Management Insights

Educational Objectives

The goals of this program are to improve outcomes of reconstructive surgery for pelvic organ prolapse (POP) and to improve diagnosis of urologic complications of type 1 diabetes. After hearing and assimilating this program, the cli­nician will be better able to:

1.   Describe the evidence for and against the use of biologic grafts in pelvic reconstructive surgery.

2.   Perform pelvic reconstruction using grafts made from biologic materials.

3.   Compare published complication and reoperation rates following traditional anterior colporrhaphy, sacrocol­popexy, and mesh procedures.

4.   List risk factors for urinary incontinence in women with type 1 diabetes and for erectile dysfunction in men with type 1 diabetes.

5.   Recognize the role of genetic factors in the susceptibility to erectile dysfunction.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Sand is a consultant and on the Speakers’ Bureaus for Allergan, Astellas Pharma US, GlaxoSmithKline, Ortho-McNeil-Janssen Phar­maceuticals, Pfizer, and Watson Pharmaceuticals; he is also an advisor for Antares Pharma and Coloplast, and an investiga­tor for Allergan, Boston Scientific, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, and Watson Pharmaceuticals. Dr. Walters is a consultant and lecturer for American Medical Systems and a consultant for Boston Scientific. Dr. Wessells and the planning committee reported nothing to disclose. In his lecture, Dr. Sand presents information that is related to the off-label or investigational use of a therapy, product, or device.

Biologic Grafts in Pelvic Reconstructive Surgery: Yes

Peter K. Sand, MD, Professor, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, and Director, Evanston Continence Center, Northwestern Healthcare, Evanston, IL

Anterior compartment repair: Kelly-Kennedy plication or anterior colporrhaphy or central plication with mattress sutures; if patient has hypermobility but no urodynamic stress incontinence, speaker uses sutures; intent to delay further hypermobility; hopefully not hastening decreased intrinsic function; risk of retention low; many patients with pelvic organ prolapse (POP); predisposing factors to POP  —  some cannot be changed; levator dysfunction from neuromuscular injury; widening of genital hiatus; levator myorrhaphy; genetic differences in connective tis­sue and smooth muscle in women destined to develop POP; numerous causes of cystocele

Algorithm: centered around looking at midline defect, paravaginal defect, or combination; first decision whether to repair; next,  whether to use graft to improve outcome, and if so, what type of graft; failure rate in anterior compart­ment repair ranges from 1% to 70%; high recurrence rates; study  —  31% of patients at 5 yr postoperatively had Baden Walker Grade II; risk factors for recurrent POP included body weight, youth (age <70yr), advanced POP; Freeman study  —  at 49 mo postoperatively, 9% of patients had POP operation; 5% needed cystocele repair; failure defined by how many patients needed subsequent operation; if failure rates high, consider need for graft

Wound healing: Masterson study  —  in animal models, vaginal tissues heal almost twice as fast as abdominal wall; first week after wounding, immature fibroblasts invade site; week 2, majority of regenerated tissue type 3 collagen with only 7% wound strength; poor convalescence number one cause of failed surgery; patients must not go back to full activities at 2 wk; in week 3, collagen matures, with type 1 collagen replacing type 3; remodeling process takes full 2 yr

Grafts: compensate for intrinsic weakness of autologous tissue, but also alter environment; polypropylene mesh  —  body reacts in long term; inflammatory response may be different in different patients

Studies assessing efficacy of adjuvant graft

Kwon et al study  —  prospective randomized study with cadaveric fascia lata patch; 162 women; study reports on first 126 who completed 1 yr follow-up; 13% of women developed recurrent cystocele to hymenal ring, 12% if no fascial patch graft used, 1.5% if fascial graft used; initially appeared that graft responsible for improved out­come; actually, only subjects who had concomitant cadaveric fascia bladder neck sling improved; sling protected against recurrent POP; at 1 yr, of those with stage II POP, recurrence seen in 48% treated without sling, vs 1.5% with sling; sling not typically used to prevent POP, but it appeared to do so in this study

Meschia study  —  augmented anterior vaginal repair with hexamethylene diisocyanate (HMDI) cross-linked porcine dermis (Pelvicol); follow-up at 1 yr showed 7% recurrence rate; 19% recurrence in controls; 1 patient eroded mesh

Cervigni et al study  —  in Pelvicol group, 3% erosion; with polypropylene soft, 8% erosion; anatomic cure rate not significantly different

Valentim-Lourenco et al study  —  equal cure rates between polypropylene mesh kit (Prolift) and suturing from arcus to arcus porcine HMDI cross-linked dermis

Mouritsen et al study  —  small intestinal submucosa (SIS) porcine product; greater recurrence of POP in anterior and posterior compartments with SIS; SIS used in tissue engineering to generate bladders and urethras in vitro; best material to allow for normal remodeling; cross-linked porcine dermis may erode through vagina

Gomelsky et al study  —  with Pelvicol slings and adjuvant grafts, 7% rate of extrusion into vagina

Speaker’s study  —  explants of porcine dermis; HMDI porcine dermis initiated massive inflammatory response; by 42 days, in many subjects, graft completely gone; may get different results with non-HMDI-cross-linked porcine dermis

Jankiewicz et al study  —  screened 37 cases and 300 controls preoperatively for interleukins and interferon-alpha (INF alfa) and interferon gamma (INF gamma); found significant increase in INF gamma in cases which went on to have extrusions of polypropylene mesh into vagina; may be individual differences in subjects

Speaker’s dermal graft technique: in theory, within 3 to 6 mo, graft should be removed by body, signaling stem cells to form new vaginal tissues (collagen, smooth muscle, vessels, fatty tissues); can place graft and anchor it from arcus to arcus and to sacrospinous ligament to handle central, paravaginal, and apical defects; speaker typi­cally does anterior colporrhaphy, then places graft over as adjuvant material; dissect anterior compartment back to pubic ramus; perforate through and separate endopelvic connective tissue from medial surface of ischial pubic ramus into paravesical space; can place retractor; speaker does not use Breisky-Navratil retractors unless bleed­ing complication present; speaker can more reliably feel arcus than visualize it; using push and catch suturing de­vice, speaker places 2 bites into arcus (one 0.5 to 1 cm distal to ischial spine  and another 2 cm distal to that [mid arcus]); also anchors graft distally; places sutures through arcus after placing sacrospinous sutures on either side; then does anterior colporrhaphy (kinks ureters in 1.4% of cases); trim graft to trapezoid shape to fit form of ante­rior compartment; run sutures through graft, tie graft down on one side and adjust on other side; unlike polypro­pylene mesh, dermal or SIS graft should be placed on tension; anchor distally with absorbable sutures at level of bladder neck beneath pubic tubercle; 70% reduction in recurrent cystoceles; no extrusions; no erosions; no harm done and significantly improved outcomes; sexual function excellent

Ashkenazi study  —  dyspareunia down from 40% to 5% postoperatively; good results in posterior compartment; fail­ure rates in posterior compartment equivalent to complication rates of using adjuvant material; goal to restore function and comfort; augment when endopelvic connective tissue too thin

Lopez et al study  —  small follow-up study of 5 yr; good anatomic resolution on defecography; poorer results with dyspareunia, splinting, and straining; attractive to remodel tissue with SIS graft, but Mouritsen study showed higher recurrences in this space with SIS graft

Paraiso et al study (Cleveland Clinic): 3-arm prospective randomized controlled trial; best data on augmentation; 106 subjects randomized to 1) posterior colporrhaphy, 2) site-specific rectocele repair, or 3) site-specific rectocele repair with SIS collagen matrix (Fortigen); outcomes best in those with just posterior colporrhaphy; adding Forti­gen led to higher recurrence rate; speaker questions proper convalescence; speaker’s comment  —  after placement of anterior or posterior SIS or dermal graft in animal models, tissues get weaker (weeks 2-12); proper restriction of patient’s activity critical to success; consider temporary placement of pessary, mold, or splint; monitor bowel func­tion

Biologic Grafts in Pelvic Reconstructive Surgery: No

Mark D. Walters, MD, Professor and Vice Chair of Gynecology, Center of Urogynecology and Pelvic Floor Disorders, Department of Obstetrics and Gynecology, and Women’s Health Institute, Cleveland Clinic Founda­tion, Cleveland, OH

Addition of graft to POP repair: sacrocolpopexy effective operation for recurrent POP; reliable cure rates with pre­dictable complications; well-defined in literature; one of proven operations for recurrent apical vault (usually posthysterectomy) POP; with vaginal POP surgery, must assess all segments of vagina, anterior, apex, posterior and visceral function of vagina and behind all walls; includes classical suture operations, classical anterior and posterior wall operations (eg, high McCall culdoplasty), uterosacral vault suspension, sacrospinous operation (probably un­derutilized); in Cleveland Clinic, back wall and apical wall operations do well, even at 14 yr; anterior wall opera­tions slowly deteriorate

Diwadkar et al study: reviewed 250 articles and 19 conference abstracts; selected best 89 articles and abstracts until early 2009; 54 studies of traditional surgeries, 45 studies of sacrocolpopexy, and 24 studies of mesh operations; in traditional vaginal repairs, »8000 patients; follow-up of 32 mo; most common complications urinary tract in­fections (UTI), hematomas, and dyspareunia; sacrocolpopexy studies »5600 patients; 26-mo follow-up; higher complication rate because peritoneal entry involved (laparotomy or laparoscopy); increased pain; 2.2% mesh ero­sion rate; visceral injuries and wound complications; mesh kits  —  »3400 patients; 17 mo follow-up; 5.8% aver­age mesh erosion rate in literature; few fistulas; low dyspareunia rate

Total complications: for all 3 surgeries, 15% to 17%; 3.9% reoperation rate for recurrence after traditional surgery; 2.3% for sacrocolpopexy; 1.3% for mesh kits

Total reoperation rates (recurrences plus complications): 5.8% for traditional repairs, 7% for sacrocolpopexy; 8.5% for mesh kits

Severity of complications: higher grade means more severe complications; Dindo Grade IIIb represents complica­tion that requires another surgery under general anesthesia; with mesh kits, complication rate requiring another surgery 7.2%; only 1.9% for traditional repairs; sacrocolpopexy in between

Conclusions of study: traditional vaginal surgeries  —  highest reoperation rates for recurrence; lowest rates of com­plications that require surgical intervention; lowest total reoperation rate; mesh kits  —  shortest period of follow-up and highest rate of complications that require surgical intervention; vaginal mesh kits highest total reoperation rate (recurrence plus complications); patients do just as well subjectively with mesh or no mesh but have more complications with mesh

Summary of literature: level 1 evidence that synthetic graft should be used in sacrocolpopexy; level 2 evidence that biologic (patient’s own fascia) should be used for bladder neck slings or pubovaginal slings; for mid-urethral slings, strip of polypropylene with sleeve recommended, whether retropubically, transobturator, or mini-sling; for recto­cele repairs, literature does not support use of graft; cystocele repair improves anatomy but not necessarily func­tion; insufficient literature to assess transvaginal apical suspension; sacrocolpopexy and slings proven mesh surgeries; grafts tend to improve anatomy but not function, quality of life, or sexual function; grafts always increase complications and costs; if surgeons could refine technique of traditional surgeries, need for use of mesh would de­crease

Urologic Complications of Type 1 Diabetes

Hunter Wessells, MD, Professor and Chair, Department of Urology, University of Washington School of Medi­cine, and Chief of Urology, Harborview Medical Center, Seattle, WA

Speaker’s study: patients had long exposure to hyperglycemia; average hemoglobin A_{1c (HbA1c) »7.7%; »10% showed increased albumin excretion or other nephropathy; 70% of women had children (important for inconti­nence); adjusted rate of urinary incontinence, 37%; not much different from general public; risk factors for urinary incontinence  —  age (risk mainly for urge type); body mass index; factors of no predictive value  —  intensive therapy, menopausal status, hysterectomy status or even HbA1c; much higher rate of incontinence with >2 UTIs in last year; submucosal vaginal bacilli may play role; lower urinary tract symptoms (LUTS)  —  20% of 44-yr-old men had moderate to severe LUTS; not associated with HbA1c or with neuropathy; main risk factor for LUTS found to be erectile dysfunction (ED); possible conflicting effect of diabetes on prostate or bladder; role of autonomic neuropathy not yet known; some believe prostate does not grow as much in diabetes; next phase of study may explore prostate-specific antigen as surrogate for prostate size; next phase to study autonomic neurop­athy; female sexual dysfunction (35%; similar to general population) associated most strongly with depression; fairly high prevalence of ED, but only 23% of men in forties with 22 yr of diabetes had ED}

Stratified data:  intensive glucose control group and conventional control group; intensive glucose control group had persistently lower rates of ED (reduced by »40%); variation in ED unexplained by data; even when controlled for treatment group, HbA_1c, age, duration of diabetes, only minority of differences explained by results

Genetic factors: considered to play important role in susceptibility to ED; goal to predict men at highest risk for ED before symptoms start; twin study  —  monozygotic twins have higher concordance for ED than dizygotic twins; 2 ways to test for genetic association  —  1) candidate approach (make list of 10 or 20 genes and genotype all); 2) genome-wide association study

Speaker’s study: candidate approach  —  speaker performed microarray analysis on rats that had been made diabetic; one gene thought to be significant (called ceruloplasmin); associated with nitric oxide impairment; ceruloplasmin expressed in lining of corpus cavernosum and smooth muscle cells; diabetic animal that has impaired endothelial relaxation (lacks ceruloplasmin) protected from ED; diabetic animals have high levels of copper, which is related to ceruloplasmin; administering chelator of copper can protect from diabetes; narrow view of pool of genes that may be important; genome-wide approach  —  study sampled whole genome with alumina chip containing million single nucleotide polymorphisms; study identified 2 loci on chromosome 3 that may achieve significance; one of these called ALCAM (activated leukocyte cell adhesion molecule); future research  —  may involve intervention studies for men in their forties with diabetes with high HbA_1c, and intervene and scan entire genome with goal of finding patients who need treatment

Note: Dr. Wessells’ name is misspelled on the CD and cassette labels for this program. Our apologies.

Acknowledgements

Drs. Sand and Walters were recorded at Advances in Urogynecology and Reconstructive Pelvic Surgery, held June 10-12, 2010, in Chicago, IL, and jointly sponsored by the University of Chicago Pritzker School of Medicine and Northshore Uni­versity Health System. Dr. Wessells was recorded in Jackson Hole, WY, at the 30th Annual Jackson Hole Seminars, held February 7-12, 2010, jointly sponsored by the University of Colorado and Jackson Hole Seminars, Inc. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Suggested Reading

Angulo J et al: Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries. J Sex Med. 2010 Feb;7(2 Pt 1):758-68; Chen CC et al: Biologic grafts and synthetic meshes in pelvic reconstructive surgery. Clin Obstet Gynecol. 2007 Jun;50(2):383-411; Chitaley K et al: Di­abetes, obesity and erectile dysfunction: field overview and research priorities. J Urol. 2009 Dec;182(6 Suppl):S45-50; Le TH et al: Update on the utilization of grafts in pelvic reconstruction surgeries. Curr Opin Obstet Gynecol. 2007 Oct;19(5):480-9; Jakus SM et al: Biologic and synthetic graft use in pelvic surgery: a review. Obstet Gynecol Surv. 2008 Apr;63(4):253-66; Kayigil O et al: Multifactorial evaluation of diabetic erectile dysfunction. Int Urol Nephrol. 1996;28(5):717-21; Murphy M: Clinical practice guidelines on vaginal graft use from the society of gynecologic surgeons. Obstet Gynecol. 2008 Nov;112(5):1123-30; Natale F et al:  A prospective, randomized, controlled study comparing Gyne­mesh, a synthetic mesh, and Pelvicol, a biologic graft, in the surgical treatment of recurrent cystocele. Int Urogynecol J Pel­vic Floor Dysfunct. 2009 Jan;20(1):75-81; Pierce LM et al: Biomechanical properties of synthetic and biologic graft materials following long-term implantation in the rabbit abdomen and vagina. Am J Obstet Gynecol. 2009 May;200(5):549; Silva WA et al: Scientific basis for use of grafts during vaginal reconstructive procedures. Curr Opin Obstet Gynecol. 2005 Oct;17(5):519-29; Sullivan CJ et al: Microarray analysis reveals novel gene expression changes associated with erectile dysfunction in diabetic rats. Physiol Genomics. 2005 Oct 17;23(2):192-205; Sung VW et al: Graft use in transvaginal pel­vic organ prolapse repair: a systematic review. Obstet Gynecol. 2008 Nov;112(5):1131-42; Van Den Eeden SK et al: Effect of intensive glycemic control and diabetes complications on lower urinary tract symptoms in men with type 1 diabetes: Di­abetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Diabetes Care. 2009 Apr;32(4):664-70.