FOR PERSONAL USE ONLY

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1 Urodinamica 16: , 2006 Epidemiological application of the condom catheter method for non-invasive urodynamics S. de Zeeuw, J.W.N.C. Huang Foen Chung, and R. van Mastrigt Department of Urology, sector Furore, Erasmus MC, Rotterdam, the Netherlands Correspondence Ron van Mastrigt, Department of Urology, sector Furore, Room Ee1630, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands. ABSTRACT. The condom catheter method for non-invasive urodynamics is applied in an ongoing epidemiological study on compensation and decompensation of the urinary bladder male volunteers are non-invasively studied 3 times in five years. The first two of these three evaluations have presently been completed. Intermediate analyses have shown that the recruited population was not urologically different from the general population, and that the reproducibility of the method was comparable to that of invasive urodynamics. Cross-sectional relations with IPSS, abdominal ultrasound estimated prostate volumes, volume dependence of the measured pressure and residual urine values were also analysed. Urodinamica 16: , 2006 INTRODUCTION The development of the condom catheter method for non-invasive measurement of bladder pressure has been described in another contribution to this issue (1). Apart from its application in the clinical setting, for instance for diagnosing and grading infravesical obstruction, the method also enables epidemiological urodynamic studies in volunteers which are not, or hardly, possible using invasive urodynamic methods. For this purpose we developed a set up for large scale application of the method. We apply this set up in a study on changes in urethral resistance and urinary bladder contractility as a function of age related prostatic enlargement. SET UP FOR LARGE SCALE APPLICATION OF CONDOM CATHETER METHOD FOR NON-INVASIVE URODYNAMICS Figure 1 shows the key elements of the set up. Modified inconti- 279

2 S. de Zeeuw, J.W.N.C. Huang Foen Chung, and R. van Mastrigt nence condoms (Rochester Medical Corp ) are connected to a modified disposable pressure dome attached to a reusable Statham pressure transducer. The dome has three metal outflow conduits, with different calibre. Tubing is attached to the outflow conduits, and is led through three pneumatic valves that enable closure of the tubes by compression. The tubes drain into a Dantec urinary flowmeter. By opening and closing the valves in different combinations, 8 different levels of outflow resistance can be applied, including a condition in which all valves are closed and flow through the system is effectively interrupted. The valves are controlled by a modified Andromeda Medical Systems urodynamic unit, which also records the urinary flowrate and pressure. Figure 2 shows an example of a measurement done with this setup. After the onset of voiding, the outflow resistance was increased by closing some valves. As a result the condom pressure rose to approximately 15 cmh 2 O. Subsequently all valves were closed and pressure rose to an equilibrium of 125 cmh 2 O. At this point there was no flow through the urethra so that this pressure represents the isovolumetric bladder pressure. Subsequently some valves were opened and flow re-established. The interruption was repeated several times, and the highest measured pressure (excluding artefacts) was considered a measure for the urinary bladder contractility. Figure 1 - The main parts of the condom catheter measurement system: a modified incontinence condom, a dome with three metal outflow conduits, and a reusable pressure transducer. Only two of the three outflow conduits are visible. AIM OF NON-INVASIVE EPIDEMIOLOGICAL STUDY With increasing age, the prostate of most men enlarges (BPE, Benign Prostatic Enlargement). In response to the increasing resistance to urinary flow caused by the enlarging prostate, the pressure generated by the bladder during voiding increases. This is called compensation of the bladder muscle. The occurrence of compensation has been disputed, but it has been demonstrated in our animal model (2). A subsequent decompensation phase is undisputed. In the decompensation phase, the urinary bladder is damaged to such a degree that effective bladder emptying is not possible anymore, even when the obstruction is relieved. However, the onset of this phase is poorly defined and no data is available on its reversibility. To make it possible to base therapeutic decisions in BPE on the prognosis of changes in the bladder wall we are studying the time course of these changes. As BPE develops over a very long period of time, such a study makes it necessary to regularly evaluate a group of (otherwise) healthy males during 40 years (ages 40-80). We have chosen a more practical implementation by following a number of age stratified cohorts during a shorter period. 8 cohorts, with initial ages of 38-42, 43-47, 48-52, 53-57, 58-62, 63-67, 68-72, and have been recruited. Each cohort will be followed for five years, so that the age of each cohort of volunteers at the end of the study matches that of the next cohort at the start of the study. Each cohort is non-invasively studied three times: at recruitment, after 2.5 years, and after 5 years. Presently, two of these evaluations have been completed. 280

3 A non-invasive epidemiological study Pcond cmh 2 O Qura ml/s Vura ml tmin:s 0:05 0:05 0:15 0:20 0:25 0:30 0:35 0:40 0:45 0:50 0:55 1:00 1:05 1:10 1:15 1:20 1:25 Figure 2 - An example of a condom catheter measurement. The upper trace shows the pressure measured in the condom, the middle trace the urinary flowrate, and the bottom trace the voided volume. The numbered flags indicate the position of the valves in a binary code. 0 means all valves are open, outflow resistance is minimal; 7 means all valves are closed, effectively interrupting the urinary flow. Intermediate values offer intermediate resistance to flow. RESULTS OF THE FIRST EVALUATION ROUND: RECRUITMENT, REPRODUCIBILITY, RELIABILITY, RESISTANCE AND RANGES Recruitment Figure 3 shows a flowchart of the recruitment of the male volunteers, and the first evaluation round. 11,914 Males aged 38-77, mentally and physically able to complete a voiding diary and to visit the outpatient clinic were invited, mainly by general practitioners (GP s) in the community of Schiedam, near Rotterdam, between November 2001 and December Written informed consent to participate in the study was obtained. The Medical Ethical Committee of Erasmus MC approved the study. Exclusion criteria were: unable to urinate in a standing position, previous lower urinary tract surgery, congenital disease of the lower urinary tract, use of med- 281

4 S. de Zeeuw, J.W.N.C. Huang Foen Chung, and R. van Mastrigt Direct invitation by 15+3 GP s (2/15 repeated) n=6349 Indirect invitation by 7+3 GP s Publicity + n= >> to colleagues AZR n=1560 =11914 Response Response Response Response n=593 (9%) n=543 (14%) n=61 n=36 (2%) Made appointment at Erasmus MC n=1233 (10%) No show Presentation at the Urological outpatient clinic, Erasmus MC n=1162 (94%) Eligible for free flowrate measurement n=1106 (95%) Succesful free flowrate measurement n=1094 (99%) Eligible for condom pressure measurement n=1073 (98%) First attempted condom pressure measurement succesful n=934 (87%) At least one attempt successful n=1020 (95%) Haematuria 67 (7%) ever Condom leakage 115 (11%) ever 38 (4%) last measurement n=71 (6%) Exclusion criteria (repeated) n=56 (5%) Unable to void or other failure n=8 (1%) Flow rate too small or other problem n=21 (2%) Unable to void through condom or measurement failure n=53 (5%) Repeated condom leakage, technical problems, no more time Two or more successful condom pressure measurements n=53 (5%) n=967 (90% of volunteers eligible for condom measurement) RvM Figure 3 - Flowchart of recruitment of the volunteers and first evaluation round. ication or other interventions for lower urinary tract symptoms, other diseases that could alter urinary function (e.g. Parkinson, CVA, DM, kidney failure, bladder/prostate cancer, current urinary tract infection) and heart failure (the volunteers had to drink a lot of water to fill the bladder between voidings). Later, volunteers using anticoagulants were 282

5 A non-invasive epidemiological study also excluded as we found that in 7% of the volunteers slight, self terminating haematuria occurred after/during the non-invasive measurements volunteers made an appointment at the outpatient clinic of Erasmus MC. Repeated application of the exclusion criteria, and exclusion of those who could not void in the presence of the investigator resulted in 1094 volunteers who underwent free flow rate measurement. Those with a maximum flow rate less than 5 ml/s were subsequently excluded (3) resulting in 1073 volunteers eligible for condom catheter measurements. In 1020 (95%) of them at least one succesful non-invasive measurement was done. Factors influencing the recruitment of the volunteers were analysed (4), and the recruited population was compared to another, proven representative population. It was concluded that the recruited population was not urologically different from the general population. Reproducibility In 967 volunteers two (or more) condom pressure measurements were done in the first evaluation round. The reproducibility of the method was analysed using the method of Bland and Altman (5). Figure 4 shows the difference between the two pressure measurements plotted as a function of the mean of those two. As the difference was independent of the mean, the standard deviation could be used as a measure for the reproducibility of the non-invasive method. This standard deviation was 18 cmh 2 O (6). For lack of a standard to decide if this reproducibility is good or bad, we developed a method for comparing the reproducibility of different methods for clinical measurement (7). We normalised the standard deviation of differences between two measurements by dividing it by the difference of the 97.5 and the 2.5 percentile of the mean of those two measurements, resulting in a relative standard deviation of This reproducibility was comparable to, or slightly better than, that of pressure-flow parameters derived from a comparable population of patients studied with conventional invasive urodynamic methods. Reliability: The volume dependence of condom pressure measurements As illustrated in Figure 2, voiding was usually interrupted several times during the noninvasive measurement. In a small group of volunteers it was established that the interruption did not influence the remainder of the voiding (8). In the present study, the (bladder) volume dependence of the measured condom pressure was studied (9). It was found that there is an optimum bladder volume for isovolumetric pressure measurements, averaging 264±122 ml (mean±standard deviation). Measurements should be taken at or above the optimum volume. At volumes below the optimum volume the pressure decreases by approximately 5% for each 10% of volume decrease. At bladder volumes smaller than 247 ml pressure readings in 50% of subjects are suboptimal. The optimum volume for isovolumetric pressure generation was only marginally related to voiding diary parameters. Probably it represents : n=967 Difference in pressure [cmh 2 O] -60 Average pressure [cmh 2 O] Figure 4 - Reproducibility of condom catheter measurements in first evaluation round. The difference between two condom pressure measurements in one session was plotted as a function of the mean of those two values. 283

6 S. de Zeeuw, J.W.N.C. Huang Foen Chung, and R. van Mastrigt mechanical properties of the bladder, whereas voiding diary parameters more likely represent neurophysiological properties, such as sensory thresholds. However, the optimum volume does not reflect the optimum (smooth) muscle length for force generation of the bladder wall: during normal voiding bladder smooth muscle always operates at a suboptimal length for force generation. Resistance of the urethra In a separate analysis, an approximation of the urethral resistance was estimated from the maximum condom pressure and the maximum free flow rate (measured separately) in 667 of the volunteers (10). Twenty-eight percent (185/667) of them had a high non-invasively estimated urethral resistance, and these volunteers had a significantly higher IPSS (7.3±5.2) (mean±sd) than those with a low urethral resistance (IPSS: 5.7±4.6), Mann- Whitney U-test: p< IPSS and urethral resistance were significantly correlated, Spearman s rho 0.20, p< The prostate volumes, 36±21 cm 3 in the high resistance vs 33±17 cm 3 in the low resistance group, did not differ significantly, p=0.18. It was concluded that an elevated urethral resistance is a necessary, but not a sufficient condition for lower urinary tract symptoms (LUTS). Range of prostate volumes, pressures and flowrates We also estimated the range of prostate volumes as a function of age in the asymptomatic males in the study (11). From the 1020 volunteers included in the first evaluation round 827 had an IPSS<10. These were considered asymptomatic. Figure 5 shows a box and whisker plot of the prostate volumes, measured by transabdominal ultrasound. The age distribution of the prostate volumes is best described by stating that the range of the prostate volumes increased with age. Between the ages of 38 and 77, the 5th percentile of these volumes increased from 11 to 24 ml, whereas the 95th percentile increased from 43 to 83 ml. Conversely the 5th percentile of the maximum flowrates decreased from 8 to 5 ml/s, whereas the 95th percentile decreased from 43 to 30 ml/s. These two changes were significant according to analysis of variance (p<0.005). The isovolumetric bladder pressure did not significantly depend on age (p=0.75), it ranged from approximately 50 to 160 cmh 2 O in all age groups. In this crosssectional analysis bladder compensation may have been obscured by age dependent bladder muscle degeneration, as observed in females (12). That will be tested in the longitudinal analysis. RESULTS OF THE SECOND EVALUATION ROUND: REPETITION AND RESIDUAL VOLUME Repetition Figure 6 shows a flowchart of the second evaluation round. The 1020 volunteers that had at least one successful non-invasive measurement in the first round were invited for a prostate volume [ml] age Figure 5 - Box and whisker plot of the prostate volumes of 827 asymptomatic males as a function of the mean age of each group, in the first evaluation round. The whiskers indicate the 5% and 95% percentiles, the box contains 50% of the measured values, the line in the box indicates the median value. 284

7 A non-invasive epidemiological study Invited by letter: subjects with at least one successful condom pressure measurement in first evaluation and no complications: n=1020 Deceased n=6 (1%) Opted out n=117 (11%) Medically excluded n=96 (9%) Eligible n=801 (79%) Successful second evaluation No response, address has to be verified, telephone reminder, contact gp or contact civil administration n=41 (4%) Appointment has been postponed to later date by subject n=23 (2%) Technical problems n=1 (0%) n=736 (72%) Figure 6 - Flowchart of the second evaluation round. second evaluation. A total of 219 volunteers did not make a second appointment at the outpatient clinic of Erasmus MC: 1% was deceased, 11% refused further participation for personal, non-medical reasons and 9% was excluded from further participation based on medical exclusion criteria. Thirty-nine of them had urological problems and 57 were excluded for other medical reasons, mostly the use of anticoagulants and heart problems. Four percent of the remaining 801 volunteers did not respond to the second invitation and addresses have to be verified to contact the volunteers for a new appointment. 736 volunteers underwent a successful noninvasive examination with at least one successful condom pressure measurement. Twenty-three volunteers postponed the appointment and still have to visit the outpatient clinic. Residual volume Post-void residual (PVR) urine volume is a well-known urodynamic parameter, although its reliability and usefulness have been questioned. In the largest part of the second evaluation round, PVR volume was measured using transabdominal ultrasound immediately after each voiding to study the influence of the condom catheter measurements on bladder emptying. The protocol was similar to the protocol used in the first round: volunteers 285

8 S. de Zeeuw, J.W.N.C. Huang Foen Chung, and R. van Mastrigt Post Void Residual Volume (ml) Free Voiding First Condom Second Condom Measurements Measurements had to void 1 time in a flowmeter to determine the maximum urinary flow rate and then underwent two condom catheter measurements for measurement of the isovolumetric bladder pressure. In 149 volunteers, PVR volume after free voiding with a voided volume of 375±192 ml (mean±sd), was 36 ml [8-74] (median [IQR]). After the two condom measurements PVR volume was significantly increased to 63 ml [37-120] and 83 ml [43-147], respectively (Wilcoxon Rank test, both p<0.01, Fig. 7). There are several possible explanations for this doubling in PVR volume. To test these hypotheses groups of subsequent volunteers in the second evaluation round were subjected to slightly modified protocols. According to the standard protocol, voiding was interrupted as many times as feasible during the bladder pressure measurements. We hypothesized that these involuntary interruptions could influence the performance of the bladder and result in incomplete emptying of the bladder. When the measurements were stratified into those with 3 or less interruptions, and those with more than 3, no difference in PVR volume after the first condom catheter measurement was found (52 [30-108] vs 71 [42-133], respectively, Mann-Whitney U-test, p=0.191). After the second condom catheter measurement, 4 or more interruptions resulted in a significantly larger PVR (70 [40-138] vs 105 [57-167], respectively, Mann- Whitney U-test, p=0.048). However, when more interruptions are made this is usually because the voided volume is larger so that the voiding takes longer. When the voided volume was taken into account, analysis of variance showed no significant influence of the number of interruptions of voiding. Thus, the number of interruptions had no influence on PVR volume. A second possible reason for increased PVR volume after condom catheter measurements is that the volunteers have to void three times in a very short period (2-3 hours). The rapid filling of the bladder and the increased voiding frequency could exhaust the bladder muscle and result in less effective emptying at the end of the protocol. Therefore, the subsequent 103 volunteers were asked to start with the two condom measurements and do the free voiding at the end of the protocol. PVR volume after free voiding was not significantly different when free voiding was done as a first or last test (36 ml [8-74] vs 30 ml [6-71], respectively, Mann Whitney U-test, p=0.778), suggesting that the bladder was not exhausted during the protocol and could still empty effectively at the end of the session (Fig. 8). Thirdly, to decrease the waiting time during the examination, diuresis was forced by drinking almost 1.5 liter fluid within a few hours. Although forced diuresis does not alter uroflowmetric parameters like maximal flow rate and voiding volume (13), in one Figure 7 - Box and whisker plot (see legend Fig. 5) of the post-void residual volume (ml) after the free voiding, and the two condom catheter measurements in the 149 volunteers. During the condom catheter measurements the number of interruptions of voiding was unlimited. Statistical significance was tested using Wilcoxon Rank test, *p<0.05 vs Free Voiding. * * 286

9 A non-invasive epidemiological study Post Void Residual Volume (ml) Post Void Residual Volume (ml) * 0 Free voiding first (n=149) Free voiding last (n=103) Figure 8 - Box and whisker plot (see legend Fig. 5) of the post-void residual volume (ml) after free voiding. In the left box (n=149) the free voiding preceded the two condom catheter measurements. In the right box (n=103) free voiding was done after the condom catheter measurements. Statistical significance was tested using Mann- Whitney U-test, *p<0.05 vs Free Voiding First. study PVR volume was found to be larger after increased water load diuresis (14). Therefore, in the above-described group of 103 volunteers who did the free voiding at the end of the measurement session, the fluid intake before the first voiding (condom measurement 1) was noted. If a volunteer had not been drinking extra fluid to increase diuresis before the first voiding, this was noted as normal fluid intake. If extra fluid was taken at home to increase diuresis or when the volunteer started drinking the extra fluid in the outpatient clinic before the first voiding, it was noted as increased fluid intake. Figure 9 shows that when diuresis was forced by increased fluid intake PVR volume after the condom catheter measurement was significantly larger than when diuresis was normal (56 ml [24-126, n=82] vs 21 ml [2-76, n=20], respectively, Mann-Whitney U-test, p=0.032). 0 Normal fluid intake (n=20) CONCLUSIONS In conclusion, during condom catheter measurements both the involuntary interruption of voiding and the forced diuresis increase PVR volume. However, the ineffective emptying is not caused by bladder exhaustion during the examination and seems independent of the number of interruptions. The increase in PVR volume does not affect the accuracy of the bladder measurements, but PVR volume measured after condom catheter measurements should not be used as a diagnostic parameter. ACKNOWLEDGEMENTS Increased fluid intake (n=82) Figure 9 - Box and whisker plot (see legend Fig. 5) of the post-void residual volume (ml) after the first condom catheter measurement (n=103). In this group the condom catheter measurements were done first, before the free voiding. If a volunteer had not been drinking extra fluid to increase diuresis before this voiding, this was noted as normal fluid intake (n=20). If extra fluid was taken at home to increase diuresis or when the volunteer started drinking the extra fluid in the outpatient clinic before the first voiding, it was noted as increased fluid intake (n=82). The fluid intake of one volunteer was not noted. Statistical significance was tested using Mann-Whitney U-test, *p<0.05 vs Normal Fluid Intake. The epidemiological study was financed by the Dutch Kidney Foundation, grants PC85 and C

10 S. de Zeeuw, J.W.N.C. Huang Foen Chung, and R. van Mastrigt REFERENCES 1. Pel J.J.M., Van Mastrigt R.: Development of the condom catheter method for non-invasive measurement of bladder pressure. Urodinamica. 16: , Kok D.J., Wolffenbuttel K.P., Minekus J.P., et al.: Changes in bladder contractility and compliance due to urethral obstruction: a longitudinal followup of guinea pigs. J. Urol. 164: (discussion 1025), Pel J.J.M., van Mastrigt R.: A flow rate cut-off value as a criterion for the accurate non-invasive measurement of bladder pressure using a condom-type catheter. Urol. Res. 31: , Avagyan V., van Mastrigt R., Huang Foen Chung J.W.N.C., et al.: A longitudinal non-invasive study of changes in urinary bladder contractility secondary to benign prostatic hyperplasia: epidemiological aspects. Urol. Int. 77: , Bland J.M., Altman D.G.: Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1: , Huang Foen Chung J.W.N.C., Bohnen A.M., Pel J.J., et al.: Applicability and reproducibility of condom catheter method for measuring isovolumetric bladder pressure. Urology 63: 56-60, van Mastrigt R., Huang Foen Chung J.W.N.C.: Comparison of repeatability of non-invasive and invasive urodynamics. Neurourol. Urodyn. 23: , Rikken B., Pel J.J., van Mastrigt R.: Repeat noninvasive bladder pressure measurements with an external catheter. J. Urol. 162: , van Mastrigt R., Huang Foen Chung J.W.N.C.: Bladder volume sensitivity of non-invasively or invasively measured isovolumetric intravesical pressure. Neurourol. Urodyn. 25: , Huang Foen Chung J.W.N.C., van Mastrigt R.: Correlation of non-invasive urodynamics with International Prostate Symptom Score (IPSS) and prostate volume. Neurourol. Urodyn. 24: 25-30, van Mastrigt R., Huang Foen Chung J.W.N.C.: Compensation and decompensation of the urinary bladder muscle studied non-invasively in 827 asymptomatic healthy males. J. Biomech. 39 (Suppl. 1): S391, van Mastrigt R.: Age dependence of urinary bladder contractility. Neurourol. Urodyn. 11-4: , Ozturk B., Cetinkaya M., Oztekin V., et al.: Effects of forced diuresis achieved by oral hydration and oral diuretic administration on uroflowmetric parameters and clinical waiting time of patients with lower urinary tract symptoms. Urol. Int. 71: 22-25, Alivizatos G., Skolarikos A., Albanis S., et al.: Unreliable residual volume measurement after increased water load diuresis. Int. J. Urol. 11: ,