Effect of thirty-two per cent dextran 70 on peritoneal adhesion formation ROBERT
S.
NEUWIRTH,
SUHAIL
M.
KHALAF,
New
M.D. M.D.
York, New York
Twenty-one female rabbits underwent laparotomy and a standardized injury was produced on the right uterine horn and Fallopian tube. Following the injury eight animals were used as controls and thirteen were injected intrapen’toneally with 50 ml. of 32 per cent dextran 70. Six weeks later the animals were killed and the adhesions graded. All control animals had dense adhesions of the injured areas to bowel or peritoneum. The dextran animals showed marked reduction in the extent and degree of adhesions. Possible mechanisms for these findings are discussed and the problems raised, by adhesion formation, to the gynecologist are reviewed.
T H E a E n u c T IO N or elimination of postoperative intraperitoneal adhesions is important to all abdominal surgery but is of particular pertinence to the gynecologist. Pelvic surgery is the most frequent cause of postoperative bowel obstruction.l The successof tubal reconstructive surgery is often impaired by the formation of postoperative adhesions. Many agents have been used to prevent adhesion formation. The use of corticosteroids as anti-inflammatory agents in the prevention of adhesion formation is controversial. Oxyphenbutazone and proteolytic enzymes from carica papaya have been reported to be successful in reducing adhesions.* Fibrinolysin has prevented adhesions in rats.3 Sakakihara and associates4reported that ten per cent dextran 40 decreasedperitoneal adhesion formation in rats and rabbits. Polishuk and Bercovici5 were unable to show an impressive effect with ten per cent dextran 40 in a series of patients undergoing tuboplasty. Similarly, Seitz and co-worker@ could not demonstrate a therapeutic effect with dextran 40 or cor-
ticosteroids in monkeys. Thirty-two per cent dextran 70” has recently been introduced asa distension fluid for the endometrial cavity during hysteroscopy. It is the purpose of this study to examine the effects of 35 per cent dextran 70 on intraperitoneal adhesion formation following injury to the upper genital tract. Mahtial ad method Twenty-one adult, nonpregnant, female rabbits (eight control, 13 treatment) with an average weight of five pounds underwent laparotomy under ether anesthesia through a midline incision with the use of sterile technique. The dorsal surfaces of the uteri and proximal 1 cm. of right Fallopian tube were denuded with the use of a fine-toothed forceps or scalpel; the right tube was transected and both ends were separated at the junction of proximal and middle thirds. Bleeding was controlled by clamping vesselsonly. The extent and depth of injury was made as standard as possiblefor each animal. The abdominal wound was closed in two layers with the use of chromic 3-O catgut sutures. A polyethylene catheter was left in the pelvis through which 50 ml. of 32 per cent dextran 70 (32 Cm. of dextran molecular weight 70,000 + 10 Gm. of dextrose United States Pharmacopeia in 100 ml. of water) was injected, the catheter removed, and the rabbits placed in their cages.
From the College of Physicians and Surgeons, Columbia University, Department of Obstetrics and Gynecology. Received for publication May 17, 1974. Accepted June 18, 1974. Reprint requests: Dr. Robert S. Neuwirth, Department of Obstetrics and GynecologyWoman’s Hos&tal, St. Luke’s Hospital Center, 114th St. and Amsterdam Ave., New York, New York 10025.
*Supplied tennial Ave.,
420
by Pharmacia Laboratories, Inc., Piscstaway, New Jm U8854.
800
Cen-
Volume Number
Fig.
121 3
1. Control
Thirty-two
animal
with
bowel
adhesions
per
Fig.
to tube.
Six weeks after surgery the rabbits were put to death, the abdomens opened, and photographs taken. The degree of adhesion formation was evaluated according to the classification of Knightly and associates7 with some modifications: Grade 0, complete absence of adhesion; Grade 1, a single thin, easily separated adhesion; Grade 2, weak adhesions which withstood traction poorly; Grade 3, numerous, extensive tubal adhesions; Grade 4, numerous extensive adhesions involving the intestine and/or extending to the abdominal wall. Results All animals survived. Unfortunately two dextran animals were lost to the study because of an error in the Animal Care Office. The control group uniformly showed massive adhesions (Fig. 1). The adhesions were dense and connected the injured genital structure to the bowel, bladder, or parietal peritoneum. The 32 per cent dextran 70 group (Fig. 2) was distinctly different from the control group (Table I). In the Grade 4 animal (Fig. 3), the right uterine horn was adherent to the lower angle of the peritoneal incision, bowel, and bladder. The Grade 3 dextran animal had the right tube densely adherent to the back of the uterus. The other animals showed either no adhesions, single adhesions, or, in two instances, several weak adhesions. In one dextran animal a sponge was accidently left in the pelvis. As shown, only 2+ adhesions developed (Fig. 4).
Comment The initial purpose of this study was to determine if there was any effect of 32 per cent dextran 70 on the formation of scar tissue after normal genital tissues were injured. This stemmed from interest
cent
dextran
70 on
2. Dextran
animal
peritoneal
with
adhesions
no adhesions.
Table I. Effect of 32 per cent dextran peritoneal
adhesion
Grade 1 No.
Control Dextran
8 13
Significant
I Lost 0 2
at 0.01
70 on
formation
Animals Grouj
421
I
of adhesion
o(1121314 0 3
by Student’s
0 4
0 2
1 1
7 1
t test.
tubal sterilization by cautery during hysteroscopy with the use of 32 per cent dextran 70. The results show a reduction in adhesion formation. Although -this is not a direct study for scar formation within the lumen of the Fallopian tube, it should be noted that such an effect could influence the closure of the tube following cautery unless the dextran is washed away. The results also suggest that 32 per cent dextran 70 may be useful in other types of gynecologic surgery in which reduction of adhesion formation may be important. The search for a method to reduce postoperative adhesions has not been fruitful. Recently Seitz and associates,‘j with the use of a double-blind technique in monkeys undergoing dissection of adhesions from previous laparotomy, found that neither dexamethasone-promethazine therapy nor dextran 40 therapy prevented adhesion reformation to any greater degree than did physiologic saline. Unfortunately, no pure surgical control or a standard injury was included in the series. Nonetheless the authors were unimpressed that the postoperative adjunctive therapy was of any value. The use of 32 per cent dextran 70 in the pelvis following tuboplasty has not been reported. To date it has been innocuous intraperitoneally in the human being, as no adverse clinical or pathologic effects have been found following its use when transtubal spill has occurred during hysteroscopy. in
422
Neuwirth
Fig. 3. Dextran bladder.
and
animal
February 1, 1975 Am. J. Obstet. Cynecol.
Khalaf
with
worst
adhesions
to bowel
and
this safety feature, it is of utmost importance that more data evaluating efficacy be obtained in order to justify use following tuboplasty. The recent reports of tubal cauterization at hysteroscopy”“” indicate that cautery done in a carbon dioxide, five per cent dextrose in water, or 32 per cent dextran 70 environment will all produce about the same closure rate. The technique reported* for 32 per cent dextran 70 includes a washout of the dextran following the procedure. No large clinical series is yet available to compare results of hysteroscopic cautery in 32 per cent dextran 70 with and without washout. The mechanism by which 32 per cent dextran 70 might reduce adhesion formation is not clear. It could act by coating the denuded surfaces and retarding blood coagulation, much as it is believed to act in prevention of thrombosis in blood vessels following trauma to the intima. This action has been called a “siliconizing effect” because it is similar to the action of silicone in retarding platelet aggregationll and fibrin polymerization.** Another possible action is a simple coating and separation effect so Despite
Fig. 4. Animal with sponge bowel and uterus shown.
left
in
pelvis;
adhesions
to
that the surfaces of adjacent structures are kept apart. Dextran is known to be removed from the peritoneal cavity slowly. Polishuk and Aboulafia13 found about 50 per cent of the volume of dextran 70 introduced was recovered from the peritoneum of rabbits ten days following surgery. Summary Twenty-one rabbits underwent a standard injury to the genital tract at laparotomy. Thirteen rabbits were treated with 32 per cent dextran 70 and the others served as controls. Six weeks later all control animals were found to have extensive adhesions. The preponderance of dextran-treated animals had either no adhesions or minimal adhesion formation. However, two of eleven dextran animals examined did have severe adhesions. This evidence suggests that 32 per cent dextran 70 exerts a retarding effect on the formation of adhesions between injured surfaces. The implication of the data, apropos hysteroscopic sterilization with the use of cautery and tubal reconstructive surgery, is potentially important so that
further
study
is warranted.
REFERENCES
1. McCune,
8.
2.
9.
3. 4. 5. 6. 7.
M’. S., and Keshishian, J. M.: Surg. Gynecol. Obstet. 96: 567, 1952. Kapur, B. M. L., Gulati, S. M., and Talwar, J. R.: Arch. Surg. 105: 761, 1972. Spagna, P. M., and Peskin, G. W.: Surg. Forum 11: 5 1960. Sakakihara, Y., Ogasa, N., and Sato, T.: Tokushima T. EXD. Med. 14: 52. 1967. Polishuk, W. Z., and Bercovici, B.: J. Obstet. Gynaecol. Br. Commonw. 78: 724, 1971. Seitz, H. M., Jr., Schenker, J. G., Epstein, S., and Garcia. C. R.: Fertil. Steril. 24: 935. 1973. Knightly, J. J., Agostino, D., and ‘Clifton, E. E.: Surgery 52: 250, 1962.
10. 11. 12. 13.
Richart, R. M., Neuwirth, R. S., Charanpat, I., and Sukhit, P.: AM. J. OBSTET. GYNECOL. 117: 801, 1973. Quinones, R.: Conference on Hysteroscopic Sterilization, Minneapolis, Minnesota, University of Minnesota, June 22 to 24, 1974. Lindemann, H. J.: Personal communication, November, 1973. Bennett, P. N., Dhall, D. P., McKenzie, F. N., and Matheson, N. A.: Lancet 2: 1001, 1966. Golub, S., and Schaefer, C.: Surg. Gynecol. Obstet. 127: 783, ‘1968. Polishuk, W. Z., and Aboulaf%r, Y.: Isr. J. Med. Sci. 3: 806, 1967.
S.
NEUWIRTH,
SUHAIL
M.
KHALAF,
New
M.D. M.D.
York, New York
Twenty-one female rabbits underwent laparotomy and a standardized injury was produced on the right uterine horn and Fallopian tube. Following the injury eight animals were used as controls and thirteen were injected intrapen’toneally with 50 ml. of 32 per cent dextran 70. Six weeks later the animals were killed and the adhesions graded. All control animals had dense adhesions of the injured areas to bowel or peritoneum. The dextran animals showed marked reduction in the extent and degree of adhesions. Possible mechanisms for these findings are discussed and the problems raised, by adhesion formation, to the gynecologist are reviewed.
T H E a E n u c T IO N or elimination of postoperative intraperitoneal adhesions is important to all abdominal surgery but is of particular pertinence to the gynecologist. Pelvic surgery is the most frequent cause of postoperative bowel obstruction.l The successof tubal reconstructive surgery is often impaired by the formation of postoperative adhesions. Many agents have been used to prevent adhesion formation. The use of corticosteroids as anti-inflammatory agents in the prevention of adhesion formation is controversial. Oxyphenbutazone and proteolytic enzymes from carica papaya have been reported to be successful in reducing adhesions.* Fibrinolysin has prevented adhesions in rats.3 Sakakihara and associates4reported that ten per cent dextran 40 decreasedperitoneal adhesion formation in rats and rabbits. Polishuk and Bercovici5 were unable to show an impressive effect with ten per cent dextran 40 in a series of patients undergoing tuboplasty. Similarly, Seitz and co-worker@ could not demonstrate a therapeutic effect with dextran 40 or cor-
ticosteroids in monkeys. Thirty-two per cent dextran 70” has recently been introduced asa distension fluid for the endometrial cavity during hysteroscopy. It is the purpose of this study to examine the effects of 35 per cent dextran 70 on intraperitoneal adhesion formation following injury to the upper genital tract. Mahtial ad method Twenty-one adult, nonpregnant, female rabbits (eight control, 13 treatment) with an average weight of five pounds underwent laparotomy under ether anesthesia through a midline incision with the use of sterile technique. The dorsal surfaces of the uteri and proximal 1 cm. of right Fallopian tube were denuded with the use of a fine-toothed forceps or scalpel; the right tube was transected and both ends were separated at the junction of proximal and middle thirds. Bleeding was controlled by clamping vesselsonly. The extent and depth of injury was made as standard as possiblefor each animal. The abdominal wound was closed in two layers with the use of chromic 3-O catgut sutures. A polyethylene catheter was left in the pelvis through which 50 ml. of 32 per cent dextran 70 (32 Cm. of dextran molecular weight 70,000 + 10 Gm. of dextrose United States Pharmacopeia in 100 ml. of water) was injected, the catheter removed, and the rabbits placed in their cages.
From the College of Physicians and Surgeons, Columbia University, Department of Obstetrics and Gynecology. Received for publication May 17, 1974. Accepted June 18, 1974. Reprint requests: Dr. Robert S. Neuwirth, Department of Obstetrics and GynecologyWoman’s Hos&tal, St. Luke’s Hospital Center, 114th St. and Amsterdam Ave., New York, New York 10025.
*Supplied tennial Ave.,
420
by Pharmacia Laboratories, Inc., Piscstaway, New Jm U8854.
800
Cen-
Volume Number
Fig.
121 3
1. Control
Thirty-two
animal
with
bowel
adhesions
per
Fig.
to tube.
Six weeks after surgery the rabbits were put to death, the abdomens opened, and photographs taken. The degree of adhesion formation was evaluated according to the classification of Knightly and associates7 with some modifications: Grade 0, complete absence of adhesion; Grade 1, a single thin, easily separated adhesion; Grade 2, weak adhesions which withstood traction poorly; Grade 3, numerous, extensive tubal adhesions; Grade 4, numerous extensive adhesions involving the intestine and/or extending to the abdominal wall. Results All animals survived. Unfortunately two dextran animals were lost to the study because of an error in the Animal Care Office. The control group uniformly showed massive adhesions (Fig. 1). The adhesions were dense and connected the injured genital structure to the bowel, bladder, or parietal peritoneum. The 32 per cent dextran 70 group (Fig. 2) was distinctly different from the control group (Table I). In the Grade 4 animal (Fig. 3), the right uterine horn was adherent to the lower angle of the peritoneal incision, bowel, and bladder. The Grade 3 dextran animal had the right tube densely adherent to the back of the uterus. The other animals showed either no adhesions, single adhesions, or, in two instances, several weak adhesions. In one dextran animal a sponge was accidently left in the pelvis. As shown, only 2+ adhesions developed (Fig. 4).
Comment The initial purpose of this study was to determine if there was any effect of 32 per cent dextran 70 on the formation of scar tissue after normal genital tissues were injured. This stemmed from interest
cent
dextran
70 on
2. Dextran
animal
peritoneal
with
adhesions
no adhesions.
Table I. Effect of 32 per cent dextran peritoneal
adhesion
Grade 1 No.
Control Dextran
8 13
Significant
I Lost 0 2
at 0.01
70 on
formation
Animals Grouj
421
I
of adhesion
o(1121314 0 3
by Student’s
0 4
0 2
1 1
7 1
t test.
tubal sterilization by cautery during hysteroscopy with the use of 32 per cent dextran 70. The results show a reduction in adhesion formation. Although -this is not a direct study for scar formation within the lumen of the Fallopian tube, it should be noted that such an effect could influence the closure of the tube following cautery unless the dextran is washed away. The results also suggest that 32 per cent dextran 70 may be useful in other types of gynecologic surgery in which reduction of adhesion formation may be important. The search for a method to reduce postoperative adhesions has not been fruitful. Recently Seitz and associates,‘j with the use of a double-blind technique in monkeys undergoing dissection of adhesions from previous laparotomy, found that neither dexamethasone-promethazine therapy nor dextran 40 therapy prevented adhesion reformation to any greater degree than did physiologic saline. Unfortunately, no pure surgical control or a standard injury was included in the series. Nonetheless the authors were unimpressed that the postoperative adjunctive therapy was of any value. The use of 32 per cent dextran 70 in the pelvis following tuboplasty has not been reported. To date it has been innocuous intraperitoneally in the human being, as no adverse clinical or pathologic effects have been found following its use when transtubal spill has occurred during hysteroscopy. in
422
Neuwirth
Fig. 3. Dextran bladder.
and
animal
February 1, 1975 Am. J. Obstet. Cynecol.
Khalaf
with
worst
adhesions
to bowel
and
this safety feature, it is of utmost importance that more data evaluating efficacy be obtained in order to justify use following tuboplasty. The recent reports of tubal cauterization at hysteroscopy”“” indicate that cautery done in a carbon dioxide, five per cent dextrose in water, or 32 per cent dextran 70 environment will all produce about the same closure rate. The technique reported* for 32 per cent dextran 70 includes a washout of the dextran following the procedure. No large clinical series is yet available to compare results of hysteroscopic cautery in 32 per cent dextran 70 with and without washout. The mechanism by which 32 per cent dextran 70 might reduce adhesion formation is not clear. It could act by coating the denuded surfaces and retarding blood coagulation, much as it is believed to act in prevention of thrombosis in blood vessels following trauma to the intima. This action has been called a “siliconizing effect” because it is similar to the action of silicone in retarding platelet aggregationll and fibrin polymerization.** Another possible action is a simple coating and separation effect so Despite
Fig. 4. Animal with sponge bowel and uterus shown.
left
in
pelvis;
adhesions
to
that the surfaces of adjacent structures are kept apart. Dextran is known to be removed from the peritoneal cavity slowly. Polishuk and Aboulafia13 found about 50 per cent of the volume of dextran 70 introduced was recovered from the peritoneum of rabbits ten days following surgery. Summary Twenty-one rabbits underwent a standard injury to the genital tract at laparotomy. Thirteen rabbits were treated with 32 per cent dextran 70 and the others served as controls. Six weeks later all control animals were found to have extensive adhesions. The preponderance of dextran-treated animals had either no adhesions or minimal adhesion formation. However, two of eleven dextran animals examined did have severe adhesions. This evidence suggests that 32 per cent dextran 70 exerts a retarding effect on the formation of adhesions between injured surfaces. The implication of the data, apropos hysteroscopic sterilization with the use of cautery and tubal reconstructive surgery, is potentially important so that
further
study
is warranted.
REFERENCES
1. McCune,
8.
2.
9.
3. 4. 5. 6. 7.
M’. S., and Keshishian, J. M.: Surg. Gynecol. Obstet. 96: 567, 1952. Kapur, B. M. L., Gulati, S. M., and Talwar, J. R.: Arch. Surg. 105: 761, 1972. Spagna, P. M., and Peskin, G. W.: Surg. Forum 11: 5 1960. Sakakihara, Y., Ogasa, N., and Sato, T.: Tokushima T. EXD. Med. 14: 52. 1967. Polishuk, W. Z., and Bercovici, B.: J. Obstet. Gynaecol. Br. Commonw. 78: 724, 1971. Seitz, H. M., Jr., Schenker, J. G., Epstein, S., and Garcia. C. R.: Fertil. Steril. 24: 935. 1973. Knightly, J. J., Agostino, D., and ‘Clifton, E. E.: Surgery 52: 250, 1962.
10. 11. 12. 13.
Richart, R. M., Neuwirth, R. S., Charanpat, I., and Sukhit, P.: AM. J. OBSTET. GYNECOL. 117: 801, 1973. Quinones, R.: Conference on Hysteroscopic Sterilization, Minneapolis, Minnesota, University of Minnesota, June 22 to 24, 1974. Lindemann, H. J.: Personal communication, November, 1973. Bennett, P. N., Dhall, D. P., McKenzie, F. N., and Matheson, N. A.: Lancet 2: 1001, 1966. Golub, S., and Schaefer, C.: Surg. Gynecol. Obstet. 127: 783, ‘1968. Polishuk, W. Z., and Aboulaf%r, Y.: Isr. J. Med. Sci. 3: 806, 1967.
