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Effect of Stent Duration on Ureteral Healing Following Endoureterotomy in an Animal Model
0022-534 7/93/1504-1302$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 150, 1302-1305, October 1993 Printed in U. S.A.
EFFECT OF STENT DURATION ON URETERAL HEALING FOLLOWING ENDOURETEROTOMY IN AN ANIMAL MODEL KURT KERBL, PARAMJIT S . CHANDHOKE, ROBERT S. FIGENSHAU, A. MARIKA STONE AND RALPH V. CLAYMAN* From the Department of Surgery, Division of Urology, and the Department of Radiology, Washington University School of Medicine, St. Louis, Missouri ABSTRACT
Ureteral strictures were created in 18 minipigs. Six weeks after stricture inducement, endourologic incision with a balloon cutting device was performed and a 7 F internal polyurethane stent was placed. After this step, 14 pigs remained in the study and were randomized into three different groups depending upon the time when the stent was removed: I, 3 or 6 weeks. Twelve weeks after stricture incision, the pigs were killed, the status of the incised ureteral segment was evaluated histologically, and a healing score was determined. There were no statistically significant overall differences among the mean values of the overall healing score throughout the three different groups. However, when the one-week and the six-week groups (p < .05) were compared with respect to strictures requiring more than one incision due to stricture length greater than 2 centimeters, a more favorable outcome occurred in the 1 week group. Based on these findings it may be reasonable to remove ureteral stents as early as 1 week after endoureterotomy and endopyelotomy. KEY WORDS: ureter; stents; swine, miniature
Due to the rapid development of new techniques and instru ments, a growing number of ureteral strictures or obstructions at the ureteropelvic junction are now treated by endourologic procedures as an alternative to open surgery. 1-4 Shortened hospital stay and a remarkably reduced period of convalescence, as compared with open surgical procedures, strongly favor endourologic treatment of ureteral strictures. Currently despite myriad techniques for incising a ureteral stricture, all endoureterotomies and endopyelotomies share one final pathway: the placement of a ureteral stent to prevent leakage of urine into the retroperitoneum and to facilitate healing of the ureteral wall. 5• 6 The ureteral stent is usually removed after 6 weeks. After Davis n, s innovative work with intubated ureterotomy in 1943, several investigators9-24 conducted studies to examine the ureteral healing process. These reports showed that the longitudinally incised, partially resected canine ureter healed in a patent fashion around a stent with regeneration of both the urothelial and muscular layers. These studies are now 30 to 50 years old. The new endourological procedures have posed many new questions. Presently there are no laboratory or clinical data concerning the histologic changes in a healing ureter after endourologic incision of an ureteral stricture. Accepted for publication April 23, 1993. * Requests for reprints: Department of Surgery, Division of Urologic Surgery, Washington University School of Medicine, 4960 Children's Place, St. Louis, Missouri 631 10. Work supported in part by Applied Medical Resources, Laguna Hills, California.
MATERIALS AND METHODS
After approval of the protocol by the Animal Studies Com mittee of the Washington University School of Medicine, 18 Yucatan minipigs (average age, 8 months; range, 7.5 to 9 months; average weight, 28 kg; range, 27 to 31 kg.) were entered in our study. The study consisted of 4 steps: (1) stricture inducement; (2) incision of stricture; (3) stent removal; and (4) harvest (table 1). Inducement of ureteral stricture. Eighteen minipigs were an esthetized, and flexible cystoscopy was performed. A 0.035-inch Bentson guidewire was passed up both ureters to the renal pelves. A 5 F angiographic catheter was passed over each guidewire and the guidewires were withdrawn. A retrograde ureterogram was performed on both sides (Conray 60, 50:50 diluted with saline and 1 ml. of G.U. irrigant- neomycin sulfate and polymyxin B sulfate- added). In one ureter, usually the. left, the angiographic catheter was exchanged for an 8 F 65cm. Teflon sheath over a 0.035 inch Bentson guidewire. After removal of the guidewire, the Teflon sheath was drawn back to the level of the iliac crest. A 2-cm., 4 flat-wire Segura stone basket was advanced to a point just above the iliac crest, and the wires were exposed from the end of the sheath. The basket was then electrified with 50 watts of coagulation current for 5 seconds for 3 consecutive times. After each activation of the electrocautery the basket was retracted into the Teflon sheath, rotated 45 degrees and then readvanced, opened, and electrified at the same level in the ureter. Following this, a retrograde ureterogram was performed to rule out extravasation; all guide-
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TABLE 1 . Study protocol First Arm (4 pigs)
6 weeks
Second Arm (5 pigs)
6 weeks
Third Arm (5 pigs)
6 weeks
1 week
stricture inducement
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3 weeks
incision of stricture 1302
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1 303
wires and catheters were removed, and the pigs were recovered. Intravenous gentamycin was given preoperatively (2 mg./lb.), and oral sulfamethoxazole (200 mg.) with trimethoprim (40 mg.) was given postoperatively. Incision of ureteral stricture. Six weeks after ureteral injury the 18 minipigs were anesthetized, and cystoscopy was per formed. If possible, a 0.035 inch Bentson guidewire was passed up the strictured ureter to the renal pelvis. Following this a 7 F, 10-cm. long, 5-mm. balloon dilation catheter was advanced over the guidewire until the superior end of the balloon was located above the upper end of the stricture. Next, the balloon, with a pressure gauge attached, was inflated with contrast medium under low pressure (<1 atm.). The diameter of the strictured ureter was measured, as were the length of the stricture and the ureteral diameter 1 cm. above and below the stricture. To correct for the magnifying effect of fluoroscopy, a dime was placed on the pig's abdomen fluoroscopically adjacent to the stricture, and its actual diameter was compared with its radiographic diameter, thereby providing a correction factor. Next, the upper and lower endpoints of the stricture were marked with a clamp on the pig's lower abdomen. After removal of the dilation balloon catheter, the Acucise cutting balloon (8 mm. balloon catheter with a 28 mm. , 150 µm. electrocautery cutting wire) was advanced over the guidewire until it traversed the area marked by the two clamps. Under fluoroscopic control, inflation of the balloon and activation of the cutting wire (100 watts) were done simultaneously for 5 seconds. In strictures longer than 2 cm., the incision was extended by repeating the described cutting maneuver. After removal of the Acucise de vice, a retrograde ureterogram was obtained to check for ex travasation. If no extravasation was seen, the cut was repeated until extravasation was visible. The grade of hydronephrosis, ureteral tortuosity and the number of ureteral bends were noted. Next, a 7 F, 26 cm. internal polyurethane stent was placed. After proper position of the stent was achieved, the pigs were recovered. After incision of ureteral structures, 14 pigs remained in the study and were randomized in consecutive order into 3 different groups. Four pigs were lost to the study, 1 because of a complete stricture and 3 because of technical problems at the time of incision of the stricture that prevented successful completion of the procedure. Removal of internal ureteral stent. Under intravenous seda tion, the ureteral stent was removed in the first group (4 pigs) after 1 week, in the second group (5 pigs) after 3 weeks and in the third group (5 pigs) after 6 weeks. This was accomplished with a flexible cystoscope and a 5 F grasping forceps. Harvest. Twelve weeks after incision of the stricture, cystos copy was performed under general anesthesia. A 0.035 inch Bentson guidewire was passed up the incised ureter and a 7 F, 5 mm./10 cm. dilation balloon catheter was used to calibrate the incised area of the ureter under low pressure (up to 1 atm.) in order to check for any persistent or recurrent stricture. Following this a retrograde ureterogram was performed to document ureteral tortuosity and ureteral bends and to define the grade of hydronephrosis, if present. Next, the pigs were killed with a lethal dose of intravenous potassium chloride. Via a laparotomy, the endosurgically operated ureter was identified; any macroscopic changes (adhesions, fibrotic tissue, or narrowing of the ureter) were noted and recorded. Then, the ureter was removed in its entirety. The ureter was incised longitudinally; a specimen was obtained from the center of the incised area and sent for histologic examination. Cross-sections were stained with hematoxylin and eosin. Histologic sections were reviewed by the same pathologist. A healing · score was developed which included: (1) urothelial resurfacing; (2) degree of mural inflammation; (3) fibrosis in the lamina propria; (4) fibrosis in the muscle layer; and (5) integrity of musculature. Scores (O = normal to 3 = worst effect) were assigned in each category, thus creating a total relative healing score ranging from O to 15. The mean values of the overall healing scores
1304
EFFECT OF STENT DURATION AFTER ENDOURETEROTOMY TABLE 3 .
Stent Duration 1 week 3 weeks 6 weeks
# of Animals 4 5 5
1. Urothelial Resurfacing 0.88 0.88 0.80
TABLE 4.
# of Stent Animals Duration 3 1 week 2 3 weeks 2 6 weeks * p < .05: 1 week vs. 6 weeks.
1. U rothelial Resurfacing 0.66 0.75 2.00
Healing scores: all study animals
3. Lamina Propria Fibrosis 1.88 1.75 1.50
2. Mural Inflammation 0,38 0.38 0.20
5. Musculature Integrity 1.13 1.75 2.30
Total Healing Score (1 5) 5.5 (range: 4-6) 6.5 (range: 5.5-8) 6.8 (range: 5 9.5)
5. Musculature Integrity 1.16 1.50 2.50
Total Healing Score (1 5) 5.16 (range: 4-6)* 6.00 (range: 5.5-6.5) 8.00 (range: 7.5 8.5)
Healing scores: two activations
2. Mural Inflammation 0.50 0.25 0.25
3. Lamina Propria Fibrosis 1.83 2.00 1.50
were compared using t tests. All tests were performed using a two-tailed p value of .05. RESULTS
At the time of incision, the 14 pigs had a mean stricture length of 23.7 mm. (range: 4.8 to 43.7 mm.) . Strictures were seen in 13 pigs. In pig number 5, no significant narrowing of the ureter was visible; however, a 34 mm. aperistaltic segment of ureter was present on fluoroscopic retrograde ureterography at the level at which stricture inducement occurred. Grade I hydronephrosis was seen in 10 pigs, one pig had grade II hydronephrosis and 3 pigs showed no hydronephrotic changes of the pelvicocaliceal system (table 2) . At the time of harvest, no stricture was present in any of the 14 pigs: 7 pigs had no hydronephrosis, grade I hydronephrosis was seen in 4 pigs and grade II hydronephrosis occurred in 3 pigs. In 7 pigs the Acucise balloon cutting device was activated only once, whereas in another 7 pigs the stricture length (mean: 30.91 .mm.) required more than one activation (2 in 6 pigs, 3 in one pig; table 2) . Of the pigs that required more than one cut two had a stent duration of 6 weeks, two for 3 weeks and thre� for 1 week. Histologic examination of the specimens obtained from the center of the incised stricture revealed a mean value of the overall healing score of 5.5 in the 1 week group, 6.5 in the 3 wee� group and 6.8 in the 6 week group. Among the 7 pigs that required more than 1 incision, the mean healing scores were 5.16 (1-week group), 6 (3-week group), and 8 (6-week group). The mean values of the different groups were compared using t-tests (table 3). All tests were performed using a two tailed p �alue o_f .05. All pigs were used in the first analysis. No signif icant differences were noted. Pigs with strictures that required more than 1 cut were also analyzed separately (table 4). A significant difference in the healing scores was found between the 1-week and 6-week group (p < .05) . DISCUSSION
4. Muscle Fibrosis 1.25 1.75 2.00
To create a biological model of ureteral stricture that resem bles the human patient as closely as possible, we used female Yucatan minipigs for our study. In these animals, whose mean weight is 28 kg. the upper urinary tract is almost identical to the urinary tract of a 70 kg. human. 25 In contradistinction to female farm pigs, which also possess multiple calyces that funnel into the ureteropelvic junction, the minipigs have a trigone more closely resembling that of the human. Also in minipigs, but not in farm pigs, there is a significant amount of ret�operitoneal fat arou�d the ureter as well as the kidney; agam the presence of penureteral and perirenal fat more closely mimics the human anatomy. In our efforts to create authentic ureteral strictures we employed a stricture model previously developed in our l�bo ratory in farm pigs. 26 We sought a stricture that could be bypassed by a guidewire and catheter assembly. In the past,
4. Muscle Fibrosis 1.00 1.50 2.25
clinical observations after endopyelotomy have indicated that in term� of treatment success, shorter stent duration (4 days, cases) 1s comparable to longer stent duration (5 weeks, 2 27 ?ases) ; shorter stent duration (3 weeks,28 113 cases) might even mfluence the outcome more favorably. So far, neither a lab oratory study examining the effect of stent duration after endoureterotomy on ureteral healing at a histologic level nor a � r� spectively �ando�ized clinical study has been reported. De fmmg the . optimal time for stent duration is of clinical impor tance, as mternal ureteral stents may cause or be associated with various problems, ranging from mere discomfort, ureteral edema and asymptomatic urinary tract infections to more seriou� �linical problems such as significant hematu�ia, pyelo nephnt1s and, rarely, urosepsis. 29-3 1 No statistical difference was found when the mean values of the overall healing scores were compared at 1, 3, or 6 weeks. Also there was no noticeable difference in postoperative hydro nephrosis, periureteral fibrosis, or ureteral tortuosity among the 3 groups at the time of ureteral harvest. No benefits were noted from following the current clinical practice of leaving a ureteral stent in place for 6 weeks after endoureterotomy or endopyelotomy. 32 Interestingly, the overall healing scores at 1 week (? ,5) were ?etter than at 3 or 6 weeks (6.5 and 6.8), suggestmg a possible favorable trend with shorter stent dura tion .. Also, when longer strictures (mean: 30.91 mm.) were studied as a separate category, a statistically significant favor able effect was noted for the 1-week group as opposed to the 6 week group. Perhaps the inflammation associated with a chronic (that is, 6 week) indwelling stent is a source of late fibrosis. From our data, it would appear in the pig that a stent duration of 6 weeks may be more harmful than beneficial. A stent duration of only 1 week may be sufficient. Whether these findings apply for endoureterotomy or endopyelotomy in the clinical situation is a question currently under investigation.
5
REFERENCES 1. Clayman, R. V. and Kavoussi, L. R.: Endosurgical techniques for noncalculous disease. In: Campbell's Urology, 6th ed. Edited by P. C. Walsh, A. B. Retik, T. A. Stamey and E. D. Vaughan. Philadelphia: W. B. Saunders Co., pp. 2268-2288, 1992. 2. Smith, A. D.: Management of iatrogenic ureteral strictures after urological procedures. J. Urol., 140: 1372, 1988. 3. Van Cangh, P. J., Jorion, J. L., Wese, F. X. and Opsomer, R. J.: Endoureteropyelotomy: percutaneous treatment of ureteropelvic junction obstruction. J. Urol., 141: 1317, 1989. 4. Meretyk, I., Meretyk, S. and Clayman, R. V.: Endopyelotomy: comparison of ureteroscopic retrograde and antegrade percuta neous techniques. J. Urol., 148: 775, 1992. 5. Clayman, R. V., Basler, J. W., Kavoussi, L. and Picus, D. D.: Ureteronephroscopic endopyelotomy. J. Urol., 144: 246, 1990. 6. Denstedt, J. D.: The endosurgical alternative for upper-tract ob struction. Contemporary Urology, January 19, 1991. 7. Davis, D. M.: Intubated ureterotomy. Surg. Gynecol. Obstet., 76: 513, 1943.
EFFECT OF STENT DURATION AFTER ENDOURETEROTOMY 8. Davis, D. M., Strong, G. H. and Drake, W. M.: Intubated ure.ter otomy: experimental work and clinical results. J. Urol., 59: 851, 1948. 9. Trautner, K. and Raaschou, F.: Histologic examination of the regeneration of the ureter in dogs after intubated ureterotomy. J. Urol., 71: 274, 1954. 10. Weaver, R. G. and Henderson, J. H.: Ureteral regeneration: exper imental and clinical. J. Urol., 72: 350, 1954. 11. Lapides, J., and Caffery, E . L.: Observations on healing of ureteral muscle: relationship to intubated ureterotomy. J. Urol., 73: 47, 1955. 12. Boyarsky, S. and Duque, 0.: Ureteral regeneration in dogs: an experimental study bearing on the Davis intubated ureterotomy. J. Urol., 73: 53, 1955. 13. Oppenheimer, R. and Hinman, F.: Ureteral regeneration: contrac tive vs. hyperplasia of smooth muscle. J. Urol., 74: 476, 1955. 14. Hamm, F. C. and Weinberg, S. R.: Experimental studies of regen eration of the ureter without intubation. J. Urol., 75: 43, 1956. 15. Hinman, F., Jr. and Oppenheimer, R.: Smooth muscle regeneration in repair of experimental ureteral defects: the significance of the double lumen. J. Urol., 75: 428, 1956. 16. Hinman, F., Jr. and Oppenheimer, R. 0. F.: Ureteral regeneration: IV. Fascia! covering compared with fatty connective tissue. J. Urol., 76: 729, 1956. 17. Oppenheimer, R. 0. F. and Hinman, F., Jr.: The effect of urinary flow upon ureteral regeneration in the absence of splint. Surg. Gynecol. Obst., 103: 416, 1956. 18. Hinman, F., Jr. and Oppenheimer, R.: Ureteral regeneration: V. Eversion of the entire wall. Surgery, 42: 276, 1957. 19. Hinman, F., Jr. and Oppenheimer, R.: Ureteral regeneration: VI. Delayed urinary flow in the healing of unsplinted ureteral de fects. J. Urol., 78: 138, 1957. 20. Weaver, R. G.: Ureteral regeneration: experimental and clinical: part II. J. Urol., 77: 164, 1957.
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21. Davis, D. M.: The process of ureteral repair; a recapitulation of the splinting question. J. Urol., 79: 215, 1958. 22. McDonald, J. H. and Calams, J. A.:Experimental ureteral stricture: ureteral regrowth following ureterotomy with and without intu bation. J. Urol., 84: 52, 1960. 23. Mahoney, S. A., Koletsky, S. and Persky, L.: Approximation and dilatation: the mode of healing of an unintubated ureterostomy. J. Urol., 88: 192, 1962. 24. Cordonnier, J. J. and Roane, J. S.: Ureteral splinting: an experi mental evaluation of prolonged ureteral splinting. Surg. Clin. North Am., 30: 1523, 1950. 25. Schwalb, D., Eshghi, M., Cord, J ., Evans, R., Braga, E., Franco, I., Durso, I. and Addonizio, J. C.: The minipig as a practical endo urological model. J. Endourol., 3: 85, 1989. 26. Figenshau, R. S., Stone, A. M., Clayman, R. V., and Wick, M. R.: Endoureterotomy in an animate model: comparison of electro surgical, mechanical and balloon treatment modalities. J. Urol., 147: 470A, 1992. 27. Abdel-Hakim, A. M.: Endopyelotomy for ureteropelvic junction obstruction: is long-term stenting mandatory? J. Endourol., 1: 265, 1987. 28. Kuenkel, M. and Korth, K.: Endopyelotomy: long-term follow-up of 143 patients. J. Endourol., 4: 109, 1990. 29. Saltzman, B.: Ureteral stents: indications, variations and compli cations. Urol. Clin. North Am., 15: 481, 1988. 30. McDougall,E. M., Denstedt, J. D. and Clayman, R. V.: Comparison of patient acceptance of polyurethane vs. silicone indwelling ureteral stents. J. Endourol., 4: 79, 1990. 31. Marx, M., Bettmann, M. A., Bridge, S., Brodsky, G., Boxt, L. M. and Richie, J. P.: The effects of various indwelling ureteral catheter materials on the normal canine ureter. J. Urol., 139: 180, 1988. 32. Badlani, G., Karlin, G. and Smith, A. D.: Complications of endo pyelotomy: analysis in series of 64 patients. J. Urol., 140: 473, 1988.
Vol. 150, 1302-1305, October 1993 Printed in U. S.A.
EFFECT OF STENT DURATION ON URETERAL HEALING FOLLOWING ENDOURETEROTOMY IN AN ANIMAL MODEL KURT KERBL, PARAMJIT S . CHANDHOKE, ROBERT S. FIGENSHAU, A. MARIKA STONE AND RALPH V. CLAYMAN* From the Department of Surgery, Division of Urology, and the Department of Radiology, Washington University School of Medicine, St. Louis, Missouri ABSTRACT
Ureteral strictures were created in 18 minipigs. Six weeks after stricture inducement, endourologic incision with a balloon cutting device was performed and a 7 F internal polyurethane stent was placed. After this step, 14 pigs remained in the study and were randomized into three different groups depending upon the time when the stent was removed: I, 3 or 6 weeks. Twelve weeks after stricture incision, the pigs were killed, the status of the incised ureteral segment was evaluated histologically, and a healing score was determined. There were no statistically significant overall differences among the mean values of the overall healing score throughout the three different groups. However, when the one-week and the six-week groups (p < .05) were compared with respect to strictures requiring more than one incision due to stricture length greater than 2 centimeters, a more favorable outcome occurred in the 1 week group. Based on these findings it may be reasonable to remove ureteral stents as early as 1 week after endoureterotomy and endopyelotomy. KEY WORDS: ureter; stents; swine, miniature
Due to the rapid development of new techniques and instru ments, a growing number of ureteral strictures or obstructions at the ureteropelvic junction are now treated by endourologic procedures as an alternative to open surgery. 1-4 Shortened hospital stay and a remarkably reduced period of convalescence, as compared with open surgical procedures, strongly favor endourologic treatment of ureteral strictures. Currently despite myriad techniques for incising a ureteral stricture, all endoureterotomies and endopyelotomies share one final pathway: the placement of a ureteral stent to prevent leakage of urine into the retroperitoneum and to facilitate healing of the ureteral wall. 5• 6 The ureteral stent is usually removed after 6 weeks. After Davis n, s innovative work with intubated ureterotomy in 1943, several investigators9-24 conducted studies to examine the ureteral healing process. These reports showed that the longitudinally incised, partially resected canine ureter healed in a patent fashion around a stent with regeneration of both the urothelial and muscular layers. These studies are now 30 to 50 years old. The new endourological procedures have posed many new questions. Presently there are no laboratory or clinical data concerning the histologic changes in a healing ureter after endourologic incision of an ureteral stricture. Accepted for publication April 23, 1993. * Requests for reprints: Department of Surgery, Division of Urologic Surgery, Washington University School of Medicine, 4960 Children's Place, St. Louis, Missouri 631 10. Work supported in part by Applied Medical Resources, Laguna Hills, California.
MATERIALS AND METHODS
After approval of the protocol by the Animal Studies Com mittee of the Washington University School of Medicine, 18 Yucatan minipigs (average age, 8 months; range, 7.5 to 9 months; average weight, 28 kg; range, 27 to 31 kg.) were entered in our study. The study consisted of 4 steps: (1) stricture inducement; (2) incision of stricture; (3) stent removal; and (4) harvest (table 1). Inducement of ureteral stricture. Eighteen minipigs were an esthetized, and flexible cystoscopy was performed. A 0.035-inch Bentson guidewire was passed up both ureters to the renal pelves. A 5 F angiographic catheter was passed over each guidewire and the guidewires were withdrawn. A retrograde ureterogram was performed on both sides (Conray 60, 50:50 diluted with saline and 1 ml. of G.U. irrigant- neomycin sulfate and polymyxin B sulfate- added). In one ureter, usually the. left, the angiographic catheter was exchanged for an 8 F 65cm. Teflon sheath over a 0.035 inch Bentson guidewire. After removal of the guidewire, the Teflon sheath was drawn back to the level of the iliac crest. A 2-cm., 4 flat-wire Segura stone basket was advanced to a point just above the iliac crest, and the wires were exposed from the end of the sheath. The basket was then electrified with 50 watts of coagulation current for 5 seconds for 3 consecutive times. After each activation of the electrocautery the basket was retracted into the Teflon sheath, rotated 45 degrees and then readvanced, opened, and electrified at the same level in the ureter. Following this, a retrograde ureterogram was performed to rule out extravasation; all guide-
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TABLE 1 . Study protocol First Arm (4 pigs)
6 weeks
Second Arm (5 pigs)
6 weeks
Third Arm (5 pigs)
6 weeks
1 week
stricture inducement
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3 weeks
incision of stricture 1302
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1 303
wires and catheters were removed, and the pigs were recovered. Intravenous gentamycin was given preoperatively (2 mg./lb.), and oral sulfamethoxazole (200 mg.) with trimethoprim (40 mg.) was given postoperatively. Incision of ureteral stricture. Six weeks after ureteral injury the 18 minipigs were anesthetized, and cystoscopy was per formed. If possible, a 0.035 inch Bentson guidewire was passed up the strictured ureter to the renal pelvis. Following this a 7 F, 10-cm. long, 5-mm. balloon dilation catheter was advanced over the guidewire until the superior end of the balloon was located above the upper end of the stricture. Next, the balloon, with a pressure gauge attached, was inflated with contrast medium under low pressure (<1 atm.). The diameter of the strictured ureter was measured, as were the length of the stricture and the ureteral diameter 1 cm. above and below the stricture. To correct for the magnifying effect of fluoroscopy, a dime was placed on the pig's abdomen fluoroscopically adjacent to the stricture, and its actual diameter was compared with its radiographic diameter, thereby providing a correction factor. Next, the upper and lower endpoints of the stricture were marked with a clamp on the pig's lower abdomen. After removal of the dilation balloon catheter, the Acucise cutting balloon (8 mm. balloon catheter with a 28 mm. , 150 µm. electrocautery cutting wire) was advanced over the guidewire until it traversed the area marked by the two clamps. Under fluoroscopic control, inflation of the balloon and activation of the cutting wire (100 watts) were done simultaneously for 5 seconds. In strictures longer than 2 cm., the incision was extended by repeating the described cutting maneuver. After removal of the Acucise de vice, a retrograde ureterogram was obtained to check for ex travasation. If no extravasation was seen, the cut was repeated until extravasation was visible. The grade of hydronephrosis, ureteral tortuosity and the number of ureteral bends were noted. Next, a 7 F, 26 cm. internal polyurethane stent was placed. After proper position of the stent was achieved, the pigs were recovered. After incision of ureteral structures, 14 pigs remained in the study and were randomized in consecutive order into 3 different groups. Four pigs were lost to the study, 1 because of a complete stricture and 3 because of technical problems at the time of incision of the stricture that prevented successful completion of the procedure. Removal of internal ureteral stent. Under intravenous seda tion, the ureteral stent was removed in the first group (4 pigs) after 1 week, in the second group (5 pigs) after 3 weeks and in the third group (5 pigs) after 6 weeks. This was accomplished with a flexible cystoscope and a 5 F grasping forceps. Harvest. Twelve weeks after incision of the stricture, cystos copy was performed under general anesthesia. A 0.035 inch Bentson guidewire was passed up the incised ureter and a 7 F, 5 mm./10 cm. dilation balloon catheter was used to calibrate the incised area of the ureter under low pressure (up to 1 atm.) in order to check for any persistent or recurrent stricture. Following this a retrograde ureterogram was performed to document ureteral tortuosity and ureteral bends and to define the grade of hydronephrosis, if present. Next, the pigs were killed with a lethal dose of intravenous potassium chloride. Via a laparotomy, the endosurgically operated ureter was identified; any macroscopic changes (adhesions, fibrotic tissue, or narrowing of the ureter) were noted and recorded. Then, the ureter was removed in its entirety. The ureter was incised longitudinally; a specimen was obtained from the center of the incised area and sent for histologic examination. Cross-sections were stained with hematoxylin and eosin. Histologic sections were reviewed by the same pathologist. A healing · score was developed which included: (1) urothelial resurfacing; (2) degree of mural inflammation; (3) fibrosis in the lamina propria; (4) fibrosis in the muscle layer; and (5) integrity of musculature. Scores (O = normal to 3 = worst effect) were assigned in each category, thus creating a total relative healing score ranging from O to 15. The mean values of the overall healing scores
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EFFECT OF STENT DURATION AFTER ENDOURETEROTOMY TABLE 3 .
Stent Duration 1 week 3 weeks 6 weeks
# of Animals 4 5 5
1. Urothelial Resurfacing 0.88 0.88 0.80
TABLE 4.
# of Stent Animals Duration 3 1 week 2 3 weeks 2 6 weeks * p < .05: 1 week vs. 6 weeks.
1. U rothelial Resurfacing 0.66 0.75 2.00
Healing scores: all study animals
3. Lamina Propria Fibrosis 1.88 1.75 1.50
2. Mural Inflammation 0,38 0.38 0.20
5. Musculature Integrity 1.13 1.75 2.30
Total Healing Score (1 5) 5.5 (range: 4-6) 6.5 (range: 5.5-8) 6.8 (range: 5 9.5)
5. Musculature Integrity 1.16 1.50 2.50
Total Healing Score (1 5) 5.16 (range: 4-6)* 6.00 (range: 5.5-6.5) 8.00 (range: 7.5 8.5)
Healing scores: two activations
2. Mural Inflammation 0.50 0.25 0.25
3. Lamina Propria Fibrosis 1.83 2.00 1.50
were compared using t tests. All tests were performed using a two-tailed p value of .05. RESULTS
At the time of incision, the 14 pigs had a mean stricture length of 23.7 mm. (range: 4.8 to 43.7 mm.) . Strictures were seen in 13 pigs. In pig number 5, no significant narrowing of the ureter was visible; however, a 34 mm. aperistaltic segment of ureter was present on fluoroscopic retrograde ureterography at the level at which stricture inducement occurred. Grade I hydronephrosis was seen in 10 pigs, one pig had grade II hydronephrosis and 3 pigs showed no hydronephrotic changes of the pelvicocaliceal system (table 2) . At the time of harvest, no stricture was present in any of the 14 pigs: 7 pigs had no hydronephrosis, grade I hydronephrosis was seen in 4 pigs and grade II hydronephrosis occurred in 3 pigs. In 7 pigs the Acucise balloon cutting device was activated only once, whereas in another 7 pigs the stricture length (mean: 30.91 .mm.) required more than one activation (2 in 6 pigs, 3 in one pig; table 2) . Of the pigs that required more than one cut two had a stent duration of 6 weeks, two for 3 weeks and thre� for 1 week. Histologic examination of the specimens obtained from the center of the incised stricture revealed a mean value of the overall healing score of 5.5 in the 1 week group, 6.5 in the 3 wee� group and 6.8 in the 6 week group. Among the 7 pigs that required more than 1 incision, the mean healing scores were 5.16 (1-week group), 6 (3-week group), and 8 (6-week group). The mean values of the different groups were compared using t-tests (table 3). All tests were performed using a two tailed p �alue o_f .05. All pigs were used in the first analysis. No signif icant differences were noted. Pigs with strictures that required more than 1 cut were also analyzed separately (table 4). A significant difference in the healing scores was found between the 1-week and 6-week group (p < .05) . DISCUSSION
4. Muscle Fibrosis 1.25 1.75 2.00
To create a biological model of ureteral stricture that resem bles the human patient as closely as possible, we used female Yucatan minipigs for our study. In these animals, whose mean weight is 28 kg. the upper urinary tract is almost identical to the urinary tract of a 70 kg. human. 25 In contradistinction to female farm pigs, which also possess multiple calyces that funnel into the ureteropelvic junction, the minipigs have a trigone more closely resembling that of the human. Also in minipigs, but not in farm pigs, there is a significant amount of ret�operitoneal fat arou�d the ureter as well as the kidney; agam the presence of penureteral and perirenal fat more closely mimics the human anatomy. In our efforts to create authentic ureteral strictures we employed a stricture model previously developed in our l�bo ratory in farm pigs. 26 We sought a stricture that could be bypassed by a guidewire and catheter assembly. In the past,
4. Muscle Fibrosis 1.00 1.50 2.25
clinical observations after endopyelotomy have indicated that in term� of treatment success, shorter stent duration (4 days, cases) 1s comparable to longer stent duration (5 weeks, 2 27 ?ases) ; shorter stent duration (3 weeks,28 113 cases) might even mfluence the outcome more favorably. So far, neither a lab oratory study examining the effect of stent duration after endoureterotomy on ureteral healing at a histologic level nor a � r� spectively �ando�ized clinical study has been reported. De fmmg the . optimal time for stent duration is of clinical impor tance, as mternal ureteral stents may cause or be associated with various problems, ranging from mere discomfort, ureteral edema and asymptomatic urinary tract infections to more seriou� �linical problems such as significant hematu�ia, pyelo nephnt1s and, rarely, urosepsis. 29-3 1 No statistical difference was found when the mean values of the overall healing scores were compared at 1, 3, or 6 weeks. Also there was no noticeable difference in postoperative hydro nephrosis, periureteral fibrosis, or ureteral tortuosity among the 3 groups at the time of ureteral harvest. No benefits were noted from following the current clinical practice of leaving a ureteral stent in place for 6 weeks after endoureterotomy or endopyelotomy. 32 Interestingly, the overall healing scores at 1 week (? ,5) were ?etter than at 3 or 6 weeks (6.5 and 6.8), suggestmg a possible favorable trend with shorter stent dura tion .. Also, when longer strictures (mean: 30.91 mm.) were studied as a separate category, a statistically significant favor able effect was noted for the 1-week group as opposed to the 6 week group. Perhaps the inflammation associated with a chronic (that is, 6 week) indwelling stent is a source of late fibrosis. From our data, it would appear in the pig that a stent duration of 6 weeks may be more harmful than beneficial. A stent duration of only 1 week may be sufficient. Whether these findings apply for endoureterotomy or endopyelotomy in the clinical situation is a question currently under investigation.
5
REFERENCES 1. Clayman, R. V. and Kavoussi, L. R.: Endosurgical techniques for noncalculous disease. In: Campbell's Urology, 6th ed. Edited by P. C. Walsh, A. B. Retik, T. A. Stamey and E. D. Vaughan. Philadelphia: W. B. Saunders Co., pp. 2268-2288, 1992. 2. Smith, A. D.: Management of iatrogenic ureteral strictures after urological procedures. J. Urol., 140: 1372, 1988. 3. Van Cangh, P. J., Jorion, J. L., Wese, F. X. and Opsomer, R. J.: Endoureteropyelotomy: percutaneous treatment of ureteropelvic junction obstruction. J. Urol., 141: 1317, 1989. 4. Meretyk, I., Meretyk, S. and Clayman, R. V.: Endopyelotomy: comparison of ureteroscopic retrograde and antegrade percuta neous techniques. J. Urol., 148: 775, 1992. 5. Clayman, R. V., Basler, J. W., Kavoussi, L. and Picus, D. D.: Ureteronephroscopic endopyelotomy. J. Urol., 144: 246, 1990. 6. Denstedt, J. D.: The endosurgical alternative for upper-tract ob struction. Contemporary Urology, January 19, 1991. 7. Davis, D. M.: Intubated ureterotomy. Surg. Gynecol. Obstet., 76: 513, 1943.
EFFECT OF STENT DURATION AFTER ENDOURETEROTOMY 8. Davis, D. M., Strong, G. H. and Drake, W. M.: Intubated ure.ter otomy: experimental work and clinical results. J. Urol., 59: 851, 1948. 9. Trautner, K. and Raaschou, F.: Histologic examination of the regeneration of the ureter in dogs after intubated ureterotomy. J. Urol., 71: 274, 1954. 10. Weaver, R. G. and Henderson, J. H.: Ureteral regeneration: exper imental and clinical. J. Urol., 72: 350, 1954. 11. Lapides, J., and Caffery, E . L.: Observations on healing of ureteral muscle: relationship to intubated ureterotomy. J. Urol., 73: 47, 1955. 12. Boyarsky, S. and Duque, 0.: Ureteral regeneration in dogs: an experimental study bearing on the Davis intubated ureterotomy. J. Urol., 73: 53, 1955. 13. Oppenheimer, R. and Hinman, F.: Ureteral regeneration: contrac tive vs. hyperplasia of smooth muscle. J. Urol., 74: 476, 1955. 14. Hamm, F. C. and Weinberg, S. R.: Experimental studies of regen eration of the ureter without intubation. J. Urol., 75: 43, 1956. 15. Hinman, F., Jr. and Oppenheimer, R.: Smooth muscle regeneration in repair of experimental ureteral defects: the significance of the double lumen. J. Urol., 75: 428, 1956. 16. Hinman, F., Jr. and Oppenheimer, R. 0. F.: Ureteral regeneration: IV. Fascia! covering compared with fatty connective tissue. J. Urol., 76: 729, 1956. 17. Oppenheimer, R. 0. F. and Hinman, F., Jr.: The effect of urinary flow upon ureteral regeneration in the absence of splint. Surg. Gynecol. Obst., 103: 416, 1956. 18. Hinman, F., Jr. and Oppenheimer, R.: Ureteral regeneration: V. Eversion of the entire wall. Surgery, 42: 276, 1957. 19. Hinman, F., Jr. and Oppenheimer, R.: Ureteral regeneration: VI. Delayed urinary flow in the healing of unsplinted ureteral de fects. J. Urol., 78: 138, 1957. 20. Weaver, R. G.: Ureteral regeneration: experimental and clinical: part II. J. Urol., 77: 164, 1957.
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21. Davis, D. M.: The process of ureteral repair; a recapitulation of the splinting question. J. Urol., 79: 215, 1958. 22. McDonald, J. H. and Calams, J. A.:Experimental ureteral stricture: ureteral regrowth following ureterotomy with and without intu bation. J. Urol., 84: 52, 1960. 23. Mahoney, S. A., Koletsky, S. and Persky, L.: Approximation and dilatation: the mode of healing of an unintubated ureterostomy. J. Urol., 88: 192, 1962. 24. Cordonnier, J. J. and Roane, J. S.: Ureteral splinting: an experi mental evaluation of prolonged ureteral splinting. Surg. Clin. North Am., 30: 1523, 1950. 25. Schwalb, D., Eshghi, M., Cord, J ., Evans, R., Braga, E., Franco, I., Durso, I. and Addonizio, J. C.: The minipig as a practical endo urological model. J. Endourol., 3: 85, 1989. 26. Figenshau, R. S., Stone, A. M., Clayman, R. V., and Wick, M. R.: Endoureterotomy in an animate model: comparison of electro surgical, mechanical and balloon treatment modalities. J. Urol., 147: 470A, 1992. 27. Abdel-Hakim, A. M.: Endopyelotomy for ureteropelvic junction obstruction: is long-term stenting mandatory? J. Endourol., 1: 265, 1987. 28. Kuenkel, M. and Korth, K.: Endopyelotomy: long-term follow-up of 143 patients. J. Endourol., 4: 109, 1990. 29. Saltzman, B.: Ureteral stents: indications, variations and compli cations. Urol. Clin. North Am., 15: 481, 1988. 30. McDougall,E. M., Denstedt, J. D. and Clayman, R. V.: Comparison of patient acceptance of polyurethane vs. silicone indwelling ureteral stents. J. Endourol., 4: 79, 1990. 31. Marx, M., Bettmann, M. A., Bridge, S., Brodsky, G., Boxt, L. M. and Richie, J. P.: The effects of various indwelling ureteral catheter materials on the normal canine ureter. J. Urol., 139: 180, 1988. 32. Badlani, G., Karlin, G. and Smith, A. D.: Complications of endo pyelotomy: analysis in series of 64 patients. J. Urol., 140: 473, 1988.