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European Journal of Obstetrics & Gynecology and Reproductive Biology 150 (2010) 111–118

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European Journal of Obstetrics & Gynecology and


Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review

Prevention of postoperative peritoneal adhesions


Remah M. Kamel a,b,*
a
European University Diploma of Operative Endoscopy, France
b
Department of Obstetrics and Gynaecology, Faculty of Medicine, Jazan University, Saudi Arabia

A R T I C L E I N F O A B S T R A C T

Article history: Adhesions are bands of tissue that connect organs together. It is frequently reported after surgery and
Received 31 August 2009 remains a major problem for health and society. Efforts to prevent or reduce peritoneal adhesions mostly
Received in revised form 15 December 2009 have been unsuccessful, hindered by their empirical basis, lack of good predictive animal models and
Accepted 1 February 2010
complexity of adhesion pathogenesis. Although a good surgical technique is a crucial part of adhesion
prevention, the technique alone cannot effectively eliminate the adhesions. Thus, there remains a room
Keywords: for further research. A comprehensive literature review of published experimental and clinical studies of
Peritoneal adhesions
adhesion prevention was carried out at the University of Bristol electronic library (MetaLib1) with cross-
Postoperative adhesions
Prevention
search of seven different medical databases (AMED—Allied and Complementary Medicine Database,
BIOSIS Previews on Web of Knowledge, Cochrane Library, Embase and Medline on Web of Knowledge,
OvidSP and PubMed) by using key words (peritoneal adhesions, postoperative adhesions, prevention) to
explore the progress in different surgical strategies and adjuvant materials used to prevent adhesions
formation and reformation. By the end of the study, recommendations formulated for surgeons to be
followed during the operations to prevent, as much as possible, the postoperative adhesions.
ß 2010 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
2. The peritoneum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3. Peritoneal healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
4. Etiology and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
5. Clinical presentation and complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
6. Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
7. Staging of adhesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
8. Prevention of peritoneal adhesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
8.1. Surgical approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
8.2. Surgical technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
8.3. Surgical adjuvants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
8.3.1. Fibrinolytic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
8.3.2. Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
8.3.3. Anti-inflammatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
8.3.4. Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
8.3.5. Mechanical separation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
8.3.6. New agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
8.3.7. Agents under research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
10. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

* Correspondence address: 4 Tyndall’s Park Road, Clifton, Bristol BS8 1PG, United Kingdom.
E-mail addresses: remah.kamel.07@bristol.ac.uk, remahmoustafa@hotmail.com.

0301-2115/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejogrb.2010.02.003
112 R.M. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 150 (2010) 111–118

1. Introduction gather together to fix the two adjacent injured peritoneal surfaces


[5]. At this stage, through peritoneal fibrinolytic activity, plasmin
Adhesions are one of the concealed secrets of modern surgery. produced from inactivated plasminogen by the action of tissue
The word ‘‘adhere’’ means stick or hold together [1]. It is a sort of plasminogen activator (t-PA) and urokinase-like plasminogen
disruption in the normal physiological process of peritoneal activator (u-PA) degrades the fibrin matrix with a resulting healing
healing. It may appear as thin sheets of tissue similar to plastic identical to the first mechanism. Conversely, if local fibrinolysis is
wraps or as thick sheets similar to rubber bands. insufficient the regeneration process leads to organization of fibrin
Peritoneal adhesions are a worldwide problem and may matrix resulting in adhesion formation.
develop following any type of pelvic or abdominal surgery. They It was a common concept that the mechanisms of de novo
may involve female reproductive organs, leading to infertility, adhesion formation and reformation after adhesiolysis are the
deep dyspareunia and chronic pelvic pains. Adhesions involving same, although there are no experimental data supporting this.
the bowels can cause bowel obstruction. Understanding However, the probability for adhesion reformation is greater than
the pathogenesis of adhesion formation is essential to further its de novo formation due to ischemia of previously damaged
develop more effective strategies and materials for its preven- tissues.
tion.
4. Etiology and risk factors
2. The peritoneum
Adhesions may occur in response to injury of various kinds.
Human peritoneum is the broadest serous membrane in the Non-surgical insults such as endometriosis, infections, chemother-
body and its surface area is more or less equal to that of the skin. It apy, radiation and malignancy may damage tissues and initiate
forms a closed sac in males and an open sac in females. adhesions. However, surgical insults are the most common cause.
Histologically, it consists of a mesothelial layer and vascular It is estimated that 55–94% of patients having open surgery have
stroma. It is in constant contact with the peritoneal fluid that the chance to develop adhesions [6].
facilitates normal functions and motility of abdominal and pelvic Surgical procedures with the highest risk of adhesion
organs. The presence of a surfactant covering the mesothelial layer formation include cholecystectomy, appendectomy, hernia
minimizes friction between the viscera [2]. repair, cancer surgery, liver surgery, and reproductive pelvic
The activity of cellular mediators within the peritoneal fluid surgery. The ovaries, due to their close proximity to other
plays an active role in the process of peritoneal healing. Because of peritoneal surfaces are the most common site for adhesion
its mobile nature, the peritoneal fluid can potentially modulate the formation [7].
inflammatory response over a large surface area. In fact, the definite etiology of pelvic adhesions is unknown, but
the following risk factors have been incriminated:
3. Peritoneal healing
 Rough manipulation of tissues during surgical procedures.
The process of peritoneal healing is of particular concern to  Tissue hypoxia and ischemia caused by devascularization.
surgeons. Classically, there are two mechanisms of peritoneal  Blunt dissection of former adhesions.
healing: the first leads to normal physiological repair and the  Tissue and serosal surface drying.
second leads to formation of adhesions (Fig. 1).  Infections such as peritonitis and pelvic inflammatory disease.
In the first healing mechanism, the peritoneal mesothelial cells  Peritoneal endometriosis.
re-epithelialize the surface defect from its floor. The time required  Presence of reactive foreign bodies such as suture materials, talc
for complete regeneration is 8 days after injury with a slight powder or lint.
difference between the parietal and visceral peritoneum.  Presence of free intra-peritoneal blood and blood clots.
The mechanism by which the peritoneal mesothelial cells
respond to surgical trauma is poorly understood and there is 5. Clinical presentation and complications
argument with regard to the origin of cells that colonise the bared
surface. According to Jacqueline and Diamond [3], the possible Although any major surgery is strongly associated with
origins of the new mesothelial cells are: adhesion formation, only a few patients will suffer from clinical
symptoms called adhesion related disorders (ARD). Patients’
1. Primitive mesenchymal cells present at the periphery of the symptoms will vary according to the tissue or organ involved. In
defect. abdominal adhesions, bowel obstruction may occur. Symptoms
2. Fibroblasts differentiated from the primitive mesenchymal cells. may include pains, intermittent cramps, vomiting, difficulty with
3. Subperitoneal fibroblasts arise from stromal differentiated bowel movements and swelling of the abdomen. In pelvic
resting fibroblasts. adhesions, ectopic pregnancy, inability to conceive, chronic pelvic
pains and dyspareunia may occur.
Mutsaers et al. [4] assumed other hypotheses for mesothelial
In recent years, ARD have been the subject of increasing
regeneration:
medicolegal litigation [8]. Large retrospective studies [9,10] have
discovered that more than 50% of hospital re-admissions after
1. Growth from the peripheral mesothelial cells.
surgery are due to ARD. Moreover, the presence of prior adhesions
2. Transformation of the totipotent mesenchymal cells or blood
during surgery may result in long operative time with increased
cells.
intra-operative complications such as internal bleeding and
3. Transplantation of free-floating mesothelial cells from adjacent
damage to bowel, bladder and ureters.
structures.
4. Transformation cells from the peritoneal fluid.
6. Investigations
In the second mechanism of peritoneal healing, surgical trauma
or inflammation triggers the release of chemical mediators (kinins Different radiological examinations have been proposed to
and histamine). Inactive fibrinogen turns into a fibrin matrix where assess the diagnosis and localization of adhesions. Yet, all of them
leucocytes, erythrocytes, platelets, mast cells and surgical debris have a poor overall sensitivity (50–60%) and the number of false
R.M. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 150 (2010) 111–118 113

Fig. 1. Mechanisms of peritoneal healing.

positive and false negative predictions make them unreliable for Laboratory plasma levels of tumor necrosis factor-alpha (TNF-
routine use. a) and interleukin-6 (IL-6) are correlated with adhesion formation
A plain abdominal X-ray film, small-bowel follow-through, and could be used as diagnostic markers [13].
ultrasound scanning and a computed tomography (CT) are well-
known diagnostic procedures in patients with a suspicion of bowel 7. Staging of adhesions
obstruction. A peritoneal CT, peritoneal magnetic resonance
imaging (MRI) and isotope imaging are more recent techniques. Staging or classification is the cornerstone for comparing
Sigel et al. [11] have described a technique of using ultrasound results of different studies. Although several clinical scoring
to examine the sliding motion of abdominal viscera. Normal systems have been considered since 1982, none of them is
motion was termed ‘‘visceral slide’’ and occurred spontaneously accepted today as universal.
during respiratory movements or was induced by manual Hulka [14] published a prognostic classification after 5 years of
palpation of the abdomen [12]. Restricted visceral slide was surgery for infertile women in his institute. The classification was
shown as a clue of intra-abdominal adhesions. It is a promising based upon two main factors: the extent of the ovarian involvement
non-invasive diagnostic technique that may be useful in identify- and the nature of the adhesions whether filmy or dense.
ing and mapping abdominal adhesions prior to laparoscopic or The French distal tube operability score (Table 1) [15] and the
open surgery. American Fertility Society (AFS) score (Table 2) [16] have great
114 R.M. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 150 (2010) 111–118

Table 1
The French distal tube operability score [15].

Preoperative tubal assessment Tubal scoring system

0 2 5 10

Permeability (laparoscopy) – Phymosis Hydrosalpinx –


Tubal mucosa (HSG) Mucosal folds present – Reduced mucosal folds No folds or synechiae
Tubal wall (laparoscopy) Normal – Fine wall Thick wall
Interpretation:
Staging Stage 1 Stage 2 Stage 3 Stage 4
Grade Minimal Mild Moderate Severe
Score results 2–5 6–10 11–15 >15

Table 2 2. Surgical technique: conventional versus microsurgical.


The American Fertility Society score [16].
3. Surgical adjuvants for prevention or reducing adhesion forma-
Affected Organ Adhesion tion.
Type Enclosure

<1/3 1/3–2/3 >2/3 8.1. Surgical approach


Ovary Rt Filmy 1 2 4
Dense 4 8 16
Laparoscopic surgical procedures with their minimal access to
Lt Filmy 1 2 4 the abdominal or pelvic cavity are associated with fewer
Dense 4 8 16 postoperative adhesions compared to the open surgery. The
Tube Rt Filmy 1 2 4 reported advantages of laparoscopic surgery include:
Dense 4a 8a 16
Lt Filmy 1 2 4 1. Reduced incision of parietal peritoneum [24].
Dense 4a 8a 16 2. Fewer foreign bodies (no gauze particles, talc powder, hairs, or
Interpretation: lint) [25].
Staging A B C D
3. Humid closed environment prevents tissue desiccation [6].
Grade Minimal Mild Moderate Severe
4. Less tissue trauma and hemorrhage at operative site [24].
Score results 0–5 6–10 11–20 21–32
5. Reduced manipulation of structures distant from the operative
Rt: right and Lt: left. site [26].
a
If the fimbrial end of the tube is completely enclosed, change score to 16.
6. Early return of bowel motility and ambulation [24].

acceptability and were in common use for years. In AFS score, four However, the reported disadvantages of laparoscopic surgery
anatomic sites are evaluated per woman: the right ovary, right compared to laparotomy include:
tube, left ovary and left tube. For each of these, a score is given
according to the extent and aspect of adhesions. The higher score 1. Improper choice and use of laparoscopic instruments may cause
represents the side with the higher adhesion. A modified AFS score more tissue injury [6].
was then developed where 24 anatomical sites are to be evaluated 2. Laparoscopy, by itself, does not eliminate adhesions completely
[17]. [27].
In 1994, the Adhesion Scoring Group [18] published their more 3. Adhesion reformation still occurs after laparoscopy [28].
comprehensive scoring system based on the evaluation of 23 sites. 4. Pneumoperitoneum with a non-humidified CO2 gas is a cofactor
Although the AFS scoring method generated a significant for adhesion [29].
agreement between surgeons, the use of this comprehensive 5. Adhesion formation is related to the time and duration of
scoring system produces a marked increase in reproducibility. pneumoperitoneum [30].
6. Subserosal ischemia is a consequence of high intra-peritoneal
8. Prevention of peritoneal adhesions gas pressure [28].

In animal models, adhesion formation has been reduced by In fact, the above-listed risks are mostly related to improper
three different strategies: laparoscopic technique and could be minimized when guidelines
for laparoscopic surgery are respected.
1. Altering the fibrinolytic pathway by using either recombinant t-
PA [19] or gonadotrophin releasing hormone agonist (GnRHa) 8.2. Surgical technique
[20].
2. Immunomodulation by using transforming growth factor (TGF)- The first use of microsurgery was described by Swolin [31] in
bl antibodies [21], IL-1 and TNF-a antibodies [13], or IL-10 and 1967. The term ‘‘microsurgery’’ implies the use of magnification to
ketorolac (NSAID) [22]. allow close tissue visualization, handling small caliber instru-
3. Disruption of cell interaction with extra-cellular matrix (ECM) ments, and use of fine sutures [32]. Other principles of micro-
[23]. surgery include minimal tissue handling, prevention of tissue
desiccation, avoidance of foreign bodies, precise re-approximation
In humans, progress for prevention of postoperative adhesion of the tissues, and meticulous hemostasis.
formation has passed through the following three main stages with Temporary ovarian suspension appears to be a simple, safe and
controversies: effective method to prevent ovarian adhesions after laparoscopy
for endometriosis [33]. Non-closure of parietal peritoneum during
1. Surgical approach: laparoscopy versus laparotomy. caesarean section is recommended as it results in a significantly
R.M. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 150 (2010) 111–118 115

shorter operative time, lower febrile morbidity, and lesser use of Table 3
Adjuvants for prevention of postoperative adhesions.
analgesics with a quicker return of bowel activity. The practice of
omitting closure of the peritoneum is well supported in the Fibrinolytic agents
Thrombokinase, fibrinolysin, streptokinase, urokinase, hyaluronidase,
literature [34].
chymotrypsin, trypsin, papain and pepsin.
Laser surgery definitely decreased the adhesion formation and Tissue plasminogen activators [36] and recombinant t-PA [37]
reformation by making a precise incision, achieving a meticulous Thromboxane synthetase inhibitors: imidazole and ridogrel [38]
hemostasis, and by reducing the operative time. Different types of Thrombin inhibitor (rec-Hirudin1) [39]
laser are in a common use now, mostly the ultra-pulse carbon Anti-proliferative medications: Paclitaxel [40] and Camptothecin [41]
Polypeptides: lysozyme, polylysine, and polyglutamate [42]
dioxide [35].
Anticoagulants
Heparin [43,45]
8.3. Surgical adjuvants
Low molecular weight heparin (Enoxaparin-Na) [44,46]

Adhesion formation is still an unavoidable event in reproduc- Anti-inflammatory agents


Low-dose aspirin [47]
tive pelvic surgery in spite of advancement in laparoscopy,
Anti-inflammatory peptides: retinoic acid, quinacrine,
microsurgery and laser use. This fact necessitates the search for or dipyridamole [48]
a material that can prevent adhesion formation. The adjuvants Antihistamines: Promethazine
discovered to date are many but none of them is effective in all Corticosteroids: dexamethasone, hydrocortisone and prednisolone [49]
cases (Table 3). Non-steroidal anti-inflammatory drugs (NSAID): Ketorolac, Tolmetin,
Ibuprofen and Indomethacin [50]

8.3.1. Fibrinolytic agents Antibiotics


Intra-peritoneal thrombokinase, fibrinolysin, streptokinase, Systemic antibiotics (cephalosporins or tetracyclines)
Peritoneal irrigation (cefazolin or tetracycline)
urokinase, hyaluronidase, chymotrypsin, trypsin, papain and
pepsin act directly by breakdown of the fibrinous mass and Mechanical separation
indirectly by stimulating plasminogen activator activity (PAA). The Peritoneal instillates
Crystalloid solutions: normal saline and Ringer’s lactate [51]
use of these agents is still waiting for appropriate human clinical Viscous solutions: 32% Dextran-70 (Hyskon1) [52,53]
trials. Carboxymethylcellulose (CMC): high MW polysaccharide gel [54–56]
The effectiveness of tissue plasminogen activator (t-PA) [36] Hyaluronic acid (HA): a naturally occurring glycosaminoglycan [57]
and recombinant t-PA [19,37] has been investigated in animal HA with phosphate-buffered-saline HAPBS: (Sepracoat1) [58]
HA with iron 0.5% ferric hyaluronate gel: (Lubricoat1) [59]
studies with promising results. Le Grand et al. [38] reported that
Auto-cross-linked hyaluronan solution or gel (ACP-gel) [60,61]
thromboxane synthetase inhibitors (imidazole and ridogrel), as N,O-carboxymethyl chitosan (NOCC): gel and solution [62]
well as thromboxane-A2 receptor blockers, demonstrated a
Barriers
remarkable efficacy in reducing adhesion in a rabbit model.
Endogenous barriers:
Rodgers et al. [39] investigated the ability of thrombin inhibitor Fetal amniotic membranes [63]
(rec-Hirudin1) in reducing postoperative adhesions. Peritoneal transplants [64]
Recently, anti-proliferative drugs such as paclitaxel [40] and Omental grafts
Bladder strips
Camptothecin [41] were shown to inhibit the adhesion formation
in the rat cecal sidewall model. Polypeptides such as lysozyme, Exogenous barriers
polylysine, and polyglutamate have drastically decreased abdom- 0.5% ferric hyaluronate gel (Intergel1): withdrawn from market [65]
HA with carboxymethylcellulose HA-CMC: (Seprafilm1) [66]
inal adhesion formation [42].
AdhibitTM: gel used after cardiac surgery
Adept1: is an intra-peritoneal fluid [67]
8.3.2. Anticoagulants Polyethylene glycol-PEG: (SprayGel1) [68]
Since heparin is an effective anticoagulant and clotting is a Poloxamer 407 of (FlowGel1) [69]
major contributor to fibrin deposition, local intra-peritoneal Polytetrafluoroethylene: (Gore-Tex1) [51,70]
Fibrin glue: composed of fibrinogen, thrombin, calcium, and
instillation of heparin [43] or low molecular weight heparin
factor-VIII [71]
(Enoxaparin-Na) [44] may result in adhesion-free healing. Tayyar Oxidized-regenerated cellulose-ORC: (Surgicel1) [72]
et al. [45] added heparin to the amniotic membrane used to cover Interceed1 (TC7) [73]
injured rabbit uterine horns while, Sahin and Saglam [46] added Modified neutralized Interceed (nTC7) [74]
Mineral oil, silicone, vaseline, gelatin, rubber sheets, metal foils, plastic
heparin to the sodium carboxymethylcellulose at laparotomy.
hoods (abandoned)
Such combinations seem to be more effective in reducing adhesion
formation rather than heparin alone. New agents
Films of polyethylene oxide and carboxymethylcellulose: (Oxiplex1) [75]
Shelhigh dome pericardial patch no-react [76]
8.3.3. Anti-inflammatory agents Pluronic F127/F68 alginate–buprofen mixture (Sol–Gel1) [77]
These agents are used to decrease the initial inflammatory Aloe vera gel [78]
response to tissue injury. Low-dose aspirin [47] could be effective
Agents under research
in reducing adhesion formation by its selective inhibition of Colchicine [79]
thromboxane-A2 over prostacyclin. A study carried out by Rodgers Medroxyprogesterone acetate (MPA) [80]
et al. [48] verified the effect of various anti-inflammatory agents as Calcium channel blockers [81]
retinoic acid, quinacrine, and dipyridamole in reducing adhesions Phosphatidylcholine instillation [82]
Vitamin E [83]
in animals. D-Penicillamine [84]
Antihistaminics with corticosteroids inhibit fibroblast prolif- Methylene blue [85]
eration [49]. The potential side effects of these agents include Pentoxifylline [86]
immunosuppression with subsequent wound infection, and Statin [87]
Epidermal growth factor (EGF) [88]
delayed wound healing with subsequent wound dehiscence or
incisional hernia. Non-steroidal anti-inflammatory drugs (NSAID)
[50] have an anti-prostaglandin effect, hence blocking the
adhesiogenic effect of prostaglandins.
116 R.M. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 150 (2010) 111–118

8.3.4. Antibiotics [65]. However, GynecareTM, the manufacturing company, with-


The rationale behind use of antibiotics is prophylaxis against drew Intergel1 from the market on March 28th 2003 after it
infections. Systemic broad-spectrum antibiotics, chiefly cephalos- received reports of late onset postoperative pain, foreign body
porins, were widely used. Today, tetracyclines are commonly used reactions and tissue adherence.
to protect against chlamydia. Peritoneal irrigation with antibiotic Seprafilm1 [66] is composed of hyaluronic acid with carbox-
solutions such as cefazolin or tetracycline has been shown to ymethylcellulose. It turns into a hydrophilic gel 24 h after
increase adhesion formation in rat model and therefore their intra- placement and provides a protective coat for traumatized tissue
abdominal use is not recommended. for up to 7 days. AdhibitTM is a gel used to reduce adhesion
formation following cardiac surgery. Adept1 [67] is a clear fluid for
8.3.5. Mechanical separation intra-peritoneal instillation. It should not be used in patients with a
Separation of raw peritoneal surfaces during early days of known allergy to starch or with maltose intolerance.
healing process is the ideal method to prevent postoperative SprayGel1 [68] is an adhesion barrier system which consists of
adhesions. two polyethylene glycol-based liquids that when mixed together
rapidly cross-link to form absorbable hydrogel in situ. It is safe and
8.3.5.1. Peritoneal instillates. Crystalloid solutions were the most well-tolerated, and has demonstrated efficacy in patients at risk for
commonly used instillate in the abdominal cavity after surgery. In adhesion formation.
addition to its mechanical action in separation of raw peritoneal Poloxamer 407 (FlowGel1) is an effective anti-adhesiogenic
surfaces it dilutes fibrin and fibrinous exudate released from agent that converts from a liquid state at room temperature into a
traumatized tissue. Ringer’s lactate has a better buffering capacity gel at body temperature [69]. Polytetrafluoroethylene (Gore-Tex1)
than normal saline. Intra-peritoneal instillation of lactated Ringer’s is an anti-thrombogenic synthetic fabric that inhibits tissue
solution in animals decreases adhesion formation and reformation adherence [51,70]. However, its use in the laparoscopy is difficult.
[51]. Fibrin glue [71] and oxidized-regenerated cellulose (Surgicel1)
Unfortunately, these fluids are absorbed from the peritoneal [72] are used more frequently to assist in the control of surgical
cavity at an estimated rate of 35 ml/h. So, a volume of 500 ml will bleeding. Interceed1 [51,73] is a commonly employed absorbable
be absorbed within 14 h, and at least 5 l of fluid are needed to cover fabric patch in open surgery for reducing postoperative adhesions
the first 6 postoperative days. Its other drawbacks include possible after meticulous hemostasis. A modified version called neutralized
risks of infection, fluid overload with pulmonary edema, and Interceed (nTC7) is characterized by being blood-insensitive [74].
leaking at puncture sites.
In an attempt to prolong the period of instillate persistence 8.3.6. New agents
inside the peritoneal cavity, more viscous solutions have been Polyethylene oxide with carboxymethylcellulose film (Oxi-
tried, such as 32% Dextran-70 (Hyskon1). It acts as a siliconizing plex1) has been tested for strength and tissue adherence in a rat
agent coating the raw surfaces and as an osmotic fluid causing model with good results [75]. A pilot study has proved the efficacy
hydroflotation of viscera. Its recorded complications are vulvar and and safety of another new non-absorbable barrier called Shelhigh
leg edema [52], right pleural effusion, and elevation of liver Dome pericardial patch No-react [76] in reducing adhesion after
transaminases [53]. However, these complications are transient myomectomy. Pluronic F127/F68 alginate–ibuprofen mixture
and resolve within days. (Sol–Gel1) [77] was highly effective and showed a low inflam-
Although carboxymethylcellulose (CMC) was found to be more matory response without toxicity. Aloe Vera gel [78] has
effective than Hyskon1 [54] and Interceed1 [55] in preventing considerably decreased postoperative adhesions.
postoperative adhesions, yet, combination of t-PA and CMC has the
best results [56]. 8.3.7. Agents under research
Hyaluronic acid (HA) is a naturally occurring biocompatible Experimental animal studies with colchicine [79], medrox-
agent [57]. HA combined with phosphate-buffered-saline (Sepra- yprogesterone acetate [80], calcium channel blockers [81],
coat1) should be applied prior to tissue dissection [58]. It phosphatidylcholine [82], vitamin E [83], D-penicillamine [84],
considered a prophylactic anti-adhesiogenic agent for patients methylene blue [85], pentoxifylline [86], statins [87], and
undergoing abdominal mesh repair for hernia. HA cross-linked epidermal growth factor [88], show reduction in adhesion
with a trivalent iron 0.5% ferric hyaluronate gel (Lubricoat1) was formation. Their efficacy in humans remains to be seen with
effective in reducing adhesions at operative sites [59]. Auto-cross- further research. Nevertheless, the use of barriers to reduce
linked hyaluronan (ACP-gel) is used to prevent adhesions with postoperative adhesions is not without risks or cost. Their use
inadequate hemostasis [60]. The ACP-gel holds promise as a novel prolongs the operative time and this directly results in an
resorbable biomaterial for reducing adhesions after laparoscopic increased hospital cost, which is compounded further by the cost
myomectomy [61]. of product or material used. If these barriers achieve what they are
N,O-carboxymethyl chitosan (NOCC) is a non-toxic absorbable designed for, however, the avoidance of ARC and adhesiolysis
agent that is also used to prevent postoperative adhesion surgery in the future outweighs these issues.
formation [62].
9. Conclusion
8.3.5.2. Barriers. The ideal mechanical barrier, besides being safe
and effective, should be non-inflammatory, non-immunogenic, Peritoneal adhesions after surgery are common and remain a
persist during the critical healing phase, be fixed in place without major problem for both health and society. Treatment of adhesion
the need for sutures or staples, remain active in the presence of is difficult but its prevention remains the key. The quality of
blood, and be completely biodegradable without the need for surgery is the cornerstone and guidelines of microsurgery are the
removal. golden rules to be followed. Development of laparoscopic surgery
While the use of endogenous barriers such as amniotic represents a major advance in adhesion prevention as it results in
membrane grafts [63] and autologous peritoneal transplants less tissue damage than laparotomy. However, the laparoscopic
[64] were effective in the prevention of severe adhesions, approach and laser use do not guarantee absence of adhesion. Anti-
exogenous barriers such as 0.5% ferric hyaluronate gel (Intergel1) adhesive adjuvants can further improve the adhesion reduction
appeared to be more effective for reducing adhesions in general achieved by the above-mentioned measures. The most effective
R.M. Kamel / European Journal of Obstetrics & Gynecology and Reproductive Biology 150 (2010) 111–118 117

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Conflict of interests
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inhibited by antibodies to transforming growth factor-beta 1. J Surg Res
The author hereby declares that there are no competing 1996;65:135–8.
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10 and interleukin-4 compared with ketorolac tromethamine for preven-
Ethical approval tion of postoperative adhesions in a murine model. Fertil Steril 1999;71(1):
This study was carried out in accordance with the requirements 67–73.
of the University of Auvergne Regulations and Code of Ethics for [23] Rout UK, Saed GM, Diamond MP. Expression pattern and regulation of genes
differ between fibroblasts of adhesion and normal human peritoneum. Reprod
Research Programmes, France. Biol Endocrinol 2005;3(1):1.
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This work was self-funded. The author did not receive any by laparoscopic surgery. Surg Endosc 2004;18(6):898–906.
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financial funding or support from any person, company, or operative adhesions. Ann Surg 1996;223.
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Acknowledgements
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