Comparison of the reduction ofpostoperative adhesions by two barriers,one solution, and two pharmacologicagents in the rat uterine model

Tevfik Yoldemir, M.D.,a Sermet Sagol, M.D.,b Saban Adakan, M.D.,b

Kemal Oztekin, M.D.,b Serdar Ozsener, M.D.,b and Nedim Karadadas, M.D.b

University of Ege, Faculty of Medicine, Izmir, Turkey

Objective: To evaluate the effects of two barriers, one solution, and two pharmacologic agents, in single orin combined use, for preventing postsurgical adhesion formation in the rat model.

Design: A randomized, prospective study to evaluate the ability of leuprolide acetate, oxidized regeneratedcellulose, medroxyprogesterone acetate, sodium hyaluronate, sodium hyaluronate/carboxymethyl cellulose, insingle or in combined use, for preventing adhesion formation in a rat model.

Animal(s): Wistar female rats.

Setting: University animal laboratory.

Intervention(s): Intramuscular injection of pharmacologic agents before surgery and intraperitoneal appli-cation of barriers and solution at the end of surgery.

Main Outcome Measure(s): Two weeks after surgery, a second laparotomy was performed and the extentof adhesion formation was determined.

Result(s): All the treatment groups had fewer, less severe adhesions when compared with controls. Thecombination of medroxyprogesterone acetate and oxidized regenerated cellulose did enhance the adhesion-reducing capacity of oxidized regenerated cellulose. The performance of sodium hyaluronate solution foradhesion prevention was statistically significant, when compared with oxidized regenerated cellulose alone, orsodium hyaluronate used with carboxymethyl cellulose film.

Conclusion(s): Pharmacologic agents, barriers, or solutions result in significant reduction of postsurgicaladhesions. The sodium hyaluronate solution alone and medroxyprogesterone acetate treatment alone had theleast adhesion prevention scores. However, neither monotherapy nor combined therapy proved to be significantly morebeneficial. (Fertil Steril� 2002;78:335–9. ©2002 by American Society for Reproductive Medicine.)

Key Words: Medroxyprogesterone acetate, sodium hyaluronate, oxidized regenerated cellulose, leuprolideacetate, sodium hyaluronate/carboxymethyl cellulose, adhesion prevention

Peritoneal adhesions that develop as a nor-mal consequence of the wound healing processcontinue to be a significant cause of postoper-ative complications. Approximately 80%–90%of abdominal adhesions are attributable to apreceding surgery, 5%–20% arise from inflam-matory causes, and only 2%–5% are congenital(1). Pelvic surgery is one of the most frequentcauses of postoperative adhesions, which canlead to bowel obstruction, chronic pelvic pain,female infertility, and difficulty at subsequentabdominal surgery. The evaluation of thecauses and prevention of adhesion formationhas been the major goal for many investiga-

tions. To reduce postoperative adhesions for-mation, many surgeons have developed a vari-ety of surgical techniques and have usedseveral agents; however, at least 50% of pa-tients still develop significant adhesions.

Increased permeability of blood vessels inthe traumatized tissue produce a serosanguine-ous inflammatory exudate rich in plasma pro-teins such as fibrinogen. Under optimal condi-tions, the majority of fibrinous attachments soformed are absorbed within a few days byfibrinolytic mechanism (2). If they persist for 3days or longer, fibroblastic proliferation mayoccur, causing adhesion formation. Organiza-

Received August 28, 2001;revised and acceptedFebruary 1, 2002.Presented at the 7thPostgraduate Course inReproductive Endocrinologyand Infertility, Ankara,Turkey, October 29–31,1999.Reprint requests: TevfikYoldemir, M.D., HalkaliToplu Konutlar 1. Etap 4.Bolge A06 Blok D:42Ikitelli, Istanbul, Turkey(FAX: 00-90-212-2341121;E-mail: dr_yoldemir@yahoo.com).a Second Obstetrics andGynecology Clinic, SisliEtfal Training and ResearchHospital, Istanbul, Turkey.b Department of Obstetricsand Gynecology, Faculty ofMedicine, University ofEge, Izmir, Turkey.

ADHESIONSFERTILITY AND STERILITY�VOL. 78, NO. 2, AUGUST 2002Copyright ©2002 American Society for Reproductive MedicinePublished by Elsevier Science Inc.Printed on acid-free paper in U.S.A.

0015-0282/02/$22.00PII S0015-0282(02)03224-7

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tion of collagen bundles begins by day 5 and small vascularchannels containing endothelial cells appear (3). Consolida-tion of these bundles with vascularized granulation tissueconstitutes an adhesion.

Research in adhesion prevention has strongly focused on[1] barrier films and viscous intraperitoneal solutions appliedat the conclusion of surgery to wounded surfaces to preventformation of the pathologic bridging connective tissue; [2]protective polymer solution coatings applied to all tissuesurfaces at the beginning of surgery and during surgery; and[3] anti-inflammatory, antifibrotic agents.

Oxidized regenerated cellulose (ORC), the first barrieragent to be used, was found to be effective in many clinicalstudies (4–9). Sodium hyaluronate/carboxymethylcellulose(NaH/CMC), a polymer film based on a combination ofhyaluronic acid and carboxymethylcellulose, has been usedto cover the abraded area after surgery for the prevention ofadhesions (10–12). Sodium hyaluronate (NaH), a very vis-cous polymer solution that is a relatively concentratedionic polysaccharide of higher molecular weight (1% NaHhas a molecular weight of approximately 3,000,000), hasbeen used as tissue precoating barrier (13–16). Leuprolideacetate (LA), a gonadotropin-releasing agonist, has anties-trogenic effects in long-term use and has been shown todecrease adhesion formation (17, 18). Progestins, particu-larly medroxyprogesterone acetate (MPA), seem to havesignificant anti-inflammatory and immunosuppressive prop-erties (19, 20); MPA has been reported to reduce antibodyproduction and to inhibit human mixed lymphocyte culturesand leukocyte migration (20).

In our double-blind, placebo-controlled study, we exam-ined the effect of MPA (Farlutal; Deva, Istanbul, Turkey),LA (Lucrin; Abbott, Istanbul, Turkey), ORC (Interceed;Gynecare, Istanbul, Turkey), NaH (Sepracoat; Atrium, Istan-bul, Turkey), and NaH/CMC (Seprafilm; Genzyme, Istanbul,Turkey), both alone and in combined use, on postoperativeadhesion formation in standardized animal models.

MATERIALS AND METHODS

Rats and Surgical ProcedureTwo hundred sexually mature, nonpregnant female

Wistar rats were used as a model for postoperative adhesionformation. The rats weighed between 230 and 260 g at thetime of medication. Animals were kept under standard lab-oratory conditions at a temperature of 20° to 25°C, a relativehumidity of 50% to 70%, a day cycle of 14 hours light and10 hours dark, and they had free access to food and water adlibitum. The animals were housed at the center for laboratoryanimal care of University of Ege. Under the supervision ofthe University of Ege Institutional Animal Care and UseCommittee, animals were treated in accordance with thestandards of the National Institutes of Health, as described inthe Guide for the Care and Use of Laboratory Animals.

Approval from the Animal Research Committee of EgeUniversity (institutional review board approval) was ob-tained before the study.

Rats were prepared for surgery with an injection of ket-amine (70 mg/kg i.m. of Ketalar; Eczacibasi, Istanbul, Tur-key); anesthesia followed, then hair removal from the lowerabdominal area. After the abdomen was cleaned with alcoholand Betadine solution, a lower ventral midline incision wasmade using sterile techniques. Preoperative or postoperativeantibiotics were not administered. A No. 15 scalpel was usedto make a transverse hysterotomy incision on the left uterinehorn. The incision was sutured with two separate sutures ofNo. 7/0 polypropylene. No incisions were made to the rightuterine horn.

In the study groups where barriers were used, 2 � 2 cmof the barrier was used to cover the incision line without anysuture. In the group where the solution was used, 2 mL of thesolution was poured into the abdominal cavity on entrance, 1mL was poured over the incision line after suturing, andanother 1 mL was poured just before closing the peritoneum.

The abdominal incision was closed in two layers with theuse of a running 3-0 polyglactin 910 suture for the perito-neum-fascia and simple interrupted 3-0 chromic catgutstitches for the skin. The operations were timed to end in 15minutes to control the effect of room air tissue drying amongthe animals. All surgery was performed by the first author,who had no knowledge of the rat’s medication status.

Two weeks later, the animals were killed randomly bycervical dislocation and the extent of peritoneal adhesionformation was assessed by the second author, who had noprior knowledge of which group was being evaluated.

Experimental DesignTwo hundred rats were divided randomly into 10 groups,

with 20 animals in each group. The decision for each com-bination of treatments was made randomly; the ease ofapplication of each preparation when used in conjunctionwith another was the main rationale for the choices.

● Group 1 was injected with 0.75 mg i.m. of LA 3 weeksbefore surgery.

● Group 2 was injected with 0.75 mg i.m. of LA 3 weeksbefore surgery. Oxidized regenerated cellulose (ORC)was used at the end of the hysterotomy.

● Group 3 was injected with 15 mg i.m. of MPA 3 weeksbefore surgery, and again at the end of the surgery.

● Group 4 was injected with 15 mg i.m. of MPA 3 weeksbefore surgery, and again at the end of the surgery.Oxidized regenerated cellulose was used at the end ofthe hysterotomy.

● Group 5 was injected with 4 mL intraperitoneally of0.4% NaH: 2 mL before the hysterotomy, 1 mL aftersuturing, and 1 mL before closing the abdomen.

● Group 6 was injected with 15 mg i.m. of MPA 3 weeksbefore surgery, and again at the end of the surgery.

336 Yoldemir et al. Operative adhesion formation prevention Vol. 78, No. 2, August 2002

Also, this group was injected with 4 mL intraperitone-ally of 0.4% NaH: 2 mL before the hysterotomy, 1 mLafter suturing, and 1 mL before closing the abdomen.

● Group 7 received 4 mL of 0.4% NaH injected intraperi-toneally: 2 mL before the hysterotomy, 1 mL aftersuturing, and 1 mL before closing the abdomen. Oxi-dized regenerated cellulose was used to cover the sutureline.

● Group 8 was the control group, and no protection wasapplied.

● Group 9 received ORC to cover the suture line after thehysterotomy.

● Group 10 received an NaH/CMC film to cover thesuture line after the hysterotomy.

The timing and dosage of the medications were all chosenaccording to the previous studies in the literature(26, 27, 29, 30).

The incidence of adhesions was evaluated in each group.The extent of adhesion formation was assessed by the secondauthor. The area of surgical incision was examined with theuse of a tissue holder and the total adhesion score for eachcase was calculated separately on a 0 to 3 scale in terms ofthe thickness/tenacity and vascularity as described previ-ously (16, 30) (Table 1). The sum of the two parameterswere used as the overall score for that particular case. Thedata was presented as the mean and variation of mean, as wewished to derive a comparative analysis on adhesion reduc-tion.

Statistical EvaluationStatistical evaluation was performed with the Kruskal-

Wallis test for the whole group; P�0.05 was consideredstatistically significant. The groups then were compared witheach other by Mann-Whitney U test in which we calculatedthe significance value as ��0.0011 (� � 0.05/45 � 0.0011).

RESULTS

The standardized surgical procedures and the administra-tion of the protocols were well tolerated by the animals. Alllaparotomy sites were intact and none of the animals had an

incisional hernia. The mortality rate was approximately 1%,or 2 of 200 rats for the whole study group; the deaths werea result of an increased dose of anesthesia for both rats. Insome rats, the ketamine anesthesia produced coughing,which let the intestines out of the abdominal cavity and ledto tissue drying.

In the group where LA was used, the uterine horns werethinner as a result of the antiestrogenic effect, which made ithard to incise and suture the horn with less trauma. Hence,the adhesion score increased in accordance to this unwantedhandling problem.

The adhesion scores are shown in Table 2. The ninetreatment groups had less severe adhesions than the controls(��0.0011). The NaH solution group had fewer adhesionsthan the ORC group (1.73 � 0.42 vs. 2.65 � 0.57, �1

�0.0011). The NaH solution group also had fewer adhesionsthan the NaH/CMC film group (1.73 � 0.42 vs. 2.27 � 0.45,�1�0.0011) and the LA group (1.73 � 0.42 vs. 2.55 � 0.98,�1�0.0011). The solution kept the tissues from contact withthe room atmosphere, and thus no tissue drying was ex-pected. Also, we found that manipulation of the horns in thesolution was much easier and less traumatic.

The MPA � ORC group had fewer adhesions than the LAgroup (1.78 � 0.49 vs. 2.55 � 0.98, �1�0.0011). The groupthat received MPA-only had fewer adhesions than the LAgroup (1.82 � 0.54 vs. 2.55 � 0.98, �1�0.0011). The

T A B L E 1

Adhesion score and vascularity grade description.

Grade Thickness-tenacity Vascularity

0 No adhesion —1 Filmy, easily separable No bleeding2 Moderate, thick, moderate

tension requiredPetechial bleeding

3 Severe, cohesive, sharpdissection required

Bleeding that requiredsuture

Yoldemir. Operative adhesion formation prevention. Fertil Steril 2002.

T A B L E 2

Summary of adhesion scores.

Treatment groupsNumberof rats Adhesion score P value � Value

1. LA 20 2.55 (�0.98)b,c,d NS �0.0011b,c,d

2. LA � ORC 20 2.30 (�0.47) NS NS3. MPA 20 1.82 (�0.54)e NS �0.0011e

4. MPA � ORC 20 1.78 (�0.49)f NS �0.0011f

5. NaH 20 1.73(�0.42)g,h NS �0.0011g,h

6. NaH � MPA 18 2.22 (�0.52) NS NS7. ORC � NaH 20 2.42 (�0.74) NS NS8. Control 20 3.95 (�0.76)a �.05a —9. ORC 20 2.65 (�0.57) NS NS

10. NaH/CMC 20 2.27 (�0.45) NS NS

Note: Values are mean � SD. NS � not significant. LA � leuprolideacetate; ORC � oxidized regenerated cellulose; MPA � medroxyproges-terone acetate; NaH � sodium hyaluronate; NaH/CMC � sodium hyaluro-nate carboxymethlycellulose.a Control group vs. each study group.b Group 1 vs. group 4.c Group 1 vs. group 5.d Group 1 vs. group 3.e Group 3 vs. group 9.f Group 4 vs. group 9.g Group 5 vs. group 10.h Group 5 vs. group 9.

Yoldemir. Operative adhesion formation prevention. Fertil Steril 2002.

FERTILITY & STERILITY� 337

MPA-only group also had a better adhesion score than that ofthe ORC-only group (1.82 � 0.54 vs. 2.65 � 0.57, �1

�0.0011). When MPA was used in conjunction with ORC,MPA lessened the adhesion severity seen when ORC wasused alone (1.78 � 0.49 vs. 2.65 � 0.57, �1�0.0011).

The distribution of adhesion scores in each study group isshown in Figure 1.

DISCUSSION

Adhesion formation may be reduced by several possiblemechanisms: reduction of the initial inflammatory responseand subsequent exudation; inhibition of coagulation, promot-ing of fibrinolysis; mechanical separation of peritoneal sur-faces; and inhibition of fibroblastic proliferation (21). Todate, clinical methods of preventing the formation of post-surgical adhesions have had limited success. A successfulpreventive strategy should include modified surgical tech-nique and protection of tissues to minimize peritoneal injury,pharmacological interference to reduce the inflammatoryresponse, and tissue separation and protection of adhesio-genic surfaces during normal healing. The ideal methodshould have an effect that begins during surgery and lasts atleast 7 days.

Barriers agents used for the prevention of postoperativeadhesion formation include both mechanical barriers andviscous intraperitoneal solutions. The ideal barrier should benonreactive, bioabsorbable, and be easy to use, and shouldpersist during critical stages of healing. Both ORC andNaH/CMC, the mechanical barriers used in our study, havebeen extensively studied and have been approved for clinicaluse (8, 9, 22, 23). In our study, the groups using ORC andNaH/CMC had lower adhesion scores compared with thecontrol group (�1�0.0011). The intraperitoneal precoatingsolution we used in our study was a high-molecular-weightNaH, which reduces postsurgical adhesion formation by

inhibiting tissue desiccation and abrasive mesothelial dam-age (13–16). We found that the NaH group provided a loweradhesion score than the control group, ORC group, andNaH/CMC group (�1�0.0011).

Of the pharmacologic agents used for adhesion preven-tion, MPA is an aqueous suspension of 17-acetoxy-6-methylprogestin administered by i.m. injection. This highly effec-tive injectable formulation of MPA has a prolonged durationof action because the progestin is released slowly from themuscle (24). It has been suggested that the efficacy ofprogestins in preventing postsurgical adhesion formationmay be mediated by their anti-inflammatory and immuno-suppressive activity (20, 25). Nakagawa et al. (26), using thecarrageenan air pouch method, reported that progesteroneexerts an anti-inflammatory action on the experimental ratmodel. Maurer and Bonaventura (27), evaluating the effectof aqueous progesterone on adhesion formation in a guineapig model, found that both i.m. and intraperitoneal admin-istrations of progesterone were effective in preventing andreducing the postsurgical adhesion formation.

Pharmacological investigations have shown that MPA isdetected in the serum within 30 minutes after i.m. injection,reaching high serum levels after 2 to 3 weeks (28). System-ically administered drugs may not reach operative sites,which often are devascularized and hypoxic. Because ade-quate prevention requires the development of an efficientdrug delivery time, MPA should be injected several daysbefore the operation to achieve the effective tissue levels,and thus to obtain the desired anti-inflammatory and immu-nosuppressive activity for reducing adhesion formation. Inour study, two extended doses of MPA administered 21 daysbefore and during the surgery improved the adhesion scoreswhen compared with the control group, ORC group, and LAgroup (�1�0.0011).

Montanino-Oliva et al. (29) reported that the administra-tion of both GnRH-analogue and MPA in laboratory ani-mals, 3 weeks before an operation, prevented postsurgicaladhesion formation when compared with controls. In thesame study, LA injected 3 weeks before the surgery resultedin a better adhesion score than that of the controls (�1

�0.0011). Grow et al. (30) showed that estradiol appears tohave an effect on the formation of utero-omental adhesionsafter myometrial surgery. Estrogens may play an importantrole in the development of postsurgical adhesions, possiblyassociated with regulation of angiogenesis in the uterinetissue, modulation of mesothelial cell proliferation, and uter-ine growth factors (31, 32). Progestins reduce the actions ofestrogens via downregulation of the estrogen receptors andother mechanisms, such as diminishing the angiogenic effectof estrogens and decreasing its serum levels (30, 33).

When we combined the two pharmacologic agents withORC, the antiadhesive effect of ORC was found to beimproved (�1�0.0011). Likewise, when ORC was used to-

F I G U R E 1

Distribution of adhesion scores in the study groups (95%confidence intervals).

Yoldemir. Operative adhesion formation prevention. Fertil Steril 2002.

338 Yoldemir et al. Operative adhesion formation prevention Vol. 78, No. 2, August 2002

gether with these agents, their preventive effect also im-proved, but the difference was not statistically significant.

When NaH was combined with ORC, it improved theantiadhesive effect of ORC in single use, although the dif-ference was not statistically significant (�1�0.0011).

Of the barriers we used, NaH had the lowest adhesionscore. Of the injectable agents, MPA had the lowest adhe-sion score. Of the combined treatments, ORC � MPA hadthe lowest adhesion score. However, the difference in adhe-sion prevention among these three study groups was notstatistically significant.

For adhesion-inhibiting surgery, we recommend usingtissue-protective solutions (NaH) at the start and duringsurgery to minimize desiccation and abrasive mechanicaltissue trauma. Bioabsorbable barrier films (ORC or NaH/CMC) should be used at the end of the surgery before closureto prevent adhesions to areas of unavoidable trauma. Phar-macologic agents (MPA or LA) should be used before andafter the surgery to minimize inflammatory response.

All the preparations studied minimized the extent of post-surgical adhesion formation. However, neither monotherapynor combined therapy provided significant benefit over theother. More adhesion prevention studies should be per-formed to explore new combinations or materials.

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