The Cutting Edge Preventing Adhesions in ObGyn

Víctor Hugo González-Quintero, MD, MPH; Jean Marie Stephan, MD; Francisco E. Cruz-Pachano, MD

Adhesive disease represents a ficulty with postoperative interventions FOCUSPOINT such as intraperitoneal chemotherapy, ra- significant cause of morbidity for More than diation, and subsequent complications dur- postoperative patients. ObGyns ing repeat operations. 400,000 surgical should keep up-to-date with data procedures are Prevention of performed daily concerning prevention Postoperative Adhesions in the US for lysis Adhesive disease is a major cause of seri- and make a reasonable and of adhesions, informed decision about whether ous morbidity among women undergoing surgical procedures. As such, adhesion with an annual to employ such techniques in their prevention has become an area of interest economic impact individual practices. for many practitioners. Traditionally, good exceeding surgical technique has been advocated as $1.3 billion. the main way to prevent postoperative ad- ost surgical procedures per- hesions. This included strict adherence to formed by ObGyns are associated the basic surgical principles of minimizing with pelvic adhesions, with po- tissue trauma with meticulous hemostasis, tential serious sequelae of small minimization of ischemia and desiccation, Mbowel obstruction, infertility, chronic pelvic and prevention of infection and foreign pain, and difficulty in postoperative treat- body retention. Historically, peritoneal clo- ment, including complexity during subse- sure has been performed to reduce postop- quent surgical procedures. More than erative complications, including adhe- 400,000 surgical procedures for lysis of ad- sions. Review of the ObGyn literature does hesions are performed daily in the United not support the closure of peritoneum to States, with an annual economic impact prevent adhesions.2 exceeding $1.3 billion.1 This article will re- Significant progress has been made on view the adjunctive methods available for the technology of adhesion prevention. the ObGyn to prevent postoperative adhe- Currently, there are 3 methods approved sion formation. by the FDA for the prevention of postopera- tive adhesions: Adept®, Interceed®, and ADHESION-RELATED MORBIDITY Seprafilm®. Adhesion-related morbidity can be divided into 2 main categories: physical- and treat- ADHESION barriers ment-related. Physical-related morbidity in- Adept has been recently added to the arma- cludes small (SBO), infer- mentarium of adhesion prevention as an tility, chronic pain, and dyspareunia. adjunct to be used intraperitoneally in pa- Treatment-related morbidity deals with dif- tients undergoing gynecologic laparoscopic adhesiolysis. Adept is a 4% icodextrin solu- Víctor Hugo González-Quintero, MD, MPH, is a Clini- tion made of an α(1-4)-linked glucose poly- cal Professor; Jean Marie Stephan, MD, is a Chief mer. Its mechanism of action is that of hy- Resident; and Francisco E. Cruz-Pachano, MD, is a Clinical Instructor, all in the Department of Obstetrics droflotation. However, its efficacy appears and Gynecology, University of Miami School of Medi- to be limited, as evidenced in a clinical trial cine, Miami, FL. that showed only marginal superiority over

Follow The Female Patient on and The Female Patient | Vol 35 september 2010 1 The CuttingEdge Preventing Adhesions in ObGyn Surgery

lactated Ringer’s solution (LRS) in the pre- ceed has been studied in more than 13 vention of postoperative adhesions.3 In the clinical studies that included more than study, 402 patients were randomized intra- 600 patients. A meta-analysis of 10 ran- operatively to Adept (n = 203) or LRS (n = domized controlled studies reported a 199), and they returned for a second lapa- 24.2% reduction in adhesion formation on roscopy within 4 to 8 weeks. In the same the side treated with Interceed compared trial, a number of treatment-related compli- with the control side.7 Despite this report, cations were identified, including excessive concerns about Interceed continue, espe- edema of the labia, vulva, and vagina. cially regarding its efficacy in preventing Current adhesion barriers include ex- adhesions and its apparent ineffectiveness panded polytetrafluoroethylene (Gore- in the presence of blood. In this setting, In- Tex®) and the 2 FDA-approved barriers: oxi- terceed may aggravate rather than prevent dized regenerated cellulose (Interceed) and adhesion formation. The safety and effec- sodium hyaluronate and carboxymethyl- tiveness of Interceed in preventing adhe- cellulose (Seprafilm). Interceed and Sepra- sion formation in laparoscopic surgery or film are not FDA approved for laparoscopic any procedures other than open gyneco- use. The Table lists adhesion barriers cur- logic microsurgical procedures have not FOCUSPOINT rently available, with their composition, been established. Adhesive disease peritoneal residence time, and indication/ delivery mode. Sodium Hyaluronate and is a major cause Carboxymethylcellulose (Seprafilm) of serious Expanded Polytetrafluoroethylene Seprafilm is perhaps the most widely stud- morbidity (Gore-Tex) ied adhesion barrier, with more than 20 among women This adhesion barrier has a microscope published studies including more than undergoing structure preventing cellular growth. It is 4,600 patients. Seprafilm is composed of noninflammatory and nonabsorbable. It chemically modified hyaluronic acid and surgery. does not adhere to the tissue and has to be carboxymethylcellulose. It is designed to Significant sutured in place. Data on clinical efficacy separate planes of tissues after surgery for progress has exist but are limited. In a trial of 27 women, 3 to 7 days. been made on the Myomectomy Adhesion Multicenter Writing for the Seprafilm Adhesion Study Study Group reported a significant reduc- Group, Diamond reported on the safety the technology tion in adhesion formation to the uterine and efficacy of Seprafilm in preventing of adhesion surface following Gore-Tex application as postoperative uterine adhesions after myo- prevention. compared with controls.4 In another clini- mectomy.8 This was a prospective, double- cal trial, Haney et al reported an 85% reduc- blinded, multicenter, randomized, con- tion in adhesion formation with Gore- Tex, trolled study. After surgical treatment with compared with 65% with Interceed (n = 32).5 or without Seprafilm, all patients were In a prospective, multicenter, observational evaluated by early second-look laparos- trial, Hurst reported on the long-term fol- copy for the incidence, severity, and extent low-up of patients who received Gore-Tex.6 of adhesions. The subjects were 146 women in whom the The Diamond study also evaluated the membrane was implanted permanently number of adhesion sites throughout the during peritoneal reconstruction from 1991 pelvis and the area of adhesions. In pa- through 1996. There was a single case of tients undergoing myomectomy, Seprafilm postoperative infection that did not neces- reduced the incidence, severity, extent, sitate removal of the membrane; all other and average surface area of uterine adhe- patients did well. These data suggest that the sions. Approximately 48% of patients ran- membrane can probably be left in place domized to Seprafilm had at least one ad- indefinitely. nexa free of adhesions, and there was no increased risk of complications such as Oxidized Regenerated Cellulose ileus, intra-abdominal bleeding, and post- (Interceed) operative fever.8 The adhesion barrier Interceed is made of Bristow and Montz studied the effective- oxidized regenerated cellulose and is avail- ness of Seprafilm (n = 14) in preventing pel- able in 3×4-in sheets. The efficacy of Inter- vic adhesions in women undergoing pri-

2 The Female Patient | Vol 35 september 2010 All articles are available online at www.femalepatient.com. González-Quintero et al

TABLE. Adhesion Barriers Currently Available

Adhesion Barrier Composition Peritoneal Residence Time Indication/Delivery Mode

Preclude Expanded Permanent Not approved for general (W. L. Gore) polytetrafluoroethlyene adhesion prevention. membrane Pericardial membrane or vessel guard

Interceed Oxidized regenerated 1-2 weeks Gynecologic pelvic (Ethicon; cellulose membrane laparotomy. Johnson & Johnson) Not FDA approved for laparoscopic use

Seprafilm Hyaluronic acid/ 7 days Abdominal or pelvic (Genzyme) carboxymethylcellulose laparotomy. membrane Not FDA approved for laparoscopic use

Adept 4% Icodextrin instillate 3-4 days Gynecologic (Baxter) mary cytoreductive surgery with radical in cesarean delivery rates and the decline oophorectomy.9 In this cohort, Seprafilm in rates of vaginal birth after cesarean in significantly reduced the mean adhesion the United States and worldwide, ObGyns score by 84% compared with the internal should expect to see a rise in complica- controls and by 90% compared with his- tions due to adhesive disease during re- torical control groups. peat cesareans. The authors concluded that 73.2% of Se- Morales et al performed a retrospective prafilm placement sites were free of adhe- study to describe the incidence of adhesions 11 FOCUSPOINT sions, compared with 35.7% for the abdom- after cesarean delivery. The charts of 542 With the rise in inal wall and 14.3% for untreated pelvis. women who had undergone primary (n = Moreover, in those Seprafilm placement 265) or repeat (n = 277) cesarean deliveries cesarean delivery sites that did have adhesions, the adhe- were reviewed. They reported on the sever- rates and the sions were significantly less severe than ity and location of adhesions, delivery time, decline in rates of untreated sites. No complications were at- cord blood pH, and Apgar score. vaginal birth after tributed to the presence of Seprafilm. The incidence and severity of adhesions The economic impact of adhesions and after cesarean delivery increased signifi- cesarean, ObGyns the cost-effectiveness of Seprafilm treat- cantly with each subsequent delivery. As should expect to ment were also studied. By creating a theo- expected, the incision-to-delivery time see a rise in retical decision model, researchers con- correlated directly with the presence and complications due cluded that Seprafilm use offers an severity of adhesions. to adhesive incremental savings of $383 (payers) and The data on adhesion prevention at the $1,122 (society) per patient over a 10-year time of cesarean delivery are limited to disease during period.10 They concluded that the use of one study. Fushiki and colleagues per- repeat cesareans. Seprafilm was cost-effective with a thresh- formed a prospective cohort (n = 52) study old of $1,571 (7 sheets). of Seprafilm placement at the time of pri- Concerns about the use of Seprafilm mary cesarean delivery with a view to re- include the learning curve required to ducing adhesive disease.12 achieve optimal placement. Also, Sepra- In all instances, the presence and severity film cannot be applied laparoscopically. of adhesions were evaluated at the time of repeat cesarean. The incidence and severity cesarean delivery of adhesions were significantly reduced in Cesarean deliveries and adhesive disease the Seprafilm group compared with the deserve separate discussion. With the rise control group (7.4% vs 48.0%, respectively,

Follow The Female Patient on and The Female Patient | Vol 35 september 2010 3 The CuttingEdge Preventing Adhesions in ObGyn Surgery

vention barriers. Surg Clin North Am. 1997;77(3): P = .001; adhesion score, 0.07 vs 1.32, respec- 671-688. tively, P = .001). 2. Tulandi T, Al-Jaroudi D. Nonclosure of peritoneum: a reappraisal. Am J Obstet Gynecol. 2003;189(2):609- 612. SUMMARY 3. Brown CB, Luciano AA, Martin D, Peers E, Scrim- Despite significant progress in the devel- geour A, diZerega GS; Adept Adhesion Reduction opment of adhesion prevention barriers, Study Group. Adept (icodextrin 4% solution) reduces adhesions after laparoscopic surgery for adhesioly- adhesive disease continues to be a major sis: a double-blind, randomized, controlled study. cause of morbidity in postoperative pa- Fertil Steril. 2007;88(5):1413-1426. tients, with both short- and long-term se- 4. Myomectomy Adhesion Multicenter Study Group. An expanded polytetrafluoroethylene barrier (Gore- quelae. The use of an adhesion prevention Tex Surgical Membrane) reduces post-myomectomy FOCUSPOINT barrier should be entertained in all ObGyn adhesion formation. Fertil Steril. 1995;63(3):491-493. Despite significant abdominal procedures, as well as in cesar- 5. Haney AF, Hesla J, Hurst BS, et al. Expanded polytet- rafluoroethylene (Gore-Tex Surgical Membrane) is progress in ean deliveries. superior to oxidized regenerated cellulose (Inter- the development When selecting the most appropriate ad- ceed TC7+) in preventing adhesions. Fertil Steril. hesion barrier, the practitioner should take 1995;63(5):1021-1026. of adhesion 6. Hurst BS. Permanent implantation of expanded into consideration the half-life of the barrier polytetrafluoroethylene is safe for pelvic surgery. prevention in the abdomen, to ensure that it remains United States Expanded Polytetrafluoroethylene Reproductive Surgery Study Group. Hum Reprod. barriers, adhesive “biologically active” for at least 5 to 7 days, 1999;14(4):925-927. disease continues its ability to be absorbed, and the inert met- 7. Wiseman DM, Trout JR, Franklin RR, Diamond MP. abolic products that need to be excreted. Metaanalysis of the safety and efficacy of an adhe- to be a major sion barrier (Interceed TC7) in laparotomy. J Reprod For procedures such as myomectomies and Med. 1999;44(4):325-331. cause of morbidity cesarean deliveries, where blood loss and 8. Diamond MP. Reduction of adhesions after uterine in postoperative contamination of the operative field are myomectomy by Seprafilm membrane (HAL-F): a blinded, prospective, randomized, multicenter clin- patients. inevitable, the clinician should be aware of ical study. Seprafilm Adhesion Study Group. Fertil the effect of blood or inflammation on the Steril. 1996;66(6):904-910. adhesion prevention barrier. 9. Bristow RE, Montz FJ. Prevention of adhesion for- mation after radical oophorectomy using a sodium hyaluronate-carboxymethylcellulose (HA-CMC) barrier. Gynecol Oncol. 2005;99(2):301-308. Dr González-Quintero reports that he is a 10. Bristow RE, Santillan A, Diaz-Montes TP, Gardner speaker for Genzyme Corporation. Drs GJ, Giuntoli RL 2nd, Peeler ST. Prevention of adhe- sion formation after radical hysterectomy using a Stephan and Cruz-Pachano report no sodium hyaluronate-carboxymethylcellulose (HA- actual or potential conflicts of interest in CMC) barrier: a cost-effectiveness analysis.Gynecol relation to this article. Oncol. 2007;104(3):739-746. 11. Morales KJ, Gordon MC, Bates GW Jr. Postcesarean delivery adhesions associated with delayed delivery of infant. Am J Obstet Gynecol. 2007;196(5):461.e1-e6. REFERENCES 12. Fushiki H, Ikoma T, Kobayashi H. Efficacy of Sepra- 1. DeCherney AH, diZerega GS. Clinical problem of film as an adhesion prevention barrier in cesarean intraperitoneal postsurgical adhesion formation fol- sections [in Japanese]. Obstet Gynecol Treat. lowing general surgery and the use of adhesion pre- 2005;91:557-561.

4 The Female Patient | Vol 35 september 2010 All articles are available online at www.femalepatient.com.