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Keywords:

  • benign prostatic enlargement;
  • bladder contractility;
  • compensation;
  • condom catheter;
  • decompensation;
  • isovolumetric bladder pressure;
  • non-invasive

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Aim

To non-invasively study if compensation and decompensation occurs in the urinary bladder of healthy male volunteers in response to benign prostatic enlargement (BPE) using the condom catheter method.

Methods

Between 2001 and 2010, 1,020 healthy male volunteers were included in a longitudinal study based on three non-invasive urodynamic examinations during a 5-year follow-up. Inclusion criteria were an informed consent, the ability to void in a normal standing position and a minimum free flow rate of 5.4 ml/sec. Study parameters were prostate volume (PV), maximum free urinary flow rate (Qmax) and bladder contractility, quantified by the maximum isovolumetric bladder pressure, measured in the condom (Pcond.max). Volunteers also completed the International Prostate Symptom Score Form (IPSS).

Results

Within limitations, the included volunteers had a flat age distribution between 38 and 72 years. This made it possible to combine longitudinal analysis in a 5-year observation interval, with cross sectional analysis in a 35-year age range. Longitudinal analysis showed that with increasing age, PV increased with 1.9% per year, whereas Qmax decreased with 1.1% per year. IPSS increased with 1.1% per year when volunteers were older than 55 years. Pcond.max increased during the 5-year longitudinal follow-up, but not in the cross sectional analysis.

Conclusions

The difference between cross sectional and longitudinal results of the Pcond.max may have been caused by compensation of the urinary bladder resulting in a selection effect. This would imply that compensation is a relatively fast process, taking approximately 5 years. Neurourol. Urodynam. 33:78–84, 2014. © 2013 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Benign prostatic enlargement (BPE) is an age-related process with a clinical prevalence of almost 50% for men in their 50s, frequently eventually resulting in bladder outlet obstruction (BOO).[1]

Numerous community-based studies have described the age dependence of BPE, but only a few of these are longitudinal studies and none of these have measured the urinary bladder response to the increasing urethral resistance.[2-7] Two urinary bladder responses have been hypothesized, that is, compensation of the bladder muscle, or decompensation which might be related to irreversible bladder damage and urinary retention.[8] The most important reason for the lack of information on the urinary bladder response to increased urethral resistance is that until about 10 years ago invasive pressure flow studies were needed to quantify bladder contractility. These measurements are patient unfriendly, expensive, time consuming, and not without morbidity.[9] With the recently developed condom catheter method[9-14] the isovolumetric bladder pressure, which is a direct measure for one aspect of the bladder contractility,[15] can be determined non-invasively. We have applied this method in a longitudinal study on 1,020 healthy male volunteers to study if compensation and decompensation occur in the urinary bladder in response to BPE.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Study Design

Between November 2001 and February 2010 we performed a longitudinal study in healthy male volunteers (not a blinded study), approved by the local Medical Ethical Committee of the Erasmus MC Rotterdam, the Netherlands. General practitioners in the municipality of Schiedam invited all male patients that satisfied the inclusion and exclusion criteria by letter. Male volunteers responding to publicity by the main sponsor of the study, the Dutch Kidney Foundation, also took part in the study, as well as employees of the Erasmus Medical Center who were invited by email.[12] The volunteers were included if: they were aged between 38 and 77 years, had signed an informed consent form and were able to continuously void in the standing position (independent of patients' preferred voiding position). They were excluded if they had congenital disease of the lower urinary tract, used medication or had had other interventions (e.g., surgery) for lower urinary tract symptoms, other diseases that could alter urinary function [e.g., Parkinson, cerebral vascular accident (CVA), diabetic mellitus (DM), kidney failure, current urinary tract infections], heart failure, or used anticoagulants. For the first study round over 10,000 men were invited, of whom 10% made an appointment at the Erasmus MC (n = 1,233). A total of 1,106 volunteers were eligible for a free flow measurement, from which eight could not void in the presence of the researcher. Twenty-one volunteers were excluded because they had a free flow rate that was lower than 5.4 ml/sec and under that condition the maximum condom pressure (Pcond.max) does not accurately reflect the bladder pressure.[11] Eventually, 1,020 male volunteers had at least one successful condom pressure measurement and were invited for the second study round.[16] In the second and third study round, 2.5 and 5 years later, 756 and 603 men successfully underwent at least one condom measurement, respectively. No men were excluded in these rounds because they had a low flow rate. A total of 170 men dropped out for medical reasons, which included treatment for LUTS at the time of the examination (42%). A flow chart of the study is given in Figure 1.

image

Figure 1. Flow chart of the first, second, and third evaluation round, illustrating progress of the study, exclusion of participants and successful measurements.

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The volunteers were stratified into eight age groups of 5 years each, based on their age at inclusion (38–42, 43–47, 48–52, 53–57, 58–62, 63–67, 68–72, and 73–77 years). Approximately the same number of volunteers was included into each age group with the exception of the age group 48–52 years, which was deliberately made larger to allow for a future longer follow-up, and the age group 73–77 years, for which we could not find enough volunteers. In each study round, the volunteers voided three times: once into a uroflowmeter to measure the maximum urinary flow rate (Qmax) and twice through the condom catheter to measure Pcond.max. Voided volume was also recorded (Vvoided). To make the study completely non-invasive, the prostate volume (PV) was determined by transabdominal ultrasonography (3.5 MHz probe, Aloka Model SSD 900).[17] All volunteers also completed the International Prostate Symptom Score form (IPSS), including the quality of life (QoL) score. Obstructive symptoms were determined by adding the outcome of Questions 1, 3, 5, and 6, whereas irritative symptoms were determined by adding the outcome of Questions 2, 4 and 7. All measurements in the first study round were done by the third author of this article, whereas in both the second and third round they were done by the first author. Post processing analysis of the data measured in all three rounds was done by the first author only.

Condom Catheter Measurements

The isovolumetric bladder pressure was measured using the condom catheter method[9-14] implemented on modified Andromeda medical systems® urodynamic equipment.

Volunteers voided through a modified incontinence condom that was connected to a tube, mounted on a reusable Statham® pressure transducer (Fig. 2). The tube had three outflow resistors that could be closed independently by pneumatic valves (not visible in the figure) and drained into a Dantec® rotating-disk flow meter. During voiding the outflow resistance could be varied stepwise by opening and/or closing a combination of the valves. Shortly after the volunteer started voiding, one or two valves were closed to build up a preload pressure in the condom. When all valves were closed (complete interruption of the flow rate), there was an interval in which an open connection still existed between the condom and the bladder via the urethra, and the condom pressure rose to an equilibrium value. It reflects the isovolumetric bladder pressure, which is a measure of one aspect of the bladder contractility. During the interruption of the urinary flow volunteers were instructed to continue voiding without straining. Straining could mostly be identified as a sudden high increase and/or peaks in the pressure signal and/or movement of the volunteer. By repeating the action of closing and reopening the valves several times, the maximum condom pressure (Pcond.max) was determined.

image

Figure 2. Left picture shows the modified incontinence condom connected to a tube with three outflow resistors connected to outflow tubes. Condom pressure was measured using a reusable Statham® pressure transducer connected to the tube. The three outflow tubes could be closed independently by pneumatic valves (not visible in the figure) and drained into a Dantec® rotating-disk flow meter (right picture).

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The pressure transducer was zeroed to the atmosphere prior to each measurement. When two or more condom measurements were done in one patient in one study round, the Pcond.max measured in the last voiding was used for statistical data analysis, as in all study rounds the Pcond.max from the last voiding was significantly higher than the Pcond.max from the previous voiding (Wilcoxon-signed rank test). During the whole study, the condom catheter method as described above did not change.

Data Analysis and Statistics

An analysis program was written in Matlab that displayed the values of the Qmax and Pcond.max for each measurement. In case of an artifact, for example, a spike in the signal, the maximum value of the Qmax and Pcond.max were manually corrected. Correction of the zero line was applied to the condom pressure signal by subtraction of the average pressure in the condom before and after the voiding from the Pcond.max. PV was calculated by making single transversal plane recordings of the largest circumference of the prostate. Volume was then calculated by the prolate spheroid approximation, based on a 3-axis ellipse (L × W × AP × π/6 (cm3)).[17, 18] In each study round PV was measured twice by the same researcher and then averaged.

In the tables, data were expressed as mean ± standard deviation (SD), except IPSS which being non-parametric was presented as median with interquartile range. In the figures, data were presented as mean with 95% confidence interval, except IPSS which was presented as median with 95% confidence interval. Longitudinal analysis was done to study the dependency of the parameters on the three study rounds using mixed model analysis (SAS®). Cross sectional analysis was done to study the dependency of the parameters on the different age groups (based on the age at inclusion) using the Spearman's correlation test (SPSS®). As PV, Qmax, and IPSS were not normally distributed, these parameters were log transformed (base 10) for longitudinal data analysis. Expert advice on study design and statistical data analysis was given by the second author, a statistician. Although several men dropped out of the study, the percentage who dropped out for urological reasons was <7%. Our statistician strongly advised us against including only men that underwent all three examinations.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

In Figure 3, an example of a successfully completed condom pressure measurement is shown. At the onset of voiding, witnessed by an increasing flow rate, the condom pressure was still zero. When one valve was closed (marker 4) to build up a preload pressure, the condom pressure started to rise. When all valves were closed (marker 7), the condom pressure rose to an equilibrium value. Notice that the flow rate was zero at that time. The highest measured condom pressure was used for analysis.

image

Figure 3. An example of a condom pressure measurement. The upper panel represents the condom pressure, the middle panel represents the interrupted urinary flow rate, and the lower panel represents the voided volume. The numbered markers represent the position of the valves in a binary code, that is, 0 means all three valves are open, 7 means all three were closed, etc.

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Table I shows results of longitudinal analysis of all data. IPSS (overall and both obstructive and irritative symptom scores) and Qmax did not change during 5-year follow-up. PV increased significantly from 35 cm3 at inclusion of the study to 37 cm3 after 5 years, whereas Pcond.max increased significantly from 98 ± 32 cmH2O at inclusion of the study to 107 ± 36 and 110 ± 36 cmH2O after 2.5 and 5 years, respectively. Cross sectional analysis of the first study round showed that PV, IPSS, Qmax, and voided volume (Vvoided) were significantly dependent on the age groups, whereas Pcond.max was not (Table II). During the subsequent study rounds the same significant and insignificant dependencies on the age groups were found (not shown).

Table I. Longitudinal Results of All Volunteers in the Three Study Rounds
ParameterRound 1Round 2Round 3P-value
  1. PV, prostate volume; IPSS, symptom score; Qmax, maximum free flow rate; Pcond.max, maximum condom pressure; Vvoided, voided volume.

  2. Data are presented as mean ± SD, except for IPSS, which is presented as median (interquartile range). P-values reflect significant dependency on the study rounds according to mixed model analysis (SAS®).

n1,020756603 
PV (cm3)35 ± 1935 ± 1737 ± 17<0.01
IPSS5 (6)5 (6)5 (5)0.31
IPSS obstructive2 (4)2 (4)2 (4)0.18
IPSS irritative3 (2)3 (3)3 (2)0.47
Qmax (ml/sec)17 ± 817 ± 717 ± 70.13
Pcond.max (cmH2O)98 ± 32107 ±36110 ± 36<0.01
Vvoided (ml)329 ± 181371 ± 190345 ± 177<0.01
Table II. Cross sectional Results From all Three Study Rounds: Mean Prostate Volume, Symptom Score, Maximum Flow Rate, and Isovolumetric Bladder Pressure in Each Age Group
 Study roundAge groupSpearman's rho
12345678
  • PV, prostate volume (cm3); IPSS, symptom score; Qmax, maximum free flow rate (ml/sec); Pcond.max, maximum condom pressure (cmH2O); Vvoided, voided volume (ml).

  • Data are presented as mean ± SD, except for IPSS, which is presented as median (interquartile range).

  • *

    Significant cross sectional dependency of the parameter on the age group at the 0.05 level (two-tailed).

  • §

    P < 0.05 significant difference between age group at study round 1 versus the previous age group at study round 3.

Age at inclusion 38–4243–4748–5253–5758–6263–6768–7273–77 
N111712422812211812712163 
 2959518510184838732 
 384801648366595418 
PV126 ± 928 ± 1030 ± 1133 ± 1638 ± 1940 ± 2250 ± 3048 ± 220.39*
 226 ± 928 ± 1030 ± 1135 ± 1740 ± 1938 ± 2047 ± 2344 ± 200.36*
 327 ± 931 ± 934 ± 1238 ± 1440 ± 1944 ± 2550 ± 2347 ± 200.39*
IPSS14 (5)5 (6)4 (5)6 (6)§6 (6)6 (7)5 (6)6 (5)0.13*
 23 (4)4 (6)4 (4)5 (6)6 (5)6 (6)6 (7)4 (7)0.15*
 33 (4)4 (5)4 (5)6 (7)6 (5)5 (7)5 (10)5 (4)0.19*
IPSS obstructive11 (3)2 (4)1 (4)2 (4)2 (4)2 (4)2 (4)2 (4)0.09*
 21 (3)1 (4)1 (3)2 (5)2 (4)2 (4)2 (5)1 (3)0.10*
 31 (3)2 (3)2 (4)2 (4)2 (3)2 (5)3 (6)2 (3)0.12*
IPSS irritative12 (3)2 (3)2 (3)3 (3)§3 (3)3 (4)3 (3)3 (3)0.14*
 22 (3)2 (3)2 (3)3 (3)3 (3)3 (3)3 (4)3 (4)0.16*
 32 (3)2 (3)2 (3)3 (3)3 (4)3 (3)3 (5)4 (3)0.21*
Qmax122 ± 1018 ± 8§19 ± 817 ± 7§16 ± 715 ± 715 ± 714 ± 6−0.27*
 220 ± 718 ± 818 ± 817 ± 717 ± 715 ± 614 ± 514 ± 6−0.24*
 320 ± 719 ± 719 ± 816 ± 717 ± 714 ± 614 ± 714 ± 5−0.30*
Pcond.max197 ± 3395 ± 32§97 ± 31§97 ± 30§102 ± 33103 ± 32100 ± 3397 ± 330.06
 2112 ± 41108 ± 37108 ± 35100 ± 36109 ± 34110 ± 36104 ± 3892 ± 32−0.07
 3115 ± 36106 ± 34112 ± 37108 ± 36111 ± 35110 ± 38104 ± 35102 ± 34−0.06
Vvoided1382 ± 230342 ± 182340 ± 195§334 ± 169§341 ± 172303 ± 155291 ± 134261 ± 164−0.13*
 2444 ± 240383 ± 186408 ± 215345 ± 144375 ± 166322 ± 157299 ± 121301 ± 165−0.19*
 3389 ± 188396 ± 182383 ± 191318 ± 144327 ± 165269 ± 147263 ± 128236 ± 118−0.28*

The mean outcome and 95% confidence interval of the study parameters were plotted against the age groups for each study round, except IPSS which was, being non-parametric, presented as median with 95% confidence interval (Fig. 4). In the same figure, a regression line was plotted. In the regression equation, the current age was used as a continuous variable instead of age group as an ordinal factor. For plotting, the middle of each age group interval was used as the x-axis value. Thus, for the age group 38–42 years the parameter value predicted was calculated by inserting age = 40 into the regression equation, etc.

image

Figure 4. Prostate volume, symptom score (IPSS), maximum urinary flow rate (Qmax), and maximum condom pressure (Pcond.max) were plotted against the eight groups of age at inclusion. Note that Qmax and Prostate Volume are on a log scale and therefore the means are geometric means. Closed circles represent the first, open triangles the second and closed squares the third study round. Prostate volume, Qmax, and Pcond.max are presented as mean and 95% confidence intervals. IPSS is presented as median and 95% confidence interval. Lines represent regression lines derived by mixed model analysis (SAS®). The relation of prostate volume and Qmax with age could be described by a single regression equation. IPSS did not depend on age when volunteers were younger than 55 years and was described by a single regression equation above 55 years. For Pcond.max, the three horizontal lines represent the three study rounds (study round 1 = drawn line, study round 2 = dotted line, study round 3 = dashed line). Note that prostate volume and Qmax are not normally distributed and therefore shown on a log scale vertical axis.

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Cross sectional analysis of PV showed an increase with increasing age in each study round. Longitudinal analysis showed a small but significant increase from the second to the third study round of 5%. Ignoring this small difference, the relation between PV and age was described by one equation: log(PV) = 0.008 × age + 1.045. With increasing age Qmax decreased in all three study rounds. Both first and second round showed a small but significantly different dependency on age of only 3.5% compared to the third study round. Again, the relation between Qmax and age was described by one equation: log(Qmax) = −0.005 × age + 1.478. IPSS did not depend on age when volunteers were younger than 55 years (median IPSS score 3.7). Above 55 years, IPSS increased with age (log(IPSS + 1) = 0.005 × age + 0.475). Both the obstructive and irritative symptom score increased with increasing age, log(IPSSobs + 1) = 0.022 × age + 1.491 and log(IPSSirr + 1) = 0.038 × age + 1.112, respectively. For Pcond.max an opposite result was found. In all three study rounds there was no significant dependency on the age groups. However, there was a significant dependency on the three study rounds, resulting in three different horizontal lines. The mean pressures were: Pcond.max.round 1 = 98, Pcond.max.round 2 = 107, Pcond.max.round 3 = 109.

During the 5-year follow-up men dropped out for several reasons as can be seen in Figure 1. Men that dropped out for urological reasons (treatment or medication for voiding problems) had larger prostates, lower urinary flow rates, and higher IPSS scores compared to men that dropped out for non-medical reasons.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Several community-based studies have shown evidence that BPE is an age-related process. Most studies are cross sectional, but there are a few longitudinal studies with follow-up times varying between 4 and 12 years, showing that with increasing age, PV, and IPSS increase, whereas Qmax decreases.[2-7] We found similar age-dependent changes. From early analysis in the first 827 asymptomatic males included in our study we concluded that the commonly observed increase in mean PV with age is caused by an increase in the range of the PV,[19] mainly caused by an increase of the 95th percentile from 43 to 83 cm3, as the 5th percentile increased from 11 to 24 cm3. As a consequence, a considerable portion of men older than 60 years (about 40%) still have a normal PV (<35 cm3). For Qmax we found a similar, but decreasing change of the outcome.

At 55 years of age, there was a sudden increase in IPSS in our volunteers. This may have been caused by excess water accumulation in the lower body, causing nocturia, which is supported by earlier published results that urine production during the night also suddenly increased from 41 ml/hr in the age group 48–52 years to 56 ml/hr in the age group 53–57 years in the same group of volunteers.[20]

The bladder contractility was not measured or estimated in any of the earlier longitudinal studies. Our non-invasive study shows that the average bladder contractility, quantified by the maximum condom pressure, increased during the 5-year longitudinal follow-up in each age group. Our first tentative conclusion is that this longitudinal pressure rise represents compensation of the urinary bladder triggered by the increasing urethral resistance due to age-related BPE. As described in the methods section, mostly two condom measurements were done in each patient in each study round and the Pcond.max measured in the last voiding was used for statistical data analysis. In the second and third study round, the Pcond.max in the last voiding was significantly higher than the Pcond.max in the previous voiding (mean difference ± SD, round 2: 8.5 ± 28.4 cmH2O, round 3: 9.7 ± 27.6 cmH2O). It may therefore be asked if this difference could have been carried over between the rounds and thus have (partly) caused the observed increase in pressure between the study rounds. However, the first measurement in round 2 was not significantly different from the first measurement in the following round 3. The same also applies to the second measurement in both round 2 and 3. Moreover, the first measurement in round 3 was significantly lower than the last measurement in round 2 (Mean Pcond.max ± SD in first and second measurement in round 2: 98 ± 37 and 107 ± 36 cmH2O and in round 3: 101 ± 38 and 110 ± 36 cmH2O). We therefore conclude that there is no systematic learning effect that continued from visit to visit and could be ascribed to a learning effect of the volunteer. Based on the pressure increase observed in the longitudinal analysis of our volunteers, one would expect the pressure to increase in the cross sectional analysis of the age groups as well. However, between the age groups, the pressures were very similar. For instance, the mean pressures in study round 1 of age group 1 (38–42 years at inclusion) and age group 2 (43–47 years at inclusion) are 97 ± 33 and 95 ± 32 cmH2O, respectively. Five years later the mean pressure of age group 1 (study round 3) had increased to 115 ± 36 cmH2O. As the mean age of the volunteers in age group 1 during study round 3 is the same as the mean age in group 2 at inclusion (45.6 ± 1.3 vs. 45.2 ± 1.4, respectively), we expected similar pressures.

Our second tentative conclusion is that this may be explained by selection. In human males, the onset of prostatic obstruction is not well defined. The longitudinal increase in urinary bladder contractility during the three study rounds found in age group 1 (38–42 years) shows that already at the age of 40 the average bladder contractility rose noticeably. By the time such early responders reached the age of 45 they probably had developed symptoms, and had sought for help, resulting in treatment which ruled out inclusion in our study. As a consequence, the volunteers recruited in age group 2 show on average the same development as those in age group 1, but at a higher age. An additional indication for this interpretation is that in all age groups the upper limit of the confidence interval of contractility is approximately the same. At even higher contractility values symptoms get serious and treatment starts, preventing inclusion in the study.

It must be noted that in the first study round the condom catheter measurements were done by a different researcher (the third author) than those in the second and third study round (the first author). Analysis of the isovolumetric bladder pressure measured with the penile cuff test by three different observers showed that one of the observers under-measured the cuff pressure relative to the other two observers.[21] To minimize the bias of interpretation by the two different researchers in our study, post processing of all study rounds was done by the first author only. Although the measurements were done by both researchers, there are not many ways in which recording of the raw data can be “influenced” by the researcher.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

With increasing age, PV, and IPSS increased, whereas Qmax decreased. Isovolumetric bladder pressure (representing bladder contractility) increased during the 5-year longitudinal follow-up, due to bladder compensation. No increase in contractility was found in a cross sectional analysis of the different age groups studied. This is probably caused by a selection effect. That would imply that the compensation of the bladder occurred relatively fast, in a period of approximately 5 years. Decompensation of the bladder could not be verified in this study, possibly because before it occurs most patients already seek for treatment. The condom catheter method is a straightforward and patient-friendly method to measure bladder contractility in non-invasive longitudinal studies, resulting in a high response rate.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES