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Adhesion prevention in gynecologic surgeryTogas Tulandi and Abdulaziz Al-Shahrani
The purpose of this review is to discuss new substances
One of the complications of abdominal surgery is intra-
and techniques to prevent post-surgical adhesion
abdominal adhesion formation. These adhesions can
cause bowel obstruction and pain, whereas adnexal
adhesions can cause infertility In an attempt to
Intraperitoneal administration of sprayable hydrogel and
decrease adhesion formation, many surgical techniques
hyaluronic acid appears to decrease postmyomectomy
have been proposed and many adhesion-reducing sub-
adhesions. Intrauterine instillation of auto-crosslinked
stances have been evaluated. Muzii conducted a
hyaluronic acid is associated with fewer intrauterine
postal survey among 42 members of the Roman Group of
adhesions. Temporary abdominal oophoropexy after
Gynecologic Endoscopy in Italy on the use of substances
surgery of stage III and IV endometriosis might be beneficial
for postoperative adhesion prevention. Approximately
two-thirds of the respondents used some method of
adhesion prevention. Prophylactic antibiotics were used
There has been a wide range of adhesion-reducing
by 87.5% of respondents. The most frequently used
substances evaluated in animal models. However, in clinical
method during laparoscopy was Ringer’s lactate, followed
situations, no adhesion-preventing substance, material, or
by ferric hyaluronate gel. Ringer’s lactate is rapidly
barrier is unequivocally effective. In view of surgical
absorbed from the peritoneal cavity and in humans is
technique, compared to laparotomy, the laparoscopic
approach is associated with less adhesion formation.
Temporary abdominal oophoropexy may provide a
In this review, we will summarize recent studies on
promising technique to prevent ovarian adhesions. Future
techniques and adhesion-reducing substances.
research should also be directed toward preventingintrauterine adhesions.
Adhesion-reducing substancesThere has been a wide variety of adhesion-reducing
substances evaluated in animal models and in humans.
adhesion, adhesion prevention, gynecologic surgery,
Some are pre-existing products or their modifications and
Curr Opin Obstet Gynecol 17:395–398. # 2005 Lippincott Williams & Wilkins.
Hyaluronic acidHyaluronic acid is a high-molecular-weight polymer that
Department of Obstetrics and Gynecology, McGill University, Canada
under aqueous physiologic conditions forms a highly
Correspondence to Togas Tulandi MD, Professor of Obstetrics and Gynecology,
viscous solution. This polymer is present during embry-
Milton Leong Chair in Reproductive Medicine, McGill University, Canada, 687 PineAve. West, Montreal, Quebec, Canada H3A 1A1
ogenesis and it may be responsible for healing without
Tel: +1 514 934 1934 ext. 31391 or +1 514 340 8222 ext. 4920;
Current Opinion in Obstetrics and Gynecology 2005, 17:395–398
Intraperitoneal instillation of hyaluronic acid coats serosal
surfaces, minimizes serosal desiccation and reduces
adhesion formation. Unlike other peritoneal instillates,it should be instilled before trauma is inflicted. Its useafter tissue injury is ineffective.
In a small study of 18 women who underwent myomec-tomy by laparotomy, hyaluronic acid was used Pelvicadhesions were encountered in five patients (27.7%). Theauthors commented that their study emphasized theneed to improve treatments for adhesion prevention.
FeHACrosslinking hyaluronic acid with ferric ion (FeHA)increases its viscosity and half-life. The first marketed
Minimally invasive gynecologic procedures
derivative of FeHA is Intergel (Lifecore, Johnson and
delivery of drugs. In a randomized study, Mettler et al.
Johnson Gynecare Unit, Medical, New Brunswick, NJ,
evaluated 66 women who underwent myomectomy
USA). The gel is supplied in a single-use bottle. In a large
with or without Spraygel application. A second-look
multicenter randomized study, Johns et al. reported
laparoscopy was performed in 40 women. They reported
that it was effective in reducing adhesions. In an animal
that seven of 22 patients (31.8%) in the Spraygel group
model, FeHA does not prevent adhesion formation
and two of 18 patients (11.1%) in the control group were
The product was withdrawn from the market due to
free of adhesions. The power of the study was low and
several reports of late-onset postoperative pain requiring
the authors did not subgroup patients to laparoscopic
repeated surgery. Other reported side effects are foreign-
myomectomy or myomectomy by laparotomy.
body reactions and tissue adherence.
This substance consists of polyethylene oxide and
Modifying hyaluronic acid to obtain an auto-crosslinked
carboxymethylcellulose stabilized by calcium chloride.
hyaluronic acid increases its adhesivity and prolongs its
In a small randomized series, 15 ml of this substance was
residence time on injured raw surfaces. In a small study,
instilled to the adnexal area in 25 patients The
this substance was found to decrease postmyomectomy
results were compared to those of 24 patients who under-
adhesion formation The authors also noted that
went surgery without the use of the gel. The authors
subserous suture was associated with less adhesion than
reported that viscoelastic gel decreases postsurgical
interrupted figure-of-eight sutures.
adnexal adhesions. However, they also found thatpatients with severe adhesions and concurrent stage IV
Guida et al. found that intrauterine application of
endometriosis did not have a reduction in adhesion score
this agent after hysteroscopic surgery is associated
with fewer intrauterine adhesions. Indeed, intrauterineadhesions can cause infertility and miscarriage. Cur-
rently, the degree of interest in preventing intrauterine
Vitamin E has antioxidant, anti-inflammatory, and anti-
adhesion formation and reformation is still not high.
fibroblastic effects. In addition, it decreases collagenformation. In theory, it may decrease adhesion formation.
Combined hyaluronic acid and carboxymethylcellulose
In a cecal abrasion model, intraperitoneal administration
of vitamin E in olive oil was effective in reducing
Sepracoat (HAL-C, Bioresorbable Membrane; Genzyme
adhesion formation Intraperitoneal instillation
Corporation, Cambridge, MA, USA) is composed of
of olive oil as well as intramuscular administration of
chemically derived sodium hyaluronate and carboxy-
methylcellulose. It coats serosal surfaces and is absorbedfrom the peritoneal cavity within 7 days. Kelekci et al.
recently confirmed that it is effective in reducing
The following are other substances that have been
adhesion in a rat uterine horn model. They also noted
evaluated for adhesion prevention. To date, only animal
less vascularization in the treated group. In a multicenter
randomized study, Diamond reported that Sepracoatdecreases de novo adhesion formation.
Camptothecin-loaded filmsAnimal studies have shown that a substance that inhibits
A slight modification of the peritoneal instillate Sepracoat
inflammation and angiogenesis might be effective in
is the bioresorbable membrane Seprafilm (Genzyme
reducing adhesion formation. Camptothecin is a drug
Corporation), supplied in 12.7 Â 15.2 cm sheets. It was
with anti-inflammatory, antiproliferative, and antiangio-
reported to be effective in reducing the incidence, extent,
genic properties. It belongs to a general class of com-
and severity of postmyomectomy adhesions .
pounds, the topoisomerase inhibitors, that includesantineoplastic drugs such as doxorubicin. The use of
crosslinked hyaluronic acid film containing camptothecin
One of the novel techniques of substance delivery into
was evaluated in a rat cecal sidewall abrasion model
the abdominal cavity is by combining two streams of
Adhesion formation was decreased in the treated rats. No
liquid polymers, delivered via catheter to the target
toxicity was observed. Whether this substance is safe for
tissue. The combination of these polymers produces
solid polymer in a few minutes. Using this technique,sprayable hydrogel was developed (Spraygel; Confluent
Surgical, Boston, MA, USA). It can be applied easily by
Sodium chromoglycate stabilizes the membranes of mast
laparoscopy. The solid polymer acts as an adhesion
cells. In a rabbit cecal abrasion model, this substance
barrier and can potentially serve as a carrier for localized
decreases adhesion formation Addition of aprotinin
Adhesion prevention Tulandi and Al-Shahrani
and dexamethasone increases its efficacy. Dexame-
the effects on adhesion formation remain unclear. Instead
thazone alone has been investigated previously and is
of modifying the temperature of the pneumoperitoneum
clinically ineffective. Aprotinin is a proteolytic enzyme
gas, Binda et al. investigated the effects of room
that inhibits kallikrein and plasmin. Its efficacy when
temperature on adhesion formation in a mouse model.
Compared to those in a chamber at 378C, rats kept at23–258C had decreased adhesion formation. It is possible
Ibuprofen-loaded poly-(L-lactic acid) polyethylene glycol
that hypothermia decreases the toxic effects of hypoxia
Using a vehicle such as polyethylene glycol, an active
and of the ischemia-reperfusion process. Most studies on
drug can be delivered to a tissue locally. In a rat model,
modifying the temperature, humidity, or consistency of
nonsteroidal anti-inflammatory drug (ibuprofen)-loaded
pneumoperitoneum gas are performed with animal
poly-(L-lactic acid) (PLLA) polyethylene glycol (PEG)
models. The implications in humans remain unclear.
decreased adhesion formation Many other sub-stances that have been tried in animal models, but their
There has been a wide variety of adhesion-reducingsubstances evaluated in animal models. Among the
newest agents are hyaluronic acid and sprayable hydro-
Despite the use of laparoscopic technique and the use of
gel. In a small study, they have been shown to be
microsurgical principals such as gentle tissue handling,
effective in reducing postmyomectomy adhesions. Sur-
use of fine instruments, and non-reactive suture material,
gical approach is an important factor with laparoscopy
postsurgical adhesions are still a problem. Furthermore,
being associated with less adhesion formation compared
to date no adhesion-reducing substance is unequivocally
to laparotomy. For laparotomy, closure of the peritoneum
effective. Surgeons are still trying to find a surgical
is unnecessary, and might be associated with more
adhesion formation. The recent practice of temporaryabdominal oophoropexy after surgery of stage of III and
IV endometriosis might be beneficial.
Randomized trials on peritoneal non-closure have shownthat closing the peritoneum – either parietal or visceral
Currently, the degree of interest in preventing intrau-
peritoneum – is unnecessary. It is associated with slightly
terine adhesion formation and reformation is still not
longer operating time, more postoperative pain, and
high. One study shows that intrauterine application of
there is a suggestion that it might cause more adhesion
auto-crosslinked hyaluronic acid decreases intrauterine
formation . Ellis noted that there have been
increasing medicolegal claims arising from adhesion-related complications. He stated that ‘peritoneal defects
Today, we are still far from finding the ideal adhesion-
and the pelvic floor should be left open since they rapidly
preventing agent There is still no adhesion-prevent-
ing substance, material, or barrier that is unequivocallyeffective. One can reduce the adhesion formation, but not
prevent it entirely. Fortunately, we are not alone; other
In an attempt to prevent ovarian adhesion, several
specialists including general surgeons, neurosurgeons,
authors have advocated transient abdominal oophor-
ophthalmologists, and others have become aware of the
opexy. Ouahba et al. performed this procedure in
problem and are actively trying to find the solution.
20 young women with stage III and IV endometriosis.
Ovarian suspension was done using 3-0 Prolene that was
inserted on the medial surface of the ovary adjacent to the
Papers of particular interest, published within the annual period of review, have
ovarian ligament, bringing the ovary laterally and appos-
ing the medial surface of the ovary to the anterior
abdominal wall. The suture was tied on the low abdo-minal quadrant and removed 4 days later. Eight patients
Al Jaroudi D, Tulandi T. Adhesion prevention in gynecologic surgery. Obstet
underwent a second-look laparoscopy and this procedure
appeared to be effective. However, a larger study is
Muzii L. Survey among members of the roman group of gynecologic endo-
scopy on the use of agents for postoperative adhesion prevention. J Am Assoc
needed to prove the benefits of this technique.
Despite its ineffectiveness, most surgeons are using Ringer’s lactate.
Carta G, Cerrone L, Iovenitti P. Postoperative adhesion prevention in gyne-cologic surgery with hyaluronic acid. Clin Exp Obstet Gynecol 2004; 31:
In laparoscopic surgery, pneumoperitoneum with CO2
gas is a necessity. However, it has been suggested that the
Johns DB, Keyport GM, Hoehler F, diZerega GS. Intergel Adhesion Preven-
low temperature of the gas might be associated with more
tion Study Group. Reduction of postsurgical adhesions with Intergel adhesionprevention solution: a multicenter study of safety and efficacy after conser-
peritoneal injury. This has led to the use of warm gas but
vative gynecologic surgery. Fertil Steril 2001; 76:595–604.
Minimally invasive gynecologic procedures
Detchev R, Bazot M, Soriano D, Darai E. Prevention of de novo adhesion by
12 Lundorff P, Donnez J, Korell M, et al. Clinical evolution of Viscoelastic gel for
ferric hyaluronate gel after laparoscopic surgery in an animal model. J Soc
reduction of adhesion following gynecological surgery by laparoscopy in
Europe. Hum Reprod 2005; 20:514–520.
Pellicano M, Bramante S, Cirillo D, et al. Effectiveness of autocrosslinked
13 Ynfante I, Bejarano D, Conde J, et al. Prevention of peritoneal adhesions by
hyaluronic acid gel after laparoscopic myomectomy in infertile patients: a
intraperitoneal administration of vitamin E: an experimental study in rats. Dis
prospective, randomized, controlled study. Fertil Steril 2003; 80:441–
Intraperitoneal administration of vitamin E diluted in olive oil can prevent adhesionformation in a rat model. Whether it is applicable to human is unknown.
Guida M, Acunzo G, DiSpiezio Sardo A, et al. Effectiveness of auto-
crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions
14 Weis C, Odermatt EK, Kressler J, et al. Polyvinyl alcohol membranes for
after hysteroscopic surgery: a prospective, randomized, controlled study.
adhesion prevention. J Biomed Materials Res 2004; 70B:191–202.
15 Cashman J, Burt HM, Springate C, et al. Camptothecin-loaded films for the
This is one of the pioneering studies on prevention of intrauterine adhesions. The
prevention of postsurgical adhesions. Inflamm Res 2004; 53:355–362.
authors found that auto-crosslinked hyaluronic acid gel was effective in reducingintrauterine adhesions.
16 Lee JH, Go AK, Oh SH, et al. Tissue anti-adhesion potential of ibuprofen-
loaded PLLA-PEG diblock copolymer films. Biomaterials 2005; 26:671–678.
Kelekci S, Yilmaz B, Oguz S, et al. The efficacy of a hyaluronate/carboxy-methylcellulose membrane in prevention of postoperative adhesion in a rat
17 Tulandi T, Al-Jaroudi D. Non-closure of peritoneum: a reappraisal. Am J Obstet
uterine horn model. Tohoku J Exp Med 2004; 204:189 –194.
Diamond MP. Reduction of de novo postsurgical adhesions by intraoperative
18 Ellis H. Medicolegal consequences of postoperative intra-abdominal adhe-
precoating with Sepracoat (HAL-C) solution: a prospective, randomized,
sions. J Roy Soc Med 2001; 94:331–332.
blinded, placebo-controlled multicenter study. The Sepracoat Adhesion
19 Ouahba J, Madelenat P, Poncelet C. Transient abdominal ovariopexy for
Study Group. Fertil Steril 1998; 69:1067–1074.
adhesion prevention in patients who underwent surgery for severe pelvic
10 Diamond MP, and the Seprafilm Adhesion Study Group. Reduction of
endometriosis. Fertil Steril 2004; 82:1407 –1411.
adhesions after uterine myomectomy by Seprafilm membrane (HAL-F): a
Temporary abdominal oophoropexy for 4 days in a small number of women
blinded, prospective, randomized, multicenter clinical study. Fertil Steril
appears to be effective in decreasing adhesion to the ovaries in women with
stage III and IV endometriosis. This could be a promising surgical technique toprevent ovarian adhesions.
11 Mettler L, Audebert A, Lehmann-Willenbrock E, et al. A randomized, pro-
spective, controlled, multicenter clinical trial of a sprayable, site-specific
20 Binda MM, Molinas CR, Mailova K, Koninckx PR. Effect of temperature upon
adhesion barrier system in patients undergoing myomectomy. Fertil Steril
adhesion formation in a laparoscopic mouse model. Hum Reprod 2004;
It appears that sprayable hydrogel is effective in reducing postmyomectomy
21 Tulandi T. Prevention of adhesion formation: the journey continues. Hum
S o u t h M i a m i O B - G Y N A s s o c i a t e s H elp fu l Res ou rces This fact sheet is meant to provide you with basic information about this medicine. As usual, any further questions should be discussed with your doctor or p 1. What is Serophene/Clomid? It is the brand name for Clomiphene citrate, which is a medicine that has been on the market since the 1960s and introd
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