A New Artificial Urinary Sphincter with Conditional Occlusion for Stress Urinary Incontinence: Preliminary Clinical Results

european urology xxx (2006) xxx xxx available at www.sciencedirect.com journal homepage: www.europeanurology.com Ageing Male A New Artificial Urinary Sphincter with Conditional Occlusion for Stress Urinary Incontinence: Preliminary Clinical Results Sarah L. Knight a,, Judith Susser a, Tamsin Greenwell b, Anthony R. Mundy a,b, Michael D. Craggs a a Institute of Urology, Royal Free & University College Medical School, London, UK b Institute of Urology, Royal Free & University College London Hospitals Foundation Trust, London, UK Article info Article history: Accepted March 31, 2006 Published online ahead of print on May 2, 2006 Keywords: Artificial urinary sphincter Stress incontinence Post-prostatectomy Abstract Objectives: To perform a preliminary clinical investigation to determine the safety and efficacy of a novel artificial urinary sphincter (AUS) with conditional occlusion for the treatment of stress urinary incontinence. Methods: Male patients with urodynamically proven stress urinary incontinence after a prostatectomy were implanted with the novel AUS. They were followed up over a period of 12 months and the device tested for efficacy by using objective measurements of urinary leakage and continence. We derived a new measure for continence called the Continence Index. Results: We have demonstrated that the patients receiving the new AUS showed a reduction of greater than 10-fold in mean daily leakage volume from 770.6 ml to 55.1 ml. There was an overall improvement in the Continence Index from 54% to 97%. Conclusions: The new AUS with conditional occlusion provides good continence rates and enables adjustment of regulating pressure in situ. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1. Introduction Hydraulically controlled artificial urinary sphincters (AUSs) have been used in the treatment of stress incontinence for nearly 30 years. The Brantley-Scott AUS was first introduced in 1973 [1] and has evolved into the current AS-800 (American Medical Systems Inc, USA), which until recently was the only commercially available device of this kind. Many studies have reported a good, long-term clinical Corresponding author. Institute of Urology, Royal Free & University College Medical School, 48 Riding House Street, London W1W 7EY, UK. Tel. +44 (0)20 7679 9379; Fax: +44 (0)20 7679 9379. E-mail address: s.l.knight@ucl.ac.uk (S.L. Knight). outcome of the AS-800 in various patient groups [2 4]. However, relatively high surgical revision rates up to 30% [5 7] have been reported. Revisions are the result of major complications including urethral erosion or atrophy (which may be attributed to high occlusion pressures), mechanical failures such as leaking connectors and infection leading invariably to removal of the whole or part of an implant. To address these problems, we designed, patented [8] and developed a new AUS. The new 0302-2838/$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.03.065 EURURO-1343; No of Pages 7

2 european urology xxx (2006) xxx xxx device incorporates many characteristics in common with the AS-800 device; however, it also includes a number of innovative features, which aim to overcome some of the disadvantages of the AS-800. The principal design features of the new implant include the following: A self-sealing port in the pump assembly for insitu pressure adjustment A stress relief mechanism providing low resting occlusion pressure and conditional occlusion of the urethra One-piece assembly to facilitate implantation and minimise mechanical failures Improved cuff design to reduce potential for creasing and fracture Patient-activated rapid cuff re-inflation facility The components of the new AUS are a stress r- elief balloon, a pressure-regulating balloon, a urethral occlusion cuff and a pump assembly unit (Fig. 1A and B). The stress relief balloon is placed extraperitoneally and transmits transient intra-abdominal pressure changes to the urethral cuff to increase occlusion pressure during periods of stress (conditional occlusion). The pressure-regulating balloon is identical to the stress relief balloon but determines the operating pressure of the device. The regulating pressure is adjustable in the range 0 80 cmh 2 O and can be altered by the injection or removal of fluid (on the basis of continence status) from the device in situ through the self-sealing port in the base of the pump assembly unit. A premoulded, adjustable circular urethral occlusion cuff m- inimises creasing and potential stress fractures, to reduce the possibility of leaking. The new device is manufactured as a single unit from medical-grade silicone rubber, sterilised with the use of gamma irradiation and supplied prefilled with sterile saline and ready for implantation. This paper describes the results of the 12-month preliminary clinical investigation (PCI) of the AUS, implanted at one centre (University College London Hospitals) in a group of male patients with urodynamically proven stress incontinence secondary to prostatectomy and pelvic trauma. 2. Patients and methods The new AUS has undergone extensive laboratory testing; a protocol for testing in patients was developed and approved by the UK Medicines and Healthcare products Regulatory Authority (MHRA) and local ethics committee for a PCI. The results of the PCI and the technical data formed the submission for CE approval, which has now been granted. 2.1. Patient selection The investigation was designed as a single-centre study, open to patients over the age of 18 years with urodynamically proven stress incontinence. The main exclusion criteria for the investigation were detrusor overactivity, previous radiation of the pelvis, previous implantation with an AUS, urinary tract infection and postresidual urine volume in excess of 50 ml. After obtaining informed consent, we recruited 11 male patients into the study, nine of whom (mean age, 66 years; range, 47 78) were found suitable to be implanted with the device and followed for a period of 12 months. Eight patients were incontinent after removal of the prostate and one after pelvic trauma. All patients had tried conservative treatment methods unsuccessfully, and three patients had undergone unsuccessful urethral-bulking procedures. All patients were relying on containment methods to manage their incontinence. 2.2. Assessment All patients were assessed before implantation and at 3, 6 and 12 months post-implantation. This included, urinalysis, a cystometrogram, flow rate, urethral pressure profiles, and completion of a 7-day voiding and leakage diary before each visit. 2.2.1. Urinalysis and culture A midstream urine sample was tested with the use of Multistix 8SG urine analysis dipsticks (Bayer plc, UK) and sent for culture if positive for leucocytes and nitrates, and treated accordingly. 2.2.2. Cystometry and flow rate Standard urodynamic equipment (Lectromed 3000, Lectromed, UK) was used to perform bladder filling and voiding cystometry. The bladder was filled via a urethral catheter by using sterile saline at room temperature at a fill rate of 60 ml/ min. Detrusor pressure was measured by subtraction and detrusor activity monitored for signs of over-activity. At full bladder capacity (V max ), filling was stopped, and patients were requested to initiate voiding; maximum flow rate (Q max ), volume voided (V v ) and residual volume were calculated. 2.2.3. Voiding diary Patients were required to complete a 7-day voiding and leakage diary before each visit. The diary included information on daily fluidintake(v i ),volumevoided(v v )andvolumeleaked(v l )either into pads or condom and leg bag. Patients were extensively educated on how to calculate leakage volume. Also, the total number of daily pads used was recorded when applicable. The diaries were analysed and a Continence Index calculated with the following formula and expressed as a percentage: Continence Index ¼ 100 V v ðv l þ V v Þ 2.2.4. Urethral pressure profiles Urethral pressure profilometry (UPP), with cuff inflated and deflated, was carried out at 3 months by using the Brown- Wickham technique.

european urology xxx (2006) xxx xxx 3 Fig. 1 (A) The new artificial urinary sphincter with conditional occlusion showing individual components: (1) urethral occlusion cuff, (2) pressure-regulating balloon, (3) stress relief balloon, (4) pump and valve assembly unit with self-sealing port for pressurisation. (B) Operation of the new AUS: (1) The urethral occlusion cuff is deflated by squeezing the pump unit located in the scrotum, fluid is transferred to the pressure-regulating balloon and the patient can void through the empty cuff. (2) The cuff re-inflates through a slow return valve; rapid re-inflation can be achieved by squeezing the top of the pump unit. The cuff exerts sufficient pressure to maintain continence without compromising the urethral tissues. (3) During periods of raised intra-abdominal pressure, the fluid from the stress relief balloon is transferred to the cuff to provide additional pressure to maintain continence. 2.3. Implantation The new AUS was implanted as a one-piece, sterile device, prefilled to atmospheric pressure with sterile saline. Implantation was carried out under general anaesthesia in the lithotomy position with two incisions: one lower abdominal and one perineal. An indwelling catheter was placed in the urethra for guidance. The urethra was exposed through the perineal incision. A purpose-made disposable trocar was passed subcutaneously from the abdominal to the perineal incision and the cuff passed to the exposed urethral site. The adjustable cuff was positioned comfortably around the bulbar urethra so that it could be gently rotated and secured by a tape, glued with medical grade silicone adhesive and sutured in place for security. The stress relief balloon and regulating balloon were placed through the abdominal incision to sit extraperitoneally at the level of the bladder. The pump unit was then located in the scrotum. At implantation, the device was left at atmospheric pressure until therapeutic pressurisation after recovery from surgery. 2.4. Device pressurisation After the resolution of scrotal swelling and inflammation (approximately 2 4 weeks), patients were recalled to pressurise the AUS. The pressurisation procedure was carried out via the self-sealing port in the base of the pump under strict aseptic conditions. The concave base of the pump was palpated to locate the self-sealing port, which was inter-

4 Table 1 Individual patient average daily leakage volumes (in ml) and Continence Index (%) calculated from 7-day voiding diaries Patient no. Reason Average daily leakage volume (ml) Pre-operative Pressurisation 3-month 6-month 12-month Mean (SD) p value Mean (SD) p value Mean (SD) p value Mean (SD) p value Mean (SD) p value 002 TURP 605 (202) 333 (278) Patient removed from study 003 OP 334 (159) 151 (32) 100 (30) 110 (65) 85 (7) 004 TURP 697 (149) 224 (46) Patient removed from study 005 OP 2228 (1068) 0 (0) 0 (0) 0(0) 0 (0) 006 OP 678 (131) 188 (31) 151 (19) 95 (26) 71 (42) 007 OP 1101 (546) 15 (5) 27 (11) 17 (6) 009 OP 85 (30) 40 (9) 38 (27) 47 (46) 010 Trauma 011 OP 437 (136) 137 (45) 228 (5) 261 (74) 87 (22) Mean (SD) 770 (659) 207 (78) Patient no. Reason Average Continence Index (%) Pre-operative Pressurisation 3-month 6-month 12-month Pads Mean Pads Mean p value Pads Mean p value Pads Mean p value Pads Mean p value 002 TURP 4 63.3 2 72.8 Patient removed from study 003 OP 86.1 94.4 96.6 95.6 97.4 004 TURP 4 46.2 3 85.4 Patient removed from study 005 OP 7.2 99.8 100.0 99.9 99.9 006 OP 3 50.2 2 87.2 2 87.0 2 91.6 2 93.7 007 OP 39.8 98.3 98.2 99.1 99.0 009 OP 2 95.4 1 98.7 1 97.6 1 98.3 1 97.9 010 Trauma 25.0 98.1 98.8 011 OP 5 72.5 4 85.6 4 87.5 4 87.10 2 94.5 89 (88) 88 (94) 51 (36) european urology xxx (2006) xxx xxx Mean (SD) 3.6 53.9 (28.5) 2.4 91.1 (9.1) 2.0 94.5 2.3 95.3 (5.0) 1.6 97.3 (2.4) SD = standard deviation; TURP = transurethral resection of the prostate; OP = open prostatectomy. p < 0.05, Statistical significance calculated by using two-tailed Student t test, compared with preoperative values. p < 0.01, Statistical significance calculated by using two-tailed Student t test, compared with preoperative values. p < 0.001, Statistical significance calculated by using two-tailed Student t test, compared with preoperative values.

european urology xxx (2006) xxx xxx 5 rogated percutaneously with a 23-G short needle. To increase the device pressure, we injected a known volume of sterile saline through the port to raise the pressure to a predetermined level. If necessary, additional fluid was added to optimise continence at a later date. 2.5. Data analysis Statistical comparisons were made with a paired, two-tailed Student t test with a significance level of p < 0.05 at the 95% confidence limit. 3. Results 3.1. Implantation Nine male patients were implanted with the device, and implantation and recovery were uneventful. The procedure was simplified because of the onepiece nature of the device and took 30 40 minutes. Mean inpatient hospital stay was 4 days; all patients were discharged on demonstrating the ability to empty the bladder by either spontaneous voiding or intermittent catheterisation. 3.2. Device pressurisation Device pressurisation was carried out 2 4 weeks after implantation. In three patients, it was decided that pressurisation was unnecessary, as sufficient fluid had been replaced at implantation to provide satisfactory continence (005, 007, 010). Two patients underwent a single-device pressurisation (004, 009), and three patients underwent additional device pressurisations to further improve continence (003, 006, 011). Patients were instructed on how to operate the pump to deflate the cuff and enable voiding. Fig. 2 Bar chart showing mean (WSD) volume intake, voided and leakage over a 7-day period before implantation, after pressurisation and at follow-up investigations for all patients. Paired Student t test performed on leakage data; p < 0.05. calculated for each patient (Table 1; Fig. 2) and a Continence Index derived. At each follow-up visit, all patients showed a statistically significant decrease in leakage volume after implantation of the new AUS. At 12 months post-implantation, there was an 85% reduction in the mean leakage volume from 770.6 (659.7) ml to 51.7 (36.4) ml. Before implantation, there was a wide range in the mean Continence Index from 7.2% to 95.4%. Post-implantation all patients showed a statistically significant increase in the Continence Index at 3, 6 and 12 months (Table 1; Fig. 3). The mean Continence Index before implantation was 54.0%, which increased to 97.3% at the end of 12 months, representing an increase of almost 100%. Before implantation, five of the nine patients used pads to manage incontinence. However, at 12 3.3. Cystometry and flow rates The implantation of the new AUS had no statistically significant effect on bladder capacity or flow rate. The mean (SD) pre-operative bladder capacity was 504.8 (143.6) ml; at 12 months, it was 545.8 (47.5). The mean pre-operative flow rate was 15.1 (7.4) ml/s; at 12 months, it was 22.2 (4.8) ml/s. None of the patients demonstrated bladder overactivity or any other adverse effect after AUS implantation. 3.4. Continence voiding diaries Eight of nine patients provided a satisfactory set of voiding diaries that could be analysed for each visit (patient 010 did not provide a complete set). The average volume intake (V i ), volume voided (V v ) and volume leaked (V l ) over the seven-diary period were Fig. 3 Continence Index derived from 7-day voiding diaries for all patients. Individual points represent mean (and SD) of Continence Index at pre-implantation, activation and postimplantation investigations for all patients. Paired Student t test; p < 0.01.

6 european urology xxx (2006) xxx xxx months, only three of the patients were still in the trial. Average pad usage in these patients changed from 3.3 per day to 1.6 per day at 12 months. 3.5. Urethral pressure profiles Urethral pressure profiles were carried out in seven patients. The intra-urethral cuff pressure was derived by taking the peak cuff pressure and subtracting the baseline urethral pressure. The mean (SD) intra-urethral cuff pressure measured post-implantation was 39.4 (14.7) cmh 2 O. 3.6. Adverse events Implants were removed in two patients; the first patient (002) never achieved satisfactory continence despite four pressurisation injections in the device. After magnetic resonance imaging (MRI) visualisation of the device, it was found that the cuff fixation had come undone and therefore no pressure was being applied to the urethra; the whole device was removed at the end of 8 weeks. The second patient (004) had satisfactory continence at the 3-month follow-up. He complained of sudden return of incontinence after lifting of heavy weight. The device was removed; on investigation it was discovered that there was a fracture at the joint between the tubing and the cuff. The manufacturing process has been changed subsequently to strengthen this joint. After these initial problems were rectified, there were no further adverse events associated with the new AUS. 4. Discussion The new AUS was developed to provide an alternative implantable device for effective control of stress incontinence. Nine male patients received the device and were followed for a minimum period of 12 months with the longest follow-up being 60 months. The results of the preliminary clinical investigation into the safety and efficacy of the device at the end of 12 months are reported in this paper. The implantation of the new AUS was quick and simple because of the one-piece assembly. This design minimised implant handling and priming time, and potentially reduced the risk of perioperative infection, improving overall implant survival time. Urethral erosion and atrophy are well-known problems associated with the use of artificial urinary sphincters; these problems have been attributed to the sustained high occlusion pressures exerted around the tissues of the urethra [9,10]. Previous studies have shown that pressures in excess of 40 cmh 2 O can compromise the blood perfusion in the urethra of healthy male volunteers [11]. The stress relief facility with conditional occlusion in the new AUS was designed to overcome the necessity of having sustained high urethral occlusion pressures to maintain continence. The stress relief balloon adds increased pressure to the urethral cuff in response to raised intra-abdominal pressures over and above the resting cuff pressure. This facility allows the device to be operated at a lower regulated pressure for the majority of the time, potentially reducing the incidence of urethral atrophy and erosion. The mean urethral pressure measured in the patients in this study was below 40 cmh 2 O. Longer-term studies will enable evaluation of this property more fully. The principal clinical outcome of the present study was continence. The most commonly used outcome measure in studies relating to the performance of the AUS devices is pad usage [2,3]. The type of pad used or criteria for changing were not clarified, making it an imprecise measure of continence. The Continence Index and leakage volumes described in the present study were derived from data collated from voiding diaries. This approach provided a more objective measure of clinical outcome after implantation of an AUS device. We have also recorded pad usage, but, as not all of the patients used pads to manage incontinence, the results of pad usage in the present study are not representative of the whole group. The mean Continence Index before implantation was 54.0%; at 12 months post-implantation, it was 97.3%, corresponding to an almost 100% improvement in the continence status of the patients with the new AUS. At 12-month follow-up, 83% of patients in the current study achieved a Continence Index greater than 97% and could be described as dry or substantially dry. These continence levels are similar to those reported with the AS-800 device [12] in which 73% of patients were dry or substantially dry and 88% showed improvement. The pressure in the new device was set 2 4 weeks post-operatively by injection of sterile saline into the self-sealing port in the base of the pump unit. Operating in the initial region of the pressurevolume curve of the regulating balloon, where pressure and volume are dependent, made it possible to adjust the pressure of the device by injection or removal of fluid. The device pressure can therefore be titrated against continence for each individual patient, removing the need to select a specific pressure range before operation. The device has the additional advantage of allowing this procedure to be

european urology xxx (2006) xxx xxx 7 repeated a number of times to optimise continence through the self-sealing port. The new artificial sphincter does not contain a radio-opaque solution and therefore cannot be imaged under plain X-ray radiography. However, use of MRI techniques has proved successful for viewing the device in situ [13]. The three-dimensional reconstruction also may be useful for determining the success of the design of the new cuff by enabling detailed imaging of its profile. The balloons also can be imaged by using ultrasound, and measurements can be taken to determine device pressure. The new cuff was moulded on a circular form to reduce potential stress fractures caused by creasing. Although at present this study is limited to the nine patients with the longest standing implant at 60 months, there have been no problems with failures of the cuff (excluding the patient whose cuff became undone because of improper fixation at surgery). 5. Conclusions We have described the preliminary clinical results of a new artificial urinary sphincter with conditional occlusion in the treatment of urodynamically proven stress incontinence in a group of male patients. The results show that this device can provide significant improvements in continence with an 85% reduction in leakage volumes and up to 100% improvement in the Continence Index. Implantation was quick and technically less demanding with no serious adverse events associated with the device. This new AUS provides adjustability in regulating pressure in situ, which may reduce the need for surgical revision. This preliminary study has shown significant improvements in continence in this group of patients. Now that CE mark approval has been granted, the device can be used more widely, allowing longer-term studies of efficacy and long-term survival, as well as comparison with other similar devices. Conflicts of interest This project was funded by the LINK Medical Implants Programme sponsored by the Department of Health and the Department of Trade & Industry, UK. It was carried out with two partners; Barloworld Scientific Limited, Stone, UK (who manufactured the implants) and Isotron plc, Swindon, UK (who sterilised the implants using gamma irradiation). References [1] Scott FB, Bradley WE, Timm GW. Treatment of urinary incontinence by an implantable prosthetic urinary sphincter. J Urol 1974;167:1125 9. [2] Venn SN, Greenwell TJ, Mundy AR. The long-term outcome of artificial urinary sphincters. J Urol 2000;164:702 6. [3] Scott FB. The artificial urinary sphincter. Experience in adults. Urol Clin North Am 1989;16:105 17. [4] Hajivassiliou CA. The development and evolution of artificial urethral sphincters. J Med Eng Technol 1998; 22:154 9. [5] Hajivassiliou CA. A review of the complications and results of implantation of the AMS artificial urinary sphincter. Eur Urol 1999;35:36 44. [6] Maillet F, Buzelin J-M, Bouchot O, Karam G. Management of artificial urinary sphincter dysfunction. Eur Urol 2004;46:241 6. [7] Hussain M, Greenwell TJ, Venn SN, Mundy AR. The current role of the artificial urinary sphincter for the treatment of urinary incontinence. J Urol 2005;174:418 24. [8] Craggs MD, inventor. Prosthetic sphincter device. UK patent [135308]. 1992. [9] Garcia-Montes F, Knight SL, Mundy AR, Craggs MD. The significance of low urethral blood flow in recurrent incontinence in patients with a long standing artificial urinary sphincter. Neurourol Urodyn 1999;18:394. [10] Hajivassiliou CA, Finlay IG. Uneven pressure application by the artificial urinary sphincter: an explanation for tissue ischaemia? BJU Int 1999;83:416 9. [11] Garcia-Montes F, Knight SL, Mundy AR, Craggs MD. Effects of artificial urinary sphincters on urethral blood perfusion measured with laser Doppler flowmetry. Eur Urol 1999; 35:16. [12] US Food and Drug Administration, Center for Devices and Radiological Health. AMS Sphincter 800 TM Urinary Prosthesis - P000053, summary of safety and effectiveness. Available from: http://www.fda.gov/cdrh/pdf/p000053b.pdf. [13] Deng J, Hall-Craggs MA, Craggs MD, et al. Three dimensional magnetic resonance imaging of the male urethrae with implanted artificial sphincters: initial results. Br J Radiol. In press.