1 Department of Obstetrics and Gynecology, Viborg Hospital, Viborg, Denmark, 2 Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium, 3 Department of Obstetrics and Gynecology, Klinikum Duisburg, Zuden Rehwiesen 9, Duisburg, Germany, 4 Institut Greenblatt France, Bordeaux, France, 5 FzioMed Inc., 231 Bonetti Drive, San Luis Obispo, California, and 6 Obstetrics and Gynecology, Livingston Reproductive Biology Laboratories, KeckUSC School of Medicine, Los Angeles, California, USA
7 To whom correspondence should be sent at: University of Southern California Keck School of Medicine, Obstetrics and Gynecology, Livingston Laboratories, 1321 N. Mission Road, Los Angeles, CA 90033, USA. Email: gsd1270{at}aol.com
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Abstract |
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Key words: adhesions/laparoscopy/Oxiplex/prophylaxis/viscoelastic gel
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Introduction |
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Adhesion prevention adjuvants became available to practising gynaecologists in 1990 with the introduction of Interceed Absorbable Adhesion Barrier (Gynecare, USA) (Interceed Adhesion Barrier Study Group, 1989). Other site-specific barriers soon followed, including Preclude (Gore-Tex, USA) (Surgical Membrane Study Group, 1992) and Seprafilm Bioabsorbable Membrane (Genzyme, USA) (Becker et al., 1996
; Diamond, 1996
). These first generation adhesion prevention devices were widely used in laparotomy procedures but were found to be a challenge when used via laparoscopy. Although the Food and Drugs Agency (FDA) approved Intergel Adhesion Prevention Solution in 2001 for use via laparotomy (Johns et al., 2001a
,b
; Lundorff et al., 2001
), many gynaecologists found Intergel easy to use via laparoscopy. When Intergel was withdrawn from the market in 2003, the only clinically available instillate in Europe indicated for the reduction of post-operative adhesion formation was Adept (diZerega et al., 2002
). Early clinical studies with N,O-carboxymethylchitosan in volumes of
300 ml showed promising clinical benefit (Diamond et al., 2003
). Development of site-specific adhesion prevention devices, which could be easily delivered during laparoscopy, was led by initial clinical studies of SprayGel (Johns et al., 2001a
,b
; Mettler et al., 2003
). Recently, Oxiplex/SP became available to spinal surgeons for the reduction of pain and weakness due to adhesion formation following laminectomy (Kim et al., 2003
). A similar formulation of Oxiplex, viscoelastic gel, was shown in preclinical studies to be most effective in reducing adhesions to peritoneal surfaces following surgery (Berg et al., 2003
). This paper reports the results of the first clinical study utilizing viscoelastic gel, a single component adhesion prevention device that can easily be administered to pelvic sites during laparoscopic surgery.
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Materials and methods |
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The study was a randomized, third party blinded, parallel-group design conducted at four centres in Europe. The study plan was approved for human evaluation by the relevant committee at each study centre. Patients were 1846 years old requiring peritoneal cavity surgery by way of laparoscopy and expected to undergo a second-look laparoscopy as part of their treatment plan 610 weeks after the initial surgery. FzioMed, Inc. provided financial assistance to the patients for the second-look laparoscopy if it was not covered by their insurance carrier. Patients with a history of diabetes, hepatic, or renal disorders, or those presenting with pelvic or abdominal infection were excluded from the study. Also excluded from the study were patients with a history of malignancy within 5 years of study initiation. Patients who received systemic corticosteroids within 30 days of the initial surgery or post-operative hydrotubation were excluded. All patients had a negative pregnancy test within 24 h of the scheduled surgery. Patients receiving any adhesion prevention adjuvant such as Interceed, Seprafilm, SprayGel or Intergel, or those receiving any peritoneal instillate including instillates containing corticosteroids, non-steroidal anti-inflammatory agents or Hyskon, or those in whom any absorbable haemostat was left in the peritoneal cavity were excluded from the study. Patients who were pregnant, including ectopic pregnancy, or those undergoing reversal of previous surgical sterilization did not participate.
At the time of the initial surgical procedure, patients were assigned the next available study number as determined by randomization schedule corresponding to study device or control which was surgery alone. All surgeries were performed with a full pneumoperitoneum. After initiation of the laparoscopic procedure and before any adhesiolysis or other surgery, the investigator evaluated the adnexa including manipulation of the ampulla and ovaries with a probe with inspection of the pelvic sidewall and ovarian fossa. The entire procedure was recorded on videotape. The patient was excluded from randomization if any of the following events occurred during the surgical procedure: no evidence of adnexal disease or endometriosis, bowel perforation, or conversion to laparotomy. At the conclusion of the operation, each patient who met all inclusion and exclusion criteria received either Oxiplex/AP Gel treatment or no additional therapy (control).
Application of Oxiplex/AP Gel
For patients who received Oxiplex/AP Gel, the following procedures were followed. At the end of the surgical procedures, subjects were placed in reverse Trendelenberg position to facilitate collection of residual fluid from the cul-de-sac. Thereafter, residual fluid was aspirated until <10 ml of fluid remained in the cul-de-sac. A single layer of gel was applied via a 30.5 cm longx5 mm canula applicator in sufficient volume to completely coat the surgical site with a viscous layer of gel. The surgical sites included anterior and posterior surface of the ovary, Fallopian tube including mesosalpinx, the surfaces between the Fallopian tube and ovary, surface of the ampulla, adjacent pelvic sidewall including the ovarian fossa, and the lateral aspect of the uterus that could come in contact with the adnexa. The amount of gel required to coat the adnexa did not exceed 30 ml. Thereafter, the surgical instruments were removed and the pneumoperitoneum evacuated.
Six to 10 weeks after the initial surgical procedure, a second-look laparoscopic procedure was performed. At that time the adnexa were evaluated in a manner similar to the initial laparoscopic surgical procedure and the image recorded on videotape.
Blinded reviews of the videotapes were performed to quantify adhesion scores by the method of the American Fertility Society (AFS, 1988). AFS adnexal adhesion score is determined by assessing the extent (area of adnexal organ covered by adhesions) and severity (severe: if the adhesion requires cutting to remove or tears peritoneal surfaces when removed bluntly or requires haemostasis; filmy if not severe) of the adhesions involving the Fallopian tube and ovary. Summing the scores for the Fallopian tube and the ovary provided a clinical category for the adhesion score: minimum (05), mild (610), moderate (1120), and severe (2132).
Safety evaluation was based on the patient's post-operative condition and recovery as well as the type and severity of adverse events recorded throughout the study.
Technique for gel application
Like any surgical device, careful attention to the details of application are important for maximal patient benefit. The following procedures for Oxiplex/AP Gel were followed. At the end of the surgical procedures, subjects were placed in reverse Trendelenberg position to facilitate collection of residual fluid from the cul-de-sac. Thereafter, residual fluid was aspirated until <10 ml of fluid remained in the cul-de-sac. A single layer of gel was applied via an applicator in single layers of sufficient volume to completely cover the surgical sites.
Statistical analysis
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 shift tables were analysed by the CochranMantelHaenszel test with the ridit scores based on the order of adhesion score categories.
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Results |
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An Oxiplex Applicator, consisting of 30 cmx5 mm cannula, was used to apply a single layer of gel to the adnexa (94±21 s). The amount of gel required to cover the adnexal surfaces with a single layer of gel with the Oxiplex Applicator was found to be 15 ml per adnexa.
Efficacy
As shown in Figure 1, the mean adnexal adhesion score for the Oxiplex/AP Gel-treated adnexa was 11.9 and for the control adnexa 8.8. At the time of second-look laparoscopy, the adnexa that were covered with Oxiplex/AP Gel showed a decrease in mean adnexal adhesion score from 11.9 to 9.1. In contrast, the control adnexa showed an increase in adnexal adhesion score from 8.8 to 15.8. The difference in second-look AFS scores (42% reduction; P<0.01) was statistically significant. The same directional difference in mean adnexal adhesion score was seen for the patient groups without (Figure 2A) and with (Figure 2B) endometriosis. Patients with grade IIII endometriosis showed a reduction in adnexal adhesion score in the Oxiplex/AP Gel-treated group compared to controls (Figure 2C). Whereas Oxiplex/AP Gel worked well to prevent an increase in adhesion score in patients with endometriosis, it did not appear to provide that benefit to patients with grade IV endometriosis (data not shown).
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The number of individual adnexal adhesion scores (Table II) that improved or stayed the same from first- to second-look laparoscopy versus those that worsened reveals a significant treatment benefit from the use of Oxiplex/AP Gel. Of the adnexa in the Oxiplex/AP Gel group, 87% did not have a worse adhesion score in contrast to 32% of the control adnexa at the time of second look. When individual adnexal adhesion scores are grouped by prognostic category (Table II), the number that improved or stayed the same, from first to second-look laparoscopy versus those that shifted to a worse category, also demonstrates a significant treatment effect of Oxiplex/AP Gel. For example, 93% of the adnexa that received treatment with Oxiplex/AP Gel did not have a worse categorical score. By contrast, 56% of the control adnexa did not have a worse categorical score at the time of second look.
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Discussion |
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Oxiplex/AP Gel was developed by complexing two polymers to maximize tissue adherence. The muco-adherent properties of the gel (Liu and Berg, 2002) allow the device to remain in place even in gravitationally dependent areas such as the anterior abdominal wall after removal of an omental adhesion or the posterior surface of the uterus after myomectomy. A similar formulation of Oxiplex was shown in preclinical studies (Oxiplex/SP Gel) to be safe and effective in reducing adhesions to dura following spinal surgery (Rodgers, 2003). Recently, clinical studies showed that patients with severe back pain and lower extremity weakness who had Oxiplex/SP Gel applied over their nerve roots following laminectomy or laminotomy experienced significantly reduced symptoms compared to surgery-only controls (Kim et al., 2003
). Here, Oxiplex/AP Gel, specifically designed for use in the peritoneal cavity (Berg et al., 2003
) was evaluated in women undergoing conservative gynaecological surgery.
In this clinical study, 49 patients underwent surgical therapy of their adnexa to remove existing adhesions or endometriosis by surgery performed via laparoscopy. Following the primary surgical procedure(s), the treated patients had Oxiplex/AP Gel applied to their adnexa. Oxiplex/AP Gel was applied over the surface of the patient's ovaries, Fallopian tubes, ovarian fossa, and lateral portion of the uterus. With experience, the principle investigators found that a single layer of gel was sufficient to cover the adnexal surface and adjacent sites. It was not necessary for multiple layers of gel to be applied over an anatomical site. In some cases, when multiple layers of gel were layered over one another, the weight of the excess gel overcame the innate tissue adherence such that gel fell off the surgical site. Typical volume to cover an adnexum was 15 ml which was administered in
90 s. Oxiplex/AP Gel was easy to apply to adnexal surfaces including the ovarian fossa and between the ovary and mesosalpinx. This process was facilitated by cessation of vascular oozing after gel coverage.
A single layer of gel was sufficient to protect the tissue during post-surgical repair. The gel was resorbed from the peritoneal cavity prior to the time of second-look laparoscopy, usually within 6 weeks. In four cases, small collections (5x5 mm) of gelatinous material (presumably residual gel) were noted in areas where multiple layers of gel had been applied or in areas deep in the cul-de-sac where intraperitoneal clearance may have been effected (Ahrenholz and Simmons, 1988
; diZerega and Rodgers, 1992
) particularly in cases of grade IV endometriosis. In two instances, biopsies of these sites were consistent with residual gel. There did not appear to be any clinical significance of the residual gel: residuum did not interconnect tissue surfaces; was not associated with adhesions; did not obstruct organ mobility. Although it is reassuring to see gel persisting at the site of application, avoidance of applying excess gel is recommended.
Adhesion reduction
Due to the study requirements for laparoscopy, many patients had no or minimal adnexal adhesions at the time of their initial surgery. All of the adnexa with no adhesions at the time of initial surgery had endometriomas. Twenty-two out of 23 of the Oxiplex/AP-treated adnexa continued to have minimal adhesion scores at second-look laparoscopy. By contrast, only 13/23 control adnexa with minimal adhesion scores were unchanged at the time of second look. At the time of second-look laparoscopy, 2/45 of the Oxiplex/AP Gel-treated adnexa demonstrated substantial adhesion formation progressing to moderate or severe adhesion category; by contrast, 11/41 control adnexa shifted into the moderate or severe category. Both of these differences are statistically significant. In this study, three of 45 treated adnexa had a change or shift in their adhesion score toward a higher or worse category. By contrast, 18 of 41 control adnexa had a shift in their adhesion score into a worse prognostic category at second-look laparoscopy (P<0.001). This reduction in post-operative adnexal adhesions demonstrates a clinically significant benefit of Oxiplex/AP Gel as categorical reduction in adnexal adhesions has been associated with better clinical outcomes (Gomel and Erenus, 1990; Stout et al., 1991
; De Bruyne et al., 1997
; Nagata et al., 1997a
,b
; Mage et al., 2000
; diZerega et al., 2003
). This is the first demonstration of a site-specific adhesion prevention device that can be easily and quickly applied to the adnexa including the ovarian fossa and between the ovary and mesosalpinx, and that significantly reduces adhesions to the ovary and Fallopian tube following surgical therapy of the adnexa by laparoscopy.
Adhesion scoring systems were developed to help establish correlations between adhesions and disease outcomes to guide in management. Adhesion scoring is not only used for prognosis, but it can also be a determinant of therapy (Mage et al., 2000). The most widely used system is the one proposed as the Adnexal Adhesion Classification of the AFS (1988)
. Clinical correlations using the AFS Adnexal Adhesion Classification have been previously summarized (diZerega et al., 2003
). In general, patients with minimal adhesion scores do well; in contrast those with severe adhesion scores do poorly. Recently, the US Food and Drug Administration recommended that the AFS Adnexal Adhesion Classification be used as a clinical outcome measure in clinical studies of devices intended to reduce post-surgical adhesion formation (Guidance for Industry (2002)
.
Limitations
Oxiplex/AP Gel did not appear to provide protection from adhesion formation in all clinical situations. Patients with severe adhesion scores at the initial laparoscopy and concurrent stage IV endometriosis did not have a reduction in adhesion score even with the use of Oxiplex/AP Gel. In situations where residual disease persists beyond the time Oxiplex/AP Gel is resorbed from the surgical site, as may occur with residual endometriosis left deep in the cul-de-sac (stage IV disease), the development of adhesions would be expected (Nisolle and Donnez, 1997). In this study when the patients had a severe adhesion score at the time of initial laparoscopy in the absence of endometriosis, presumably from prior surgery or previous infection, three out of three patients who received Oxiplex/AP Gel had an improvement in adhesion score to the moderate category at the time of second-look laparoscopy. There are no data available in the literature indicating that patients with a moderate adnexal adhesion score derive a clinical benefit different from those that have a score in the severe category. Some suggestion of benefit due to ease of oocyte retrieval at the time of IVF was reported by Nagata et al. (1998)
.
At present, Oxiplex/AP Gel seems well suited to address the need for general adhesion prophylaxis in peritoneal cavity surgery. However, clinical needs remain. Patients with intraperitoneal infections as well as those with severe endometriosis represent remaining challenges to devise technologies. Strategies combining pharmaceuticals with devices to provide prolonged, physiological effects at the site of potential adhesion formation appear promising.
In summary, the use of Oxiplex/AP Gel in this multicentre evaluation showed a significant reduction in the number of adnexa that developed adhesions following surgery. In the Oxiplex/AP Gel-treated group, 93% of the adnexa did not have a worse adhesion category in contrast to 56% of the control adnexa at the time of second look. These differences are highly significant and demonstrate the overall benefit of Oxiplex/AP Gel when used together with good surgical technique to enhance the likelihood of a good response to surgical therapy. The gel was safe and no complications or adverse events were observed in the treatment group. A specially designed applicator facilitated rapid coating of anatomical sites where clinical concern of adhesion formation was directed. Although confirmation of these data awaits additional clinical studies, the use of Oxiplex/AP Gel appears to provide a unique benefit to patients undergoing gynaecological surgery. Additional clinical trials are currently underway.
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Acknowledgements |
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Submitted on August 8, 2004; resubmitted on September 20, 2004; accepted on October 26, 2004.