Current Status of Heparin Dissolution of Gallstones Experimental and Clinical Observations Bernard Gardner, MD,’ Brooklyn, New York Charles Ft. Dennis, MD, Brooklyn, New York Joseph Patti, MS, Brooklyn, New York We recently reviewed six successful cases of hepa- rin dissolution of retained common duct stones [1,2]. Since then we have accumulated a larger ex- perience totaling forty-three cases in which there were twelve treatment failures. The purpose of this report is to discuss several aspects of the hep- arin treatment that we consider important and to review the experimental evidence on which the treatment is based. In a previous study [3], we measured the elec- trophoretic movement of particles and determined that bile tends to promote agglomeration of sus- pended particles. Although bile is a better stabiliz- ing fluid than is plasma because of its lower pro- tein content, both minusil particles and dried gall- stone powder develop a zeta potential of -10 to -20 mv in bile [3,4]. The critical level of zeta po- tential is in the range of -5 to -15 mv, since below that level particles will agglomerate and above that level particles will disperse. We did not examine a wide range of human bile but found that in general the zeta potential of mi- nusil particles in different species was directly re- lated to the ease with which they could be made to form gallstones. Many human patients had levels close to zero in undiluted bile, whereas in dogs lev- els averaged -41 mv. Rodents had levels some- what in between. (Figure 1.) If agglomeration of micelles were a step in the formation of gallstones, then any substance that could increase the negative surface charge of the micelle would lead to dispersion in bile and would prevent the development of gallstones. We discov- ered in our previous work on the effect of heparin From the Department of Surgery, State University of New York, Down- state Medical Center, Brooklyn, New York. This work was supported in part by Grant #12-5003 of the John A. Hartford Foundation, Inc. Reprint requests should be addressed to Bernard Gardner, MD, State University of New York, Downstate Medical Center, 450 Clarkson Ave- nue, Brooklyn, New York 11203. *John and Mary R. Markle Scholar in Academic Medicine. on tumor cells that heparin was highly negative and had the tendency to adhere to surfaces, al- tering the zeta potential. The addition of heparin to minusil in bile, for example, produced a marked alteration in zeta potential [3]. A simple experi- ment was set up that involved the precipitation of material from human bile using a positively charged substance (protamine) and its subsequent dissolution by heparin. A few drops of protamine produces prompt precipitation of material in bile (Figure 2A) that can be seen clearly in a centri- fuged specimen (Figure 2B); the subsequent addi- tion of a few drops of undiluted heparin produces a redissolution of the precipate (Figure 2C). This suggested the use of heparin in postoperative pa- tients who had sediment in the drainage from the T tube. We have noted occasional occlusion of the bile ducts by this vbiliary sand, and a flush of heparinized saline seemed an effective method for treating the condition. Recent in vitro experiments [5] have demon- strated the efficacy of heparin alone and in combi- IO v) w 9 i I 8 a 7 VI cl RABBIT HUMAN cl 0 5 IO 15 20 25 30 35 40 45 50 55 60 65 70 75 60 ZETA POTENTIAL Figure 1. The wide variation in zeta potential of minusil particles in bile is species-related. 293 Volume 130, September 1975
Transcript
Current Status of Heparin Dissolution of Gallstones
Experimental and Clinical Observations
Bernard Gardner, MD,’ Brooklyn, New York
Charles Ft. Dennis, MD, Brooklyn, New York
Joseph Patti, MS, Brooklyn, New York
We recently reviewed six successful cases of hepa- rin dissolution of retained common duct stones [1,2]. Since then we have accumulated a larger ex- perience totaling forty-three cases in which there were twelve treatment failures. The purpose of this report is to discuss several aspects of the hep- arin treatment that we consider important and to review the experimental evidence on which the treatment is based.
In a previous study [3], we measured the elec- trophoretic movement of particles and determined that bile tends to promote agglomeration of sus- pended particles. Although bile is a better stabiliz- ing fluid than is plasma because of its lower pro- tein content, both minusil particles and dried gall- stone powder develop a zeta potential of -10 to -20 mv in bile [3,4]. The critical level of zeta po- tential is in the range of -5 to -15 mv, since below that level particles will agglomerate and above that level particles will disperse.
We did not examine a wide range of human bile but found that in general the zeta potential of mi- nusil particles in different species was directly re- lated to the ease with which they could be made to form gallstones. Many human patients had levels close to zero in undiluted bile, whereas in dogs lev- els averaged -41 mv. Rodents had levels some- what in between. (Figure 1.)
If agglomeration of micelles were a step in the formation of gallstones, then any substance that could increase the negative surface charge of the micelle would lead to dispersion in bile and would prevent the development of gallstones. We discov- ered in our previous work on the effect of heparin
From the Department of Surgery, State University of New York, Down- state Medical Center, Brooklyn, New York. This work was supported in part by Grant #12-5003 of the John A. Hartford Foundation, Inc.
Reprint requests should be addressed to Bernard Gardner, MD, State University of New York, Downstate Medical Center, 450 Clarkson Ave- nue, Brooklyn, New York 11203.
*John and Mary R. Markle Scholar in Academic Medicine.
on tumor cells that heparin was highly negative and had the tendency to adhere to surfaces, al- tering the zeta potential. The addition of heparin to minusil in bile, for example, produced a marked alteration in zeta potential [3]. A simple experi- ment was set up that involved the precipitation of material from human bile using a positively charged substance (protamine) and its subsequent dissolution by heparin. A few drops of protamine produces prompt precipitation of material in bile (Figure 2A) that can be seen clearly in a centri- fuged specimen (Figure 2B); the subsequent addi- tion of a few drops of undiluted heparin produces a redissolution of the precipate (Figure 2C). This suggested the use of heparin in postoperative pa- tients who had sediment in the drainage from the T tube. We have noted occasional occlusion of the bile ducts by this vbiliary sand, and a flush of heparinized saline seemed an effective method for treating the condition.
Recent in vitro experiments [5] have demon- strated the efficacy of heparin alone and in combi-
IO v) w 9
i I 8
a 7 VI
cl RABBIT
HUMAN cl
0 5 IO 15 20 25 30 35 40 45 50 55 60 65 70 75 60
ZETA POTENTIAL
Figure 1. The wide variation in zeta potential of minusil particles in bile is species-related.
293 Volume 130, September 1975
Gardner, Dennis, and Patti
.
. * c
A
:“T, t; _-.. -.++ _-M*
-w--u
*-.-c
--.--
- t -7-
i
Figure 2. A, Bile plus protamine produces an immediate precipitate; B, the precipitate can be seen best after centrifuga- ‘tion; C, the addition of protamine to bile produces a precipitate that is redissolved upon addition of heparin.
Figure 3. A case of fragmentation of a stone during intrachoiedochal heparin infusion with subsequent disappearance.
F&we 4. Thrfs patient had three re- tained stones that d&appeared after intrachoiedochai heparin infu- Slon.
294 The American Jcuriml ol Surgery
Dissolution of Gallstones
nation with bile salts for stone dissolution. Frag- mentation of the stone was observed by these in- vestigators, as it was in our own unpublished ob- servations.
We have treated a patient in whom we observed fragmentation of the stones. Figure 3 details the results of treatment with a heparinized saline drip. Our previous experience indicated that this may occur, since several patients reported fleeting back pain, which suggested the passage of stone frag- ments. In some of our patients the common duct stone was large enough to preclude direct passage without fragmentation or complete dissolution [I].
Figure 4 shows results in a patient with multiple retained stones before and after treatment with heparin. We have had three such patients, one with stones proximal to the T tube that disap- peared with treatment.
Our results to date consist of thirty-one patients with successful treatment and twelve with failure. Seven of the twelve who had failure were treated for less than a week and underwent reoperation at that time. Failure of the heparin treatment may be related to an inadequate course, a too solidly com- pacted stone, or heavy calcification.
We recommend the use of heparin, 25,000 units in 250 ml of saline every eight hours, as a constant continuous drip. Cholangitis has not occurred. One patient had bleeding from the T tube after treatment was begun on the sixth postoperative day. Treatment was discontinued and the patient was discharged. After readmission three weeks later and reinstitution of treatment, the stone, demonstrated on cholangiogram one week earlier,
disappeared. No changes in clotting times oc- curred in any patient in whom they were mea- sured.
On the basis of our observations we continue to recommend irrigation of the common duct with heparinized saline for treatment of retained stones as an alternative to early reoperation.
Summary
Investigation of the use of heparin in bile indi- cates that it has the ability to disperse suspended particles. Clinical experience using a heparinized saline flush in forty-three patients with retained gallstones demonstrated disappearance of the stones in thirty-one of the patients. On this basis we would recommend this treatment for further clinical trials in patients with retained common duct stones.
References
1. Gardner 8: Experiences with the use of intracholedochal heparinized saline for the treatment of retained common duct stones. Ann Surg 177: 240, 1973.
2. Gardner B, Ostrowitz A, Masur R: Reappraisal of the possible role of heparin in solution of gallstones: a clinical extension of laboratory studies in removal of retained common duct stones. Surgery 69: 854, 1971.
3. Ostrowltz A, Gardner B: Studies of bile as a suspending medic urn and its relationship to gallstone formation. Surgery 68: 329, 1970.
4. Gardner B: Studies of the zeta Rotential of cells and silica par- ticle in varying concentrations of albumin, calcium, sodium, plasma and bile. J Lab Clin Med 73: 202, 1969.
5. Lahana DA, Bononis 00, Schoenfield LJ: Gallstone dissolution in vitro by bile acids, heparin and quaternary amines. Surg Gynecol Obstet 138: 683, 1974.
