Deborah J. Lightner1 and John J. Knoedler1
Department of Urology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA
Deborah J. Lightner
Why are bulking agents used for stress urinary incontinence? Mentally-based urinary incontinence occurring with increases in intra-abdominal pressure is the sign qua non of stress urinary incontinence and results from urethral failure to resist increases in intra-abdominal pressure. The proximate cause may be related to poor anatomic support of the urethra and bladder neck; this generally responds well to pelvic floor resuspension procedures of various types. Urethral failure, however, may be also intrinsic, meaning the urethral closure pressure is inefficient at resisting increases in intra-abdominal pressures; this is generally treated with sphincter augmentation procedures, which include periurethral bulking agents . Of course, while there is considerable overlap between these two causes of stress urinary incontinence, treatment success with bulking agents used in the patient with predominantly poor anatomic support do not differ markedly from the treatment success in the patient with predominantly intrinsic sphincteric deficiency (ISD) [2, 3]. Conventionally, however, the use of bulking agents is more widely applied if the urinary loss related to poor urethral function without hypermobility.
Why are bulking agents used for stress urinary incontinence? Meatally-based urinary incontinence occurring with increases in intra-abdominal pressure is the sign qua non of stress urinary incontinence and results from urethral failure to resist increases in intra-abdominal pressure. The proximate cause may be related to poor anatomic support of the urethra and bladder neck; this generally responds well to pelvic floor resuspension procedures of various types. Urethral failure, however, may be also intrinsic, meaning the urethral closure pressure is inefficient at resisting increases in intra-abdominal pressures; this is generally treated with sphincter augmentation procedures, which include periurethral bulking agents . Of course, while there is considerable overlap between these two causes of stress urinary incontinence, treatment success with bulking agents used in the patient with predominantly poor anatomic support do not differ markedly from the treatment success in the patient with predominantly intrinsic sphincteric deficiency (ISD) [2, 3]. Conventionally, however, the use of bulking agents is more widely applied if the urinary loss related to poor urethral function without hypermobility.
Due to the low long-term efficacy of these agents in the treatment of urinary incontinence, these agents are not frequently chosen as first line therapy. It is in the nuanced or more difficult clinical situation where these agents are considered: in the elderly , in the denervated sphincter of a spinal cord injured [5, 6] or neobladder patient  who is leaking between catheterizations and/or is a Valsalva voider, in the multiply-operated urethra of a patient  who has failed multiple prior attempts at treatment, or has had partial urethrectomy , in the frozen pelvis and pipestem urethra after radiation therapy or for the patient in whom continence procedures have largely ameliorated his or her symptoms, but who still desires moderate improvement over his or her current level of continence . Male patients with postprostatectomy incontinence may choose a bulking agent, carefully informed that the success rates are low . Complications in each of these patient groups are of more consequence as appropriate and acceptable alternatives are few.
Bulking agents are used for soft tissue augmentation in many other specialties, including plastic surgery, dermatology, otolaryngology, and within urologic subspecialties, pediatric urology for ureteric reflux, in reconstructive urology for male sphincteric incontinence [11–14] and in restoration of continence in catheterizable stomas . There is renewed interest in bulking agents for fecal incontinence  and for GERD . These soft tissue bulking agents continue to improve over their 70 year history. The commercially available agents currently are potentially more durable , generally safe, inducing a minimal local inflammatory reaction and with a low prevalence of significant adverse events.
The discussions herein will concentrate on the currently available FDA-approved bulking agents for periurethral use: calcium hydroxylapatite (Coaptite®, Merz Aesthetics, Inc., formerly BioForm Medical, Inc., Frankfurt, DE), pyrolytic carbon-coated zirconium beads (Durasphere® EXP, Carbon Medical Technologies, Inc., Saint Paul, MN, USA), and vulcanized silicone microimplant (Macroplastique®, Uroplasty, Inc., Minneapolis, MN, USA), each material purportedly forms a scaffold promoting secondary tissue infiltration with variable degrees of inflammatory reaction [19, 20] rather than the less desirable encapsulation , which risks extrusion . The discontinuation of several older injected materials, including tetrafluoroethylene, autologous fat, and ethylene vinyl alcohol copolymer resulted from unreliable safety reports as well as the failure to deliver satisfactory rates of success . They should not be used. Off-label use of other soft tissue bulking agents will be discussed to decry the practice.
Given these caveats of experience, the evaluation of future bulking agents, autologous myoblasts , or cartilage , or polyacrylamide hydrogel  (Bulkamid®, currently undergoing investigational studies, Contura International A/S, Soeborg, Denmark) should be subject to the same high degree of scrutiny regarding the unique complications related to the material as previous soft tissue bulking agents.
Of note, the complications seen in one surgical discipline generally mirror the experience of bulking agents across the spectrum of care. Polytetrafluoroethylene is one well-known example of granulomata formation [27–30]. Local migration with radio-opaque carbon-coated zirconium beads is another [31–33], although without clinical consequences. When considering newer periurethral agents, these should therefore be cross-linked for complications across specialties, as similar adverse events might occur in alternative applications.
Parenthetically, the discontinuation of Contigen (Bard™, Covington, GA, USA) was related to the lack of a primary supplier of the bovine product and neither due to lack of efficacy, nor significant complications with the material.
Complications from soft tissue bulking agents will be presented as local or systemic, acute or delayed in presentation, with emphasis on the extremely low risk of significant complications of any type.
Acute local complications of the current bulking agents used in a periurethral application are associated with very low rates of repetition complications. In 5–10% of patients, an uncomplicated or urinary tract infection from instrumentation, transient hematuria from the mucosal injection, transient urinary retention from periurethral edema can occur. A small French catheter is used if retention occurs, and applied for either intermittent catheterization or a short period of indwelling catheterization until resolution of this infrequent complication. Anecdotal concerns regarding the possible deformation of the injected bulking agents, leading to decreased efficacy, has lead to the recommendation that only a small French-sized catheter be used with acute transient urinary retention. As with any periurethral procedure for incontinence, there is an acceptable low incidence of de novo urge incontinence. In patients with either persistent acute urinary retention or secondary obstruction-related urge incontinence, the remote possibility of overbulking leading to obstruction should be considered. This can be treated early with simple aspiration [34, 35] with most agents. A transurethral approach is favored due to the theoretical, albeit never reported, risk of a secondary urethrovaginal fistula.
The type of complication is reported with periurethral bulking agents appear to be partially independent of the material used, in so far that local chronic complications of urethral prolapse, periurethral pseudoabscesses are reported in extremely low prevalence and are, at least, theoretically possible with each of these FDA-approved agents. This implies that some of these adverse events may be characteristic of the procedure and location and less likely resultant of the material.
Long-term local complications with the current commercially available bulking agents are also acceptably low and are reported only as small case series. A periurethral collection variously described as a pseudocyst  or pseudoabscess  or a noncommunicating diverticulum  each appear to reflect the same process and present with a palpable well circumscribed mass and secondary obstructive or irritative voiding symptoms. The mass may be tender or not. Several authors have reported that these collections may be infected , although the microbiological reports have not been conclusive. Imaging can be definitive  if clinically needed. Aspiration alone may lead to recurrence of the pseudoabscess, whereas transurethral unroofing of these periurethral masses is invariably associated with reoccurrence of their presenting symptom of stress urinary incontinence. The periurethral pseudocyst is thick-walled, containing cystic or loculated cavities which may or may not communicate with the urethral lumen; none have been associated with malignant or premalignant changes on explorations occurring up to 19 months postinjection . Historically, pseudoabscess formation was thought secondary to delayed hypersensitivity to the bovine dermal product ; however, repeated skin tests do not show conversion . Furthermore, pseudoabscesses can be reported with low prevalence with each of the bulking agents applied either peri- or transurethrally, suggesting that the etiology may be partially related to the specific urethral application. Consistent with this is the fact that pseudoabscess as described is not reported with either ureteral or dermatologic applications, although rarely, other local complication of overlying skin or mucosal erosion, and granulomata formation are common to each application site. Hence, the etiology of pseudoabscess remains enigmatic.
Pseudoabscess is described with virtually all bulking agents used in a periurethral application for stress urinary incontinence. This is not to discount that some agents are associated with this complication in an unacceptable percentage of those treated; dextranomer-hyaluronic acid is an agent particularly associated with granulomata [43, 44] and/or pseudoabscess formation .
The classical presentation of a pseudoabscess is outlined in this case: a otherwise healthy female with mixed urinary incontinence but without prior operative management opted for treatment of her stress urinary incontinence component with an injectable bulking agent; bovine glutaraldehyde-cross-linked collagen was chosen. After a negative skin test for bovine collagen allergy, a periurethral injection of a total of 5 cc was performed uneventfully. Six weeks later, she complained of terminal dysuria, her symptoms progressing rapidly to obstructive symptoms with straining to void, and increasing urethral discomfort and dysuria. Her physical examination demonstrated a large nonexpressible periurethral fluctuance. Urine analysis and urine culture were both negative for infection. Imaging demonstrated a large fluid collection periurethrally (Figs. 20.1, 20.2, and 20.3).
CT imaging reveals a large periurethral fluid collection, Collagen pseudoabscesses can be challenging to diagnose on unenhanced CT imaging, the avascular fluid collection becomes readily apparent after administration of contrast agents. Also, the pseudoabscess is always considerably larger than the injected total bulking agent volume; these cases do not result from obstruction due to overbulking. Due to the acute nature of the process, the pseudoabscess was vaginally drained through a inverted-U incision, taking care to preserve the periurethral fascia. A simple longitudinal incision is made directly into the pseudoabscess, in order to establish complete drainage. The pseudoabscess fluid here is typical: nonodiferous viscous toothpaste-appearing fluid compresses adjacent tissues, with negative gram stains for bacteria and negative cultures even for fastidious organisms. The high pressures on the surrounding tissues are putatively the cause of the urethral pain, and reoccurrence of the pain should precipitate an evaluation for recurrence of the pseudoabscess (Image courtesy of Howard B. Goldman)
(a) An inverted-U incision for transvaginal drainage of a pseudoabscess assures a watertight secondary closure minimizing the risk of fistula. (b) The pseudoabscess should be expressed and drained completely; loculations can occur and should be adequately drained (Image courtesy of Howard B. Goldman)
Coronal image of a large periurethral pseudoabscess associated with obstructive voiding symptoms
Parenthetically, in this case, there was no pointing of the pseudoabscess towards the urethral lumen on cystoscopy as the cystoscopic presence of obvious thinning of the urethral luminal mucosa over pseudoabscess can facilitate performing a complete transurethral drainage of the pseudoabscess.
Pseudoabscess formation and subsequent drainage of the submucosal space into the true urethral lumen is the presumptive mechanism for another small set of chronic local complications: pseudodiverticulum formation .
Urethral prolapse has also been reported in case reports with several agents of both current and historic interest [46–48]. Theoretically, this could occur with any bulking agent if it is causes separation of the supporting periurethral stroma. Treatment is local excision, if symptomatic.
Misdiagnosis of periurethral and bladder masses can occur if the history is not available ; imaging can be definitive .
Local tissue necrosis and subsequent erosion of the overlying mucosa has been described with a bulking agent leading to its removal from the market [22, 50]. Most currently available agents are rarely associated with this in small case series, as the submucosal injection may reduce blood supply to the thin overlying mucosal leading to erosion prior to tissue ingrowth. Fistulation to the vagina has been described [51, 52] as might occur rarely with any soft tissue expansion occurring in a limited space.
Chronic urinary retention may develop secondary to overbulking [53, 54]. The necessity of transurethral aspiration, or failing this, resection will lead to the reoccurrence of stress urinary incontinence. However, in the elderly, the author has seen the late development of urinary retention due to progressive loss of detrusor power, without intervening outlet obstruction or other complication of the outlet. These rare patients require treatment as clinically indicated for their detrusor failure; the bulking agent itself does not require other management.
Acute systemic complications are exceedingly rare. Any injected agent—injected at any pressure in juxtaposition to lymphatics or vessels—could be potentially migratory or embolic. Construction of bulking agents above a threshold size of 80 μm reduces but does not eliminate that potential risk . There have been no reports of symptomatic embolic phenomenon with the currently available agents, in contradistinction to older agents, particularly dangerous is autologous fat . The embolic and migratory potentials of agents injected adjacent to lymphatics and blood vessels has been a concern since the initial investigations of these agents : it is generally accepted that bulking agents be larger than 80 μm in diameter to reduce the risk of these occurrences . The injection of agents under pressure into a highly vascular area with abundant lymphatics is likely associated with migration and/or embolism, but clinical consequences have not been reported with Durasphere® EXP, Coaptite® or Macroplastique®. Asymptomatic particle migration, presumptively into lymphatics and submucosal tissues, has been described with those agents which are radiographically visible . Submucosal urethral migration clearly occurs in men with traumatically injured sphincters treated with radiographically visible bulking agents, but these have a low therapeutic efficacy in this setting, limiting their use. Particle size is also directly related to phagocytic activity, with larger particle (herein, of Macroplastique) less likely to be phagocytosed ; there have been no clinically reported sequelae of this phenomenon.
There are no chronic systemic complications of soft tissue bulking agents reported, in large part because of the care taken to ensure that these agents are nonimmunogenic, hypoallergenic and biocompatible .
This is not to dismiss that fact that several agents are simply unsafe! Agents producing high-grade complications such as obstruction from the granulomata (as in polytetrafluoroethylene), truly embolic phenomenon (as in autologous fat ) should simply not be used. Likewise, agents with a high prevalence of adverse reactions (as in urethral erosion with ethylene vinyl alcohol copolymer , or pseudoabscess formation with dextranomer-hyaluronic acid ) should not be used, as has occurred with the use of these off-label.
In summary, the judicious use of the currently approved bulking agents, Coaptite, Durasphere, and Macroplastique, in the treatment of sphincteric incontinence are associated with an extremely low prevalence of local complications, the most serious of which occur chronically in the form of pseudoabscess formation and/or outlet obstruction. The treatment of these two complications is invariably associated with the reoccurrence of the urinary incontinence. The reader is cautioned that other bulking agents may not have the same clinical safety profile particularly when applied in the urethra; off-label use of other soft tissue bulking agents is specifically discouraged.
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