Anesthesia, nausea,vomiting, duodenitis

Brandon, Telpic,1988

10 9 Percutaneous approach. Balloon catheterswere inflated in distal common bile ductto prevent MTBE from enteringduodenum.

8 Days None stated

Murray, Laferia,1988

10 3 complete,5 partial

Used in patients who failed endoscopicmanagement.

Not applicable



advantage of being digestible by pancreatic lipase intobenign end products. This is evident in clinical series ofMO trials (Table VI) showing fewer toxic side effects.However, as with all solvents there is some direct irritationof the biliary tree evident and MO dissolution requiresmany days of therapy. MTBE, on the other hand (TableVII), has been shown to work much faster, but is a directtoxin to both liver and duodenal mucosa, requiring com-plicated strategies to prevent passage of the solventthrough the sphincter of Oddi. Therefore, the ideal solventhas not yet been produced, and retained choledocholithi-asis continues to be a difficult clinical problem.

Because reoperation for this situation carries with it in-creased risks for bleeding, ductal injury and infection, andbecause many patients with retained choledocholithiasisare poor candidates for reoperation, technology hasevolved to enable nonoperative management using disso-

lution therapy as part of a combined approach appears themost attractive. Several early trials using dissolution incombination with endoscopic retrieval or lithotripsy havebeen published and are encouraging.81,85 Therefore, theauthors propose that the modern minimally-invasive ap-proach to choledocholithiasis should include dissolutionand lithotripsy as adjunctive measures to laparoscopic com-mon duct exploration.

We advocate the selective use of cholangiography at theinitial operation, and when common duct stones are seen,laparoscopic common duct exploration should be carriedout. In experienced hands, this should be successful in 90%of cases.86 Biliary lithotripsy can be used to increase thisfigure to 95% to 98%.87 In cases where the common ductis not cleared, or in cases of small common bile duct notamenable to exploration, a cholangiocatheter can be in-serted via the cystic duct stump, or as a T-tube, and

Figure 1. Decision-making tree summarizes approach to managing suspected choledolithiasis.



Hofmann’s regimen70 for mono-octanoin can be at-tempted. Even with a 50% failure rate, this regimen can beused to soften and shrink impacted stones, thereby improv-ing the chances of success with ERCP or T-tube tractextraction. Finally, the prudent surgeon should always havea “fail-safe” procedure selected that will provide permanentrelief of biliary obstruction, should complications of theabove procedures occur. In the authors recommend chole-dochoduodenostomy, which can be performed either lapa-roscopically or open. Our favored approach is summarizedas a decision-making tree in Figure 1.

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a history of the dissolution of retained choledocholithiasis

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