Patient Selection

UBT has traditionally been reserved for patients with isolated intrinsic sphincter deficiency (ISD) (ie, urodynamically proven low abdominal leak point pressure [ALPP] <100 cm H ₂ O), limited urethral mobility, and absence of detrusor instability. However, a broader range of patients with all types of SUI has been treated with UBT.

In general, good candidates for UBT include those who :

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  Are poor surgical candidates

  
  
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  Are elderly and at greatest risk of retention after a sling procedure

  
  
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  Must continue anticoagulation therapy at all times

  
  
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  Desire nonsurgical therapy using only local anesthesia

  
  
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  Are unable to follow postoperative activity limitations required after anti-incontinence procedures

  
  
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  Are young and desire more children in the future

  
  
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  Have mild persistent SUI after an anti-incontinence procedure

  
  
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  Have SUI and poor bladder emptying

  
  
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  Have mild SUI associated with exercise.

In addition, UBT may be an adjuvant treatment after an incomplete response to more definitive treatment. Durable responses of 80% have been reported in patients treated with collagen injection for persistent SUI after failed suspension procedure or urethral surgery. In other series, previous incontinence or prolapse surgery has not affected the success of subsequent UBT.

Managing patient expectations is important. Almost all women have expectations that their urine leakage will be eliminated by anti-incontinence surgery. Patients need to understand that injection therapy should be viewed as a process rather than a single intervention, and multiple injections may be required to achieve continence.

Mechanism of Action

The mechanism of action of UBT is unclear. The goal of injecting bulking agents into the urethra is to obtain coaptation of the urethra during the storage phase and maintenance of that coaptation during periods of increased abdominal pressure. Some investigators have proposed that collagen injection causes cephalad elongation of the urethra at the bladder neck that results in increased abdominal pressure transmission to the first quarter of the urethra. This is shown by an increased ALPP, which has been correlated with successful urethral injection outcomes. As opposed to surgical procedures that may create a functional obstruction, injectable agents restore continence by increasing urethral resistance only at rest and allow the urethra to funnel and open during micturition. This results in low urethral resistance during micturition and thus avoids a compensatory increase in detrusor pressure to overcome an increased urethral resistance resulting from surgical incontinence procedures, which may contribute to overactive bladder symptoms and/or upper tract damage.

Technical Aspects of UBT

The 2 most accepted techniques for injection of bulking agents are retrograde suburothelial approaches. In the transurethral technique, the bulking agent is injected submucosally via a needle inserted through a conventional cystourethroscope under direct visual guidance. In the periurethral technique, the material is injected with a needle or specialty injector device placed percutaneously from a perimeatal injection site. The needle is localized and positioned submucosally under direct endoscopic vision in the urethra. The target of implantation via either technique is placement of the material in the wall of the urethra at the level of the bladder neck or proximal urethra.

Most patients can be injected under local anesthesia, with either topical lidocaine jelly in the urethra or periurethral infiltration with injectable lidocaine. The patient is placed in the lithotomy position and prepared in a typical sterile fashion as for a cystoscopic procedure. In the transurethral technique, the cystoscope is positioned in the midurethra and the injection needle inserted through the urethral wall into the proximal urethra so the bulking material can be deployed at the bladder neck and proximal urethra. With most agents on the market today, the material is inserted at different locations (eg, 3 and 9 o’clock; 12, 4, and 8 o’clock) such that coaptation, either horizontal or concentric, of the urethral mucosa is achieved with material injection. Care must be taken to inject slowly enough that the tissue can accommodate the material without extrusion of the material either from a new rent in the mucosa or from the needle puncture site after the needle is withdrawn. In general, enough material is injected until complete coaptation is achieved.

In the periurethral technique, the injection needle or device is inserted just lateral to the urethral meatus at the 4 and 8 o’clock positions and advanced within the wall of the urethra through the lamina propria to the proximal urethra/bladder neck area. Localization of the needle is performed with cystoscopic guidance. Gentle rocking of the injection needle can help to localize the needle tip and confirm the proper location of injection site. Submucosal instillation of methylene blue can assist in needle localization. The use of a 15° angled injection needle (the so-called bent-needle technique) can also facilitate needle localization as well as ease of injection (ie, under lower pressure). Care must be taken to avoid any puncture of the mucosa or extrusion of the injected material will occur. The material is injected in a similar fashion to the transurethral technique, with the appearance of raised mounds of mucosa until apposition is achieved from both sides. If extrusion of material develops, the needle can be repositioned more anteriorly and injection resumed. Once coaptation is achieved, then the procedure is completed and the needle and cystoscope are removed.

In female patients, either injection technique can be performed. Theoretic benefits of the periurethral approach are the avoidance of mucosal leakage and less local trauma and bleeding, although benefits of the transurethral approach include a direct visualization of the needle with more precise localization of the material. Both techniques seem to be reasonably efficacious and safe.

In addition to these 2 techniques, an antegrade, transvesical technique has been described for use in men. In addition, injection with ultrasound guidance has been used, both transvaginally and transurethrally. Several proprietary, agent-specific techniques and devices have emerged in an attempt to simplify and standardize administration, often without the need for visual guidance. The Macroplastic Implantation System (MIS) (Uroplasty Inc, Minneapolis, MN, USA) and the Implacer (Q-Med, Uppsala, Sweden) are 2 such devices. Both devices rely on blind placement and localization of the device within the urethra, with designated injection sites to direct the material into the proximal urethral/bladder neck. This technique theoretically helps to simplify the procedure by not requiring cystoscopic equipment and thus can be performed in a standard outpatient clinic. However, neither of these devices is approved for use in the United States.

Historical Agents

The original report of UBT for the treatment of SUI described the use of sodium morrhuate in 1938. Additional materials used historically include paraffin wax and various sclerosing agents. In the 1970s and 1980s, polytetrafluoroethylene (PTFE; Teflon) was used extensively, but was never approved for use in the United States because of safety concerns of distant particulate migration. Autologous fat also showed poor clinical results with safety concerns and is not recommended for UBT.

Ethylene vinyl alcohol (EVA) copolymer (Tegress, CR Bard, Inc., Covington, GA, USA) is an injectable solution of EVA dissolved in a dimethyl sulfoxide (DMSO) carrier that allows ease of injection and subsequent precipitation of EVA into a mass within the urethral submucosa. Clinical experience with Tegress showed equivalence in outcomes with collagen and objective and subjective cure rates of 45% and 55%, respectively. However, unacceptable rates of treatment-related complications, including a 37% urethral erosion rate, have been reported, and the manufacturer voluntarily withdrew Tegress from the market in 2007.

Dextronomer/hyaluronic acid (Dx/HA) (Deflux, Zuidex, Q-Med, Uppsala, Sweden) is a copolymer of dextranomer microspheres and nonanimal stabilized hyaluronic acid (NASHA) gel. Deflux is commonly used for endoscopic treatment of vesicoureteral reflux with great efficacy. However, for UBT, clinical results were disappointing. A multicenter US clinical trial of Zuidex was not able to achieve equivalency with transurethral collagen injection in 344 randomized women with ISD. Furthermore, an unacceptably high complication rate occurred, particularly for sterile pseudoabscesses (up to 16%), and efforts to obtain US Food and Drug Administration (FDA) approval were abandoned.

The best-studied urethral bulking agent is glutaraldehyde cross-linked bovine collagen (Contigen, CR Bard, Covington, GA, USA), which has been considered the gold standard of urethral bulking materials and the FDA required direct comparison with collagen for any new bulking agent in clinical trials. However, despite a long track record, albeit with mediocre results, collagen for urethral injection is no longer available as of August 2011, because the manufacturer (Allergan, Inc, Irvine, CA, USA) ceased production.

Silicone Particles (Macroplastique)

Macroplastique (Uroplasty Inc, Minneapolis, MN, USA) is a nonbiodegradable hydrogel composed of vulcanized polydimethylsiloxane (silicone) elastomer suspended in a water-soluble carrier gel (polyvinylpyrrolidone) that also serves as a lubricant for the injection system. The elastomer is a particulate of various shapes and configurations, with marked variability in particle size: particles range from less than 50 μm to 400 μm in largest dimension, with 25% of the particles less than 50 μm, raising some concern for potential particulate migration. Histologic examination in porcine injection models reveals the particles to be organized in collagen-encapsulated, firm nodules with evidence of fibroblast and small-vessel in-growth, and no evidence of loss of volume at 6 weeks.

Macroplastique requires no preadministration hypersensitivity testing, and the material does not require refrigeration or special handling. It is supplied in preloaded 2.5-mL syringes. Silicone injection can be performed using standard cystoscopic equipment, with an 18-gauge Uroplasty rigid endoscopic needle, or using a proprietary, nonendoscopic transurethral injection device, the MIS (Uroplasty Inc, Minneapolis, MN, USA). The MIS consists of a multichanneled needle positioning device with 3 angled needle entry ports orientated at the 6, 2, and 10 o’clock positions for injections of 2.5 mL, 1.5 mL, and 1.5 mL of material, respectively. Ease of use and operator satisfaction with the device has been objectively reported with acceptable 3-month safety and efficacy, although this is not currently available in the United States. The recommended endoscopic Macroplastique injection technique, similarly to the MIS, involves injection at the 6, 2, and 10 o’clock positions with 2.5 mL, 1.5 mL, and 1.5 mL of material, respectively.

General concerns regarding implantation of permanent silicone material in patients have tempered enthusiasm for Macroplastique in the United States., whereas its use in Europe has been more widespread. Recently, a North American trial of 12 sites in the United States and Canada has been reported, randomizing 247 patients with ISD to transurethral injection of either Macroplastique or Contigen. With 12 months’ follow-up, the investigators reported statistically significant clinical improvement and dry/cure rates in 61.5% and 36.9% of patients treated with Macroplastique, respectively, and in 48% and 24.8% of patients treated with Contigen, respectively. Safety profiles and adverse events were similar between the 2 groups, with no serious treatment-related complications occurring with Macroplastique. Tamanini and colleagues reported on 15 patients (out of the original 21-patient observational cohort) with 60 months’ follow-up and showed subjective success rates of 80%, and statistically significant decreases in daily pad usage, pad weight, and Valsalva leak point pressure. In another study with 60 months’ follow-up, Zullo and colleagues reported on 61 patients with ISD with cure rates of 18% and improvement rates of 39%. In a systematic review, a wide variety of cure and improvement rates (0%–66% and 0%–37%, respectively) have been reported with follow-up time periods of 3 to 36 months.

Adverse events are reported with Macroplastique and include short-lived, self-limited dysuria, frequency, and hematuria in many patients and transient urinary retention in 6% to 10% of patients.

Carbon Beads (Durasphere)

Durasphere (Boston Scientific, Natick, MA, USA) is composed of pyrolytic carbon-coated zirconium beads (ranging in diameter from 251to 300 μm) suspended in a water-based carrier gel composed of 2.8% glucan (a simple polysaccharide). It is considered a sterile, nonpyrogenic, nonreactive, injectable bulking agent that gained FDA approval for use in patients with ISD in 1999. Because of safety concerns of particle migration with other injectable agents, Durasphere was designed with larger-caliber particles (>80 μm) to prevent migration ; however, asymptomatic local lymphatic and periurethral carbon bead migration has been reported.

Durasphere requires no special storage or handling precautions and is injected using standard endoscopic instruments and a proprietary 18-gauge injection needle device. In addition, a bent needle is available (18 or 20 gauge) for periurethral injection. The system comes with 1-mL or 3-mL filled syringes and transurethral injection of the material can be performed under local anesthesia. Technical difficulty injecting Durasphere has been encountered, with the carbon beads clogging the injection needle, resulting in increased resistance with higher pressures required to inject the material. Madjar and colleagues proposed a modified injection technique to overcome this difficulty by using submucosal hydrodissection with 1.5 mL of 1% lidocaine before Durasphere injection. In addition, the manufacturer has reformulated the carbon bead size and carrier gel to allow more efficacious injection (Durasphere EXP) via a customized, side-firing 18-gauge or 20-gauge injection needle.

The use of carbon beads has met with moderate clinical success. In a randomized controlled study of 355 women with ISD comparing bovine collagen injection with Durasphere, no significant difference was noted between Durasphere and collagen: 80.3% treated with Durasphere and 69% treated with collagen were improved by 1 or more continence grade at 12 months. Similar results were seen in a trial comparing 52 patients treated either with Durasphere or Contigen in which 80% and 62% of women improved greater than 1 incontinence grade at 2.6 years’ follow-up, respectively. Forty percent of patients receiving Durasphere and 14% of patients receiving Contigen were reported as dry.

As is the case with many injectable agents, long-term follow-up shows a reduction in clinical success. Chrouser and colleagues reported on 56 patients treated with Durasphere, with clinical efficacy of 33% and 21% at 24 and 36 months of follow-up, respectively. Nevertheless, a third of patients thought that treatment was a success.

In addition to adverse effects common to urethral injection therapy (eg, dysuria, hematuria), noninfectious periurethral abscess and urethral prolapse have been described in a few cases.

Calcium Hydroxylapatite (Coaptite)

Coaptite (Boston Scientific, Natick, MA, USA) is an injectable material that is nonpyrogenic, composed of particles of calcium hydroxylapatite (CaHA) ranging in diameter from 75 to 125 μm (mean 100 μm) suspended in an aqueous gel carrier composed of sodium carboxymethylcellulose and glycerin. The gel carrier facilitates injection and provides the initial bulk mass of the treatment; it is designed to degrade over time, allowing in-growth of tissue around the CaHA particles. CaHA is identical to constituents of bone and teeth and has been used in orthopedic and dentistry procedures with excellent biocompatibility. Coaptite does not require refrigeration or special handling precautions and is dispensed in 1-mL prefilled syringes. A preprocedure skin test for hypersensitivity is not required.

Injection is performed via standard endoscopic instruments with a supplied 21-gauge rigid injection needle with either end-firing or side-firing capability (Sidekick needle). The material is injected at the proximal urethra at multiple sites until circumferential coaptation is achieved, and approximately 2 to 4 mL of material is required. Because CaHA is radiopaque, the material can be visualized on radiographic studies, facilitating accurate localization and placement.

In a pilot study, Mayer and colleagues injected 10 patients with a mean of 4 mL of Coaptite and reported that 7 of the 10 patients noted substantial improvement in pad use or cure (3 patients) at 1 year. The daily mean pad use decreased from 2.59 to 1.64 and the mean 24-hour pad weight declined 90%. The investigators reported that the agent was well tolerated with no significant safety issues.

In the first large, multicenter clinical trial of Coaptite, Mayer and colleagues randomized 296 women with ISD to either CaHA or cross-linked collagen. At 12 months’ follow-up, 63.4% of patients treated with CaHA and 57% of patients treated with collagen reported improvement of 1 Stamey incontinence grade or more (no statistical difference). Fewer patients required repeat or multiple injections with CaHA compared with collagen (62% vs 74%, respectively) with a significantly smaller volume of injected material required for CaHA. Patient tolerability was equivalent for the 2 injection materials; however, 2 patients undergoing CaHA injection had technical complications, with improper placement of the material resulting in vaginal erosion in 1 and subtrigonal placement of another. No long-term sequelae of these 2 events were noted.

Urethral prolapse after CaHA injection has been reported in 2 patients. Both were treated with local excision with resolution of persistent voiding complaints.

Polyacrylamide Hydrogel (Aquamid, Bulkamid)

Bulkamid (Contura International, Soeborg, Denmark) is a polyacrylamide hydrogel (PAHG) composed of nonpyrogenic water and cross-linked polyacrylamide. It is biocompatible, nonresorbable, and nonallergenic, and, because of its hydrogel nature, it contains no solid particles (ie, microspheres or microcrystals), thereby eliminating any risk of particle migration. PAHG (Aquamid, Contura International, Soeborg, Denmark) has been extensively used clinically in Europe as a soft-tissue filler in aesthetic enhancement and reconstructive procedures.

Bulkamid requires no special handling or refrigeration and is supplied in a 1-mL preloaded sterile syringe. It can be injected transurethrally using a 23-gauge needle and standard endoscopic equipment or using a proprietary endoscopic system, the Bulkamid Urethral Bulking System (Contura International, Soeborg, Denmark). This system is a specially designed endoscopic instrument, with an 11-cm female urethra urethroscope and a disposable rotatable sheath that includes a working channel for the needle, a 2.7-mm lumen for an endoscopic lens, and water flow tubing (in and out). The rotatable sheath allows 360° rotation of the working channel. Approximately 0.5 mL of material is injected each at the 3, 6, and 9 o’clock positions to achieve full coaptation.

Bulkamid (and its predecessor Aquamid) has been used clinically for endoscopic treatment of SUI. Lose and colleagues injected 25 women with SUI with Aquamid. At 12 months’ follow-up, 38% and 43% of patients were subjectively dry or improved after 1 or 2 injections. At 12 months, urine leakage (by 24-hour pad test) was objectively decreased by 93% (from a baseline of 56 g to 4 g) and the number of incontinence episodes (by voiding diary) by 87% (from a baseline of 4.6/24 hours to 0.6/24 hours). Adverse events included UTI (10 patients), transient urinary retention (5 patients), and transient de novo urgency and urge incontinence (3 patients).

In another study by this group investigating the effects of urethral injection therapy on urethral pressure reflectometry measurements, 15 women with SUI were injected with polyacrylamide hydrogel and followed for 3 months after surgery. Ten patients were considered cured/improved and showed improvements in urethral pressure measurements compared with baseline. In a recently published case series, two-thirds of 135 women reported being cured or improved after 12 months’ follow-up, with significant reductions in incontinence episodes per 24 hours and pad weight testing.

Bulkamid and Aquamid are not presently available in the United States; however, clinical trials are currently ongoing.