Comparison of the precision of transurethral endoscopic versus ultrasound-guided application of injectables

Investigative Urology TRANSURETHRAL ENDOSCOPIC vs US-GUIDED APPLICATION OF INJECTABLES MITTERBERGER et al.

Comparison of the precision of transurethral endoscopic versus ultrasound-guided application of injectables Michael Mitterberger, Germar M. Pinggera, Alexandre Pelzer, Georg Bartsch, Daniela Colleselli, Hannes Neuwirt, Johann Gradl*, Leo Pallwein*, Friedrich Aigner*, Ferdinand Frauscher* and Hannes Strasser Departments of Urology and *Radiology II, Innsbruck Medical University, Austria Accepted for publication 6 July 2007

Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVE To compare the precision of transurethral endoscopic- vs ultrasound (US)-guided injections, as transurethral application of various injectables under endoscopic view are widely used to treat urinary incontinence.

depots were injected periurethrally under endosocopic guidance. In group III collagen was injected into the urethral wall under US control. In group IV collagen depots were injected periurethrally under US guidance. A transurethral US probe (6 F, 15 MHz) and injection device were used for transurethral US-guided injections. In all pigs the urethra and the periurethral tissue were removed after injection and investigated using anatomical preparations and histological sections.

MATERIAL AND METHODS RESULTS Bovine collagen was injected into the lower urinary tract in 20 dead female pigs. In each pig five depots of collagen were injected and there were five pigs in each group. In group I collagen was injected into the urethral wall under endoscopic control. In group II collagen

INTRODUCTION Injectables have been used for the management of stress urinary incontinence (SUI) for >60 years. With the development of new materials, the use of bulking agents has increased and cross-linked collagen has been particularly popular [1].

In group I only two collagen depots were actually located in the urethral wall in two pigs (two of 25 depots, 8%). In group II five depots in two pigs were located in the urethral wall (five of 25 depots, 20%). The

Therefore, we assessed the precision of endoscopic- vs ELUS-guided injections. To our knowledge this has not yet been compared in an experimental study. It was the aim of the present study to determine if ELUS might lead to a more precise application of injectables.

MATERIALS AND METHODS Retrograde transurethral injection under endoscopic view is the most widely used application technique, although different injection techniques have been described [2]. Endoluminal ultrasonography (ELUS) is a noninvasive diagnostic technique used in urology to visualize tubular structures of the urinary tract. ELUS can be used to directly investigate the sphincter mechanism and identify defects or atrophies [3]. The benefit of ELUS-guided injection is direct visualization of the urethral wall and periurethral structures.

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Bovine collagen was injected into the lower urinary tract in 20 dead female pigs. Injections and US examinations were done with the pigs supine. The pigs were divided in to four groups (five pigs in each group) and in each pig five depots of 0.5 mL of collagen were injected. In group I collagen was injected into the urethral wall under endoscopic control, in group II collagen depots were injected periurethrally under endosocopic guidance, in group III collagen was injected into the urethral wall under ELUS control, and in group IV collagen depots were injected

periurethral collagen depots were found to spread out in the loose connective and fat tissue around the urethra. In group III all USguided injections of collagen were situated in the urethral wall and in group IV they were all located periurethrally. CONCLUSIONS The present study shows that endoscopic application of injectables is an inaccurate technique, while US-guided injections are precise. US-guided injection enables excellent control of the therapeutic procedure. KEYWORDS animal model, endoluminal ultrasound, endoscopy

periurethrally under ELUS guidance (25 depots in each group). All transurethral endoscopic injections (Fig. 1) were performed by one urologist (H.S.) using bovine collagen, using a transurethral approach with a 18 F Wolf cystoscope and 30° lens. The five depots of 0.5 mL of collagen were injected at the 1-, 4-, 6-, 8- and 11o’clock positions around the urethra, with the needle inserted at the level of the mid-urethra into the urethral wall and periurethrally (total injected volume 2.5 mL; one syringe). The cystoscope was not passed proximally into the urethra after injection. For ELUS-guided injections (Fig. 2) a 15-MHz miniature US transducer (6 F, Fujinon, Japan) was connected to conventional US equipment (Hitachi, Japan), which gave 360° crosssection real-time images with very high resolution and a depth of penetration of 2–3 cm.

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The transurethral US probe and a separately designed injection device were used for transurethral US-guided injections. Collagen was then injected under ELUS guidance using a 22-G needle passing through the injection device at the same location like the endoscopic injections. ELUS-guided injection was done by a different, also experienced urologist (G.P). Collagen was injected either into the urethral wall or periurethrally at the mid-level of the urethra. Collagen (0.5 mL) was injected at each site. The collagen was injected at five sites corresponding to the endoscopic 1-, 4-, 6-, 8-, and 11-o’clock positions. In ELUS examination the tip of the needle as well as the hyperechoic collagen depots were identified in the urethral wall and in the periurethral tissue. The rhabdosphincter was also identified before injection of collagen. In the protocol of the study it was decided not to inject the collagen into the rhabdosphincter. For the histopathology, the urethra and the periurethral tissue were removed after injection in all pigs and investigated using anatomical preparations and histological sections. The specimens were fixed in 3.8% formalin and embedded in paraffin wax. The tissue was mounted for histopathological examination and stained with haematoxylin and eosin. In all pigs the position of the collagen depots was controlled to determine the accuracy of both injection techniques. To compare the precision of the four study groups, the Fisher’s exact test and chi-square test were used to determine whether there was a statistically significant difference. A P < 0.05 was considered to indicate statistical significance.

RESULTS All the transurethral endoscopic injections were given with no problems. There was good coaptation of the urethra after injection of collagen into the urethral wall, while periurethral injection did not show a good bulking effect. Using ELUS the urethra, the relatively hypoechogenic rhabdosphincter and the surrounded hyperechogenic fat and connective tissue could be identified in all pigs. For the ELUS-guided injections the tip of

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FIG. 1. (a,b) Standard transurethral endoscopic injection. Standard endoscopic techniques of injection have been proven to be inaccurate for injectable guidance. The inserted injection needle is mostly situated outside the urethra as shown on this porcine urethra. a

FIG. 3. ELUS-guided injection. A, In the schematic drawing the transurethral US probe and injection device (dark blue) have been inserted into the urethra. The tip of the needle is situated in the urethral submucosa (yellow) and in the periurethral tissue outside the rhabdosphincter (red). The rhabdosphincter is shown in red surrounding the smooth musculature of the urethral wall (brown). B, In the US image the needle (marked with arrow) is placed at the inner aspect of the rhabdosphincter (RS). T, US transducer. a

b

FIG. 2. ELUS-guided injection. A new device has been developed for transurethral US guidance of injectables. With this device the exact localization of the injection needle can be adjusted individually.

the needle and its position in the urethra and the rhabdosphincter were clearly visualized. The injected collagen presented as a hyperechoic mass. (Fig. 3) After histological evaluation, only two depots were actually located in the urethral wall in two of the pigs in group I, i.e. two of 25 depots (8%) under endoscopic injection control. In group II, five depots were located in the urethral wall (five of 25 depots, 20%) in two pigs and of these three depots were localized in the rhabdosphincter. (Fig. 4) The periurethral collagen depots were found to spread out in the loose connective and fat tissue around the urethra. In group III, all the US-guided injections of collagen were situated in the urethral wall and in group IV all were located periurethrally. None of the injected collagen was localized in the rhabdosphincter of pigs in groups III and IV, i.e. US-guided injections.

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FIG. 4. An example of an anatomical preparation of porcine urethra after periurethrally (under endosocopic guidance) injected collagen. The collagen depots injected under endoscopy are not only situated periurethrally but also in the rhabdosphincter and the submucosa. 1, submucosa; 2, rhabdosphincter; 3, periurethral tissue; 4, collagen depots.

There was statistically significant higher precision for the ELUS-guided injection

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TRANSURETHRAL ENDOSCOPIC vs US-GUIDED APPLICATION OF INJECTABLES

technique when comparing group I with group III (P < 0.001 Fisher’s exact and chisquare tests), and group II and group IV (P ≤ 0.05 Fisher’s exact test and P < 0.001 chi-square test).

DISCUSSION Injection therapy for the management of SUI has been used for nearly six decades. The goal of endoscopic injection therapy for SUI is to provide a minimally invasive, effective and safe alternative to open surgery [1]. The agent can be injected either into the urethral submucosa or periurethrally. To date, these manipulations have been guided by means of urethroscopy. An alternative has been a ‘blind’ mid-urethral technique that has been applied for injection of hyaluronic acid containing dextranomers, using a simple injection device [4]. Although these techniques have been available for decades, endoscopic injection techniques obviously cannot provide exact guidance for the application of injectables into the urethral wall, rhabdosphincter or periurethrally. Two-dimensional US (2D-US) has been the most widely applied technique for imaging of bulking agents, primarily because of its availability and significantly lower cost compared with cross-sectional imaging using CT or MRI [5]. As with 3D-US, most publications utilizing 2D-US to assess urethral bulking agents have applied the technique after injection of collagen [6–8]. Most have tried to define imaging characteristics and the periurethral position/configuration in an attempt to determine the mechanism by which collagen treats SUI [8]. Fewer studies have used 2D-US to compare the localization of injected collagen with the clinical outcome [9]. In this respect, transabdominal (transvesical), transperineal, transvaginal, transrectal and endoluminal (transurethral) techniques have been used. In one reported porcine study, ELUS was used to image the wall of the urethra to compare the cross-sectional data obtained by ELUS images and the actual anatomical cross sections. The results showed high-quality images detailing different anatomical layers of the urethra. The accuracy of the study was later confirmed by histological cross-sectional studies [10].

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The efficiency of ELUS as a technique to guide surgical procedures has also been tested in animal studies. Rivas et al. [6] injected glutaraldehyde cross-linked collagen in pigs to test the therapeutic efficacy of collagen for treating UI. Submucosal, intramucosal, and periadventitial depths of collagen into the urethra and bladder walls in two pigs were studied using ELUS. It was shown that ELUS aids in accurately identifying the submucosal location of collagen injection and avoids dispersion of the material. In the present study, the depots were injected in the urethral wall and periurethrally, whereas the study conclusion that ELUS allows precise injection of material is the same. Preliminary ELUS validation studies in animal models show the efficiency, accuracy, and feasibility of this technique for intraluminal use in humans [11]. In further clinical studies, Gottfried et al. [9] compared the outcome of ELUS controlled and transurethral submucous collagen injection in SUI. In the first group of female patients, the collagen injections were given under ELUS guidance. In the second group, an endoscopic system was used. There was no major difference in patient selection for the two groups. SUI symptoms became less severe in only five of 15 patients in the ELUS group, who then had moderate SUI. Endoscopic collagen treatment resulted in social continence in 15 of 22 (68%) patients. They concluded that endoscopic collagen injections are superior to ELUS-guided collagen injection in the treatment of SUI. In contrast to this clinical study, it was not the aim of the present study to evaluate clinical outcome but to determine the accuracy of implantation techniques in an animal model. A state of the art US system allowing precise delineation of the anatomical structures was used for guided injections. In 1997, Khullar et al. [12] investigated 23 women after periurethral collagen injection, using either perineal or transvaginal 2D-US at ≥3 months after injection. They correlated clinical continence and urodynamic variables (increased maximum urethral closure pressure and increased functional urethral length) with US findings. They found that the height of collagen intrusion into the bladder base (‘bump’ height), but not the crosssectional area of collagen, was correlated with an improvement in both continence and urodynamic variables. Based on these data, they concluded that increased amounts of collagen at the bladder neck were not

associated with continence, and that apposition of the urethral mucosal surface is not the mechanism of continence achieved by collagen. Elia and Bergman [13] also reported that the relative position of the periurethral collagen to the bladder neck determined continence outcome. They studied 31 women with intrinsic sphincteric deficiency after collagen injection using transvaginal 2D-US and correlated US findings with continence outcomes after 1 year using subjective assessments and a cough-stress test. A successful outcome was associated with a distance of collagen from the bladder neck of