Percutaneous dissolution of gallstones

Percutaneous Dissolution

of Gallstones

By Eric vansonnenberg, Horatio B. D’Agostino, Alan F. Hofmann, Robert B. Sanchez, Brian B. Goodacre, Oliver Esch, and Giovanna Casola

ERCUTANEOUS chemolitholysis of gallstones is an investigational technique that has been performed in over 500 patients worldwide.‘-14The method has proven to be highly effective and has a substantial margin of safety. Despite these attractive aspects, its application has been limited to a few centers. In this article, we will discuss the indications, technique, and benefits of gallstone dissolution with methyl teti-butyl ether (MTBE). Likewise, the disadvantages and reasons for lack of widespread use of the method are addressed.

P

INDICATIONS

MTBE may be applied to a broad range of patients with gallbladder stones. Estimates range from 60% to 75% of patients who might undergo successful gallstone dissolution with the solvent (Fig 1). Requirements for MTBE therapy of gallstones include (1) clinical assessment that the patient is symptomatic from the gallstones, (2) the gallbladder is of sufficient size to admit a catheter and at least a few cc’s of solvent, and (3) that at least an appreciable portion of the stone is cholesterol and not calcified.2,4,7,1s,‘6 The latter criterion has changed; during the initial experience with MTBE, any calcium within the stone was an exclusion criterion. Recent studies have shown that if the cholesterol matrix of the stone becomes dissolved, inorganic components may be flushed out or extracted by ancillary basketing procedures.4’X.17 Cystic duct occlusion is controversial as a decision-making factor for gallstone dissolution; some groups reject patients on this basis2.” whereas others do not.4,8Stones may be dissolved in the cystic duct or may undergo mechanical extraction apart from the dissolution process.4.8 Cannulation of the cystic duct is difficult in some patients but straightforward in others. Consideration of the site of the stone within the cystic duct, the size of the stone, and the degree of calcification influence the decision as to whether patients with cystic duct stones are amenable to percutaneous therapy; smaller and more proximal cystic duct stones are easier to treat. Seminars

m Roentgenology,

Vol XXVI, No 3 (July), 1991: pp 251-258

CONTRAINDICATIONS

Infusion of MTBE may be contraindicated or not preferred for a variety of reasons. Acute complications of gallstone disease including cholecystitis, cholangitis, and pancreatitis preclude MTBE therapy in the acute setting. MTBE is not permitted during pregnancy. Heavily calcified stones cannot be dissolved by MTBE. The shrunken gallbladder of chronic cholecystitis is an exclusion criterion because catheterization may be difficult, impossible, or risky for the patient.2’4.7.‘4 Finally, a bleeding dyscrasia that is uncorrectable is a contraindication, similar to other Interventional Radiology procedures. Acceptable parameters for gallbladder catheterization include a prothrombin time greater than 3 seconds over control, partial thromboplastin time no greater than the low 40-second range, and platelets greater than 50,00O/cm’.‘” It is preferable for the hematocrit to be greater than 30% before undertaking the gallbladder puncture. STATUS

OF METHYL TERT-BUTYL

ETHER

MTBE is controlled by the Food and Drug Administration (FDA) as an investigational drug. To use the drug, one must obtain an investigational new drug consent from the FDA and permission must be current. Strict control, follow-up, and reporting of problems is essential. On a case by case basis, the FDA may be petitioned for compassionate use.

ABBREVIATIONS CT, computed tomography; EDTA, ethylenediaminetetraacetic acid; MTBE, methyl teti-butyl ether: OCG, oral cholecystogram; PC, percutaneous cholecystostomy; US, ultrasonography

From the Depatiments of Radiology and Medicine, University of California San Diego Medical Center, San Diego, CA. Address reprint requests to Eric vanSonnenberg. MD, UCSD Medical Center, Department of Radioloo, 225 Dickinson St, San Diego, CA 92103. Copyright 0 1991 by W.B. Saunder,y Cornpam 0037- 198X19112603-0010$5.OOlO 251

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Fig 1. Successful contact dissolution of gallstones. (A) OCG shows multiple small gallstones in a functioning gallbladder. (B) Catheter cholecystogram shows dissolution after 6 hours of MTBE infusion and lavage.

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DISSOLUTION

OF GALLSTONES

253

The FDA has limited the use of MTBE in the common duct. The proposed patient should be discussed with the FDA for all common duct cases. On the other hand, monooctanoin is approved by the FDA for treatment of cholesterol stones in the bile ducts. IMAGING

STUDIES

The number and size of stones are not major considerations for contact dissolution with MTBE, unlike decision-making factors for some of the other nonoperative methods. The solvent is effective against all cholesterol components of stones. As such, detection of gallstones either by ultrasonography (US) or by oral cholecystogram (OCG) is sufficient; however, a major amount of calcification precludes effective dissolution. Use of plain film of the abdomen versus computed tomography (CT) spurs controversy because the amount of calcium in a gallstone has different implications for different authors.‘X,‘yIt is argued that if there is not enough calcium to be seen on plain film, then MTBE should be at least partially effective. Although this may be true, most groups do obtain a preprocedure CT.“,“,’Although extensive calcification cannot be dissolved, a thin broken rim of calcium and laminated stones surrounding an underlying cholesterol core can be penetrated by the solvent. The attenuation value of the rim, rather than its thickness, is the main determinant of dissolution efficacy.” Another reason to obtain a preprocedure CT is for catheter pathway mapping. CT permits the best delineation of the catheter route vis a vis structures adjacent to the gallbladder that may be (liver) or should not be (colon and lung) punctured.‘4.‘hMagnetic resonance imaging with T,-weighted sequences is not helpful in determining solubility of stones.17 PERCUTANEOUS METHYL

CHOLECYSTOSTOMY TERT-BUTYL ETHER

FOR

PC for contact dissolution is preferably performed through a transhepatic pathway that traverses the bare area of the gallbladder at its attachment to the liver.z34This route has proven to be safe. The advantages of this pathway are ease of tract dilatation for catheter entry, and

that bile, contrast, or solvent may be less likely to leak intraperitoneally. The preprocedure CT scan provides the operator with information on gallbladder position, gallbladder capacity, stone composition, and structures that are juxtaposed to the gallbladder. PC may be performed either electively or emergently; the latter is used for acute cholecystitis or gallbladder empyema, often in an elderly or medically compromised patient. Portable US guidance alone is frequently used for these acute cases.“-” For elective cases, fluoroscopy with OCG for gallbladder opacification or a combination of US with fluoro-OCG is preferred.2’5.7.‘4Electively, the procedure is performed by coaxial Seldinger technique; in the acute setting with a dilated gallbladder, trocar technique is usually preferred.“.” Catheters from 5F to 7F are used routinely.2.‘4 Locking gallbladder catheters are preferred to ensure that catheter dislodgement does not occur.‘4.‘1’ Those patients who initially present for PC with acute cholecystitis, hydrops, or empyema of the gallbladder may have the PC inserted by any route or method because drainage is the immediate goal.‘J,‘h.2” Under these circumstances, trocar insertion of the PC is typical, and the catheter occasionally is placed subhepatitally. Both trocar insertion and the transperitoneal approach are far easier in the dilated gallbladder than for typical elective cases. As long as the catheter is well secured and the drainage procedure is effective, contact dissolution may be performed after an interim period for the patient to recover from the acute episode. METHYL

TERT-BUTYL

ETHER

MTBE is an aliphatic ether that differs from the anesthetic ether in that it remains as a fluid at body temperature due to its high boiling point, 55.20C.2”-2h MTBE is low viscosity (0.747) an essential factor for dissolution. The solvent powerfully dissolves cholestero124.z7; this action is augmented by high concentration, good mixing, and agitation. Contrast medium added to the gallstone and bile has been reported as enhancing the dissolution effect of MTBE.” Laser fragmentation2’ and transcutaneous Us’” markedly accelerate gallstone dissolution in

VANSONNENBERG

MTBE in vitro. Inorganic calcium and bilirubinate compounds are refractory to MTBE. MTBE is both potentially flammable and explosive. It must be stored in a safe area and delivered with great care; glass and metal must be used. MTBE also has a noxious odor that must be eliminated. Experimentally, MTBE is not particularly mutagenic.26,31 It may cause mild gastrointestinal toxicity. Absorption through the gallbladder wall and the gastrointestinal tract into the bloodstream has been demonstrated.32In pigs, MTBE caused mild superficial ulceration and chronic inflammatory changes in the gallbladder.33MTBE was reported to cause bile duct dilatation after direct ductal infusion in rabbits.34 A cardinal principle of MTBE is that all infused MTBE should be recovered and eliminated. MTBE is potentially dangerous if the solvent is not retrieved. In humans, MTBE has been linked to hemolysis, duodenal ulceration, coma, and renal failure when appreciable MTBE was not recovered.*x3’However, when retrieved carefully, MTBE has not caused deleterious effects. One study of five patients who underwent cholecystectomy after MTBE infusion showed no specific effects of MTBE on gallbladder histopathology.36 DELIVERY OF METHYL TERT-BUTYL

ETHER

Different methods have been used to administer and retrieve MTBE. To date, most cases have been performed by hand injection. Automated pumps have been introduced to speed dissolution and to decrease the time burden on personne1.37 Whatever method is used, the essential principle is to maintain the solvent within the gallbladder rather than allow leakage into the common duct and duodenum. By hand, the amount of MTBE for infusion is determined by contrast injection through the PC catheter; the volume at which spill of contrast from the gallbladder into the cystic duct is halved to determine the initial volume to be administered.14 To and fro MTBE lavage then commences. The MTBE is changed periodically to maintain high concentration. Two types of pumps are in developmental and investigational use. One is pressure con-

ET AL

trolled36 and the other is volume governed.* Each needs to have the MTBE changed at regular intervals to enhance effectiveness of dissolution. Hand lavage of MTBE is personnel dependent. Someone must sit with the patient and constantly infuse and withdraw the solvent. Solvent infusion without stirring is inefficient and much less effective than constant agitation and frequent solvent change. Pumps hopefully will automate the process, thereby decreasing this human input. Nevertheless, patients will need to be monitored closely throughout the infusion and dissolution period itself. MATERIALS

FOR METHYL

TERT-BUTYL

ETHER

The materials used with MTBE must be resistant to the effects of the solvent. MTBE avidly destroys many synthetics, such as plastics. Metal and glass are used preferentially over standard plastic syringes and stopcocks. Soft catheters (such as Percuflex, Meditech, Watertown, MA, C-Flex, Cook, Inc., Bloomington, IN; and silicone) will dissolve with MTBE.’ Catheter material that is resistant includes polyethylene, polyurethane, and Teflon; the former generally is used. MTBE should be kept in a hooded area to evacuate fumes, both because of the malodor and the potential for explosion and fire. Care must be taken with MTBE not to allow spillage. Various hoods are available to evacuate the fumes of MTBE. MONITORING

OF METHYL

TERT-BUTYL

ETHER

The in vivo effects of MTBE are assessed periodically by fluoroscopic contrast sinography. Fluoroscopically, dissolution by MTBE initially appears as a shaggy margin on the stone(s). Those calculi in proximity to the catheter are dissolved most readily because they receive a greater concentration of the solvent.* Stones shrink in size with ongoing dissolution. Occasionally stones cleave and fragment during dissolution. Due to complexities in the composition and geometry of gallstones, dissolution can be effective initially without visible radiographic effects. Leeching of internal contents and circumferential initial peeling off of outermost layers may be difficult to appreciate on contrast cholecysto-

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DISSOLUTION

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OF GALLSTONES

grams in the early stages of dissolution. US is not helpful until more macroscopic changes become apparent with ongoing dissolution. Newer methods to monitor dissolution appear to be useful in the early stages of dissolution and help to determine the endpoint of solvent infusion. These methods help to deter fruitless attempts at dissolution of pigment stones and to indicate when organic components have been dissolved effectively. Thinlayer chromatography and gas chromatography have been beneficial in providing specific information on cholesterol extraction from gallstones.3R Conventional contrast cholecystography and US lag behind thin-layer chromamatography and gas chromatography in providing this information.

RESULTS

Effectiveness of MTBE can be assessedby several parameters. These include reduction of gallstone mass,clearance of gallstones, improvement in symptoms, and lack of recurrence. MTBE may be combined with other modalities (extracorporeal shock-wave lithotripsy, ursodeoxycholic acid, mechanical fragmentation, and removal) and hence assessmentof the efficacy of MTBE may be complicated. Laser fragmentation is reported to augment MTBE dissolution.2y.48 Several series list successfrom 84% to 96%.‘-’ Thistle et al reported that 72 of 75 patients had effective dissolution when “complete” and “partial” dissolution were combined. However 51 of 75 patients had debris remaining within the gallbladder, although only 7 of 51 had symptoms. The time for dissolution averaged OTHER SOLVENTS 12.5 hours and ranged from 3.8 to 30.8 hours. Few contact solvents other that MTBE have Solitary stones dissolved on average of 8.4 hours found a role in clinical practice in the gallbladand multiple stones at 13.8 hours. Nausea was a der. Ethylenediaminetetraacetic acid (EDTA) common side effect, occurring in about one substances have been used with a modicum of third of patients. Sedation was another adverse success at best. There are reports of some effect.’ benefit by the addition of EDTA bile acid In our updated series of 50 patients, we have against inorganic components of gallstones.9,39.4” had slightly less than 90% success.We reported A new agent being explored currently for our initial results in 18 patients.j Complete dissolution occurred in 11 of 13 patients with gallbladder usage is ethyl propionate. Its effecgallstones, in the one patient with intrahepatic tiveness against cholesterol appears comparastones, and in 2 of 4 patients with common duct ble to MTBE.4’ Ethyl propionate lacks the foul stones. We supplemented MTBE with percutaodor of MTBE and the flammable potential. It neous basketing to remove residual inorganic has not yet been entered in clinical trials. fragments (Fig 2). Monooctanoin is another anticholesterol solHellstern et al had 96% success rate for vent that has been used for years to treat MTBE dissolution of gallstones. They had two common duct stones.42-46 Its use has been refailed PC cases. Complications or adverse efplaced largely by mechanical endoscopic techfects occurred in 28%, the worst being bile leak niques, percutaneous basketing, and extracorand hemobilia.7 poreal shock-wave lithotripsy.47 Although it has been shown to be effective in dissolving bile COMPLICATIONS duct stones in 30% to 80% of patients, it has The worst in vivo complication from MTBE disadvantages that limit its use.42,“‘-46 Monoresulted in renal failure and coma. The coma octanoin administration is time-consuming, takwas reversible and the renal failure resolved ing days to achieve dissolution in many cases. partially. This complication was considered to Complications include nausea, vomiting, and be due to loss of MTBE (at least 20 cm3).li elevation of liver function in up to 15% to 20% Another patient in a different series suffered systemic effects including hypoxof cases42.4h; ulcerative duodenitis from MTBE; this problem emia and flushing are reported.& Monooctanoin resolved in 4 days on follow-up endoscopy. The has caused duodenal ulceration in patients and patient also had intravascular hemolysis.’ gallbladder ulceration in animals.33x4” MonoocAnother series of four patients reported two tanoin is not in clinical use in the gallbladder.

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Fig 2. MTBE plus supplemental basketing of gallstones for stones of mixed composition. (A) Multiple small gallstones on OCG. Some of the gallstones are faceted. (B) The patient had pain with MTBE infusion and only 5 hours of contact dissolution were undertaken. Thin-layer chromatography demonstrated high cholesterol levels and partial dissolution occurred. At that point, a tract was dilated and the remainder of the fragments were basketed and removed. The extracted stones were of mixed composition with a pigment core.

complications. Catheter dislodgement occurred in one patient (causing termination of the procedure) and another patient had a bile leak.’ We have not yet seen a major complication from MTBE itself. However, over one third of our patients have experienced discomfort or pain with MTBE.14 In most patients, pain is tolerable or resolves. Inability to tolerate MTBE is rare. TREATMENT

OF BILE DUCT STONES

Both MTBE and monooctanoin have been used to treat intrahepatic and extrahepatic bile duct stones.“621’13S4649 Catheters must be positioned adjacent to the stones for optimal effect. With MTBE infusion, the distal common duct should be blocked to prevent flow into the duodenum because duodenal ulceration and absorption of MTBE may occur. Because bile duct stones are more likely to be composed of bile pigment and calcium than are gallbladder stones, MTBE is not expected to be as effective in the ducts as in the gallbladder.

Teplick et al reported three patients who had MTBE infusion for common duct stones. The stones dissolved in one patient, did not dissolve in another, and were reduced by about one half in the third patient.49 Brandon et al reported complete dissolution of 3 of 13 ductal stones within 30 minutes, another 7 stones were reduced in size, and 3 were unaffected.13Percutaneous basketing may be facilitated by MTBE to decrease stone size.4,5S10S13,47 MTBE has been used by retrograde catheterization to treat choledocholithiasis. In a multiinstitutional British series, MTBE was considered helpful in only 36% of 33 patients.” There was a high complication rate and adverse effects (79%) with retrograde instillation in this survey. Other studies from single institutions have not noted a similar degree or frequency of complications.4S~10311 THE FUTURE

Although contact dissolution has proven highly safe and effective, the future is uncertain.

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DISSOLUTION

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OF GALLSTONES

There are competitive techniques that are either less personnel-dependent (for the 1 to 15 hours that dissolution requires), less invasive (extracorporeal shock-wave lithotripsy), or eliminate the gallbladder (cholecystectomy).‘4’50Automated pumps obviously would be helpful to reduce logistical problems of MTBE. As laparoscopic cholecystectomy becomes standard treatment for gallstone disease,nonoperative therapies must find their adjunctive roles. Contact dissolution will likely be reserved for patients who have a mitigating medical reason that precludes surgery, or for those patients who opt not to undergo general anesthesia with laparoscopic or open cholecystectomy.50 Another unanswered issue with contact dissolution is the use (or not) of supplemental oral bile acids. Whether urso should be used routinely after contact dissolution, or whether it is

more prudent to reserve its use until a recurrence occurs requires further evaluation. SUMMARY

Contact dissolution with MTBE is an effective and safe method to treat symptomatic patients with cholesterol gallstones. Personnel, time, and safety factors have limited widespread use of the procedure. With current competing methods to treat gallstones, it is likely that MTBE use will be reserved for those patients who elect percutaneous therapy due to fear of surgery or anesthesia and in those elderly patients who are compromised by underlying medical conditions. ACKNOWLEDGMENT Our appreciation to Claudio Schteingart, PhD, and Peggy Chambers.

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gallbladder stones. IEEE Trans Biomed Eng 37:410-416, 1990 38. D’Agostino HB, vansonnenberg E, Schteingart CD, et al: Thin-layer chromatography to monitor cholesterol gallstone dissolution by methyl-tert-butyl ether. AJR (in press) 39. Leuschner U, Wosiewitz U, Baumgartel H, et al: Dissolution of calcified cholesterol stones and of brown and black pigment stones of the gallbladder. Digestion 39:100110,1988 40. Peine CJ, Nagorney DM, Madson TH, et al: Dissolution of radiopaque gallstones: Safety of alternating methyl tert-butyl ether (MTBE) with EDTA-polysorbate 20 (E-P) and/or N-acetylcysteine (NC) with and without prior extracorporeal shock wave lithotripsy (ESWL) in dogs. Gastroenterology 92:1763,1987 (abstr) 41. Hofmann AF, Schteingart CD, Lillienau J, et al: Solvents for contact dissolution of cholesterol stones. Presented at the Third International Symposium on Biliary Lithotripsy, Munich, Germany, September 13-15, 1990 42. Thistle JL, Carlson GL, Hofmann AF, et al: Monooctanoin, a dissolution agent for retained cholesterol bile duct stones: Physical properties and clinical application. Gastroenterology 78:1016-1022,1990 43. Teplick SK, Pavlides CA, Goodman LR, et al: In vitro dissolution of gallstones: Comparison of monooctanoin, sodium dehydrocholate, heparin, and saline. AJR 138:271273,1982 44. Minuk GY, Hoofnagle JH, Jones EA: Systemic side effects from the intrabiliary infusion of monooctanoin for the dissolution of gallstones. J Clin Gastroenterol 4:133135,1982 45. Train JS, Dan SJ, Cohen LB, et al: Duodenal ulceration associated with monooctanoin infusion. AJR 141:557558,1983 46. Butch RJ, MacCarty RL, Mueller PR, et al: Monooctanoin perfusion treatment of intrahepatic calculi. Radiology 153:375-377,1984 47. Stokes KR, Falchuk KR, Clouse ME: Biliary duct stones: Update on 54 casesafter percutaneous transhepatic removal. Radiology 170:999-1001,1989 48. Smith BF: Effect of laser fragmentation of cholesterol and mixed gallstones on in vitro dissolution in methyl tert-butyl ether. Dig Dis Sci 35:236-241,1990 49. Teplick SK, Haskin PH, Goldstein RC, et al: Common bile duct stone dissolution with methyl tertiary butyl ether: Experience with three patients. AJR 148:372-376, 1987 50. vansonnenberg E, Hofmann AH: Horizons in gallstone therapy-1988. AJR 150:43-46,1988