Injectable Therapies for Incontinence in Women
STEPHEN MOCK
MELISSA R. KAUFMAN
W. STUART REYNOLDS
ROGER R. DMOCHOWSKI
Injecting material into the wall of the urethra to bulk the submucosal tissue layer, increase urethral resistance, and improve urethral coaptation is nothing new. Initially described in 1938, Murless et al. (1) reported on 22 women who had either morrhuate sodium or cod liver oil injected into the anterior vaginal wall to provoke an inflammatory response resulting in scar formation and contracture of tissue around the urethra. Seventeen patients reported being cured or improved, but pulmonary infarction and cardiopulmonary arrest were reported (1). In 1955, Quackels (2) reported on the first injections into the urethra using paraffin wax. Two patients were treated successfully without complications. In 1963, Sachse (3) used Dondren, a sclerosing agent, to treat 7 women and 24 men. Four women and 12 men were reported as cured, but several patients experienced pulmonary embolism (3). In the 1970s and 1980s, polytetrafluoroethylene (PTFE; Teflon) was used extensively (4) but was never approved for use in the United States, owing to safety concerns including distant particulate migration and foreign body reaction (5). Autologous fat was studied and in a randomized double-blind controlled trial of women with urethral hypermobility was found to be as effective as the saline control group at 6 months (6). Additionally, serious adverse events including systemic embolization and death have been reported (7,8). Ethylene vinyl alcohol copolymer (Tegress), a permanent, hypoallergenic, nonimmunogenic implant, demonstrated equivalence in outcomes with collagen (9,10) and was approved by the U.S. Food and Drug Administration (FDA) in 2004. However, the high rate of urethral erosion, although generally self-limited with spontaneous resolution, contributed to bothersome dysuria and necessitated multiple office visits (11), and as a result, the manufacturer voluntarily withdrew Tegress from the market in 2007. As illustrated, these bulking agents were far from ideal. Such an ideal agent would be nonimmunogenic; hypoallergenic; biocompatible; permanent; nonerosive; heal with minimal fibrosis; be nonmigratory; easily stored, handled, and injected; painless; and retain its bulking effect over a long period of time (be durable) (12,13). The components of the agent should not separate or dissociate on injection, and if the agent contains microcrystalline or micropolyermic components, they should be reasonably uniform spheres of particle sizes above 110 µm so as to minimize the risk of migration. If the substance used is not successful, it should not interfere with subsequent surgical intervention (12). To date, no agent has satisfied all these requirements, and the search continues for improved materials and modes of delivery.
MECHANISM OF ACTION
Injectable agents work by forming a “hermetic seal” through restoration of mucosal coaptation during the storage phase and maintain this coaptation during periods of increased abdominal pressure. It is generally thought that these agents improve intrinsic sphincter function, as evidenced by an increase in postinjection abdominal leak point pressure (ALPP), which is the amount of abdominal pressure necessary to overcome the bladder’s continence mechanism (14). They have several advantages over surgical procedures in treating stress urinary incontinence (SUI). Compared to surgical procedures that create a functional obstruction, injectable agents restore continence by increasing urethral resistance at rest. With bulking agents, the urethra maintains its ability to funnel and open, keeping urethral resistance low during micturition. This spares a resultant increase in detrusor pressure, which could lead to overactive bladder symptoms and/or upper tract damage. In comparison, surgical procedures may result in increased resistance at rest and during micturition by not allowing the urethra the same physiologic movement. Most bulking agents are placed at the level of the bladder neck within the smooth muscle in the area of the continence mechanism. Since the placement is within the urethra, intraurethral is a more accurate term than the commonly used terms periurethral or submucosal.
CRITERIA FOR SELECTION
Traditionally, intraurethral bulking agents were reserved for women who have SUI due to intrinsic sphincter deficiency (ISD), a normal contractile bladder, and limited urethral mobility (<30 degree change in axis on cotton swab test from rest to strain). However, multiple reports have demonstrated clinical efficacy in patients with urethral hypermobility. In one study, both those with and without hypermobility had equal success, although more injections and a greater amount of material were injected in the group with urethral hypermobility (15). In a later study by Herschorn and Radomski (16), no statistically significant difference was found between those with and without urethral hypermobility. Over time, 72% remained dry at 1 year, 57% at 2 years, and 45% at 3 years, with no significant difference between the type of incontinence and time to failure. Others have documented similar findings (17,18,19,20).
Currently, good candidates for bulking agents include those who are poor surgical candidates and are at high anesthetic
risk, are elderly and at greater risk of retention after a sling procedure, must continue anticoagulation at all times, are unable to follow postoperative activity limitations required after anti-incontinence procedures, are young and desire more children in the future, have mild persistent SUI after an antiincontinence procedure, have SUI and poor bladder emptying, have mild SUI associated with exercise, do not wish to undergo more invasive procedures, and are willing to accept an improvement rather than a cure of their SUI symptoms (13). Patients must understand that efficacy and duration of these agents are inferior to surgery and follow-up injections may be required.
risk, are elderly and at greater risk of retention after a sling procedure, must continue anticoagulation at all times, are unable to follow postoperative activity limitations required after anti-incontinence procedures, are young and desire more children in the future, have mild persistent SUI after an antiincontinence procedure, have SUI and poor bladder emptying, have mild SUI associated with exercise, do not wish to undergo more invasive procedures, and are willing to accept an improvement rather than a cure of their SUI symptoms (13). Patients must understand that efficacy and duration of these agents are inferior to surgery and follow-up injections may be required.
Urodynamics should be performed to rule out other causes of urinary incontinence, such as detrusor overactivity. Urethral function can be assessed by measuring the ALPP, and the definition of ISD by ALPP has varied from a low ALPP (60 cm H2O) to an ALPP <100 cm H2O. An absolute value for ALPP suggesting ISD has become unimportant due to limitations in urodynamic testing as well as different values used by different clinicians. With videourodynamics, radiographic evidence of an open bladder neck and proximal urethra without detrusor contraction during the storage phase of the bladder is felt to imply ISD.
As more is understood about the continence mechanism, it appears that most women with SUI have some component of ISD, since there are numerous women with urethral hypermobility who do not leak with significant intra-abdominal pressures. Women who do have a fixed, nonmobile urethra are, however, more likely to have a greater degree of ISD (21). Exclusion criteria for intraurethral bulking would include urinary incontinence due to abnormal detrusor contractions, active urinary tract infection (UTI), or allergy to the material used as a bulking agent.
Key Concepts
Ideal patients for intraurethral bulking have SUI due to ISD, a normally contractile bladder, and urethral mobility less than 30 degrees.
The efficacy and duration of bulking agents are inferior to surgery and follow-up injections may be required.
Most women with SUI have depressed ALPP and some components of ISD.
INJECTION TECHNIQUES
Bulking agents are generally administered with cystoscopic assistance under local anesthesia. The two most accepted techniques are periurethral and transurethral and both are retrograde suburothelial approaches. The transurethral approach is more commonly performed today. Antegrade placement has also been described but is rarely used today because it necessitates suprapubic access. Precise placement of the bulking material into the wall of the proximal urethra near the bladder neck in the area of the continence mechanism is of the utmost importance. The plane of delivery, the tissue quality at the injection site, and the cause of incontinence are all important factors in successful therapy. If material is delivered too distally, the treatment is likely to fail and may cause irritative voiding symptoms. Prior to injection, patients are placed in lithotomy position and prepared in standard sterile fashion. Preoperative and postoperative antibiotics are frequently administered. A local anesthetic in the form of 20% benzocaine ointment or cream may be applied to the vestibule covering the urethra, and a topical 2% lidocaine jelly may be applied to the urethra. Perimeatal blebs are raised with 1% or 2% lidocaine at the 3 and 9 o’clock or 4 and 8 o’clock positions 3 to 4 mm lateral to the urethral meatus using a 25-gauge needle and then, approximately 4 mL of 1% or 2% lidocaine is injected periurethrally.
Key Concepts
Precise placement of the bulking material into the wall of the proximal urethra near the bladder neck in the area of the continence mechanism is of the utmost importance.
TRANSURETHRAL INJECTION
The transurethral technique consists of the bulking agent injected submucosally via a needle inserted through a conventional cystourethroscope under direct vision (22). Endoscopic instrument companies have an array of equipment designed for transurethral injections. The needle size depends on the viscosity of the agent, and some require special ratcheted injection guns to generate enough pressure to overcome this viscosity. A 0-, 12-, or 30-degree lens is best for providing a good view of the urethra as well as the injection needle. Once the cystourethroscope is placed into the urethra and passed into the bladder, the bladder is usually drained because the patient’s bladder may become distended toward the end of the procedure. The endoscope is then backed to the midurethra, at which time the needle can be deployed. Injections have been described at different locations (e.g., 3 and 9 o’clock; 4 and 8 o’clock) such that coaptation, either horizontal or concentric, is achieved. For the initial injection, the 6 o’clock position is often an ideal starting point. The distance from the point of penetration of the urethra to the bladder neck has to be greater than the length of the needle to prevent extravasation of the agent into the bladder. The needle is then inserted submucosally into the urethral muscle beyond the midurethra and advanced to the proximal urethra near the bladder neck. Once the desired positioning is achieved, the bulking agent is slowly delivered to allow it to spread underneath the urethral mucosa. Once the mucosa on that side has expanded to the midline, the needle is slowly withdrawn while injecting. In general, the amount of material needed is the amount that achieves complete coaptation. Of note, once this point is reached, the cystoscope should not be advance past the bulked-up urethra and bladder neck so as to avoid possibly compressing or causing extravasation of the injected agent.
Key Concepts
Injections have been described at different locations (e.g., 3 and 9 o’clock; 4 and 8 o’clock) such that coaptation, either horizontal or concentric, is achieved.
In general, the amount of material needed is the amount that achieves complete coaptation.
PERIURETHRAL INJECTION
Injections may also be performed periurethrally via a needle placed percutaneously lateral to the urethral meatus and parallel to the urethra. While the needle is placed, the urethra is visualized through a cystourethroscope (23). Localization of the needle tip may be facilitated by preinjecting the urethra with methylene blue during the periurethral approach (24). With the periurethral approach, there is often less bleeding, which can improve visualization. There is also less extrusion of the material injected, although this also depends on the type of material injected. The desired amount of coaptation is the same as when performed via a transurethral technique. After the periurethral block, a 20-gauge spinal needle is placed at the 3 or 4 o’clock position into the periurethral tissue within the lamina propria. Urethroscopy is then performed as the needle is further inserted with minimal resistance up to the level of the bladder neck. The surgeon can hold the cystoscope in one hand and advance the needle with the other, but in our experience, an assistant is beneficial. The needle is then rocked in a horizontal plane to assess the location of the needle tip and ensure placement at the proper depth. The material is then injected slowly while observing for coaptation, similarly to the transurethral technique, and the process is repeated at the 8 or 9 o’clock position. If material is noted in the lumen of the urethra, the needle is removed and relocated to a more anterior position, where the injection is repeated again. Once sufficient coaptation is noted, the procedure is ended. A needle with a “bent tip” has been manufactured (Boston Scientific Inc, Natick, Massachusetts) to facilitate placement into the proper plane. With advancement of the needle, the tip is brought more medially. These needles are of a larger bore size (18 or 20 gauge) and were originally designed to ease the injection of the larger caliber particles of Durasphere, but they certainly can be used for the periurethral injection of other bulking agents.
The differences between the transurethral and periurethral techniques were reviewed by Faerber et al. (25), and they found similar outcomes with no significant differences in adverse events using collagen as the test bulking agent. Of significance, the amount of material injected was less using a transurethral approach. A prospective, randomized comparison was later performed in women with no noted differences in efficacy, but a higher rate of urinary retention and an increased volume of injected material were seen in the periurethral group (26). It appears that a periurethral approach tends to use larger volumes of material and has been noted to have a longer learning curve than the transurethral approach. This is important as greater volumes are associated with higher cost and may increase the potential for postoperative complications.
Key Concepts
The desired amount of coaptation is the same as when performed via a transurethral technique.
Efficacy is similar between periurethral and transurethral techniques, but the periurethral approach tends to use larger volumes of material and has been noted to have a longer learning curve than the transurethral approach.
POSTOPERATIVE CARE
Immediate postoperative complications are rare. After completion of the procedure, the patient should demonstrate the ability to void. If the patient is in acute urinary retention, most often the patient will be able to urinate shortly after the periurethral block loses effect. In the meantime, the patient is usually catheterized with a small 10Fr to 14Fr catheter to relieve the patient’s full bladder after cystourethroscopy. An indwelling Foley catheter should be avoided since there is a theoretical risk of the bulking agent molding around the catheter and losing its effect, although there is no evidence to support that short-term catheterization decreases the efficacy of intraurethral bulking. If long-term catheterization is necessary, a suprapubic catheter until return of voiding would be best to avoid disrupting the placement of the bulking agent. Although there are no randomized trials on the use of prophylactic treatment with antibiotics, a fluoroquinolone or trimethoprimsulfamethoxazole for 24 hours or less can be recommended (27). An additional 2 to 3 days has also been suggested (28).
Many patients will require more than one treatment session to achieve maximal continence. Different waiting periods are required for each individual bulking agent. Bulking agents such as glutaraldehyde cross-linked bovine collagen (GAX-collagen) can be repeated after 7 days (in the original multicenter study, a 4-week waiting period was used), but most clinicians wait 4 weeks or longer to assess response and the need for reinjections (28). With Teflon, a 4-month wait is required because improved coaptation occurs with time. Macroplastique injections can be repeated after 12 weeks. Durasphere can be reinjected after a minimum of 7 days and Coaptite can be reinjected after 1 month or less. On repeat injection, if erosion is noted, injection into that side should be avoided until re-epithelialization occurs.
Irritative voiding symptoms may also develop after placement of bulking agents. Surprisingly, in a study by Steele et al. (19), 50% of patients were reported to have developed de novo detrusor overactivity. In a study by Cross et al. (29), 28% of patients were found to have de novo urge incontinence without ISD when undergoing urodynamics for posttreatment incontinence. Stothers et al. (30) reported a 12.6% rate of de novo urgency with urge incontinence in 337 women enrolled in a prospective trial of which 21% failed anticholinergic treatment.
Reports have been published on rare complications including urethral mucosal prolapse, abscesses, periurethral pseudocyst formation, and urethral diverticuli (13). Additionally, the periurethral approach is associated with higher injection volumes, which may contribute to higher urinary retention rates (26).
Key Concepts
Although uncommon, if a patient is in acute urinary retention, catheterization with a small 10Fr to 14Fr catheter to relieve the patient’s full bladder is indicated.
INJECTABLE AGENTS
Many different agents have been studied for use as bulking material with varying success and adverse events (Table 42.1). A Cochrane review from 2012 that identified 14 clinical trials
and over 2,000 women found trials to be small and of moderate quality. They concluded that due to the “lack of long term follow up and health economic data … injection therapy cannot be recommended as an alternative for women fit for other surgical procedures,” but for “women with extensive co-morbidity precluding anesthesia, injection therapy may represent a useful option for relief of symptoms, at least for a 12 month period” (31). Patients should be counseled that greater symptomatic improvement is observed after surgery but at the expense of higher risks. Women should be made aware that repeat injections are likely to be required, efficacy diminishes over time, and that this therapy is inferior to more invasive techniques.
and over 2,000 women found trials to be small and of moderate quality. They concluded that due to the “lack of long term follow up and health economic data … injection therapy cannot be recommended as an alternative for women fit for other surgical procedures,” but for “women with extensive co-morbidity precluding anesthesia, injection therapy may represent a useful option for relief of symptoms, at least for a 12 month period” (31). Patients should be counseled that greater symptomatic improvement is observed after surgery but at the expense of higher risks. Women should be made aware that repeat injections are likely to be required, efficacy diminishes over time, and that this therapy is inferior to more invasive techniques.
TABLE 42.1 PAST AND CURRENT INJECTABLE AGENTS FOR STRESS URINARY INCONTINENCE | |||
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