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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


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