Gut, 1990,31,922-925

Gall stone dissolution with methyl tert-butyl ether:how to avoid complications

A Hellstern, M Leuschner, H Frenk, H W Dillinger,W Caspary, U Leuschner

AbstractFifty of 52 patients with cholesterol gallbladder stones were treated with methyl tert-butyl ether. In 48 of 50 (96%) patients thestones dissolved after an average interval of9*5hours. Mean stone size was 1-7 cm (0.5-3.3cm), mean stone number was 14-6 (1-70).Twelve patients (24%) complained ofnausea, aburning sensation, or vomiting. In one patientbile leakage occurred and another sufferedhaematobilia (4%). The puncture set wasimproved, and a special basket was developedto extract stones that had escaped into thecystic duct. To prevent bile leakage orhaemorrhage from the incision channel, atissue adhesive was injected into the channelor ceruletid was administered subcutaneouslybefore removing the catheterto induce contrac-tion of the gall bladder. Thus we were able totreat 44 patients without any complications.Nausea and vomiting could be reduced if thetreatment time was kept short and the per-fusion volume was as low as possible. Methyltert-butyl ether treatment is a successful treat-ment of gall bladder stones with few complica-tions.

Centre of InternalMedicine, Department ofGastroenterology,Johann Wolfgang GoetheUniversity, Frankfurt/Main,W GermanyA HellsternM LeuschnerH FrenkHW DillingerW CasparyU LeuschnerCorrespondence to:Dr U Leuschner, Zentrum derInneren Medizin,Universitatsklinik, Theodor-Stern-Kai 7, 6000 Frankfurt/Main 70, Federal Republic ofGermany.Accepted for publication16 October 1989

In 1985 Thistle's group introduced direct gallstone dissolution with methyl tert-butyl ether. 2

The gall bladder is punctured percutaneouslyand transhepatically via the gall bladder bedunder fluoroscopy. The puncture is technicallyeasy and the treatment is speedy and in-expensive. There are, however, four hazardsassociated with percutaneous transhepaticlitholysis:

(1) The gall bladder wall may be injuredopposite the puncture site, either by the needleor the plastic introducer.

(2) Haematobilia may develop3 if a large vesselis punctured in the gall bladder bed.

(3) When the catheter is removed at the end oftreatment, a bile leakage or a haemorrhage at theliver surface may develop.4

(4) Stone impaction may occur in the cysticduct during perfusion.

Besides these complications there are otherundesirable side effects such as nausea, gasproblems, vomiting, or abdominal discomfort.We have now treated 50 patients with choles-

terol stones of the gall bladder with methyl tert-butyl ether and have learned to prevent the abovementioned problems, or at least to cope withthem. We report our experience.

Patients and methodPatient selection for methyl tert-butyl ethertreatment was done by oral or intravenous chole-

cystography and computed tomography at 5 mmintervals. Only patients with radiolucent choles-terol stones of the gall bladder were selected. In50 of 52 patients we succeeded in puncturing thegall bladder under local anaesthesia (Scandicain1%) and sedation (lormetazepam, Noctamid: 1-2 mg iv) with a needle (0-028", 45 cm). In twopatients we failed because of extreme obesity.Using the needle, a catheter (introducer: 5 FG,20 cm) was propelled into the gall bladder. Aguide wire (0-035", 145 cm) was inserted inseveral loops through the introducer enablingplacement of the perfusion catheter (5 FG, 70cm) (all instruments by William Cook Europe,Bjaeverskov, Denmark). We subsequentlyinjected enough contrast medium to produceoverflow via the cystic duct. For stone dissolu-tion we used methyl tert-butyl ether (Merck,Darmstadt, FRG). The methyl tert-butyl etherwas high performance liquid chromatographygrade and was not prepared further by us.Treatment started with 2 ml. The perfusionvolume was increased but never exceeded theoverflow volume, which was assessed fluoro-scopically by contrast medium. Methyl tert-butyl ether was aspirated immediately from thegall bladder, at the latest within two minutes ofcontact time. Routine laboratory tests such aswhite cell count, red cell count, alanine aminotransferase, aspartate transaminase, lactatedehydrogenase, and lipase were done beforetreatment, after treatment, and one week later.

Results(1) The most important results are found inTable I. In five of the first 15 patients the gallbladder was very slender. Because of this thepyramid-shaped needle tip pressed the wall inthe area of the gall bladder bed up to thecontralateral wall. In two patients the needleeven protruded into the contralateral wall beforeit penetrated. The same happened with theintroducer. From patient 16 onwards thereforewe used a needle with an oblique cut and a betterintroducer, slanted at its tip at an angle of 300(Angiomed, Karlsruhe, FRG). These instru-ments were used successfully on 35 patients.With the use of the oblique cut needle, punctureof the gall bladder was especially easy when thewall was thickened. The slanted introducercannot injure the gall bladder wall and the guidewire propelled through it is immediately bentinto the gall bladder lumen when leaving theintroducer tip.(2) Just after insertion of the catheter a haema-tobilia developed in patient 8 (Fig 1). Weaspirated blood for 3 5 hours via the perfusioncatheter. At the same time a large clot formed inthe gall bladder. After perfusion with an 0 9%

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Gall stone dissolution with methyl tert-butyl ether: how to avoid complications

TABLE I Results ofmethyl tert-butyl ether treatment in 50 patients with gall bladder stones

Age Stone Dissolution Side(yrs) No size (cm) Volume (cm)* time (h)t Success effectst Complications5

Mean 46-2 14 6 1-7 24-8 9 5 48 (96%) 12 (24%) 2 (4%)

Range 23-69 1-70 0 5-3 3 1 1-44-6 2 5-21 - - -

*Stone volume: number x size (cm).tTreatment was interrupted during the night.tNausea, vomiting, burning, pain, leucocytosis up to 16 000/mm3.§Bile leakage, haematobilia.

saline and a 1% ethylenediaminetetra-acetic acidand 5%-N-acetyl-cysteine-containing aqueoussolution' for nine hours the clot dissolved com-pletely and the gall stone was then dissolved withmethyl tert-butyl ether (Table II, Fig 2). Sincebile seems to be able to dissolve blood clots,however, the question arises as to whether it isnecessary to do anything in such a case.(3) In two of six patients (patients 3 and 4), bile-containing contrast medium was seen on themonitor to follow the catheter tip through theliver when the perfusion catheter was removed(Fig 3). Both patients, plus patient 2, com-plained of pain on the right side. Necropsystudies on three livers of patients other than gallstone patients showed that the incision channel isnot occluded after removal of the catheter andmay be completely rechannelled from the liversurface by injection of methylene blue. Patient 6had a bile leakage from the liver surface lasting10 hours after the catheter was removed. Thepatient did not develop peritonitis but had severepain and was able to be operated on withoutcomplications. Another option might have beenthe placement of a nasobiliary tube, but we didnot try this in our patient.

For treatment of haematobilia and preventionof haemorrhage or bile leakage from the liversurface, we have developed the followingmethod in three post mortem livers and three gallstone patients. The fibrin sticker Tissucol(Immuno GmbH, Heidelberg, FRG) is mixed ina ratio of 10:1 with x ray contrast medium - forexample, Conray 50 (Schering, Berlin, FRG). Aguide wire is introduced, the perfusion catheteris removed after complete evacuation of the gall

Figure 1: Patient 8. The gall bladder is completely filled with blood clots (arrows), and thestones are not visible. C=catheter in the liver.

Figure 2: Patient 8. Four days after the gall bladder has beenflushed with anEDTA solvent (Table II) and 0 9% saline thegall bladder isfree and the stones have been dissolved withmethyl tert-butyl ether.

bladder, and a hollow needle is inserted via thewire into the channel of the liver. Tissucol, in anamount corresponding to the idle space of theneedle, is carefully injected into the hollowneedle. After 20-30 seconds the sticker is viscousand may be deposited under fluoroscopy any-where in the incision channel (Fig 4(a) and (b)),in the case of treatment of a haematobilia, forinstance, in the gall bladder bed. By depositingmultiple plaques, the entire channel may beoccluded. The sticker must be allowed to congealin the hollow needle, in its liquid state it wouldflow through the incision channel into the gallbladder and provide a nucleus for new stones.To prevent a bile leakage we used a different

method from patient 7 onwards. After stonedissolution the gall bladder is completelyevacuated with a syringe while the catheter isslowly removed. When only 3-5 cm of theperfusion catheter are still positioned in the gallbladder, we inject 5 [tg ceruletid (Takus,Farmitalia, FRG) subcutaneously into the thigh.After three minutes the gall bladder has con-tracted and the catheter can be removed. Subse-quent ultrasound scans showed marked con-traction in 38 patients, and appreciable contrac-tion in six patients. Only five of the patientstreated this way reported pain at the incision site.In none of them did we see the incision channelfilled with contrast medium in the liver, nor didwe see bile leakage.(4) Impaction of a small stone in the cystic ductoccurred in patient 4 during perfusion treat-ment. We manoeuvred the catheter tip near thestone after failing to move it with the guide wire:the stone was dissolved. To be able to handle thiscomplication more easily we have developed abasket (similar to a Dormia basket) which can be

TABLE II Solvent usedfor treatment ofhaematobilia

BA-EDTA-NAC % (w/w) mmwl/lEDTA-2Na 1-0 26-9Cholic acid 0 5 12-3Ursodeoxycholic acid 0 5 12-7Carnosin 05 18-0Arginin 1-9 109-0Nacetyl-cysteine 5N-aOH, H20: pH 9-2

EDTA=ethylenediaminetetra-acetic acid.

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924 Hellstern, Leuschner, Frenk, Dillinger, Caspary, Leuschner

GB

Figure 3: Patient 4. The catheter has been removed, and bile mixed with contrast medium(arrow) hasfollowed the tip ofthe catheter through the incision channel. GB=gall bladder.

easily introduced through the 5 FG introducerand will move impacted stones (available fromPauldrach, Garbsen, FRG).

Adverse reactions to methyl tert-butyl ethertreatment such as nausea, vomiting, gas, aburning sensation, or tenderness can easily bereduced or even prevented if the catheter isplaced early in the morning and, if possible,removed on the same day after treatment. Com-plaints will increase if the catheter is left in thegall bladder for two days. So that methyl tert-butyl ether does not flow into the gut, theperfusion volume should not exceed an amountwhich just envelops all the patient's stones.Usually, 10 ml of methyl tert-butyl ether aresufficient as a maximum individual dose. Afterfour to six hours, when the stones have reduced,the catheter position must be checked. Thus, wecan reduce the perfusion volume, whichprevents side effects. If these recommendationsare taken into account, administration of antie-metics or analgesics can be completely avoided.

'. [V;~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..........

Figure 4 (a): The hollow needle (N) is still in the liver. The arrow marks a plaque ofthefibrinadhesive Tissucol (ftibrinogen, fibronectin, FXIII in aprotinin thrombin) mixed with contrastmedium located in the incision channel.

(b) The entire channel (arrows) is closed by thefibrin adhesive.

DiscussionStone dissolution was achieved in 48 of 50patients (96%). In one patient in whom a bileleakage occurred we decided to operate. In twopatients we saw bile-containing contrast mediumin the incision channel of the liver when thecatheter was removed. Since these two and athird patient complained ofpain in the area oftheincision site, we presume that they experiencedbile leakage at the liver surface too.

In the following 46 patients we did not observeany bile leakage after administering ceruletid.Only rarely were there reports ofmild pain at thepuncture site and the gall bladders weremarkedly contracted in almost all patients. Nobile is able to pass into the incision channel andwe believe that ceruletid is an excellent means ofpreventing this.The fibrin sticker Tissucol was not used as a

routine measure. The placing of Tissucolplaques in the incision channel is technically veryeasy, and haematobilia can be treated in this way.Haemorrhage from the liver surface and bileleakage cannot be treated, however, since theinstruments have been removed at this point. Ifthese complications are a possibility, the fibrinsticker should be inserted into the entire incisionchannel as a preventive measure, and only thenshould the instruments be removed.

Side effects such as haemolysis6 or renalfailure7 were not observed.

After improvement of the puncture instru-ments and the development of simple measuresfor prevention and treatment of leakages, weconsider methyl tert-butyl ether treatment to besafe. To limit the patient's side effects to a mini-mum, one should try not to let the perfusionduration exceed half a day (approximately 12hours). Fast, continuous treatment is the safestway to prevent undesirable side effects.While percutaneous transhepatic methyl tert-

butyl ether treatment in the gall bladder could beexpanded to include treatment of gall stonecholecystitis,8 or by admixture of other solventsto treating pigment stones,9 '° we do not believethat it is suitable for the treatment of bile ductstones because of the considerable sideeffects."1-4 In agreement with J Thistle et al,5who have recently published data on 75 patients,we believe methyl tert-butyl ether treatment iseasily manageable and highly effective treatmentfor gall stones.

1 Allen MJ, Borody TJ, Bugliosi TF, May GR, LaRusso NF,Thistle JL. Cholelitholysis using methyl tertiary-butylether. Gastroenterology 1985; 88: 122-5.

2 Allen MJ, Borody TJ, Bugliosi TF, May GR, LaRusso NF,Thistle JL. Rapid dissolution of gallstones by methyl tert-butyl ether. N EnglJ Med 1985; 312: 217-20.

3 Hellstern A, Leuschner M, Fischer H, et al. Perkutantrans-hepatische Lyse von Gallenblasensteinen mit Methyl-tert-Butyl-Ather. Dtsch Med Wochenschr 1988; 113: 506-10.

4 Leuschner U, Hellstern A. Perkutan-transhepatischeLitholyse (PTL) mit Methyl-tert-Butyl-Ather (MTBE). DerInternist 1988; 29: 788-91.

5 Wosiewitz U, Guldutuna S, Fischer H, Leuschner U. Pigmentgallstone dissolution: solubilization of brown bilirubinateand black polybilirubinate stone material by bufferedsolvents containing EDTA, bile salts, and reducing thiols.ScandJGastroenterol 1989; 24: 373-80.

6 Thistle JL, May GR, Nelson PE, Peine CJ. Dissolution ofcholesterol gallbladder stones using methyl tert-butyl ether.In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids andthe liver. Lancaster, England: MTP Press, 1987: 369-70.

7 Ponchon T, Baroud J, Pujol B, Valette PJ, Perrot D. Renalfailure during dissolution of gallstones by methyl tert-butylether. Lancet 1988; i: 276-7.

8 Tazuma 5, Nakai S, Mizuno S, Saraki H, Horiuchi I,

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Kaiiyama G. A new approach for acute cholecystitis com-bined with rapid dissolution therapy of radiolucent gall-stones using methyl tert-butyl ether (MTBE). Gastro-enterology 1988; 84: A520.

9 Leuschner U, Wurbs D, Baugmartel H, Helm EB, Classen M.Alternating treatment of common bile duct stones with amodified glyceril-l-monooctanoate preparation and a bileacid-EDTA solution by nasobiliary tube. Scand J Gastro-enterol 1981; 16: 497-503.

10 Leuschner U, Wosiewitz U, Baugmartel H, et al. Dissolutionof calcified cholesterol stones and of brown and blackpigment stones of the gallbladder. Digestion 1988; 39: 100-10.

11 Leuschner U, Baumgartel H, Fischer H, David R, LeuschnerM, Hubner K. The dissolution of CBD cholesterol and

pigment stones with methyl tert-butyl ether (MTBE) in vitroand in vivo. [Abstract]. Gastroenterology 1985; 88: 1674.

12 Tritapepe R, DiPadova C, DiPadova F. Methyl tertiary-butylether fails to dissolve cholesterol retained biliary tract stones.[Abstract]. Hepatology 1985; 5: 981.

13 DiPadova C, DiPadova F, Montorsi W, et al. Methyl tert-butyl ether fails to dissolve retained radiolucent commonbile duct stones. Gastroenterology 1986; 91: 1296-300.

14 Teplick StK, Haskin PH, Goldstein RC, et al. Common bileduct stone dissolution with methyl tert-butyl ether:experience with three patients. AJR 1987; 148: 372-4.

15 Thistle JL, May GR, Bender CE, et al. Dissolution ofcholesterol gallbladder stones by methyl tert-butyl etheradministered by percutaneous transhepatic catheter. N EnglJ Med 1989; 320: 633-9.

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