Reduction of post-surgical adhesions with ferric hyaluronate gel: a European study

Per Lundorff1,, Hans van Geldorp2,, Sven Erik Tronstad3,, Othon Lalos4,, Bertil Larsson4,, Douglas B. Johns5,7, and Gere S. diZerega6,

Departments of Obstetrics and Gynecology, 1 Viborg Sygehus, Denmark, 2 University Hospital Rotterdam, The Netherlands, 3 Skovde Hospital, Sweden and 4 Danderyd Hospital, Sweden, 5 Ethicon Inc., Somerville, New Jersey 08876 and 6 School of Medicine, University of Southern California, Los Angeles, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: The objective of this study was to assess the safety and efficacy of a 0.5% ferric hyaluronate gel, in reducing adhesions in patients undergoing peritoneal cavity surgery by laparotomy, with a planned `second-look' laparoscopy. METHODS: The study was a randomized (by computer-generated schedule), third party blinded, placebo-controlled, parallel-group design conducted at five centres in Europe. Females aged 18–46 years received 300 ml ferric hyaluronate (n = 38) or lactated Ringer's (n = 39) as an intraperitoneal instillate at the completion of surgery. At second-look 6–12 weeks later, the presence of adhesions was evaluated at 24 abdominal sites. RESULTS: Patients treated with ferric hyaluronate had significantly fewer adhesions compared with controls. When adhesions formed, they were significantly less extensive and less severe in the treated group. The American Fertility Society score for adnexal adhesions was reduced by 69% in the treatment group compared with controls. The safety profile of ferric hyaluronate-treated patients was comparable with those treated with lactated Ringer's solution. CONCLUSIONS: In conclusion, ferric hyaluronate was safe and highly efficacious in reducing the number, severity and extent of adhesions throughout the abdomen following peritoneal cavity surgery.

Key words: adhesion prevention/clinical/ferric hyaluronate/peritoneal cavity surgery/lactated Ringer's solution


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Adhesion formation after peritoneal surgery is a major cause of post-operative bowel obstruction, infertility and chronic pelvic pain (Miller and Winfield, 1959Go; Bronson and Wallach, 1977Go; Kresch et al., 1984Go; Steege et al., 1991Go; Howard, 1993Go; Strickler et al., 1994Go; Tulandi et al., 1998Go). Therefore, a method by which post-surgical adhesion formation could be reduced or prevented would be of great benefit in reducing post-operative morbidity and failed surgical therapy. Studies have indicated that placement of an absorbable barrier of oxidized regenerated cellulose (INTERCEED® [TC7] Absorbable Adhesion Barrier, Ethicon Inc., Somerville, NJ, USA), expanded polytetrafluoroethylene (Preclude® Surgical Membrane, W.L. Gore and Assoc., Flagstaff, AZ, USA) or hyaluronic acid/carboxymethylcellulose (Seprafilm® Surgical Membrane, Genzyme Corp., Cambridge, MA, USA) between injury sites or addition of a viscous solution (dextran, Hyskon® Solution, Pharmacia Inc., Piscataway, NJ, USA; hyaluronic acid, Sepracoat®, Genzyme Corp.) into the peritoneal cavity during or after surgery can reduce post-operative adhesion formation (Sekiba et al., 1992; Azziz, 1993Go; Haney and Doty, 1993Go; Franklin et al., 1995Go; Mais et al., 1995aGo,bGo; Nordic Adhesion Prevention Study Group, 1995Go; The Myomectomy Adhesion Study Group, 1995Go; Diamond et al., 1996Go; Keckstein et al., 1996Go; diZerega, 1997Go; Diamond et al., 1998Go). In the case of INTERCEED® barrier, Preclude® membrane or Seprafilm® membrane, the surgeon must predict potential sites of adhesion formation in order to determine placement and optimize barrier benefit. Sepracoat®, a dilute solution of hyaluronic acid, has only been shown to be effective at reducing the number of de-novo adhesions at sites remote from the surgical trauma, while the use of Hyskon® in clinical practice has shown some undesirable side effects resulting from the accumulation of intraperitoneal ascites due to oncotic properties (Gauwerky et al., 1986Go). In addition, several reports indicate that Hyskon® is ineffective in pelvic surgery due to gravitational pooling in the cul-de-sac (Rosenberg and Board, 1984Go; Jansen, 1985Go; Larsson et al., 1985Go; diZerega, 1994Go).

Hyaluronic acid is a linear polysaccharide with repeating disaccharide units composed of sodium D-glucuronate and N-acetyl-D-glucosamine. It is a major component of many body tissues and fluids where it provides mechanically protective and physically supportive roles (Asplund et al., 1993Go; Yung et al., 1994Go). It undergoes degradation and replacement (turnover) and has been extensively studied in animal and human disease. Viscous hyaluronic acid solutions were shown to reduce adhesion formation in several situations including subcutaneous tissue, arthritic joints, tendons and peritoneal tissues (Thomas et al., 1982Go; Weiss et al., 1986Go,1987Go; Urman and Gomel, 1991Go; Shushan et al., 1994Go; West et al., 1996Go; Rodgers et al., 1997Go).

The viscosity and intraperitoneal residence time of a hyaluronic acid solution can be dramatically increased by chelation or crosslinking with ferric ion. Crosslinking between the carboxylate groups on the hyaluronate and the trivalent iron (Fe+3) is ionic in nature, and produces a significant increase in solution viscosity compared with the starting sodium hyaluronate solution (Johns et al., 1997Go). Preclinical studies of ionically crosslinked hyaluronic acid were highly effective in reducing adhesion formation in two standardized animal models. This paper reports the results of a single administration of a 0.5% ferric hyaluronate gel, a formulation with the critical variables optimized in a clinical study in peritoneal cavity surgery.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Intergel Adhesion Prevention Solution, a 0.5% ferric hyaluronate gel, was manufactured by Lifecore Biomedical Inc., Chaska, MN, USA. The 0.5% ferric hyaluronate adhesion prevention gel is a sterile, non-pyrogenic gel of highly purified sodium hyaluronate, which is ionically crosslinked with ferric ion and adjusted to isotonicity with sodium chloride. The placebo control was lactated Ringer's solution purchased from B.Braun-McGraw, Irvine, CA, USA.

The study was a randomized, third party blinded, placebo-controlled, parallel-group design conducted at five centres. All Investigational Review Boards approved the study plan for human evaluation. Patients were 18–46 year old females requiring peritoneal cavity surgery via laparotomy and expected to undergo a second-look laparoscopy as part of their treatment plan from 6–12 weeks after the initial surgery.

Patients with diabetes, haemochromatosis, hepatic, renal, autoimmune, lymphatic, haematological or coagulation disorders, or those presenting with pelvic or abdominal infection were excluded from the study. Also excluded from the study were patients receiving cancer therapy, post-operative hydrotubation, anticoagulants, fibrin glue or other thrombogenic agents at the initial surgical procedure. Patients receiving any adhesion prevention adjuvant such as INTERCEED® (TC7) Absorbable Adhesion Barrier, Seprafilm® Membrane or Preclude® Surgical Membrane, or those receiving any peritoneal instillate containing corticosteroids, non-steroidal anti-inflammatory agents or Hyskon®, or those in whom any absorbable haemostat was left in the abdominal/peritoneal cavity were excluded from the study. Patients undergoing peritoneal grafting or any surgical procedure involving opening of the gastrointestinal or urinary tract, or those undergoing tubal implantation, reversal of previous surgical sterilization only, or tubal sterilization only did not participate.

Within 2 weeks prior to the initial surgical procedure, the following baseline data were collected: demographic, medical and surgical history, current medications, physical examination, vital signs, and laboratory evaluations (haematology, blood chemistries, urinalysis and urine pregnancy test). Haematological evaluations consisted of haemoglobin, haematocrit, red blood cells, white blood cells and differential. Blood chemistries consisted of blood urea nitrogen, creatinine, phosphorus, calcium, uric acid, total protein, albumin, total bilirubin, serum glutanic oxalacetic transaminase (aspartate aminotransferase), seum glutamic-pyruvic transaminase (alanine amino transferase), alkaline phosphatase, sodium, potassium and chloride.

At the time of the initial surgical procedure, patients were assigned the next available study number corresponding to study device or control solution as determined by the computer-generated randomization schedule. Prior to any adhesiolysis, the investigator assessed the overall presence, extent, and severity of adhesions at each of the following 23 anatomical sites: the anterior peritoneum (three quadrants), small bowel, anterior uterus, posterior uterus, omentum, large bowel left and right, rectosigmoid portion of the large bowel, cul-de-sac (posterior), right pelvic sidewall, left pelvic sidewall, right ovary medial aspect, right ovary lateral aspect, left ovary medial aspect, left ovary lateral aspect, right tube, right ampulla, left tube, left ampulla, right ovarian fossa (posterior broad ligament) and left ovarian fossa (posterior broad ligament). The extent of adhesions was classified as localized (i.e. <1/3 of the site covered with adhesions), moderate (i.e. 1/3 to 2/3 of the site covered) or extensive (i.e. >2/3 of the site covered with adhesions) for the above 23 sites, except for the following four: large bowel left and right (difficult to visualize the entire structure), omentum and small bowel (the size precludes adequate evaluation of the extent). If an adhesion was present at any of these four sites, the extent was assigned an intermediate score (moderate) in the calculation of an adhesion score as discussed below. The severity of adhesions was classified as mild (i.e. filmy, avascular) or severe (i.e. organized, cohesive, vascular, dense).

At the conclusion of the operation, each patient who met all inclusion and exclusion criteria received 300 ml of either ferric hyaluronate (treatment) or lactated Ringer's solution (control) before closure of the abdominal peritoneum. The assigned study solution was removed from the sealed carton and administered into the peritoneal cavity by the surgeon or a surgical assistant depending on the method of blinding employed, after the primary surgical procedure, completion of haemostasis, aspiration of all irrigants, and the removal of all packs and sponges. Six to 12 weeks after the initial surgical procedure, a second-look laparoscopic procedure was performed to re-evaluate the 23 anatomical sites as previously described during the initial surgery. A 24th site, the anterior peritoneum incision (from the first operation), was also evaluated.

Blinding was maintained by either of two methods. In the first method, the study device or control solution, as determined by the randomization schedule, was administered into the peritoneal cavity by a surgicial assistant (third party) after the surgeon had completed the primary surgical procedure and had left the operating area. The surgeon then conducted the second-look laparoscopy at the appropriate time interval. In the alternative method, the surgeon conducting the initial surgery instilled the study material, and the second-look laparoscopy was carried out by a different surgeon (third party). In both cases, the study device or control solution, depending on the randomization, was maintained in a sealed carton until the decision to enroll the patient was made. The two alternative methods were necessary since some patients did not want a different surgeon performing the second-look laparoscopy, and some centres did not have readily available `surgical assistants'.

A blinded independent review of the adhesion data from the primary operation and second-look laparoscopy, as well as a videotape from the second-look was carried out as a quality assurance check to confirm that the investigators were consistent in recording their assessments. Any discrepancies noted by the Medical Review Officer were returned to the Principal Investigator for their consideration. The Principal Investigator determined if any changes were to be made.

The number and proportion of sites with adhesions were determined. The mean proportion was based on the number of sites with adhesions divided by the number of possible adhesion sites, which equalled 23 at the initial surgery and 24 at second-look (which included the peritoneal incision from the first procedure), except when sites were not present (e.g. a missing tube or ovary), or if an adhesion was present at the initial surgery that was not lysed. The severity and extent of adhesions were evaluated; severity was scored on a three-point scale where 0 = none, 1 = mild, and 2 = severe, and extent was scored on a four-point scale where 0 = none, 1 = localized, 2 = moderate, and 3 = extensive.

The adnexal adhesion score was determined by the method of the American Fertility Society, termed the AFS score (American Fertility Society, 1988Go). In addition, the adhesion scoring method of the AFS for the adnexa was extended to include 24 anatomical sites to determine a total adhesion score, termed the modified AFS score (Thornton et al., 1998Go). Adhesions occurring at each of the 24 potential adhesion sites were scored as shown in Table IGo.


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Table I. Scoring of adhesions occurring at 24 potential adhesion sites (averaged to yield a total adhesion score)
 
Safety evaluation was based on concomitant medications and conditions as well as on the type and severity of adverse events recorded throughout the study. Safety was also based on gross evaluation at second-look laparoscopy and on clinical laboratory tests performed within 2 weeks before the initial surgery, immediately prior to discharge from the hospital, and 7 to 28 days after the initial surgery. Length of hospital stay was also evaluated.

The treatment and control groups were compared using Student's t-test for continuous variables and Fisher's exact test for categorical variables. The number and proportion of sites with adhesions were compared using Student's t-test. Adhesion scores were compared using the Wilcoxon rank sum test and the AFS score shift table was analysed by the Cochran–Mantel–Haenszel (CMH) test with ridit scores based on the order of adhesion score categories.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
A total of 77 patients completed the study: 38 in the ferric hyaluronate (treatment) group and 39 in the lactated Ringer's solution (control) group. As shown in Table IIGo, the type and frequency of surgical procedures were similar for the two groups. There were no statistically significant differences between the two groups in the number of nights spent at the hospital (4.0 ± 1.5 versus 4.6 ± 1.9 respectively), the number of days to second-look laparoscopy (65.1 ± 22 versus 63.9 ± 25 respectively), or the operative time (1.58 ± 0.59 versus 1.62 ± 0.60 h respectively). In both groups, bowel function returned to normal within 3 days, there was no evidence of ascites, and there were no cases of post-operative sepsis.


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Table II. Frequency of surgical procedures
 
No deaths occurred during this study and there were no study discontinuations due to an adverse event. All patients in both study groups reported at least one adverse event. The three body systems with the highest patient incidence of adverse events were: body as a whole, with 100% of patients in both groups; digestive, with 49% of patients in the treatment group versus 50% in the control group; and nervous system, with 15 versus 23% respectively. Of events affecting the body as a whole, the largest proportions were attributable to pain, with 90% of patients in the treatment group versus 85% in the control group. Digestive system disorders were frequently attributable to nausea (42% treatment versus 43% control) and constipation (9% treatment versus 10% control) whereas the nervous system disorders were mostly attributable to insomnia (9% treatment versus 8% control). These expected events (given that patients were undergoing anaesthesia and surgery) were generally mild to moderate and resolved spontaneously or with standard post-operative care.

As shown in Table IIIGo, the mean number of sites at baseline with adhesions, number of adhesions which were lysed, and the number of surgical sites (which includes adhesiolysis, surgical treatment of endometriosis, and other surgical procedures) were comparable for the two groups. However, at second-look laparoscopy, the mean number of sites with adhesions (excluding sites with adhesions that were not lysed at the first procedure) as well as the proportion of possible adhesion sites was significantly reduced in the ferric hyaluronate group compared with control (P = 0.040 and 0.031 respectively). Ferric hyaluronate was effective in reducing both surgicial site adhesions and reformed adhesions (Figure 1Go).


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Table III. Number and proportion of adhesions
 


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Figure 1. Percentage of anatomical sites that were adhesion-free at second-look laparoscopy in patients who received 300 ml of an intraperitoneal instillate of 0.5% ferric hyaluronate gel or lactated Ringer's solution at the end of surgery. Patients that received ferric hyaluronate had a statistically significant increase in adhesion-free sites where adhesions were lysed (reformation sites), or where there was no adhesion at the initial surgery (de-novo surgical sites). The P-values were determined using Student's t-test.

 
The severity and extent of adhesions at baseline and at second-look laparoscopy were also evaluated. While the two groups were comparable at baseline, ferric hyaluronate significantly reduced the severity and extent of adhesions that were seen at second-look laparoscopy. (P = 0.035, Table IVGo). Adhesion formation was also assessed via a composite score adopted from the method proposed by the AFS modified (termed modified AFS) as applied to all 24 anatomical sites (American Fertility Society, 1988Go). As shown in Table IVGo, baseline adhesion scores were comparable, and ferric hyaluronate significantly reduced the modified AFS score at second-look laparoscopy compared with control (P = 0.026).


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Table IV. Severity, extent, and mAFS scores
 
To look for trends based on the surgical procedure performed, patients were subgrouped into those who underwent myomectomy, adhesiolysis, tubal procedures, or those who had ovarian surgery including those patients with ovarian dermoids or endometriomas. Ferric hyaluronate was found to reduce the modified AFS score at second-look by at least 60% for each procedure (Table VGo), although statistical significance was not achieved in all of the subgroups.


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Table V. Second-look mAFS score results by surgical procedure
 
The effect of ferric hyaluronate on reducing adnexal adhesions was shown by a significant reduction in the AFS score compared with control by way of shift tables. As shown in Table VIGo, the number of patients with minimal (AFS score = 0–5), mild (6–10), moderate (11–20), and severe (21–32) adhesions at baseline and second-look were determined. At baseline, there were 28 patients in the ferric hyaluronate group with minimal adhesions, and all 28 remained within the minimal group at second-look (some of the patients may have improved or worsened slightly, but they did not change AFS category). In the control group, 22 of the 24 patients who were originally in the minimal group remained there at second-look, whereas two patients shifted to a worse category, i.e. mild adhesions. Overall, in the ferric hyaluronate group, no patients shifted to a worse category, 36 of the 38 patients were in the minimal AFS category, whereas two were in the mild category, and no patients had moderate or severe adhesions. In the control group, four patients shifted to a worse category, only 28 of the 39 patients were in the minimal category, whereas four were categorized as mild, six as moderate and one as severe. Analysis using the CMH test controlling for baseline level indicates a highly significant P value (0.011), suggesting significant differences between treatment groups in the shift of patients from one AFS category to another.


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Table VI. AFS score shift table
 
As a quality assurance check, the inter-observer correlations between the investigators and the Medical Review Officer were compared and weighted {kappa}-scores were determined to assess the level of agreement. The overall agreement between the initial investigators' assessments and the Medical Review Officer were very good ({kappa} = 0.928). After consideration of the Medical Review Officer comments, the {kappa}-score increased to 0.975, indicating the investigators agreed with the Medical Review Officer more often than not.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The clinical safety and effectiveness of 0.5% ferric hyaluronate gel was initially demonstrated in a single centre pilot study (Thornton et al., 1998Go). In the pilot study, 23 patients were studied (ferric hyaluronate = 13; lactated Ringer's solution = 10). At the end of the initial laparotomy procedure, 300 ml of study device were instilled. At second-look laparoscopy, 4–12 weeks after the laparotomy, patients treated with ferric hyaluronate had significantly fewer adhesions than control patients. When adhesions did form they were significantly less extensive and severe. Accordingly, a multicentre study was performed to confirm and extend the results of the pilot.

This study was designed to evaluate safety and efficacy of ferric hyaluronate in humans after peritoneal cavity surgery for reduction of adhesion formation at 24 sites throughout the entire abdomen. The 0.5% ferric hyaluronate gel was shown to be easy to use and significantly reduced the number, severity, and extent of adhesions after laparotomy throughout the abdominal cavity. The safety profile was comparable with that of lactated Ringer's solution. There were no statistically significant differences between treatment groups as to concomitant medications or adverse events. There were no clinically meaningful changes in laboratory values in either treatment group. There were no statistically significant differences between treatment groups in hospital stay.

Coating the abdominal surfaces with solutions to inhibit adhesive contact of injured tissues has previously met with moderate success. Although this approach appears to be convenient and uncomplicated, no solution has provided universal benefit. A substantial body of clinical data is available to assess the benefit of crystalloid instillates, such as saline and lactated Ringer's solution, in adhesion prevention. During the early 1980s, four clinical studies were published which compared dextran with crystalloid used as instillates. A combination of these studies showed an adhesion reformation rate of ~80% in patients who received crystalloid instillates (diZerega and Campeau, 1994Go). This high rate of adhesion formation with the use of intraperitoneal instillates was confirmed by another study (Fayez and Schneider, 1987Go). Reports have recently appeared describing the use of crystalloid solutions to reduce adhesion formation after laparoscopic ovarian surgery. Naether and Fischer instilled 300–500 ml of saline into the peritoneal cavity after laparoscopic coagulation of the ovarian surface in patients with polycystic ovarian syndrome (PCOS) (Naether and Fischer, 1993Go). When compared with a previous series treated in a similar fashion by these authors without the crystalloid instillation, they found no difference in the incidence of adhesions (17 versus 19% respectively). Gurgan et al., instilled 150 ml of lactated Ringer's solution into the pelvis after laparoscopic electrocautery or laser vapourization of the ovarian surface in PCOS patients: 82% were found to have adhesions to the ovarian surface at second-look laparoscopy (Gurgan et al., 1991Go). More recently, Gurgan et al., and Tulandi et al., both reconfirmed the failure of crystalloid solution (lactated Ringer's solution, 500 ml) to reduce adhesion formation in patients undergoing laparoscopic ovarian surgery (Tulandi et al., 1993Go; Gurgan et al., 1996Go). In order to significantly reduce adhesion formation and reformation, the device must effectively separate damaged surfaces during the crucial phases of post-surgical repair. The rapid rate of absorption of crystalloid solution from the peritoneal cavity (35 ml/h) may preclude its residence during the crucial time of adhesion formation (Shear et al., 1965Go; Hart and Magos, 1996Go; Sites et al., 1997Go). Meta-analysis of clinical studies using crystalloid solution conclusively showed no reduction in adhesion with instillation of lactated Ringer's solution or saline (Wiseman et al., 1998Go).

Hyaluronic acid is a naturally occurring component of peritoneal fluid (Yung et al., 1994Go). Peritoneal mesothelial cells were shown to synthesize hyaluronic acid in vitro, and hyaluronic acid is thought to play a role in lubrication of cells, maintenance of the structural integrity of tissues as well as regulation of fluid retention (Asplund et al., 1993Go). A number of investigators previously studied the efficacy of hyaluronic acid solutions in adhesion prevention. Urman and Gomel evaluated the effectiveness of hyaluronic acid solution in preventing intraperitoneal adhesions in rats after CO2 laser injury of the serosa (Urman and Gomel, 1991Go). Although precoating of the serosa reduced de-novo adhesion formation, no significant reduction of adhesions was seen when hyaluronic acid was added at the end of the procedure, e.g. post-treatment. The effectiveness of reducing de-novo adhesions by precoating prior to injuring the serosa of rats was confirmed in a recent study (West et al., 1996Go). A similar reduction of de-novo adhesions in rats after serosal abrasion was noted by Shushan et al., following administration of hyaluronic acid as an instillate, as well as application of an hyaluronic acid membrane after laser injury to the rat uterine horn (Shushan et al., 1994Go). Diamond et al., reported the clinical effectiveness of Sepracoat® Hyaluronic Acid Coating Solution used as a precoating solution in 245 patients undergoing laparotomy (Diamond et al., 1998Go). The solution was applied upon entry into the abdominal cavity and periodically thereafter.

The results reported here are with hyaluronic acid ionically crosslinked by ferric chloride to produce a viscous gel. In animal studies, ferric hyaluronate gel was more efficacious than hyaluronic acid, even when the concentration of hyaluronic acid was increased to produce a viscosity similar or greater than ferric hyaluronate gel (Johns et al., 1997Go). In addition, a 0.5% ferric hyaluronate gel reduced adhesion formation not only at sites of application, but throughout the abdominal cavity of laboratory animals suggesting widespread distribution by the intra-abdominal circulation. The effectiveness of Adhesion Prevention Solution, a 0.5% ferric hyaluronate gel was subsequently demonstrated in a pilot clinical study in the USA (Thornton et al., 1998Go), and was found to be more than twice as effective as lactated Ringer's solution in reducing adhesion formation. The results reported here, from a multicentre clinical trial in Europe, confirm and extend the results of the pilot clinical trial, as well as those of a similar multicentre clinical trial conducted at 11 centres in the USA (Johns and diZerega, 1999Go). The efficacy difference between the ferric hyaluronate and non-crosslinked hyaluronic acid formulations appears to result primarily from a longer residence time relative to hyaluronic acid in the peritoneal cavity. This may be due to a greater tendency of ferric hyaluronate to adhere to the tissue or a delayed dilution with peritoneal fluids compared with hyaluronic acid.

In summary, a 0.5% ferric hyaluronate gel (Intergel Adhesion Prevention Solution) was shown to be easy to use in this multicentre study and significantly reduced the number, severity, and extent of adhesions after laparotomy at 24 sites throughout the abdominal cavity. A significant reduction in the AFS score (adnexal adhesions) as well as a modified AFS score (applied to 24 anatomical sites throughout the abdominal-pelvic cavity) was also demonstrated. The safety profile was comparable with that of lactated Ringer's solution (control). There were no statistically significant differences between treatment groups as to concomitant medications and adverse events. There were also no clinically meaningful changes in laboratory values in either treatment group.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was sponsored by Lifecore Biomedical Inc., Chaska, MN, USA.


    Notes
 
7 To whom correspondence should be addressed. E-mail: djohns{at}ethus.jnj.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
American Fertility Society (1988) The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian anomalies and intrauterine adhesions. Fertil. Steril., 49, 944–955.[ISI][Medline]

Asplund, T., Vershel, M.A., Luarent, T.C. et al., (1993) Human mesotheleoma cells produce factors that stimulate the production of hyaluronan by mesothelial cells and fibroblasts. Cancer Res., 53, 388–392.[Abstract]

Azziz, R. (1993) Microsurgery, alone or with INTERCEED absorbable adhesion barrier for pelvic sidewall adhesion reformation. Surg. Gynecol. Obstet., 177, 135–139.[ISI][Medline]

Bronson, R.A. and Wallach, E.E. (1977) Lysis of periadnexal adhesion for correction of infertility. Fertil. Steril., 28, 613–619.[ISI][Medline]

Diamond, M.P. and The Seprafilm Adhesion Study Group (1996) Reduction of adhesions after uterine myomectomy by Seprafilm® membrane (HAL-F®): a blinded, prospective, randomized, multicenter clinical study. Fertil. Steril., 66, 904–910.[ISI][Medline]

Diamond, M.P. and the Sepracoat Adhesion Group (1998) Reduction of de novo postsurgical adhesions by intraoperative precoating with Sepracoat (HAL-C) solution: a prospective, randomized, blinded, placebo-controlled multicenter study. The Sepracoat Adhesion Study Group. Fertil. Steril., 69, 1067–1074.[ISI][Medline]

diZerega, G.S. (1994) Contemporary adhesion prevention. Fertil. Steril., 61, 219–235.[ISI][Medline]

diZerega, G.S. (1997) Use of adhesion prevention barriers in pelvic reconstructive and gynecologic surgery. In diZerega, G.S., DeCherney, A.H., Diamond, M.P., et al., (ed.) Pelvic Surgery. Springer-Verlag, New York, pp. 188–209.

diZerega, G.S. and Campeau, J.D. (1994) Use of instillates to prevent intraperitoneal adhesions: Crystalloids and dextran. Inf. Reprod. Med. Clinics N. Am., 5, 463–478.

Fayez, J.A. and Schneider, P.J. (1987) Prevention of pelvic adhesion formation by different modalities of treatment. Am. J. Obstet. Gynecol., 157, 1184–1188.[ISI][Medline]

Franklin, R.R., Malinak, R.L., Larsson, B. et al., (1995) Reduction of ovarian adhesions by the use of Interceed. Obstet. Gynecol., 86, 335–338.[Abstract/Free Full Text]

Gauwerky, J.F., Heinrich, D. and Kubli, F. (1986) Complications of intraperitoneal dextran application for prevention of adhesions. Biol. Res. Pregnancy Peritatol., 7, 93–97.

Gurgan, T., Kisnisei, H., Yarali, H. et al., (1991) Evaluation of adhesion formation after laparoscopic treatment of polycystic ovarian disease. Fertil. Steril., 56, 1176–1178.[ISI][Medline]

Gurgan, T., Urman, B., Yarali, H. et al., (1996) Adhesion formation and reformation after laparoscopic removal of ovarian endometriomas. J. Am. Assoc. Gynecol. Laparosc., 82, 213–215.

Haney, A.F. and Doty, E. (1993) Expanded polyterafluoroethylene but not oxidized regenerated cellulose prevents adhesion formation and reformation in a mouse uterine horn model of surgical injury. Fertil. Steril., 60, 550–554.[ISI][Medline]

Hart, R. and Magos, A. (1996) Laparoscopically instilled fluid: the rate of absorption and the effects on patient discomfort and fluid balance. Gynaecol. Endos., 5, 287–291.

Howard, F.M. (1993) The role of laparoscopy in chronic pelvic pain: Promise and pitfalls. Obstet. Gynecol. Surg., 48, 357–358.

Jansen, R.P. (1985) Failure of intraperitoneal adjuncts to improve the outcome of pelvic operations in young women. Am. J. Obstet. Gynecol., 153, 363–371.[ISI][Medline]

Johns, D.B. and diZerega, G.S. (1999) Development and clinical evaluation of Intergel Adhesion Prevention Solution for the reduction of adhesions following peritoneal cavity surgery. In diZerega, G.S. (ed.) Peritoneal Surgery. Springer-Verlag, New York, pp. 351–366.

Johns, D.B., Rodgers, K.E., Donahue, W.D. et al., (1997) Reduction of adhesion formation by postoperative administration of ionically cross linked hyaluronic acid. Fertil. Steril., 68, 37–42.[ISI][Medline]

Keckstein, J., Ulrich, U., Sasse, V. et al., (1996) Reduction of postoperative formation after laparoscopic ovarian cystectomy. Hum. Reprod., 11, 579–582.[Abstract]

Kresch, A.J., Seifer, D.B., Sachs, L.B. et al., (1984) Laparoscopy in 100 women with CPP. Obstet Gynecol., 64, 672–674.[Abstract]

Larsson, B., Lalos, O., Marsk, L. et al., (1985) Effect of intraperitoneal instillation of 32% dextran 70 on postoperative adhesion formation after tubal surgery. Acta Obstet. Gynecol. Scand., 64, 437–441.[ISI][Medline]

Mais, V., Ajossa, S.A., Marongiu, D. et al., (1995a) Reduction of adhesion formation after laparoscopic endometriosis surgery; a randomized trial with an oxidized regenerated cellulose absorbable barrier. Obstet. Gynecol., 86, 512–515.[Abstract/Free Full Text]

Mais, V., Ajossa, S.A., Piras, B. et al., (1995b) Prevention of de-novo adhesion formation after laparoscopic myomectomy: a randomized trial to evaluate the effectiveness of an oxidized regenerated cellulose absorbable barrier. Hum. Reprod., 12, 3133–3133.

Miller, E.M. and Winfield, J.M. (1959) Acute intestinal obstruction secondary to postoperative adhesions. Arch. Surg., 78, 148–153.

Naether, O.G.J. and Fischer, R. (1993) Adhesion formation after laparoscopic electrocoagulation of the ovarian surface in polycystic ovary patients. Fertil. Steril., 60, 95–98.[ISI][Medline]

Nordic Adhesion Prevention Study Group (1995) The efficacy of Interceed (TC7) for prevention of reformation of postoperative adhesions on ovaries, fallopian tubes, and fimbriae in microsurgical operation for fertility: a multicenter study. Fertil. Steril., 63, 709–714.[ISI][Medline]

Rodgers, K.E., Johns, D.B., Girgis, W. et al., (1997) Reduction of adhesion formation with hyaluronic acid following peritoneal surgery in rabbits. Fertil. Steril., 67, 553–558.[ISI][Medline]

Rosenberg,S.M. and Board, J.A. (1984) High-molecular weight dextran in human infertility surgery. Am. J. Obstet. Gynecol., 148, 380–385.[ISI][Medline]

Sekiba, K. (1992) Use of Interceed (TC7) absorbable adhesion barrier to reduce postoperative adhesion reformation in infertility and endometriosis surgery. Obstet. Gynecol., 79, 518–522.[Abstract]

Shear, L., Swartz, C., Shinaberger, J. et al., (1965) Kinetics of peritoneal fluid absorption in adult man. N. Engl. J. Med., 272, 123–127.[ISI]

Shushan, A., Mor-Yosef, S., Avgar, A. et al., (1994) Hyaluronic acid for preventing experimental postoperative intraperitoneal adhesions. J. Reprod. Med., 39, 398–402.[ISI][Medline]

Sites, C.K., Jensen, B.A., Jacob, B.S. et al., (1997) Transvaginal ultrasonographic assessment of Hyskon or lactated Ringer's solution instillation after laparoscopy: Randomized, controlled study. J. Ultrasound Med., 16, 195–199.[Abstract]

Steege, J.F., Stout, A.L. and Somkuti, S.G. (1991) Chronic pelvic pain in women: Toward an integrative model. Obstet. Gynecol. Surg., 48, 95–110.

Strickler, B., Blanco, J. and Fox, H.E. (1994) The gynecologic contribution to intestinal obstruction in females. J. Am. Coll. Surg., 178, 617–621.[ISI][Medline]

The Myomectomy Adhesion Study Group. (1995) An expended-polytetrafluoroethylene barrier (Gore-Tex surgical membrane) reduces post-myomectomy adhesion formation. Fertil. Steril., 63, 491–493.[ISI][Medline]

Thomas, S.C., Jones, L.C. and Hungerford, D.S. (1982) Hyaluronic acid and its effects on postoperative adhesions in the rabbit flexor tendon. Clin. Ortho., 206, 281–289.

Thornton, M.H., Johns, D.B., Campeau, J.C. et al., (1998) Clinical evaluation of 0.5% ferric hyaluronate adhesion prevention gel for the reduction of adhesion following peritoneal cavity surgery: open-label pilot study. Hum. Reprod., 13, 1480–1485.[Abstract]

Tulandi, T., Murray, C., and Guralnick M. (1993) Adhesion formation and reproductive outcome after myomectomy and second-look laparoscopy. Obstet. Gynecol., 82, 213–215.[Abstract]

Tulandi, T., Chen, M.F., Al-Took, S. et al., (1998) A study of nerve fibers and histopathology of postsurgical, postinfectious, and endometriosis-related adhesions. Obstet. Gynecol., 92, 766–768.[Abstract/Free Full Text]

Urman, B. and Gomel, V. (1991) Effect of hyaluronic acid on postoperative intraperitoneal adhesion formation and reformation in the rat model. Fertil. Steril., 56, 568–570.[ISI][Medline]

Wallwiener, D., Meyer, A. and Bastert, G. (1998) Adhesion formation of the parietal and visceral peritoneum: an explanation for the controversy on the use of autologous and alloplastic barriers? Fertil. Steril., 68, 132–137.

Weiss, C., Levy, H.J., Delinger, J. et al., (1986) The role of Na-Hylan in reducing postsurgical tendon adhesions. Bull. Hosp. Jt. Dis. Orthop. Inst., 45, 9–15.

Weiss, C., Suros, J.M., Michalow, A. et al., (1987) The role of Na-hylan in reducing postsurgical tendon adhesions: Part 2. Bull. Hosp. Jt. Dis. Orthop. Inst., 47, 31–39[Medline]

West, J.L., Chowdhury, S.M., Sawhney, A.S. et al., (1996) Efficacy of adhesion barriers: resorbable hydrogel, oxidized regenerated cellulose and hyaluronic acid. J. Reprod. Med., 41, 149–154.[ISI][Medline]

Wiseman, D.M., Trout, J.R. and Diamond, M.P. (1998) The rates of adhesion development and the effects of crystalloid solutions on adhesion development in pelvic surgery. Fertil. Steril., 70, 702–711.[ISI][Medline]

Yung, S., Coles, G.A., Williams, J.D. et al., (1994) The source and possible significance of hyaluronan in the peritoneal cavity. Kidney Int'l., 46, 527–533.[ISI][Medline]

Submitted on July 26, 2000; accepted on May 31, 2001.