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Pelvic adhesion formation after intraperitoneal installation of gallstones in a rabbit model
FERTILITY AND STERILITY威 VOL. 72, NO. 5, NOVEMBER 1999
SURGERY
Copyright ©1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Pelvic adhesion formation after intraperitoneal installation of gallstones in a rabbit model Keith A. Hansen, M.D.,* Leah Lowman, M.D.,† Eric P. Fiedler, M.D.,‡ Sandra P. T. Tho, M.D.,* Robert Martindale, M.D., Ph.D.,§ and Paul G. McDonough, M.D.* Medical College of Georgia, Augusta, Women’s Health Care Specialists of Georgia, Athens, Georgia; and National Fertility Center of Texas, Dallas, Texas
Received January 4, 1998; revised and accepted June 18, 1999. Presented at the16th World Congress on Fertility and Sterility and 54th Annual Meeting of the American Society of Reproductive Medicine, San Francisco, California, October 4, 1998. Reprint requests and present address: Keith A. Hansen, M.D., Department of Obstetrics and Gynecology, University of South Dakota School of Medicine, 1400 West 22nd Street, Sioux Falls, South Dakota 57105 (FAX: 605357-1528; E- mail: [email protected]). * Department of Obstetrics and Gynecology, Medical College of Georgia. † Women’s Health Care Specialists of Georgia. ‡ National Fertility Center of Texas. § Department of General Surgery, Medical College of Georgia. 0015-0282/99/$20.00 PII S0015-0282(99)00398-2
868
Objective: To investigate whether intraperitoneal gallstones increase the risk of pelvic adhesions in a rabbit model. Design: Prospective, randomized, blinded, sham and human antigen controlled trial. Setting: An academic research environment. Subject(s): Twelve New Zealand white rabbits. Intervention(s): Twelve rabbits were divided into three groups of four each; a sham operation group, a gallstone and bile group (study group), and a human serum albumin and bile group (antigenic control). Three weeks after the operation individual subjects were randomized, with groups concealed to observers, and a necropsy was performed on each rabbit. Main Outcome Measurement(s): Necropsy was performed on each rabbit, and the adhesions were scored for extent, type, tenacity, inflammation, and gallstone involvement. Result(s): There was a statistically and biologically significant increase in gallstone involvement in adhesions, especially pelvic adhesions, in the study group. Conclusion(s): This study, along with an increasing number of case reports, suggests that gallstones inadvertently left in the peritoneal cavity may increase the morbidity of laparoscopic cholecystectomy. In females of reproductive age these gallstones may induce pelvic adhesions that may interfere with fertility or be associated with pelvic pain. (Fertil Steril威 1999;72:868 –72. ©1999 by American Society for Reproductive Medicine.) Key Words: Intraperitoneal gallstones, laparoscopic cholecystectomy, pelvic adhesion
Cholelithiasis affects more than 20 million individuals in the United States (1). Cholecystectomy is the third most common operation performed in the United States and is the treatment of choice in gallstone disease. Charles Filipi performed the first laparoscopic cholecystectomy in a dog in the early 1980s; Mouret was the first to perform this laparoscopic operation in humans in 1987 (2). Since the late 1980s laparoscopic cholecystectomy has become the most common method for treatment of symptomatic patients. Laparoscopy offers several advantages over open cholecystectomy, including decreased hospital stay, better patient tolerance, less postoperative pain, earlier return to work, and better cosmesis (3).
Perforation of the gallbladder occurs in 30% with spillage of gallstones in 20% of laparoscopic cholecystectomies (4). Most surgeons leave inadvertently spilled gallstones because of the impression that they do not increase morbidity of the operation. Using a rat model, Cline et al. (5) demonstrated no increase in adhesions in a group of rats where gallstones were placed in the peritoneal cavity compared with controls. More than 20 case reports describe complications arising from intraperitoneal gallstones left after laparoscopic cholecystectomy. These complications include abdominal abscesses (6), erosion into the sigmoid colon (7), fistulas (8), and granuloma formation (9). More un-
usual complications include gallstones lodged in a femoral hernia mimicking an incarcerated hernia (10), cholelithoptysis hypothesized to be due to transdiaphragmatic extension of an intraperitoneal abscess (11, 12), and two cases of ovarian cholelithiasis (13, 14). The increasing number of reported complications related to spilled gallstones raises the question of the importance of retrieving gallstones lost during laparoscopic cholecystectomy. This study was performed to determine if intraperitoneal gallstones will increase adhesions in a rabbit model.
TABLE 1 Clinical scoring of intraperitoneal adhesions and gallstones. Variable Extent of the adhesions
Type of adhesion
MATERIALS AND METHODS Gallstones were collected from a single individual at the time of cholecystectomy. Most gallstones were small, uniform stones with a few large stones. These large gallstones were mechanically fractured to achieve a relatively homogenous group of stones.
Tenacity of adhesion
Imflammation of the adhesions
Subjects Twelve New Zealand white rabbits were maintained at the Medical College of Georgia Animal Facility. They were acclimated for 1 week in a 14-hour light/10-hour dark cycle with ad libitum water and food. This protocol was approved by the Medical College of Georgia institutional review board. These 12 rabbits were ear tagged and divided into three groups of four: a sham operation group, a rabbit bile with gallstone group, and a rabbit bile with human serum albumin group. The rabbits were anesthetized with 3.25–3.50 mL of ketamine and 0.5– 0.75 mL of xylazine. After adequate anesthesia, an upper midline celiotomy was performed with use of the sterile technique for each rabbit. In the sham operation group, upper and lower abdominal structures were visualized and palpated. The fascia and skin were closed with separate layers of No. 1 Maxon (U.S. Surgical, Norwalk, CT).
Gallstone involvement in adhesions
Description
Score
No adhesions ⬍25% adhesions ⬍50% adhesions ⬍75% adhesions ⬎75% adhesions No adhesions Filmy, transparent, avascular Opaque, translucent, avascular Opaque, capillaries present Opaque, larger vessels present No adhesions Adhesions fall apart Adhesions lysed traction Adhesions lysed sharp dissection None Mild erythema, localized Moderate erythema and edema Severe erythema and edema Severe erythema, edema, and widespread involvement No stones seen Stones free in cavity Stones adhered, lysed with traction Stones densely adhered, sharp dissection
0 1 2 3 4 0 1 2 3 4 0 1 2 3 0 1 2 3 4 0 0 1 2
Hansen. Pelvic adhesion formation. Fertil Steril 1999.
mixture was then placed into the right lower quadrant of the peritoneal cavity. The fascia and skin were closed in a similar manner to the sham group. The rabbits were then returned to their separate cages and allowed to recover. They were maintained on a 14hour light/10-hour dark cycle with ad libitum food and water.
In the second group (study group), an upper midline celiotomy was performed, and the upper and lower abdomen was inspected and palpated in a similar fashion to the sham group. One milliliter of rabbit bile was aspirated from the gallbladder with a 21-gauge needle. The rabbit bile was mixed with 250 mg of human gallstones. This gallstone bile mixture was then poured into the right lower quadrant. The fascia and skin were reapproximated in a similar manner as the sham group.
The rabbit ear tag numbers were randomly selected with use of a random number table and placed in sequentially numbered, opaque, sealed envelopes. Three weeks after the initial laparotomies, each envelope was consecutively opened, and the appropriate rabbit was selected by an animal handler. This rabbit was then anesthetized with 3.25 mL of intramuscular ketamine and euthanized with direct intracardiac injection of 1 mL of pentobarbital (325 mg/5 mL). This rabbit was brought to the necropsy room where its identity was concealed from the two observers.
In the third group (antigenic control), an upper midline celiotomy was performed, and the upper and lower abdomen was inspected and palpated similar to the sham operation. One milliliter of rabbit bile, extracted from the gallbladder with a 21-gauge needle, was mixed with 1 mL of human serum albumin (0.5 mL/11.5 mL of lactated Ringer’s solution for a total of 10 mg of human protein). This bile albumin
A midline incision was made and carefully dissected down to the peritoneal cavity. The entire abdominal cavity was inspected by the two observers. The observers independently scored the adhesions and affected organs on the basis of a grading scale shown in Table 1 and modified from Fiedler et al. (15). The examiners estimated the percent of the total peritoneal cavity involved in adhesions. The two
FERTILITY & STERILITY威
869
FIGURE 1 Peritoneal cavity of a rabbit in the study group shows the involvement of gallstones in adhesions of the uterine horn, fallopian tube, and ovary to the parietal peritoneum.
Hansen. Pelvic adhesion formation. Fertil Steril 1999.
examiners independently recorded their scores, which were kept concealed until data analysis.
Statistics The kappa statistic was calculated to compare observer variation in grading adhesions. Differences in extent, type, tenacity, inflammation, and gallstone involvement in adhesions between groups were compared with the use of a Kruskal-Wallis test. The presence of pelvic adhesions in the three groups were compared with a 2 analysis.
RESULTS Twelve rabbits were initially operated on in this study. One of the rabbits in the study group died from an anesthetic complication during surgery, and one of the rabbits in the antigenic control group died on postoperative day 4. Figure 1 illustrates a typical necropsy specimen with gallstones involved in adhesions of the ovary, tube, and uterine horn to the peritoneal sidewall. The mean scores for extent, type, tenacity, inflammation, and gallstone involve-
TABLE 2 Grade for peritoneal adhesions for all three groups. Mean (confidence interval) grade for peritoneal adhesions for the indicated group Variable Extent Type Tenacity Inflammation Gallstone involvement
Group I
Group II
Group III
0.75 (0.26, 1.24) 1.88 (0.65, 3.10) 2.25 (0.78, 3.72) 0 (0, 0) 0 (0, 0)
1 (1, 1) 2.67 (1.8, 3.53) 2.67 (2.01, 3.32) 1.33 (0.68, 1.99)* 2.83 (2.51, 3.16)†
0.83 (0.51, 1.16) 1.67 (1.01, 2.32) 2.17 (1.3, 3.03) 0 (0, 0) 0 (0, 0)
* P ⫽ .0126. † P ⫽ .0126. Hansen. Pelvic adhesion formation. Fertil Steril 1999.
870
Hansen et al.
Gallstones and pelvic adhesion formation
Vol. 72, No. 5, November 1999
mate the amount of measured protein (Martindale) quantified in 250 mg of gallstones.
TABLE 3 Number of rabbits with pelvic adhesions in all three groups. Group I II III
No pelvic adhesions
Pelvic adhesions present
4 0 3
0 3* 0
* P⫽.007 ( 2). Hansen. Pelvic adhesion formation. Fertil Steril 1999.
ment of the adhesions in each of the three groups are listed in Table 2. Each group was compared using a KruskalWallis analysis. There was a statistically significant increase (P⫽.0126) in gallstone involvement in adhesions and inflammation in the study group compared with the sham and antigenic control groups. In the study group, approximately 15% (6.60, 23.40) of the peritoneal cavity was involved in adhesions. The sham and antigenic control groups had only 3.75% (1.66, 5.84) and 4.33% (0.45, 8.21) involvement, respectively, of the peritoneal cavity in adhesions, and most of these adhesions were in the upper right quadrant. By evaluating the pelvic cavity separately from the entire peritoneal cavity for the presence or absence of adhesions, a statistically significant increase was found in the study group (P⫽.007, Table 3). The kappa statistic measured agreement between the two observers’ scoring of peritoneal adhesions and inflammation. There was no significant interobserver variation for grading extent, type, tenacity, and gallstone involvement in adhesions. However, there was a difference between observers in grading inflammation.
DISCUSSION This study demonstrates a statistically and biologically significant increase in pelvic adhesions when gallstones are left in the peritoneal cavity, and this increase was confirmed by two independent observers. These adhesions primarily involved the reproductive and gastrointestinal organs. In a female of reproductive age, these adhesions could significantly interfere with fallopian tube function, resulting in infertility or possibly pelvic pain. In our study, the gallstone mixture and antigenic control mixture was injected into the right lower quadrant of the rabbits. This material was injected into the right lower quadrant in our animal model to mimic distribution of intraperitoneal materials in the upright human, where the most dependent portion of the peritoneal cavity is the pelvis. Human serum albumin mixed with rabbit bile was used to control for differences in antigenicity between rabbits and humans. Ten milligrams of human serum albumin was used to approxiFERTILITY & STERILITY威
A previous animal study suggested that intraperitoneal gallstones do not increase adhesion formation (5). An apriori power analysis suggested the need for a larger number of animals in our study; however, because of changes in our protocol, a pilot study was necessary. The results in our pilot study reached statistical significance, suggesting powerful adhesion-forming properties of gallstones in our model. Gallstones for this study were obtained from a single individual at the time of laparoscopic cholecystectomy, and most were small in diameter and would be considered “gravel.” However, there were a few large stones that were mechanically fractured to obtain a homogenous sample of like-sized stones. The possibility exists that fracturing the larger stones increased the adhesion-forming properties of our mixture. Laparoscopic cholecystectomy is increasingly used as the surgical approach of choice for symptomatic gallstones. Currently, if gallstones are spilled into the peritoneal cavity, attempts will be made to remove them, but many times they are left because of the impression that they will not increase morbidity and difficulty with retrieval. Our data combined with recent case reports suggest that gallstones can significantly increase morbidity in select patients, which suggests the importance of minimizing spillage of gallstones at the time of laparsocopic cholecystectomy. A recent article suggests the following techniques to minimize spillage of gallstones: decompression of a tense gallbladder by needle aspiration; avoiding the use of toothed-graspers, excessive traction, or use of high electrical settings when operating on the gallbladder; and using a durable sack with a large enough incision to extract the gallbladder (16). It is also important to consider intraperitoneal gallstones in the differential diagnosis of patients who present with infertility, chronic pelvic pain, or intraabdominal complaints after a laparoscopic cholecystectomy.
Acknowledgment: The authors thank Mark S. Litaker, Ph.D., for his statistical consultation.
References 1. Foster DA, Kleinke JD, Young-Hasler J, Klar RM, Kongstved PR. Increased cholecystectomy rate after introduction of laparoscopic cholecystectomy [Letter]. JAMA 1994;271:500 –1. 2. Mouret P. How I developed laparoscopic cholecystectomy. Ann Acad Med Singapore 1996;25:744 –7. 3. Kelley JE, Burrus RG, Burns RP, Graham LD, Chandler KE. Safety, efficacy, cost, and morbidity of laparoscopic versus open cholecystectomy. Am Surg 1993;59:23–7. 4. Fitzgibbons RJ, Annibali R, Litke BS. Gallbladder and gallstone removal: open vs. closed laparoscopy and pneumoperitoneum. Am J Surg 1993;165:497–504.
871
5. Cline RW, Poulos E, Clifford EJ. An assessment of potential complications caused by intraperitoneal gallstones. Am Surg 1994;60:303–5. 6. Gallinaro RN, Miller FB. The lost gallstone: complication after laparoscopic cholecystectomy. Surg Endosc 1994;8:913– 4. 7. Nicolai P, Foley RJE. Complications of spilled gallstones. J Laparoendosc Surg 1992;2:362–3. 8. Kraft K, Butters M, Bittner R. Der verlorene Gallenstein-Komplikation nach laparoskopischer Cholecystektomie. Chirug 1994;65:142–3. 9. Walshaw CF, Deans H, Krukowski ZH. Free intra-peritoneal gallstones following laparoscopic cholecystectomy. Clin Radiol 1993; 48:258 –9. 10. Campbell WB, McGarity WC. An unusual complication of laparoscopic cholecystectomy. Am Surg 1992;58:641–2. 11. Lee VS, Paulson EK, Libby E, Flannery JE, Meyers WC. Cholelithoptysis and cholelithorrhea: rare complications of laparoscopic cholecystectomy. Gastroenterology 1993;105:1877– 81.
872
Hansen et al.
Gallstones and pelvic adhesion formation
12. Downie GH, Robbins MK, Souza JJ, Paradowski LJ. Cholelithoptysis: a complication following laparoscopic cholecystectomy. Chest 1993; 103:616 –7. 13. Tursi JP, Reddy UM, Huggins G. Cholelithiasis of the ovary. Obstet Gynecol 1993;82:653– 4. 14. Pfeifer ME, Hansen KA, Tho SPT, Hines RS, Plouffe L. Ovarian cholelithiasis after laparoscopic cholecystectomy associated with chronic pelvic pain. Fertil Steril 1996;66:1031–2. 15. Fiedler EP, Guzick DS, Guido R, Kanbour-Shakira A, Kransnow JS. Adhesion formation from release of dermoid contents in the peritoneal cavity and effect of copious lavage: a prospective, randomized, blinded, controlled study in a rabbit model. Fertil Steril 1996;65: 852–9. 16. Cohen PV, Pereira PR, de Barros MV, Ferreira EA, de Tolosa EM. Is the retrieval of lost peritoneal gallstones worthwhile? Surg Endosc 1994;8:1360.
Vol. 72, No. 5, November 1999
SURGERY
Copyright ©1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Pelvic adhesion formation after intraperitoneal installation of gallstones in a rabbit model Keith A. Hansen, M.D.,* Leah Lowman, M.D.,† Eric P. Fiedler, M.D.,‡ Sandra P. T. Tho, M.D.,* Robert Martindale, M.D., Ph.D.,§ and Paul G. McDonough, M.D.* Medical College of Georgia, Augusta, Women’s Health Care Specialists of Georgia, Athens, Georgia; and National Fertility Center of Texas, Dallas, Texas
Received January 4, 1998; revised and accepted June 18, 1999. Presented at the16th World Congress on Fertility and Sterility and 54th Annual Meeting of the American Society of Reproductive Medicine, San Francisco, California, October 4, 1998. Reprint requests and present address: Keith A. Hansen, M.D., Department of Obstetrics and Gynecology, University of South Dakota School of Medicine, 1400 West 22nd Street, Sioux Falls, South Dakota 57105 (FAX: 605357-1528; E- mail: [email protected]). * Department of Obstetrics and Gynecology, Medical College of Georgia. † Women’s Health Care Specialists of Georgia. ‡ National Fertility Center of Texas. § Department of General Surgery, Medical College of Georgia. 0015-0282/99/$20.00 PII S0015-0282(99)00398-2
868
Objective: To investigate whether intraperitoneal gallstones increase the risk of pelvic adhesions in a rabbit model. Design: Prospective, randomized, blinded, sham and human antigen controlled trial. Setting: An academic research environment. Subject(s): Twelve New Zealand white rabbits. Intervention(s): Twelve rabbits were divided into three groups of four each; a sham operation group, a gallstone and bile group (study group), and a human serum albumin and bile group (antigenic control). Three weeks after the operation individual subjects were randomized, with groups concealed to observers, and a necropsy was performed on each rabbit. Main Outcome Measurement(s): Necropsy was performed on each rabbit, and the adhesions were scored for extent, type, tenacity, inflammation, and gallstone involvement. Result(s): There was a statistically and biologically significant increase in gallstone involvement in adhesions, especially pelvic adhesions, in the study group. Conclusion(s): This study, along with an increasing number of case reports, suggests that gallstones inadvertently left in the peritoneal cavity may increase the morbidity of laparoscopic cholecystectomy. In females of reproductive age these gallstones may induce pelvic adhesions that may interfere with fertility or be associated with pelvic pain. (Fertil Steril威 1999;72:868 –72. ©1999 by American Society for Reproductive Medicine.) Key Words: Intraperitoneal gallstones, laparoscopic cholecystectomy, pelvic adhesion
Cholelithiasis affects more than 20 million individuals in the United States (1). Cholecystectomy is the third most common operation performed in the United States and is the treatment of choice in gallstone disease. Charles Filipi performed the first laparoscopic cholecystectomy in a dog in the early 1980s; Mouret was the first to perform this laparoscopic operation in humans in 1987 (2). Since the late 1980s laparoscopic cholecystectomy has become the most common method for treatment of symptomatic patients. Laparoscopy offers several advantages over open cholecystectomy, including decreased hospital stay, better patient tolerance, less postoperative pain, earlier return to work, and better cosmesis (3).
Perforation of the gallbladder occurs in 30% with spillage of gallstones in 20% of laparoscopic cholecystectomies (4). Most surgeons leave inadvertently spilled gallstones because of the impression that they do not increase morbidity of the operation. Using a rat model, Cline et al. (5) demonstrated no increase in adhesions in a group of rats where gallstones were placed in the peritoneal cavity compared with controls. More than 20 case reports describe complications arising from intraperitoneal gallstones left after laparoscopic cholecystectomy. These complications include abdominal abscesses (6), erosion into the sigmoid colon (7), fistulas (8), and granuloma formation (9). More un-
usual complications include gallstones lodged in a femoral hernia mimicking an incarcerated hernia (10), cholelithoptysis hypothesized to be due to transdiaphragmatic extension of an intraperitoneal abscess (11, 12), and two cases of ovarian cholelithiasis (13, 14). The increasing number of reported complications related to spilled gallstones raises the question of the importance of retrieving gallstones lost during laparoscopic cholecystectomy. This study was performed to determine if intraperitoneal gallstones will increase adhesions in a rabbit model.
TABLE 1 Clinical scoring of intraperitoneal adhesions and gallstones. Variable Extent of the adhesions
Type of adhesion
MATERIALS AND METHODS Gallstones were collected from a single individual at the time of cholecystectomy. Most gallstones were small, uniform stones with a few large stones. These large gallstones were mechanically fractured to achieve a relatively homogenous group of stones.
Tenacity of adhesion
Imflammation of the adhesions
Subjects Twelve New Zealand white rabbits were maintained at the Medical College of Georgia Animal Facility. They were acclimated for 1 week in a 14-hour light/10-hour dark cycle with ad libitum water and food. This protocol was approved by the Medical College of Georgia institutional review board. These 12 rabbits were ear tagged and divided into three groups of four: a sham operation group, a rabbit bile with gallstone group, and a rabbit bile with human serum albumin group. The rabbits were anesthetized with 3.25–3.50 mL of ketamine and 0.5– 0.75 mL of xylazine. After adequate anesthesia, an upper midline celiotomy was performed with use of the sterile technique for each rabbit. In the sham operation group, upper and lower abdominal structures were visualized and palpated. The fascia and skin were closed with separate layers of No. 1 Maxon (U.S. Surgical, Norwalk, CT).
Gallstone involvement in adhesions
Description
Score
No adhesions ⬍25% adhesions ⬍50% adhesions ⬍75% adhesions ⬎75% adhesions No adhesions Filmy, transparent, avascular Opaque, translucent, avascular Opaque, capillaries present Opaque, larger vessels present No adhesions Adhesions fall apart Adhesions lysed traction Adhesions lysed sharp dissection None Mild erythema, localized Moderate erythema and edema Severe erythema and edema Severe erythema, edema, and widespread involvement No stones seen Stones free in cavity Stones adhered, lysed with traction Stones densely adhered, sharp dissection
0 1 2 3 4 0 1 2 3 4 0 1 2 3 0 1 2 3 4 0 0 1 2
Hansen. Pelvic adhesion formation. Fertil Steril 1999.
mixture was then placed into the right lower quadrant of the peritoneal cavity. The fascia and skin were closed in a similar manner to the sham group. The rabbits were then returned to their separate cages and allowed to recover. They were maintained on a 14hour light/10-hour dark cycle with ad libitum food and water.
In the second group (study group), an upper midline celiotomy was performed, and the upper and lower abdomen was inspected and palpated in a similar fashion to the sham group. One milliliter of rabbit bile was aspirated from the gallbladder with a 21-gauge needle. The rabbit bile was mixed with 250 mg of human gallstones. This gallstone bile mixture was then poured into the right lower quadrant. The fascia and skin were reapproximated in a similar manner as the sham group.
The rabbit ear tag numbers were randomly selected with use of a random number table and placed in sequentially numbered, opaque, sealed envelopes. Three weeks after the initial laparotomies, each envelope was consecutively opened, and the appropriate rabbit was selected by an animal handler. This rabbit was then anesthetized with 3.25 mL of intramuscular ketamine and euthanized with direct intracardiac injection of 1 mL of pentobarbital (325 mg/5 mL). This rabbit was brought to the necropsy room where its identity was concealed from the two observers.
In the third group (antigenic control), an upper midline celiotomy was performed, and the upper and lower abdomen was inspected and palpated similar to the sham operation. One milliliter of rabbit bile, extracted from the gallbladder with a 21-gauge needle, was mixed with 1 mL of human serum albumin (0.5 mL/11.5 mL of lactated Ringer’s solution for a total of 10 mg of human protein). This bile albumin
A midline incision was made and carefully dissected down to the peritoneal cavity. The entire abdominal cavity was inspected by the two observers. The observers independently scored the adhesions and affected organs on the basis of a grading scale shown in Table 1 and modified from Fiedler et al. (15). The examiners estimated the percent of the total peritoneal cavity involved in adhesions. The two
FERTILITY & STERILITY威
869
FIGURE 1 Peritoneal cavity of a rabbit in the study group shows the involvement of gallstones in adhesions of the uterine horn, fallopian tube, and ovary to the parietal peritoneum.
Hansen. Pelvic adhesion formation. Fertil Steril 1999.
examiners independently recorded their scores, which were kept concealed until data analysis.
Statistics The kappa statistic was calculated to compare observer variation in grading adhesions. Differences in extent, type, tenacity, inflammation, and gallstone involvement in adhesions between groups were compared with the use of a Kruskal-Wallis test. The presence of pelvic adhesions in the three groups were compared with a 2 analysis.
RESULTS Twelve rabbits were initially operated on in this study. One of the rabbits in the study group died from an anesthetic complication during surgery, and one of the rabbits in the antigenic control group died on postoperative day 4. Figure 1 illustrates a typical necropsy specimen with gallstones involved in adhesions of the ovary, tube, and uterine horn to the peritoneal sidewall. The mean scores for extent, type, tenacity, inflammation, and gallstone involve-
TABLE 2 Grade for peritoneal adhesions for all three groups. Mean (confidence interval) grade for peritoneal adhesions for the indicated group Variable Extent Type Tenacity Inflammation Gallstone involvement
Group I
Group II
Group III
0.75 (0.26, 1.24) 1.88 (0.65, 3.10) 2.25 (0.78, 3.72) 0 (0, 0) 0 (0, 0)
1 (1, 1) 2.67 (1.8, 3.53) 2.67 (2.01, 3.32) 1.33 (0.68, 1.99)* 2.83 (2.51, 3.16)†
0.83 (0.51, 1.16) 1.67 (1.01, 2.32) 2.17 (1.3, 3.03) 0 (0, 0) 0 (0, 0)
* P ⫽ .0126. † P ⫽ .0126. Hansen. Pelvic adhesion formation. Fertil Steril 1999.
870
Hansen et al.
Gallstones and pelvic adhesion formation
Vol. 72, No. 5, November 1999
mate the amount of measured protein (Martindale) quantified in 250 mg of gallstones.
TABLE 3 Number of rabbits with pelvic adhesions in all three groups. Group I II III
No pelvic adhesions
Pelvic adhesions present
4 0 3
0 3* 0
* P⫽.007 ( 2). Hansen. Pelvic adhesion formation. Fertil Steril 1999.
ment of the adhesions in each of the three groups are listed in Table 2. Each group was compared using a KruskalWallis analysis. There was a statistically significant increase (P⫽.0126) in gallstone involvement in adhesions and inflammation in the study group compared with the sham and antigenic control groups. In the study group, approximately 15% (6.60, 23.40) of the peritoneal cavity was involved in adhesions. The sham and antigenic control groups had only 3.75% (1.66, 5.84) and 4.33% (0.45, 8.21) involvement, respectively, of the peritoneal cavity in adhesions, and most of these adhesions were in the upper right quadrant. By evaluating the pelvic cavity separately from the entire peritoneal cavity for the presence or absence of adhesions, a statistically significant increase was found in the study group (P⫽.007, Table 3). The kappa statistic measured agreement between the two observers’ scoring of peritoneal adhesions and inflammation. There was no significant interobserver variation for grading extent, type, tenacity, and gallstone involvement in adhesions. However, there was a difference between observers in grading inflammation.
DISCUSSION This study demonstrates a statistically and biologically significant increase in pelvic adhesions when gallstones are left in the peritoneal cavity, and this increase was confirmed by two independent observers. These adhesions primarily involved the reproductive and gastrointestinal organs. In a female of reproductive age, these adhesions could significantly interfere with fallopian tube function, resulting in infertility or possibly pelvic pain. In our study, the gallstone mixture and antigenic control mixture was injected into the right lower quadrant of the rabbits. This material was injected into the right lower quadrant in our animal model to mimic distribution of intraperitoneal materials in the upright human, where the most dependent portion of the peritoneal cavity is the pelvis. Human serum albumin mixed with rabbit bile was used to control for differences in antigenicity between rabbits and humans. Ten milligrams of human serum albumin was used to approxiFERTILITY & STERILITY威
A previous animal study suggested that intraperitoneal gallstones do not increase adhesion formation (5). An apriori power analysis suggested the need for a larger number of animals in our study; however, because of changes in our protocol, a pilot study was necessary. The results in our pilot study reached statistical significance, suggesting powerful adhesion-forming properties of gallstones in our model. Gallstones for this study were obtained from a single individual at the time of laparoscopic cholecystectomy, and most were small in diameter and would be considered “gravel.” However, there were a few large stones that were mechanically fractured to obtain a homogenous sample of like-sized stones. The possibility exists that fracturing the larger stones increased the adhesion-forming properties of our mixture. Laparoscopic cholecystectomy is increasingly used as the surgical approach of choice for symptomatic gallstones. Currently, if gallstones are spilled into the peritoneal cavity, attempts will be made to remove them, but many times they are left because of the impression that they will not increase morbidity and difficulty with retrieval. Our data combined with recent case reports suggest that gallstones can significantly increase morbidity in select patients, which suggests the importance of minimizing spillage of gallstones at the time of laparsocopic cholecystectomy. A recent article suggests the following techniques to minimize spillage of gallstones: decompression of a tense gallbladder by needle aspiration; avoiding the use of toothed-graspers, excessive traction, or use of high electrical settings when operating on the gallbladder; and using a durable sack with a large enough incision to extract the gallbladder (16). It is also important to consider intraperitoneal gallstones in the differential diagnosis of patients who present with infertility, chronic pelvic pain, or intraabdominal complaints after a laparoscopic cholecystectomy.
Acknowledgment: The authors thank Mark S. Litaker, Ph.D., for his statistical consultation.
References 1. Foster DA, Kleinke JD, Young-Hasler J, Klar RM, Kongstved PR. Increased cholecystectomy rate after introduction of laparoscopic cholecystectomy [Letter]. JAMA 1994;271:500 –1. 2. Mouret P. How I developed laparoscopic cholecystectomy. Ann Acad Med Singapore 1996;25:744 –7. 3. Kelley JE, Burrus RG, Burns RP, Graham LD, Chandler KE. Safety, efficacy, cost, and morbidity of laparoscopic versus open cholecystectomy. Am Surg 1993;59:23–7. 4. Fitzgibbons RJ, Annibali R, Litke BS. Gallbladder and gallstone removal: open vs. closed laparoscopy and pneumoperitoneum. Am J Surg 1993;165:497–504.
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Vol. 72, No. 5, November 1999