Persistent detrusor overactivity after transurethral resection of the prostate is associated with reduced perfusion of the urinary bladder

Authors


Michael Mitterberger, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.e-mail: michael.mitterberger@uibk.ac.at

Abstract

In an interesting study, authors from Austria attempted to elucidate how often detrusor overactivity persists after TURP, and if perfusion of the lower urinary tract influences the outcome. They found that increased vascular resistance of the bladder vessels leads to reduced perfusion, and provide a possible explanation for the persistent symptoms.

In a multicentre, community-based randomized study conducted in the USA and UK, the transdermal oxybutynin system improved the quality of life in adults with overactive bladder.

The final paper in this section is from Turkey, presenting the long-term results of transurethral vaporisation using plasmakinetic energy.

OBJECTIVES

To elucidate, in patients with benign prostatic hyperplasia (BPH), how often detrusor overactivity (DOA) is persistent after transurethral resection of the prostate (TURP) and if perfusion of the lower urinary tract influences postoperative outcomes.

PATIENTS AND METHODS

Fifty men with urodynamically confirmed DOA and bladder outlet obstruction due to BPH had a TURP. Before and 1 year after TURP the International Prostate Symptom Score (IPSS), quality of life (QoL) score, prostate-specific antigen (PSA) level and total prostatic volume (TPV) were evaluated. Also, the lower urinary tract was evaluated using pressure-flow studies and transrectal colour Doppler ultrasonography to assess the vascular resistive index (RI) as a variable of the perfusion of the lower urinary tract.

RESULTS

After TURP the IPSS, QoL score, PSA level and TPV decreased. Cystometric measurements showed that in 15 (30%) patients DOA was persistent after TURP. The mean (sd) maximum urinary flow rate increased from 9.20 (4.03) to 15.98 (4.62) mL/s and postvoiding residual urine volumes decreased from 109.38 (73.71) to 29.24 (45.00) mL. When men with persistent DOA (15 patients; group 1) were compared with those with no DOA after TURP (35; group 2) there was a statistically significantly higher RI of the bladder vessels in group 1, at 0.86 (0.068) than in group 2, at 0.68 ( 0.055) (P < 0.001).

CONCLUSIONS

Persistent DOA in men after TURP seems to be associated with increased vascular resistance of the bladder vessels with subsequent reduced perfusion and hypoxia.

Abbreviations
BPE

benign prostatic enlargement

DOA

detrusor overactivity

CD(US)

colour Doppler ultrasonography

CPI

colour pixel intensity

ROI

region of interest

RI

resistive index

QoL

quality of life

TPV

total prostatic volume

PFS

pressure-flow studies

Qmax

maximum urinary flow rate.

INTRODUCTION

Benign prostatic enlargement (BPE) is one of the most common diseases in older men and is caused by BPH, which usually develops after the age of 40 years. Clinical manifestations of BPH can include voiding symptoms that frequently result from BOO and/or storage symptoms often due to detrusor overactivity (DOA); these conditions are two main causes of LUTS in men with BPE [1].

According to the ICS, BOO is defined as a low urinary flow rate that occurs during voiding despite a detrusor contraction of adequate force, duration and speed. DOA is defined as a urodynamic observation characterized by involuntary detrusor contractions during the filling phase, which can be spontaneous or provoked [2].

Although many theories have been proposed to explain the development of DOA, its pathogenesis remains unclear. Since 1786, when Hunter first described an ‘increased irritability’ of the bladder associated with BOO, many studies, most using animal models, suggested a relationship between DOA and BOO [3].

Recently, several experimental studies in the rat reported a significant reduction in detrusor blood flow in obstructed compared with unobstructed bladders. These studies also noted that BOO in rats is characterized by pathophysiological changes, such as muscle hypertrophy and connective tissue infiltration, previously related to obstruction in affected human bladders [4,5].

Others report that in vivo ischaemia of the bladder in animal models results in DOA and the expression of apoptotic markers in intrinsic neurones in the bladder wall. In humans, bladders from patients with DOA show patchy denervation, suggesting that periodic ischaemia and neuronal death might predispose to overactivity [6].

The use of colour Doppler ultrasonography (CDUS) opened new fields for ultrasonography in medicine by allowing the real-time display of blood flow. CDUS is highly sensitive in depicting blood flow, and the number, course and continuity of vessels more readily than other imaging methods. Although CDUS is a useful noninvasive method for assessing blood flow, it is only of limited value if the data are quantified subjectively. On the contrary, computer-assisted quantification by calculating colour pixel intensity (CPI) is a reliable technique that allows an accurate assessment of organ and tissue perfusion. A method for quantifying CDUS data in organs was developed using statistical image analysis. Based on standardized image recording, data are acquired from the video output of any ultrasound scanner using a colour frame-grabber in a personal computer. The digitized colours are recognized according to their position in the CDUS palette bar, typically resulting in an 8-bit colour image with a proportion of identified pixels of >99.9%. Within the region of interest (ROI) the statistics of the detected flow patterns can be calculated. It was shown clearly that this analysis can be used for comparative or longitudinal studies, and for an objective evaluation and assessment of CDUS in complex vascular studies. Its diagnostic impact was reported in several studies [7,8]. The resistive index (RI) obtained by pulsed-wave CDUS is related to both blood flow and pressure, and is one of the most reliable indicators of vascular resistance to small vessels [9,10].

In the present study we investigated the clinical, urodynamic and vascular outcome in a group of patients with BOO and DOA who were treated with TURP. In addition the blood supply of the bladder was assessed before and after TURP to ascertain if persistent DOA is associated with reduced perfusion of the bladder.

PATIENTS AND METHODS

In all, 50 patients with LUTS due to BPE were included in this study. The patients completed the IPSS quality-of-life (QoL) score and the PSA level and total prostatic volume (TPV) were evaluated. In addition, the lower urinary tract was evaluated using pressure-flow studies (PFS) and by transrectal CDUS to assess the vascular RI as a variable for assessing perfusion of the lower urinary tract.

For the PFS a standard urodynamic system was used (Sedia, Switzerland). For bladder pressure measurement and bladder filling we used an 8 F transurethral microtip catheter. Before cystometry the bladder was emptied through the lumen of the transurethral catheter. The bladder was then filled with 0.9% NaCl at 20 °C at a filling speed of 25 mL/min. Cystometrograms were obtained, recording first desire, maximal cystometric capacity, detrusor compliance and presence of DOA. All 50 patients had idiopathic DOA before TURP. The latter was defined as involuntary detrusor contraction during the filling phase with no underlying neurological disease. The grade of BOO was quantified using the Schafer nomogram (0, no obstruction, to 6, severe obstruction). Urodynamic variables analysed included maximum urinary flow rate (Qmax), voided volume, residual volume after flowmetry, maximum bladder capacity at cystometry and detrusor pressure at maximum flow. Urinary sediment and culture were negative at the urodynamic evaluation. The methods, definition and units for urodynamic study conformed to the standards proposed by the ICS [2].

All US investigations were done by one experienced radiologist (F.F.) using contrast-enhanced CDUS with the high-frequency end-fire probe EC10C5 fitted to a Sequoia unit (Acuson, Mountain View, CA, USA). All patients were examined twice while supine. The patient was examined with a full (defined as the point of strong desire to void) and an empty (or nearly empty) bladder. Contrast-enhanced CDUS was used to measure the RI and visualize the arterial blood flow at three distinct sites of the bladder, the two lateral bladder walls and the centrally located trigone, followed by spectral waveform analysis. The arterial flow velocity was measured, and the RI was calculated for each site as follows: RI = (VMAX − VMIN)/VMAX, where V is the bladder volume. For the purposes of analysis, the RI of the entire detrusor for an individual patient was defined as the arithmetic mean of RIs obtained from the three aforementioned bladder sites. RI was measured 30 s after injection with contrast medium; 18 clinically healthy men of a comparable age served as controls.

The Doppler signal intensity of the bladder was determined using computer-assisted quantification of CPI. The ROI was placed in areas with the highest detectable blood flow. For this purpose the red-green-blue output of the ultrasound unit was digitized with an IBM-compatible computer. The digitized images were post-processed with the USA National Institutes of Health image software package (version 1.62). The digitized colour image was divided into its three colour components; each colour channel consists of 256 brightness values according to the brightness of the colour. To minimize background noise the threshold value for the blue and red colour channels was set in the middle of the brightness value dynamic range, i.e. at 128 for both colours. Within the defined ROI only colour pixels showing a brightness value of >64 were counted. Thereafter all 50 patients underwent TURP, using standard techniques by experienced surgeons.

All 50 patients were invited and participated in a second clinical (IPSS, QoL, PSA level) and urodynamic evaluation with PFS (one examination) and a transrectal contrast-enhanced CDUS after 12 months.

All studies were carried out in accordance with the principles of the Declaration of Helsinki, and all patients had provided consent.

Student’s t-test was used for the statistical analysis; if this indicated statistical significance, then Welch’s correction was applied, with statistical significance defined as P < 0.05. Data are presented as the mean (sd).

RESULTS

DOA was urodynamically confirmed in all 50 men. Of these, 35 (70%) were classified as obstructed (grade 3–6) and 15 as equivocal (grade 2). No patient was unobstructed (grade 0–1) according to the Schafer nomogram grade of BOO. The mean TPV, as estimated by transrectal CDUS, was 68.30 (16.3) mL (Table 1).

Table 1.  The clinical characteristics of the patients; values are the mean (sd). Differences among the three groups were analysed with Student’s t-test, which when statistically significant, was followed by the Welch’s correction, with statistical significance defined at P < 0.05
GroupsNAge, yearsBladderIPSSQoL scorePSA, ng/mLTPV, mL
CPIRI
  • *

    Statistically significant

Before TURP
 BPH5075 (9.1)215 (15.6) 0.82 (0.085)15.46 (4.3) 3 (0.7) 2.87 (1.9)68.3 (16.3)
After TURP
 BPH, no DOA3576 (10.6)289.5 (16.2) 0.68 (0.055) 8.5 (5.4) 1 (0.8) 1.44 (0.93)23.6 (8.33)
 BPH, with DOA1575 (6.4)195 (15.5) 0.86 (0.068)11.0 (4.8) 1 (2.1) 1.5 (0.8)20.0 (5.1)
Control1875 (9.1)295.5 (18.2) 0.66 (0.03) 0 0 0.47 (0.5)19.0 (2.3)
P:
 Before vs after, no DOA  0.64 <0.001<0.001*<0.001<0.001<0.001*<0.001*
 Before vs after, with DOA  1 <0.001<0.001* 0.001 0.003*<0.001*<0.001*
 After, no DOA vs control  0.64  0.226 0.093*<0.001*<0.001*<0.001* 0.004*
 After, with DOA vs control  1 <0.001<0.001*<0.001* 0.086<0.001* 0.492*
 Before vs control  1 <0.001<0.001*<0.001*<0.001*<0.001*<0.001*

As there was no statistically significant difference in the measured CPI and RI between the full and empty bladder states (data not shown) the presented results show CPI and RI of the full bladder state only.

Perfusion of the bladder was significantly lower in patients with BPH, with a median CPI of 215 (15.6), than in healthy controls, at 295.5 (18.2; P < 0.001). In patients with BPH and obstruction, perfusion of the bladder was worse, with a median CPI of 190 (13.5), than in patients with BPH with equivocal obstruction (P < 0.001).

By contrast, the RI of the bladder in BPH patients was significantly higher than in the controls, with a median RI of 0.82 (0.09) vs 0.66 (0.03) (P < 0.001), and in patients with BPH and obstruction the RI of the bladder was even higher, at 0.85 (0.074) (P < 0.001).

All 50 patients had a complete evaluation at 12 months after TURP and the control group had a US evaluation. Cystometric measurements showed that in 15 patients DOA was persistent after TURP (30%). All the patients were unobstructed, according to the Schafer nomogram, after TURP. The Qmax increased from 9.20 (4.03) to 15.98 (4.62) mL/s and the postvoid residual urine volumes decreased from 109.38 (73.71) to 29.24 (45.00) mL.

After TURP there was an improvement in Qmax in patients with initial urodynamic obstruction compared with patients with equivocal obstruction. Patients with no persistent DOA after TURP had a statistically significant improvement in the IPSS and QoL score compared with those with persistent DOA. The mean TPV after TURP, as estimated by TRUS, was 23.60 (8.33) mL.

There were statistically significant differences between bladder perfusion in patients with persistent DOA (15 men, group 1) compared to those with no DOA after TURP (35, group 2). Perfusion of the bladder in patients in group 2 was similar to that in the healthy controls, at a median CPI of 289.5 (16.2). The patients in group 1 had worse perfusion of the bladder, with a median CPI of 195.0 (15.5), than patients in group 2 (P < 0.001). By contrast, the RI of the bladder in patients in group 1 was significantly higher than in the controls, with a median RI of 0.86 (0.068) vs 0.66 (0.03) (P < 0.001), and in the patients in group 2 the RI was equal to the controls 0.68 (0.03).

DISCUSSION

DOA is one of the most common causes of LUTS, and is often associated with BOO and BPE. Urodynamic studies of patients with BOO due to BPE have shown DOA in more than half of men undergoing prostatectomy. After prostatectomy, two-thirds of patients with previous DOA had normal detrusor function on a cystometrogram. However, in a series of 100 patients with BOO, Abrams et al. [11] reported a 63% conversion from unstable to stable detrusor after prostatectomy, and the only factor that was predictive of conversion was the severity of the preoperative DOA.

In the present study, 70% of patients with DOA before surgery presented with normal bladder behaviour at 1 year after surgery and there was a statistically significant improvement in all obstruction variables measured. Therefore, surgery seems to have a significant effect on the progress of this condition.

The response of the detrusor muscle to BOO is associated with several morphological changes, i.e. an increase in muscle mass (hypertrophy) and proliferation of smooth muscle fibres (hyperplasia), which ultimately results in a dramatic increase in the size and weight of the bladder [12]. Because no compensatory vascular proliferation accompanies these pathophysiological changes, there might be a relative decrease in bladder blood flow. In the present study, we showed, and concur with the findings of others, that patients with BOO, as confirmed by PFS, had significantly reduced detrusor blood flow in the filled, as well as empty, bladder state compared with patients with LUTS and otherwise no urodynamic evidence of BOO. This was reflected in a significantly greater detrusor RI in the obstructed group.

Although these data seem to show a relationship between DOA and BOO, the pathophysiology of the former remains unclear. Different studies have shown that increased bladder pressure such as that observed with BOO can lead to partial denervation of the detrusor muscle, resulting in DOA caused by post-junctional supersensitivity [13,14]. To date, follow-up studies of patients who have had a prostatectomy show re-innervation of the bladder and recovery of detrusor stability after the relief of obstruction [4]. Other studies suggested that abnormal sensory stimuli from an anatomically altered prostatic urethra, as in patients with BPE, can induce DOA [15]. Permanent surgical ablation of sensory stimuli from the prostatic urethra would be beneficial. The incidence of DOA consistently increases with age in more than half of men aged >70 years, but not with BOO [16]. Holm et al. [17] reported that changes in detrusor nerve density and fibrosis seen in BOO are not distinguishable from those of ageing, suggesting that DOA and BOO are unrelated events occurring in elderly men, with an incidence increasing with age. Other mechanisms proposed include altered adrenoceptor function, neurotransmitter imbalance and a myogenic deficit [16,18]. All of these findings seem to indicate that DOA is not just a consequence of BOO, but might be related to many other factors, and probably what is known only represents the ‘tip of a large iceberg’[1].

Another underlying mechanism of DOA could be chronic hypoxia. In vivo ischaemia in animal models results in DOA and the expression of apoptotic markers in intrinsic neurones in the bladder wall. In humans, bladders from patients with DOA show patchy denervation, suggesting that periodic ischaemia and neuronal death might predispose to overactivity [6].

This concept agrees with the present finding that the 30% of the patients with persistent DOA after TURP were associated with a statistically significantly higher RI of bladder perfusion than in the control group, which is an indicator for increased vascular resistance, representing decreased blood flow, which results in hypoxia.

Presently, there are few diagnostic methods to predict whether preoperative DOA will resolve or persist after prostatectomy. However, it is probable that DOA associated with BOO is more likely to resolve after TURP than DOA without BOO, because in the present and previous studies, DOA resolved in 73% of patients with BOO and DOA, compared with 40% in patients with equivocal obstruction and DOA [19].

The present results suggest that CDUS can be used to inspect the bladder from both anatomical and functional standpoints, and thus provide important clinical information. The RI measurements were obtained from three different sites and averaged, rather than assuming one location along the bladder wall represented the true RI of the entire detrusor muscle. Contrast medium improved the signal-to-noise ratio and therefore the detection of small vessels. In accordance with the study of Belenky et al. [20], in the present study there was no statistically significant difference in the measured RI between the full and empty bladder, and therefore the RI results only of the full bladder are presented.

Several previous studies reported similar alterations in detrusor muscle cells but contrary to the present study they were associated with BOO only. Saito et al. [21,22], using a rat urinary BOO model, suggested a linear correlation between the severity of obstruction and the degree of reduction in blood flow to the bladder. Likewise, Lin et al. [23] used laser Doppler flowmetry to assess detrusor blood flow in New Zealand white rabbits, and found a substantial decrease in the regional blood flow in obstructed compared with unobstructed urinary bladders.

As there were few patients, additional studies with larger groups are required to validate the feasibility of the present method. Another limitation of the present study, with probably a major impact that could otherwise redound to our advantage, is that the US investigations were done by one professionally experienced examiner (F.F.) and therefore no data were obtained on the inter- and intraobserver variability.

Although this should be considered a pilot study with a small sample, our data support the hypothesis that increased vascular resistance of the bladder vessels with subsequent reduced perfusion and hypoxia of the bladder is associated with persistent DOA in patients after TURP.

In conclusion, 35 (70%) of the patients with preoperative DOA showed a stable detrusor activity after TURP. In these patients a statistically significant improvement in bladder perfusion could be verified after TURP, whereas in the 15 (30%) patients with persistent DOA there was decreased perfusion of the bladder.

CONFLICT OF INTEREST

None declared.

Ancillary