Pathophysiology of Adhesion
Michael P. Diamond, MD
Professor, Department of Obstetrics &
Gynecology, Wayne State University, USA
Director, Division of Reproductive Endocrinology
Diaa M. EI-Mowafi, MD
Associate Professor, Department
of Obstetrics & Gynecology, Benha Faculty of Medicine, Egypt
Researcher & Educator, Wayne
State University, USA
Fellow, Geneva University, Switzerland
Pelvic adhesions observed in gynecologic
patients are a major contributing factor to infertility, pelvic pain and/or
intestinal obstruction. Such adhesions may be the sequelae to inflammatory
processes, endometriosis, and prior surgical intervention. The latter will
be the main topic of this article.
It has been recognized that pelvic adhesions
occur in 55-95% of women following a laparotomy.1
This occurs in clinical trials in spite of different meticulous methods
used to achieve this goal, including microsurgical technique, operative
laparoscopy, the use of carbon dioxide laser and the use of medical and
This chapter explores the pathophysiology of adhesion formation and the
different methods of its prevention or reduction. These different methods
include: different ways to get into the abdomen (i.e. via laparotomy or
laparoscopy), the variable surgical methods used either during the initial
pelvic surgery or adhesiolysis which include macrosurgery, microsurgery,
laser surgery and endoscopic surgery, and lastly, the different medical
and/or surgical adjuvants used to prevent adhesion formation.
Pathophysiology of Adhesion Development
Adhesion development represents a disruption
in the normal physiological process of peritoneal healing, although it
is probably incorrect to call it abnormal healing since adhesion development
can be thought of teleologically as a way for the body to resupply oxygen
and nutrients to devascularized tissues. Following peritoneal injury, the
process of healing without adhesions is initiated by release of histamine
and vasoactive kinins causing an increase in capillary permeability with
subsequent outpouring of serosanguinous fluid within three hours. This
proteinacious fluid will coagulate, producing fibrinous bands between the
A variety of inflammatory cells, including monocytes,
plasma cells, polymorphonuclear cells, and histiocytes migrate to these
fibrinous bands. Importantly, the fibrinolytic system is triggered to
lyse these bands, usually within 72 hours. The denuded area of peritoneum
is then reepithelized, probably within three to five days, with healing
completed within 3 to 4 weeks. In contrast to skin which reepithelizes
from the edges in, reepithelization of the peritoneal injury begins with,
mesothelial migration from underlying primitive cells to line the denuded
area into the peritoneal supportive matrix. If a disturbance in this equilibrium
between fibrin deposition and fibrinolytic activity occurs, the fibrinous
strands will persist, and will subsequently be infiltrated by proliferating
fibroblasts, and later, new angiogenesis will take place and if tissue
ischemia exists, thus an adhesion is created.4
In fact, the definite etiology of pelvic adhesion
formation is not clearly well known, but the following risk factors have
been incriminated in this process:
Tissue hypoxia or ischemia.
Rough manipulations of tissues during surgery.
Presence of reactive foreign body.
Presence of intraperitoneal blood.
Dissection of prior adhesions.
Ischemia of the tissues may result from excessive
or rough tissue handling, ligating, suturing, crushing, cauterizing or
stripping of the peritoneum. These may cause adhesion formation via inhibition
of the fibrinolytic activity (which resides in peritoneal tissue) and stimulation
of angiogenesis from a non-ischemic area to that devoid of its adequate
blood supply. In addition, desiccation of the peritoneal tissue during
prolonged surgical procedures may result in mesothelial cell desquamation
with a resultant raw basement membrane and fibrin deposition.5
The common reactive foreign bodies that may be
introduced into the field during surgery include: sutures, talc powder
from surgical gloves, lint from drapes, cans, gowns, masks or laparotomy
pads. Such foreign bodies lead to niduses excessive formation of the fibrin
mass, which may result in adhesion formation. Interestingly, however, adhesions
are less likely to develop in the presence of foreign body without coincidental
The presence of intraperitoneal blood has been
proposed to cause adhesions formation, although its actual role is not
In general, intraperitoneal blood usually does not cause adhesion formation,
except in the presence of tissue ischemia.7
It was a common concept that the mechanism of
de novo adhesions formation and reformation after adhesiolysis is the same,
although there is no experimental data supporting this. Nevertheless, in
both experimental and clinical investigations the probability for adhesion
reformation was greater than its de novo formation.1
This may be attributed to the higher degree of tissue ischemia in the previously
damaged tissues than the native one.
Staging of Adhesions
Staging or classification of any medical or surgical
disorder is the cornerstone to reach a univocal understanding facilitates
communication among physicians and investigators, give a true judgment
on the different modalities of treatment and clarify the expected prognosis
for every individual case. Going into a medical or surgical disorder without
staging or classification is like looking for luggage without an identification
tag at Heathrow Airport.
In 1982, Hulka8
published a prognostic classification after five years of surgery for infertile
patients in his institute. His classification was based upon 2 main factors;
the extent of ovarian involvement and the nature of adhesions, whether
filmy or dense. The poorest prognoses for achieving a spontaneous conception
were in those patients with dense adhesions covering more than 50% of the
ovarian surface visible at laparoscopy. The American Fertility Society
(AFS) classification of adnexal adhesions (1985) had a great acceptability
and became a universal one for many years.
Recently, the Adhesion Scoring Group (1994)1
published their more comprehensive adhesion scoring system based on evaluation
of 23 individual locations in the abdominal cavity for severity (0, none;
1, filmy, avascular; 2, dense and/or vascular; 3, cohesive) and extent
of total area or length (0, none; 1£ 25%; 2, 26-50%; 3, >50%;4).
The Adhesion Scoring Group reported that although
the AFS adhesion scoring method generated significant agreement between
pairs of surgeons, the use of the more comprehensive adhesion scoring method
specifically demonstrating locations, severity, and the extent of adhesions
produces a marked increase in reproducibility between surgeon pairs in
scoring pelvic adhesions.
Unfortunately, none of these systems have been
validated with clinical outcomes, and it is unlikely that they ever will
The latter is because at second-look to score
adhesions, additional surgical intervention is usually conducted; thus,
clinical outcomes reflect the results of the second look procedure as opposed
to the status of the pelvis at the beginning of the procedure.
As the previous classifications need the usage
of an invasive procedure (usually laparoscopy) to achieve it,
ultrasonography as a non-invasive tool was used
recently to attempt to classify the pelvic adhesions.4
Surgery or Assisted Reproductive Techniques?
For many decades, surgical adhesiolysis was the
only realistic option for an infertile patient with pelvic adhesions. After
the birth of the first "test tube" baby, Louise Lesley Brown, in 1978 in
England, a revolution in the use of assisted reproductive techniques (ART)
took place. These techniques include9:
in vitro fertilization and embryo transfer (IVF-ET), gamete intrafallopian
transfer (GIFT) and zygote intrafallopian transfer (ZIFT). Microinjection
(micro-manipulation), which entails mechanical transfer of sperm into the
oocyte by a special micropipette is the most recently introduced assisted
reproductive technique if there is an additional contributing factor for
infertility such as severe oligospermia or athenospermia, or inability
of sperm to penetrate the oocyte due to immunologidal factors. The main
procedure for microinjection is intracytoplasmic sperm injection (ICSI),
where the micropipette carrying the sperm is introduced through the zona
pellucida into the oocyte cytoplasm and one sperm deposited. Now, the question
is, which is more beneficial to the infertile female with pelvic adhesions;
surgery or ART? Reported pregnancy rates after surgical treatment of pelvic
adhesions vary from 25% to 75%. Rock et al.,10
reported normal pregnancy rates after surgery on severe, moderate and mild
distal tubal obstruction to be 5%, 17% and 80% respectively, while the
ectopic pregnancy rates were 0%, 13% and 6% respectively. The 17% rate
of normal pregnancy reported after surgical treatment of moderate disease
is comparable to the clinical pregnancy rate of 16% per retrieval for IVF-ET
which was reported consistently over four years by the United States National
However, the 13% rate of ectopic pregnancy seen after surgical repair of
moderate disease is nearly three times the approximately 5% rate expected
Before choosing between surgery or ART, one must
consider the severity of adhesions (the more extensive and dense, the poorer
the prognosis of surgery)13,
the patient's age, previous reproductive surgery, coexistent infertility
factors as poor semenogram, suspected cervical or immunological cause and
last, but not least, the financial constraints.
If the surgical approach is the wisest decision,
the rational now is to reduce adhesion formation following both the primary
reproductive surgery and/or adhesiolysis. This rationale passes through
the following three main stations:
I. Getting into the abdomen.
II. Surgery inside the abdomen.
III. Adjuvants for adhesion reduction.
Getting into the abdomen:
Laparoscopy versus Laparotomy
The era of operative laparoscopy started in the
1980s and expanded to involve most of the previous traditional pelvic surgery.
The advantages of endoscopic surgery are claimed to be reduction of hospital
stay, postoperative pain, length of abdominal incision, and expense. One
of the claims is the reduction of subsequent postoperative adhesion formation.
This view is supported in theory by the concepts of lack of retractors
and packs usage at laparoscopy, maintaining a closed abdomen with presumed
reduction in peritoneal drying, less likelihood of introduction of foreign
bodies, decreased possibility of blind dissection of adhesions during abdominal
exploration and less tissue damage at the abdominal wall incision(s) compared
to that of laparotomy. Luciano and co-worker14
have demonstrated no intra-abdominal adhesions in rabbits with the lesions
created laparoscopically, whereas those lesions created at laparotomy were
consistently followed by adhesion formation. Furthermore, the investigators
then assigned those animals with adhesions to adhesiolysis at laparotomy
or laparoscopy and demonstrated greater reduction in adhesion reformation
adhesiolysis. In their study, Nezhat and co-worker15
reported no de novo adhesion formation at non-operated sites at a second
look laparoscopy done 4-8 months after laser laparoscopy for the treatment
of endometriosis associated infertility in 157 patients. An overall 60-79%
reduction in adhesions in patients undergoing adhesiolysis was observed.
Diamond and co-workers16
described in a multicenter study a high (97%) incidence of adhesion reformation
seen at early (90 days) second-look laparoscopy following laparoscopic
adhesiolysis. Moreover, adhesion reformation occurred regardless of the
consistency or vascularity of the initial adhesion.
This incidence is consistent with that previously
reported following adhesiolysis at laparotomy, therefore they concluded
that adhesion reformation would not be able to be eliminated by utilization
of endoscopic surgery per se. Their report also pointed to a 12% of patients
who developed de novo adhesions.
At this time, it seems that there is no clear
and convincing evidence that laparoscopic adhesiolysis in humans is superior
to microsurgical lysis of adhesions at laparotomy in terms of adhesion
reformation or subsequent pregnancy.
Surgery inside the Abdomen
The use of microsurgery in reproductive pelvic
surgery was first described by Swolin in 1967.17
The term microsurgery basically implies the use of magnification to allow
close visualization, differentiation between healthy and pathologic tissues,
handling the small caliber microsurgical instruments, and use of fine sutures.
The fine sutures should be non-reactive, such as Vicryl, Dexon, or non-absorbable.
The other main principles of microsurgery have included: minimization of
tissue handling, prevention of tissue desiccation, avoidance of introduction
of foreign bodies such as talc into the operative field, precise reapproximation
of tissue planes and meticulous hemostatis.18
However, probably of greater controversy among these dictums is the benefit
of precise approximation of tissue planes. Tulandi and his colleagues19
reported that leaving the anterior abdominal wall peritoneum unsutured
after laparotomy results in less postoperative adhesions than its closure.
However, they used chromic suture for closure; if a less reactive suture
had been used, more difference might be noticed. Moreover, several studies
recently suggested that ovarian bisection in animals results in fewer adhesions
when the ovary is left open rather than closed. 20,21
In general, the use of microsurgical technique
for adhesiolysis has improved the pregnancy outcome. It is difficult to
interpret the results of the reports in the literature because of the variation
in adhesion extent, consistency, and vascularity in addition to the personal
skill variation. However, the following table shows a comparison between
the results of use of macrosurgery versus microsurgery for adhesiolysis.
Table (1) Comparison between the results of
macrosurgery versus microsurgery for adhesiolysis.
Total No. of Patient
Ongoing Pregnancies (%)
& co-workers 22
O’Brien & co-workers 24
Betz & co-workers 25
Caspi & co-workers 13
Donnex & Casanas-Roux 28
Frantzen & Schlosser 30
Laser Endoscopic Surgery:
Different types of laser now used in the reproductive
pelvic surgery include argon, potassium-titanyl-phosphate
(Nd:YAG); but the most frequently used to date is the carbon dioxide, employed
for its superficial site of action and variable spot size. It has been
postulated that laser surgery will decrease dramatically the incidence
of adhesion formation and reformation by virtue of making precise incisions,
minimization of tissue handling, maintenance of meticulous hemostasis and
reduction in operative time. However, in rabbits and rats, no reduction
in post-operative adhesion was seen when the CO2 laser
was compared with fine needle cautery.31,32
In a multicenter prospective study, an early
(within 12 weeks) second-look laparoscopy was performed by Diamond and
his colleagues 33to
assess tubal patency and adhesion formation after intra-abdominal laser
surgery. Procedures performed included neosalpingostomy, fimbrioplasty,
lysis of adhesions, vaporization of endometriosis, and ovarian wedge resection.
The results were compared with those of another multicenter prospective
study that utilized non-laser reconstructive pelvic surgery. Use of CO2
laser was found to result in a greater tubal patency rate and adhesions
were reduced from initial presentation at most sites. However, non-laser
infertility surgery appeared to have equal or greater efficacy in the prevention
of adhesion formation. It was concluded that the CO2
laser does not appear to be a panacea for the treatment of tuboperitoneal
causes of infertility.
examined 11 patients at second-look laparoscopy 12 to 21 days following
laser laparoscopic adhesiolysis. No intraoperative agents were used for
adhesion prevention. Fifteen sites were evaluated for adhesions. All patients
had adhesion reformation in at least one site. Fifty-six percent of available
sites had adhesions at second-look laparoscopy, which was not a significant
change from the 60% of sites with adhesions of initial laparoscopy. De
novo adhesions formed in seven of the patients at 23% of available sites.
utilized early second-look laparoscopy, done 6 to 12 weeks postoperatively,
to evaluate recurrent adhesion formation following laser ovarian wedge
resection. Forty-nine ovaries in 25 consecutive infertile patients underwent
laser surgery for deep endometriosis or polycystic ovarian disease, refractory
to medical treatment. On second-look laparoscopy, 36.7% of the ovaries
had recurring adhesions; 83.3% of these adhesions were mild and filmy,
and 16.7% were moderate and dense. Additionally, 2 ovaries that had mild
and filmy adhesions lysed at 6 weeks during the second-look laparoscopy,
have been found to have no recurrent adhesions when viewed one year later
postoperatively. The actual pregnancy rate in this study is 60%, with 15
of the 25 patients conceiving at least once and two patients conceiving
twice. The majority of pregnancies occurred within the first six months
postoperatively, with the longest initial pregnancy occurring 22 months
postoperatively. The author concluded that laser ovarian surgery, coupled
with early second-look laparoscopy, appears efficacious in minimizing adhesion
reformation and seems to have little adverse effect on subsequent conception.
stated that CO2 laser remains the most precise laser,
especially in the ultrapulse mode, for the division of adhesions and the
accurate and safe vaporization of deposits of endometriosis. The neodymium:YAG
laser, because of its greater depth of penetration, is more suited to hysteroscopic
surgery. Carbon dioxide laser energy is strongly absorbed by the water
molecule and is rendered ineffective in the presence of blood, so the visible
light lasers, argon and KTP-532, are more suitable for the treatment of
ovarian endometriomas and ectopic pregnancies. The author concluded that
the main advantage of the various lasers is that they allow fertility surgeons
to perform operative surgery by the minimally invasive approach of laparoscopy
To summarize these and other studies appearing
in the literature, it appears that lasers are useful for the performance
of gynecological procedures when utilized by surgeons experienced in their
use. However, it does not appear that use of a laser per se reduces postoperative
adhesions or the complications they cause as compared to other surgical
modalities. Furthermore, it appears that the use of lasers is generally
decreasing, as surgeons become more experienced with alternative means
of incising/excising tissue and in establishing hemostasis
VALUE OF SECOND-LOOK LAPAROSCOPY (SLL)
The principle of SSL was first introduced by
Swolin to evaluate the result of some surgical procedures.1
This principle soon became a routine used by many gynecological surgeons
and investigators allowing a chance to perform adhesiolysis for the de
novo or recurrent adhesions encountered during SLL. This is assumed to
give the infertile patient a better opportunity to get pregnant. Trimbos-Kemper
went to further "third-look laparoscopy" in patients who had undergone
an early second-look procedure with adhesiolysis at that time. They reported
that more than half of the adhesions that were separated at the second-look
laparoscopic procedure did not recur. The same was shown by Jansen38,
who reported that second-look laparoscopy resulted in a significant reduction
in adhesions at the time of a "third-look laparoscopy". The next logical
question is: does the second-look laparoscopy provide benefit in terms
of increasing the incidence of intrauterine pregnancies and/or decreasing
that of ectopic pregnancy? Trimbos-Kemper37
reported a reduction in the incidence of ectopic pregnancy in women who
had undergone SLL, although the intrauterine pregnancy rate was unchanged.
Surry and colleagues39
reported a 52.1% intrauterine pregnancy in 31 patients who had undergone
early SLL after reconstructive pelvic surgery. Unfortunately, none of these
studies have been properly designed to provide a definitive answer to the
value of second-look laparoscopy.
Other potential advantages of second-look laparoscopy
include the ability of the surgeon to assess the efficacy of surgical techniques
or adjuvants, as well as to provide the patient a reasonable assessment
of likely prognosis. If the patient is among the approximately ten percent
of subjects in whom adhesions worsen, that patient may benefit from early
referral to ART as opposed to protracted lengths of time spent trying to
conceive against very long odds.
What is the reasonable time for SLL? Even now,
it is still a matter of personal opinion and controversy, varying from
few days 37,38,40
to three years41
postoperatively. Swolin's opinion encouraged 6 weeks postoperatively as
an optimum period for SLL42.
Some surgeons feel that adhesiolysis performed via SLL carried out less
than 2 weeks after the initial surgery is associated with increased bleeding
from granulation tissue at adhesion sites; others prefer this interval
because it is before patients have fully recuperated from their initial
surgery and they anecdotally feel adhesions are easier to separate at this
early time. Clinical studies, however, have not been able to identify differences
in the frequency or severity of adhesions from intervals of 1-2 weeks to
3-4 months between the two procedures. Importantly, this suggests that
if adhesions are going to develop postoperatively as a consequence of the
surgical procedure that they will do so during the initial week after surgery.1
On the other hand, bleeding will also be considerable if the procedure
is done more than 12 weeks after surgery as the adhesions become more dense
Adjuvants for Adhesion Reduction
Adhesion formation and reformation are still
an unavoidable event in reproductive pelvic surgery in spite of the variable
skills in microsurgery, endoscopic or laser surgery. This fact necessitates
the search for an adjuvant(s) that can be used in the perioperative period.
The field of these adjuvants becomes large enough to require a classification.
Table (2): Classes of adhesion-reduction adjuvants
and their proposed mechanism of action
I. Fibrinolytic agents (fibrinolysis,
stimulation of plasminogen activators)
II. Anticoagulants (prevention of clot
and fibrin formation)
III. Anti-inflammatory Agents (reduce
vascular permeability, reduce histamine release and, stabilize lysozomes)
Nonsteroidal anti-inflammatory agents
Calcium channel blockers
VI. Antibiotics (prevent infection)
V. Mechanical Separation (surface separation,
A. Intra-abdominal Instillates:
Chelated hyaluronic acid
Oxidized regenerated cellulose
Modified from Diamond MP, DeCherney AH: Pathogenesis
of adhesion formation/reformation: Application to
reproductive pelvic surgery. Microsurgery 1987:
8: 103 and Diamond MP, Hershlag A: Adhesion formation/reformation: in Treatment
of postsurgical Adhesions, Wiley-Liss, Inc. 1990: 23-33.
Fibrinolytic agents act directly by reducing
the fibrinous mass and indirectly by stimulating plasminogen activator
Plasminogen activator is a serine protease that
converts plasminogen into plasmin, which causes fibrin degradation. Recombinant
tissue plasminogen activator (rtPA), delivered locally, was investigated
by Vipond and colleagues44
in rats and found to be successive in reduction of adhesion formation significantly.
It was even superior to carboxymethylcellulose (CMC) gel used in another
group in the same study. CMC is another chemical component widely investigated
for prevention of adhesions. Again, LeGrand and co-workers45
reported in their study on a rabbit model that imidazole, a thromboxane
synthetase inhibitor, showed significant efficacy in prevention of adhesion
formation to theuterine horn. They also found that Ridagrel, an inhibitor
of thromboxane synthetase as well as a thromboxane A2 receptor blocker,
also showed significant efficacy in reducing peritoneal adhesion severity.
These results were contradictory to that of two other studies. The first
was carried out by Gehlbach and others on rabbits46.
They concluded that the combination of intraperitoneal rtPA and carboxymethylcellulose
(CMC), did not reduce postsurgical adhesion reformation, and was associated
with hemorrhagic complications. The second study was carried out by Bothin47
and reported the rtPA and oxidized regenerated
cellulose (ORC), which is an exogenous barrier, were unable to decrease
adhesion formation. Nevertheless, rtPA mitigated the adhesion-increasing
effect of ORC. Another worse drawback was reported by Evans and colleagues48
as they noticed that the levels of rtPA reguired to alter or prevent intra-abdominal
adhesion formation also produce a significant impairment of the early phase
of wound healing as measured by the wound content of hydroxyproline. Prior
investigations have shown a strong correlation between wound-bursting strength
and hyroxyproline content. The use of fibrinolytic agents in humans awaits
Heparin is the most widely investigated
anticoagulant used for prevention of adhesions. Its mechanism of action
is probably through one of the following: first, heparin may interact in
the clouding cascade by a combination with antithrombin III.49
Second, heparin directly stimulates the activity of plasminogen activators,
thereby promoting breakdown of fibrin clots once they form.50
Lastly, heparin may act by binding to fibroblast growth factor (FGF) leading
to considerable improvement in healing of cutaneous wounds.51
Heparin has been added to peritoneal irrigants with concentrations around
In animal studies, this route of administration proved its efficacy.53,54
In rat uterine horn model, Sahin and Saglam55
added the low molecular weight heparin to the sodium carboxymethylcellulose
solution instilled at laparotomy. They reported that this combination is
highly effective in reducing postoperative adhesions in this animal model.
Heparin has also been added to the local mechanical barriers to enhance
its anti-adhesive benefit. Tayyar and co-worker56
added heparin to the amniotic membrane used to cover experimentally injured
rabbit uterine horns. They showed that this combination was effective in
reducing adhesion formation. In a rabbit uterine horn model study, Diamond
reported that heparin delivery by intraperitoneal lavage, intravenous injection,
or intra-abdominal instillation failed to reduce adhesion formation. Similarly,
heparin delivery with other intraperitoneal instillates as
carboxymethylcellulose or 32% Dextran 70 failed
to demonstrate efficacy. In their study, a significant reduction in adhesion
formation was only observed with the combination of Interceed (TC7) and
heparin where Interceed was utilized as a carrier to deliver heparin to
traumatized surfaces. In another study, the same group of investigators
reported that combination of the Interceed plus heparin in a dose of 500
and 1000 USP units per rabbit uterine horn resulted in a significant reduction
of the adhesion reformation scores.58
This improvement in efficacy was not able to be demonstrated in a clinical
trial done by Reid and co-workers59
where, after ovarian cystectomy and/or ovariolysis at laparotomy, one ovary
was wrapped in Interceed TC7, and the contralateral ovary was wrapped in
Interceed TC7 saturated with a heparin solution (1,000 U/ml). They noted
that addition of heparin did not enhance significantly the adhesion-reducing
capacity of the Interceed TC7 barrier when applied to ovarian surfaces.
However, it should be noted that the efficacy
of Interceed alone in the trial exceeded its efficacy in another recent
This group of agents was used to reduce the initial
inflammatory response to tissue injury and hence, subsequent adhesion formation.
This goal is probably achieved through the capability of these agents to
reduce vascular permeability, inhibit synthesis and release of histamines
and/or stabilize lysosomes. Anti-inflammatory agents that have been investigated
included corticosteroids, nonsteroidal agents, progesterone and progestogens,
antihistaminics and calcium channel blockers.
Corticosteroids have been shown to decrease
adhesion formation in small animals.61,62
Because of the large dosages required, the high risk of immunosuppression,
infection and wound disruption have been noted.63
Corticosteroids were probably used on a large scale in clinical practice
following Swolin's report that intraperitoneal hydrocortisone reduced adhesion
formation as proved at SLL.64
But it is of importance to mention that all patients who received adjuvant
for adhesion reduction were operated by Swolin, whereas those who did not
receive corticosteroids had other primary surgeons. In fact, most of the
animal studies failed to prove any reduction in adhesion formation with
diZerega and Hodgen65
found perioperative dexamethasone and promethazine to be ineffective in
preventing adhesion formation after trauma to the fallopian tube. Seitz
investigated adhesion reformation after adhesiolysis in monkeys. Normal
saline, low molecular weight dextran and dexamethasone/promethazine are
three different adjuvant therapies given for separate groups. Adhesion
reformation was similar in each of the three groups. The other few clinical
trials for corticosteroid usage failed to prove its efficacy in reduction
of adhesion formation.67
Nonsteroidal anti-inflammatory drugs (NSAIDs)
are acting through several postulated mechanisms. NSAIDs have an anti-prostaglandins
effect, thereby blocking the adhesiogenic action of prostaglandins instillated
They have also been shown to inhibit platelets’ aggregation, leucocyte
migration and phagocytosis, and lysosome release.5
Tolmetin, an NSAID was presumed to enhance macrophage function, and hence,
allow rapid phagocytosis of tissue debris or fibrin.69
Tolmetin and ibuprofen have also been shown to increase fibrinolysis through
decreasing the secretion of plasminogen inhibitors resulting in enhanced
Most of the animal studies showed the effectiveness of NSAIDs in prevention
of adhesions. Perioperative administration of oxyphenbutazone,72
and interaperitoneal instillation of indomethacin73
have been reported to reduce postoperative adhesion formation in rats and
monkeys. In a recent study45,
a rabbit uterine horn adhesion model was used to directly compare several
commonly used NSAIDs of different chemical classes in a single animal study
to evaluate their ability to prevent adhesion formation, Tolmetin, ibuprofen,
aspirin and indomethacin all showed significant and comparable efficacy.
These results support the view that there is a common mechanism through
which NSAIDs act to prevent adhesions. In spite of that, other studies
failed to prove any beneficial effect of intramuscular or intraperitoneal
administration of ibuprofen in reduction of peritoneal adhesions in rat
and rabbit models.73,74
Unfortunately, no clinical trials with NSAIDs have been published up until
now, although several have been conducted.
Antihistamines, such as promethazine,
inhibit the inflammatory response, stabilize lysosomal membranes and inhibit
fibroblast proliferation. The use of antihistamines to prevent adhesions
was in conjunction with corticosteroids and has not been shown to be effective
in human studies.75
Progesterone was investigated for reduction
of postoperative adhesions after the initial observation that adhesions
were less after ovarian wedge resection if that ovary was containing an
active corpus luteum at time of operation.76
Actually, the previous laboratory studies have elicited the anti-inflammatory
and immunosuppressive effects of the progesterone. It was also shown that
progesterone inhibits leukocyte migration77,
and T-cell activation78,
and reduces humoral antibody production. In addition, progesterone was
found to decrease vascular permeability and the resulting volume of transudate
Maurer and Bonaventura81
reported a decrease in adhesion formation if progesterone has been given
by interaperitoneal and intramuscular route. Other studies were contradictory,
finding an increase in adhesion development after intraperitoneal instillation
In addition, intraperitoneal and intramuscular medroxyprogesterone acetate
(MPA) has also resulted in an increase in postoperative adhesion formation82,84despite
a significant reduction in antibody titers to peritoneum and myometrium.84
This concept was present until Montanino-Oliva85
and others published their recent study showing that preoperative IM administration
of 15mg MPA into a rat model results in the most significant reduction
of postoperative adhesion formation, even when it has been compared to
leuprolide acetate and Ringer's lactate. They postulated that the action
of MPA might be mediated by the induction of both a progestational and
a hypoestrogenic milieu.
Calcium channel blockers have been shown
to inhibit the release of vasoactive inflammatory mediators such as histamine
and prostaglandins E and F.86
Tjssue ischemia is reduced as well by calcium antagonists.87
In addition, they have been demonstrated to inhibit platelet aggregation88,
protect against granulocyte-mediated tissue injury89,
and inhibit fibroblast migration into fibrin matrices.90
In a hamster animal model, Steinleitner and co-workers91
have demonstrated a reduction in pelvic adhesions with the use of subcutaneous
verapamil, nifedipine, and diltiazam. Continuous intraperitoneal verapamil
instillation was as effective as subcutaneous administration in the reduction
of primary adhesion formation92,
as well as adhesion reformation after lysis of peritoneal adhesions.93
These findings were unable to be confirmed in an animal study (Diamond
and Linsky, Unpublished data).
Colchicine, which is known to inhibit
histamine secretion, mitotic activity, and collagen synthesis and secretion,
has been shown to decrease adhesion formation in two studies using a rat
Unfortunately; no further studies have been carried out in this field.
The rationale behind the use of antibiotics is
prophylaxis against infection, and hence the inflammatory response, that
leads to adhesion development. Systemic broad-spectrum antibiotics, particularly
cephalosporins, were widely used in the past. Nowadays, tetracyclines are
commonly used to protect from chlamydia, a potentially infectious organism
in the female genital tract.96
Unfortunately, there is no sufficient published
data from animal or human studies supporting this practice. In contrast,
intraperitoneal irrigation with antibiotic-containing solutions has been
demonstrated to increase peritoneal adhesion formation in rat model.
Mechanical separation of peritoneal surfaces
of the pelvic organs during the early days of the healing process
postoperatively was a practical way to prevent
postoperative adhesions. This separation may be accomplished by intra-abdominal
instillates and barriers whether endogenous tissue or exogenous material.
Crystalloid solutions were the most commonly
used instillate put into the abdominal cavity after completion of the surgical
procedure. In addition to its mechanical action in separation of the raw
peritoneal surfaces, crystalloid solutions dilute fibrin and fibrinous
exudate released from the traumatised surfaces.12
Unfortunately, crystalloid solutions are absorbed
from the peritoneal cavity at an estimated rate of 35 ml/hr. Thus a volume
of 500 ml will be absorbed within about 14 hours and 5 liters of crystalloid
solution are needed to cover the first six days postoperatively. The process
of peritoneal repair, fibrin deposition, and adhesion formation extends
quite beyond the time during which a reasonable volume of crystalloid persists.
The other drawback is the possible increased risk of infection with instillation
of such a large volume of fluid into the peritoneal cavity.3
an attempt to prolong the period of instillate persistence inside the peritoneal
cavity, more viscous solutions have been tried in both experimental and
clinical studies. A 32% dextran-70 solution (Hyskon) was among the most
commonly used viscous solutions. Usually 200 ml of it is instilled into
the posterior cul-de-sac at completion of the surgery. Hyskon acts as a
siliconizing agent, coating raw surfaces. As an osmotic agent, it results
in hyrdroflotation of the pelvic viscera, and additionally it stimulates
Hyskon was investigated in four large clinical trials; the first initial
two reports demonstrated a significant reduction in postoperative adhesions.99,100
The subsequent two studies failed to detect a beneficial effect to Hyskon.101,102
Complications from its use in humans have been reported, including anaphylaxis,
pleural effusion, vulvar edema, transient liver function abnormalities,
wound separation, disseminated intravascular coagulation, and abdominal
bloating after its instillation.3
Carboxymethylcellulose (CMC) is a high
molecular weight polysaccharide that acts as an adjuvant for prevention
of adhesion by coating the intraperitoneal surfaces and creating hydroflotation
of intra-abdominal structures. Using the rabbit uterine horn model, Diamond
and co-workers found that intraperitoneal instillation of CMC significantly
reduced postoperative adhesion formation and reformation.103,104
Yaacobi and colleagues105
reported that tissue coating with CMC prior to cecal abrasion in rat significantly
reduced the formation of postoperative adhesion while coating following
cecal abrasion failed to inhibit adhesion formation. A novel CMC sponge
has been developed for prevention of surgical wound adhesions. It has been
investigated by Ryan and Sax106
by performing by performing cecal denudation in rats.
They concluded that CMC sponge was more effective
than Interceed in preventing postoperative adhesions. Its action was not
due to inhibition of cytokine transforming growth factor beta (TGF-beta)
expression or macrophage-derived fibrogenic factors.
Hyaluronic acid is a glycosaminoglyucan
that under aqueous conditions forms a viscous solution. In rat studies,
instillation of hyaluronic acid before cecal
abrasion reduced adhesion formation107
while coating serosa surfaces after tissue injury was ineffective.108
Grainger and others109used
the hyaluronic acid polymers at three different molecular weights and in
form of a polymer slab to prevent adhesions in a rabbit animal model. None
of the formulations of hyaluronic acid solutions resulted in a reduction
of ovarian adhesions. Only the polymer slab significantly reduced adhesion
formation. In a recent study110,
a modified hyaluronate-carboxymethylcellulose gel was effective for reduction
of adhesion formation in rat and rabbit models after surgery in the abdominal
cavity. Treatment with this bioabsorbable gel increased the number of animals
without any adhesions by 70% in a rat cecal abrasion model and by >70%
in a rabbit sidewall defect bowel abrasion model compared with non-treatment
Poloxamers are groups of surfactants characterized
by their ability to convert from a liquid state at room temperature to
a gel form at temperatures higher than 25oC. If recooled, the polymer returns
to its liquid state and conversion can be repeated. Poloxamer 407 of Flowgel
is derived from a 4000 Kd hydrophobe and is composed of polyoxythylene
and polyoxypropylene. Rice and colleagues111
used 0.5-1.5 ml of this poloxamer solution to cover uterine and sidewall
defects in rabbit models. They noted a significant reduction in primary
postsurgical adhesions; 95% of the control side had adhesions compared
to 40% of the treated side.
Endogenous barriers as human amniotic membrane
graft was tried to cover the traumatized surfaces for prevention of adhesions.
In a rabbit-uterine horn model, Arora and co-workers112
showed that amniotic membrane graft failed to have the preventive effect
on adhesion formation it is claimed to possess. Even worse amniotic membrane
graft resulted in higher adhesion scores and subserosal inflammation score
than the uncovered control side. Other data showed that when heparin was
added to the amniotic membrane, it was an effective combination in reducing
Exogenous barriers such as metal foils, plastic
silk and rubber sheets were used in the past to reduce postoperative adhesions.
However, these substances have been abandoned because of lack of success
and the need for its removal by a second surgical procedure.113
Gore-Tex surgical membrane is an exogenous
barrier. It is composed of a polytetrafluoroethylene (PTFE) which is nontoxic,
non-reactive and antithrombogenic; it is not absorbed and is unaffected
by tissue enzymes.114
Therefore, it is a permanent membrane unless it is surgically removed later
on. Placement requires suturing or some other form of fixation.
In the animal studies, Gore-Tex has been proven
to be an effective barrier for reducing primary adhesions, as well as reformation
This encouraged its clinical trials. March and colleagues116
carried out their study where 18 patients with extensive pelvic adhesions
and 10 with myomas had Gore-Tex applied over the adhesiolysis or myomectomy
sites. At second-look laparoscopy, the membranes were removed easily with
minimal adhesions to the traumatized site noted. However, it is common
for a membrane to envelop the PTFE. In a multicenter nonblinded randomized
clinical trial, Haney and his co-operatives117
studied 32 women with bilateral pelvic sidewall adhesions undergoing reconstructive
surgery and second-look laparoscopy. They found that Gore-Tex was associated
with fewer postsurgical adhesions to the pelvic sidewall and even superior
to oxidized regenerated cellulose (Interceed TC7). To date, third-look
studies to assess operative sites after removal of the enveloping membrane
at second-look have not been systematically performed.
Fibrin glue is a combination of highly
concentrated fibrinogen, thrombin, calcium, and factor VIII. It is postulated
that fibrin glue acts by separating the raw surfaces through its rapid
In a rat model, a reduction in intra-abdominal
adhesion formation was demonstrated with the administration of fibrin glue
with a high fibrinogen concentration (from cryoprecipitate) but not when
the fibrinogen concentration was low (from fresh frozen plasma).118
the use of human blood products for fibrin glue production limits its attractiveness
as a surgical adjuvant. Using rat models, a recent randomized, controlled
study was carried out by Evrard and co-workers,119
showed that although the mean adhesion score was reduced by >50% with application
of fibrin glue, there was no statistically significant difference concerning
adhesion formation or peritoneal healing with the use of fibrin glue.
Surgicel is an oxidized regenerated cellulose
(ORC) that was initially designed as a hemostatic agent. It was investigated
as an adjuvant for prevention of adhesions because it is easy to apply
and becomes a gel within hours after application.
Initial studies showed that Surgicel is effective
in preventing adhesions in rat cecal trauma model.l20,121
However, other studies failed to realize any reduction in adhesion formation
in the same animal.122
The same controversy has been found with the use of a uterine horn model.
In spite of most studies123
that found Surgicel to be effective in preventing adhesion formation, some124
did not confirm this observation.
Interceed (TC7) is an "altered relative"
to Surgicel also composed of oxidized regenerated cellulose but differs
in several characters including its degree of oxidation, weave, and smaller
pore size. Interceed becomes a gel about eight hours after its intra-abdominal
application. The material usually cannot be identified in the field within
3-4 days, and usually is degraded by the body without evidence of a foreign
body reaction at the site of application.124
Interceed is metabolized into glucose and glucoronic acid within a few
Initial rabbit studies using a uterine horn model
showed a decrease in adhesion formation.126
This observation was confirmed by Diamond et al,127
using a sidewall model in which each animal could be its own control. These
encouraging results initiated a human clinical trial conducted by multicenters.
This study showed a significant reduction in the incidence and area of
postoperative adhesion reformation in an actual report of 74 patients,128
and a follow up report of 134 patients.130
The use of Interceed necessitates meticulous hemostasis in the area prior
to its application, otherwise it becomes ineffective. Wiseman et al129
used thrombin to achieve hemostasis in a rabbit uterine horn adhesion model
facilitating the effect of interceed barrier. They added that the efficacy
of Interceed was further enhanced by adding heparin to the fabric. A large
multicenter study included 134 patients who underwent bilateral pelvic
wall microsurgical adhesiolysis. In this study, Interceed was shown to
further reduce the incidence, extent and severity of postoperative adhesion
reformation and 90% of the patients benefits from the use of Interceed.130
To evaluate the efficacy of Interceed in prevention of postsurgical ovarian
adhesions many studies were carried out. Franklin and The Ovarian Adhesion
published a multicenter randomized study including 55 patients with bilateral
ovarian disease. One ovary was randomly wrapped with Interceed at the completion
of laparostomy and the other was left uncovered. At the time of second-look
laparoscopy, they found that treatment of ovaries with Interceed significantly
reduced the occurrence and severity of postsurgical ovarian adhesions.
As regards laparoscopic ovarian surgery, Interceed was found to be safe
and effective also in reducing the incidence of postoperative adhesion
formation in patients undergoing laparoscopic ovarian cystectomy.132
These results are consistent with those of Larsson et al.,102
who also reported the ability of Interceed to reduce adhesions to the fallopian
tubes. In contrast, in a small study (n=21), Saravelos et al.,133
were able to demonstrate a difference in reduction of adhesions on the
Interceed-treated and control side after laparosopic electro-surgical treatment
of polycystic ovarian syndrome.
In more studies, Haney and Doty134
found that Interceed, but not Gore-Tex surgical membrane has a localized
injurious effect on the peritoneum of the mouse, resulting in de novo adhesions.
However, in these studies the Interceed wasn't moistened and a 1 cm2 piece
was used in the small abdominal cavity of the mouse. In spite of that,
a recent report from the Nordic Adhesion Prevention Study Group135
showed in a randomized, multicenter, controlled study that by using a protocol
in which other adjuvants have been shown not to be efficacious, Interceed
was shown to significantly reduce the incidence and severity of adhesion
reformation to the ovary, fallopian tube, and fimbria after infertility
A modified version of Interceed is neutralized
Interceed (nTC), that is blood insensitive, has also proved efficacious
in reducing adhesion formation and reformation in animal studies.136
The results using the nTC7 Interceed are comparable to those obtained with
Interceed in combination with heparin. Further animal and human studies
are needed, but the results thus far appear quite promising.
Seprafilm is a bioresorbable membrane
composed of chemically modified sodium hyaluronate/carboxymethylcellulose.
It has been investigated recently by Diamond and The Seprafilm Adhesion
in a large randomized multicenter study, which includes 127 women who underwent
uterine myomectomy with at least one posterior uterine incision 11 cm in
length. In this study treatment of patients after myomectomy with Seprafilm
significantly reduced the incidence, severity, extent, and area of postoperative
uterine adhesions. Additionally, Seprafilm treatment was not associated
with an increase in postoperative complications.
Pelvic adhesion development after gynecological
operations and their reformation after adhesiolysis still, up until now,
a problem that presents itself in the form of infertility, pelvic pain
and/or intestinal obstruction. The following questions still need more
investigations to be answered: Why some patients are more susceptible for
adhesion formation and others are not? Can those patients be identified
pre-operatively? Which stage of adhesion formation is more suitable to
interfere with by an agent to reduce it?
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