Urethral injection of bulking agents for intrinsic sphincter deficiency

Introduction

In 1938 Murless reported the use of morrhuate sodium for injection management of urinary incontinence. In the early 1990s, transurethral and periurethral injection of bovine collagen was introduced for the treatment of stress urinary incontinence and was the gold standard with which all later studies have been compared, although production of this material ceased in 2011. Since the 1990s, several urethral bulking agents have been introduced for this purpose, although some have been removed from the market because of a high rate of adverse events, difficulties with injection, or expense. The ideal urethral bulking material is biocompatible, nonimmunological, and hypoallergenic. It should retain its bulking characteristics for a prolonged interval and therefore should not biodegrade, nor should it migrate (particle size should be >80 μm). The material should be easy to prepare and easy to inject. The ideal material is safe, readily obtainable, inexpensive, efficacious, and durable and induces minimal tissue reaction. Bulking agent injection is thought to treat stress incontinence by mucosal coaptation of the bladder neck and proximal urethra, with subsequent increased urethral resistance to outflow of urine. Although transmission of pressure to the urethra during increased intraabdominal pressure may not change in patients treated with urethral bulking injections, the pressure forcing the urine from the bladder through the urethra is resisted by the bulking of the mucosa in the immediate proximal urethra; this essentially prevents involuntary bladder neck opening.

Indications and contraindications

The ideal patient for urethral bulking has both limited mobility of the urethra and bladder and a compromised urethral sphincter. More often she is older because repeat injections are often necessary, and a younger patient could be facing decades of treatment over time to maintain effect. Exceptions would include patients who are surgical candidates but who have not completed their family, or others who are putting off surgery for other reasons. In this new era of concern over permanent mesh implants, and possibly reduced availability, many women are seeking solutions without mesh, and bulking agents provide an option.

The most common indications for urethral bulking agents are: (1) intrinsic sphincter deficiency with or without urethral hypermobility, (2) persistent stress urinary incontinence after a urethral sling or urethropexy, (3) stress urinary incontinence in women who cannot undergo surgery because of multiple comorbidities (e.g., poor surgical candidate and/or cannot discontinue anticoagulation), and (4) stress urinary incontinence in women who do not desire a more invasive antiincontinence surgery (e.g., prefer to avoid mesh material, desire future fertility, require treatment for occult stress incontinence after successful pessary placement, etc.). Relative contraindications to the use of urethral bulking injections include active urinary tract infection, high postvoid residual urine (>100 mL), urinary stricture/obstruction, severe detrusor overactivity, and fragile urethral mucosa.

Midurethral slings work poorly in women with a fixed (nonhypermobile) urethra and intrinsic sphincter deficiency. Urethral hypermobility is diagnosed when the angle of the urethra with the patient supine exceeds 30 to 40 degrees from horizontal during straining efforts (Valsalva or cough). In classic teaching, intrinsic sphincter deficiency is diagnosed when (1) the maximal urethral closure pressure is less than 20 to 25 cm H ₂ O, and/or (2) the abdominal (Valsalva) leak point pressure is less than 60 cm H ₂ O when the bladder is filled to 150 to 250 mL.

Certain patients respond better to urethral bulking injections. Should the procedure provide no relief after two or three injections, it is usually futile to attempt subsequent injections. Incontinence surgery, whether sling or retropubic urethropexy, can be performed before or after urethral bulking injections. Theoretically, in a woman with a previous urethral bulking injection, there is a risk of encountering the bulking material during the dissection for a urethral sling. Conversely, in a woman with a previous urethral sling, there may be difficulty placing the bulking material in the correct space, because the sling may compress the urethra and not allow sufficient room for tissue expansion. If stress incontinence persists or recurs after a urethral sling or other pelvic reconstructive surgery, a urethral bulking agent may be used, and often it is very effective. This may be done as early as 6 weeks after surgery, except for Macroplastique, which is not recommended until after 12 weeks.

Bulking agents generally are not the first-line treatment for patients with urethral hypermobility and stress urinary incontinence because the midurethral sling is highly effective. However, there are situations in high-risk patients who are poor surgical candidates with pelvic organ prolapse and stress incontinence when a pessary has provided excellent control of prolapse and has provided temporary stabilization of bladder neck mobility. Urethral bulking may be used in these patients to treat occult stress incontinence that was unmasked after the prolapse was reduced. Similarly, in patients who develop de novo stress urinary incontinence after prolapse surgery, urethral bulking agent injection gives patients an office-based option that can be performed as soon as 6 weeks after surgery that may temporize their new urinary complaint. In addition, treatment of stress urinary incontinence in women who have not completed childbearing is a difficult situation in which urethral bulking may be considered as an alternative to physical therapy, midurethral sling, or expectant management. Some women may require or prefer nonmesh alternatives, and some may choose bulking after discussion of all options.

Evaluation

Evaluation before therapy consists of a history and physical examination to include a postvoid residual urine determination and urinalysis and/or urine culture. This is sometimes complemented by a bladder diary and urodynamic evaluation to establish the diagnosis of intrinsic sphincter deficiency. Multichannel urodynamic studies that include abdominal (Valsalva) leak point pressure determination and/or a urethral pressure profile to assess maximum urethral closure pressure can aid in the diagnosis of intrinsic sphincter deficiency. Another evaluation technique that may aid in diagnosis of intrinsic sphincter deficiency is direct urethroscopic visualization of the bladder neck and proximal urethra to evaluate for urethral coaptation/open bladder neck at rest and during Valsalva or cough.

Materials

All currently available materials are nonbiodegradable and nonimmunological, do not require refrigeration, and do not require skin testing ( Table 18.1 ).

Durasphere was initially approved by the US Food and Drug Administration (FDA) in 1999. The second-generation material, Durasphere EXP (Coloplast Corporation, Minneapolis, MN), consists of pyrolytic carbon–coated graphite beads suspended in a water-based carrier gel containing 3% β-glucan. β-glucan is a simple polysaccharide that causes a subtle inflammatory response. The current preparation has a particle size of 90 to 212 μm and is injected through a 20-gauge needle. The material is nonbiodegradable. According to the manufacturer, it should not migrate because the particle size is greater than 80 μm and thus theoretically cannot be engulfed by macrophages. The product is versatile and is the only material that is approved for periurethral methods, as well as transurethral methods. It is available in 1- and 3-mL syringes. Typically, 2 to 4 mL is injected at the 4 and 8 o’clock positions. Importantly, for women with “fragile urethral mucosa” (possibly from prior radiation therapy or prior urethral surgery), Durasphere EXP is the only material that is not contraindicated.

Coaptite (Boston Scientific Corporation, Natick, MA) was approved by the FDA in 2005. It consists of 75- to 125-μm (average 100-μm) calcium hydroxylapatite spheres suspended in an aqueous gel of sodium carboxylmethylcellulose. This synthetic material is a natural constituent of bones and teeth and has been used in dental and orthopedic applications for many years. In the urethra, it does not encapsulate but allows for ingrowth of native tissues with time as the gel carrier dissolves. It has not been shown to induce heterotopic bone formation. It is biocompatible, nonbiodegradable, and radiopaque; is injected through a 21-gauge needle; and is available in 1-mL syringes. Typically, 2 to 4 mL is injected at the 4 and 8 o’clock positions. According to the manufacturer’s instructions for use, Coaptite is contraindicated in patients with a “fragile urethral mucosal lining.”

Macroplastique (Uroplasty, Geleen, the Netherlands, and Minnetonka, MN) has been approved for use in Europe since 1991 and was approved by the FDA in 2006 for use in the United States. It is made from highly textured polydimethylsiloxane macroparticles suspended in a bioexcretable carrier hydrogel of polyvinylpyrrolidone. It consists of silicone microimplants of 120 to 600 μm (average 140 μm) and is prepared in 2.5-mL syringes injected through an 18- or 20-gauge needle. Typically, two syringes are required, with 2.5 mL delivered to the 6 o’clock position and 1.25 mL each delivered to the 2 and 1 o’clock positions, for a total of 5 mL. It requires a special administration device for transurethral injection ( Fig. 18.1 ). According to the manufacturer’s instructions for use, Macroplastique is contraindicated in patients (1) with “fragile urethral mucosal lining” (e.g., postradiation therapy or postsurgery to the bladder neck) or (2) within 12 weeks of previous Macroplastique injection or a minimally invasive sling procedure.

Bulkamid (Contura International, Soeborg, Denmark, and Ethicon, Somerville, NJ) is newly FDA approved in 2020 in the United States. It is a nonparticulate, nonresorbable polyacrylamide hydrogel made of cross-linked polyacrylamide and water. Bulkamid is the only FDA-approved material that contains no solid particles (crystals or particulates), theoretically abolishing the risk of migration. Being a gel, it can be injected through the operative channel of a regular cystourethroscope using a special 23-gauge needle or the Bulkamid Urethral Bulking System—a specially designed lightweight urethroscopic instrument that facilitates injection ( Fig. 18.2 and Video 18.1 ).

Permacol (Tissue Science Laboratories PLC, Aldershot, Hampshire, UK) is approved for use in Europe but is not currently under study protocol in the Unites States. It is a sterile, injectable suspension of acellular cross-linked porcine collagen matrix. It is available in 2.5-mL syringes and is injected through a 19-gauge needle.

Urethral bulking materials no longer available for clinical use include: Contigen, Zuidex, and Uryx or Tegress. Approved by the FDA in 1993, Contigen (Bard Inc., Covington, GA) was the primary urethral injectable agent until 1999. It consists of glutaraldehyde cross-linking of bovine dermal collagen. The manufacturing of bovine collagen was halted in June 2011. Of note, this was the only material that was biodegradable and not permanent. Additionally, this was the only material that required skin testing, as allergic reactions occurred in 2% to 5% of women. All currently marketed urethral bulking materials have used bovine collagen as the control material in their representative comparative studies.

Zuidex gel (Q-Med AB, Uppsala, Sweden) was a combination of dextranomer (cross-linked polysaccharides) and hyaluronic acid. Dextranomer has been used in wound treatment for many years. Biotechnological (nonanimal) stabilized hyaluronic acid is similar to natural hyaluronic acid found in the body. The material is prepared in 0.7-mL syringes; it is used periurethrally with an implantation device (Implacer) and requires the injection of four syringes of material. The Implacer allows transurethral injection without visualization of the injection site. The material was FDA-approved in the United States in 2001 for ureterovesical reflux and is marketed as Deflux. Zuidex has been available in Europe for urethral bulking since 2002. The FDA initially approved the use of Zuidex for clinical trials in the United States in 2003, although the results were not superior to those with bovine collagen. Also, granuloma/abscess formation rates as high as 14% to 28% were found in case series; thus, it is not FDA approved and has been withdrawn from the market.

Uryx or Tegress (Bard Medical, Covington, GA) was an ethylene vinyl copolymer dissolved in dimethylsulfoxide. It was discontinued in 2007 owing to more than 200 adverse events being reported to the FDA, mostly related to urethral erosion.

Future injectable materials may come from tissue engineering and autologous cellular therapy, using myoblasts, fibroblasts, or stem cells. Another possibility is the use of transplanted stem cells that may differentiate and regenerate the urethral sphincter. This was briefly studied in the past by the use of autologous ear cartilage and in vitro expansion of cells for implant. The technology was not advanced, because of the ready availability of less expensive products.

Techniques

The procedure must be fully explained to the patient, including the predicted effectiveness and the possible need for repeat injections. Patients should have a basic understanding that all currently marketed bulking procedures involve the injection of nonbiodegradable material. Despite good initial subjective success by the patient and coaptation of the proximal urethra noted by the surgeon, the improvements may be short-lived, as the carrier medium is absorbed over time, leaving behind the permanent implant. The permanent material volume may be less than the volume of the material plus the carrier medium, leading to reduced coaptation in the initial few weeks after surgery. Thus, setting the expectation that additional bulking procedures may be required is essential.