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International Journal of Urology (2014)
doi: 10.1111/iju.12601
Original Article
α1-Blockers for the treatment of recurrent urinary tract infections in women with dysfunctional voiding: A prospective randomized study Daniele Minardi, Francesco Pellegrinelli, Alessandro Conti, Donatella Fontana, Michela Mattia, Giulio Milanese and Giovanni Muzzonigro Department of Clinic and Specialistic Sciences, Institute of Urology, Polytechnic University of the Marche Region, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy
Abbreviations & Acronyms α1-AR = α1-adrenoceptor AUASI = American Urological Association Symptom Index ITT = intention to treat PVR = post-void residual urine UTI = urinary tract infection Correspondence: Daniele Minardi M.D., Ph.D., Clinica Urologica, Università Politecnica delle Marche, A.O. Ospedali Riuniti, Via Conca 71, 60020 Ancona, Italy. Email: [email protected] Received 2 May 2014; accepted 18 July 2014.
Objectives: To evaluate the therapeutic effects of tamsulosin on recurrent urinary tract infections in women with dysfunctional voiding. Methods: A total of 155 women with recurrent urinary tract infections and dysfunctional voiding were included and randomly assigned to the following groups: uroflowmetry biofeedback (group 1), α1-adrenoceptor antagonists (group 2), uroflowmetry biofeedback combined with α1-adrenoceptor antagonists (group 3) and no treatment (group 4). Patients were evaluated by the American Urological Association Symptom Index at 3, 6 and 12 months. Urodynamics was carried out in patients of groups 1, 2, and 3 at 3, 6 and 12 months, whereas urodynamics was only carried out at 12 months in group 4. All patients were followed up for 1 year with monthly urine cultures. Results: The incidence of storage and emptying symptoms decreased significantly at 3, 6 and 12 months. Mean flow rate, flow time and voiding volume increased significantly (with a better outcome in patients of group 3), whereas post-void residual urine decreased. Mean opening detrusor pressure and detrusor pressure at maximum flow decreased significantly (with a better outcome in patients of group 3). Mean urethral closure pressure and maximum urethral closure pressure decreased significantly with a more significant decrease for patients in group 3. The prevalence of urinary tract infection decreased significantly in all groups after treatment, and this decrease remained stable during the follow up. Conclusions: In women with dysfunctional voiding and recurrent urinary tract infection, tamsulosin associated with uroflowmetry biofeedback might be an effective and safe treatment option for improving urinary symptoms and quality of life.
Key words: α1-blockers, dysfunctional voiding, recurrent urinary tract infection, uroflowmetry biofeedback.
Introduction The prevalence of voiding dysfunction in women has been reported to be 2–25.5% among those referred for evaluation of lower urinary tract symptoms;1 recurrent UTI can occur in up to 42% in patients with dysfunctional voiding.2 This is an abnormality of bladder emptying in neurologically normal individuals in whom there is increased external sphincter activity during voluntary voiding; it is thought to be a learned behavior.2,3 There are reports of this condition in children, but in adults much less has been written.4 The main objective of treatment of dysfunctional voiding is restoration of a normal micturition pattern, reduction of excess detrusor and pelvic floor activity, and elimination of storage symptoms, emptying symptoms and urinary tract infections. Biofeedback therapy is a recognized treatment option for children with dysfunctional voiding, but has been applied to a lesser extent in adult women.5 Reduction of urethral resistance by α-blockers might provide a therapeutic rationale. α1-AR antagonists were first used to treat patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia; however, very little is known about its effects in women. Some studies have shown that α1-AR antagonists effectively improve symptoms and voiding parameters in women with functional bladder outlet obstruction.6–10 Because α1-AR appear to play roles in lower urinary tract function, it seems logical that α1-AR antagonists can be used in female patients with voiding dysfunction. However, little clinical evidence is available to show that α1-AR antagonists are effective in female patients with dysfunctional voiding. © 2014 The Japanese Urological Association
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D MINARDI ET AL.
In the present study, we evaluated the therapeutic effects of α1-AR antagonists (using tamsulosin) on recurrent urinary tract infections in women with dysfunctional voiding, with particular regard on lower urinary tract symptoms, and urodynamic and voiding parameters.
Methods A prospective study was carried out at the Institute of Urology, Ancona, Italy, between 2008 and 2012. The study population comprised women referred to our department with more than a 3-year history of recurrent UTI, with at least three or more symptomatic episodes over a 12-month period, and the diagnosis of UTI being made using clean catch urine specimens sent for urinalysis and culture.5 The population included only nulliparous patients aged younger than 40 years without genital prolapse, previous surgery for incontinence or other pelvic procedures, or behavioral causes of recurrent UTI.11,12 The institutional review board approved the study design. All the patients provided informed consent to adhere to the study protocol. They provided history, and underwent physical examination, abdominal ultrasound, cystoscopy and neurological investigation as necessary. Those with morphological abnormalities and/or neurological disease were excluded from the study. The selected patients completed the AUASI before further testing.13 The index was divided into a total score (sum of all seven questions), a voiding score (sum of questions 1, 3, 5 and 6) and a storage symptom score (sum of questions 2, 4 and 7).12,13 For the purpose of the present study, only patients with recurrent UTI and dysfunctional voiding were considered. The diagnosis of dysfunctional voiding was made by multichannel video urodynamic investigation and perineal ultrasound as described.5 Multichannel video urodynamic investigation was then carried out in all the patients by one operator (DM), according to International Continence Society criteria,14 using a Duet multi-P Medtronic (Medtronic, Brescia, Italy). Patients had negative urine cultures at the time of investigation, or antibiotic treatment was started at least 10 days before urodynamics in those with positive urine cultures. Free urine flow measurement preceded the conventional fluid-fill pressure-flow studies, which were carried out using a 7-Fr dual lumen catheter for bladder filling, with simultaneous measurement of intravesical pressure, a 6-Fr vented rectal catheter for recording of intra-abdominal pressure, and needle electrodes for electromyography of the pelvic floor.15 Simultaneous fluoroscopic images were obtained. The fill rate was 20 mL/min with X-ray contrast material.2,5 Attention was given to the fluoroscopic appearance of the bladder outlet during voiding, including the bladder neck, and urethral and external sphincter. Urethral pressure profilometry was carried out using the perfusion catheter technique with a 7-Fr urethral catheter.5 Patients with anatomical abnormalities were excluded from further investigations. The others were sent for perineal ultrasound at the same session.5 A total of 297 patients were referred to our institution for recurrent UTI during the study period, including 155 who fulfilled the selection criteria and were enrolled. 2
The patients were then randomly assigned by a randomization table to receive a treatment schedule as follows: (i) uroflowmetry biofeedback (group 1); (ii) α1-AR antagonists (group 2); (iii) uroflowmetry biofeedback combined to α1-AR antagonists (group 3); or (iv) no treatment (group 4) – these patients received only antibiotics in case of symptomatic UTI (Fig. 1). The training programs began with the recording of a voiding and drinking chart; the patients were asked to record for 5 days their voiding frequency, urine volume and liquid intake. To achieve an increase of the bladder capacity, the recognition of the feeling of a full bladder and eventually remedying wet and/or dirty underpants during the day and night, the voiding frequency and liquid intake were adjusted and further supervised.12 During treatment, all patients received antibiotics, as necessary, in case of UTI.
Uroflowmetry biofeedback Patients were instructed to drink liquid and arrive with a full bladder. Biofeedback was carried out by two operators (FD, MM), using a Duet multi-P Medtronic urodynamic system, which enabled simultaneous recording of urine flow and electromyography, and visual display of flow-electromyography activity. The procedure was discussed clearly with the patients before starting. Surface electromyography patches were placed at the 3 and 9 o’clock positions on the perineum to measure electrical activity of the pelvic floor muscle group. An additional surface electrode patch was placed on the rectus abdominis to measure muscle activity. The muscle activity was presented to the patients as a visual signal (a red line) on a display unit; in this way the patients were aware of the grade of relaxation and tone of the pelvic floor muscles, as the shape of the red line changed proportionally with contraction and relaxation. The urinary flow rate was measured regularly to quantify the woman’s ability to relax the pelvic floor; once voided into the flowmeter, she was asked to predict the shape of the voiding curve, the amount of urine and the PVR. This prediction was then compared with the curve produced, again as a form of biofeedback. The true PVR was then assessed by ultrasonography. At the beginning of the study, biofeedback training was carried out weekly for 10 weeks. The results of each session were compared with those of previous sessions. After the patients understood the concept, sessions were scheduled at 4-week intervals and continued for 12 months. Between sessions, patients were reminded about exercises, periodically mentioning the need to relax during voiding.16,17
α1-AR antagonists Tamsulosin 0.4 mg once daily was given for 3 months and then stopped. Patients were evaluated by AUASI also at month 3 and 6 after study beginning, and at year 1; urodynamic investigation was carried out in patients of group 1, 2, and 3 at month 3 and 6 after study beginning and at 1 year, and in patients of group 4 at 12 months. All of the patients were followed up for 1 year with monthly urine cultures and clinical assessment. Patients of © 2014 The Japanese Urological Association
α1-Blockers and dysfunctional voiding
Assessed for eligibility (n = 297)
Excluded (n = 142) because • Not meeting inclusion criteria (n = 99) • Refused to participate (n = 43) Randomized (n = 155)
Fig. 1
Group 1 n = 38
Group 2 n = 42
Group 3 n = 39
Group 4 n = 36
ITT population n = 35 (92%)
ITT population n = 38 (90.5%)
ITT population n = 37 (94.9%)
ITT population n = 18 (50%)
Lost to follow-up n = 3 (0.9%) Discontinued intervention n = 8 (2.1%)
Lost to follow-up n = 4 (0.9%) Discontinued intervention n = 8 (1.9%)
Lost to follow-up n = 2 (0.5%) Discontinued intervention n = 9 (2.3%)
Lost to follow-up n = 18 (50%)
The Consolidated Standards of Reporting Trials diagram of the study protocol.
group 4 received therapy as necessary after 1 year, and therefore were not followed up any further. Patients of group 1, 2, and 3 did not receive uroflowmetry biofeedback and/or α1-AR antagonists in the period between months 12 and 24, but continued to carry out urine cultures every second month up to 24 months. A further evaluation was carried out in these patients at month 24 by AUASI and free uroflowmetry with measurement of residual urine. Treatment results were documented as subjective and objective improvements; the subjective improvement was assessed by the reported changes in urinary symptoms (storage and emptying symptoms), the objective improvement was defined by changes in flow pattern, decrease of bladder outlet obstruction and incidence of urinary tract infections; the following parameters were analyzed: mean flow rate, flow time, voiding volume and PVR volume, mean opening detrusor pressure, detrusor pressure at maximum flow, and mean and maximum urethral closure pressure; therapy was considered successful when the patients stayed free of infection during a follow up of at least 6 months.3 People who administered the questionnaires and those who carried out urodynamics were blinded to the treatment groups; personnel who carried out uroflowmetry biofeedback were blinded to the results of questionnaires and of urodynamics. For the analysis of the subjective and objective variables, differences between each treatment were tested in the ITT population (all participants who had a baseline assessment and at least one valid post-baseline assessment). The normality of the numeric variables was evaluated by Kolmogorov–Smirnov test. Data were then analyzed by ANOVA, using the Bonferroni © 2014 The Japanese Urological Association
post-hoc test for repeated measures, for differences of parameters in each group and then comparing the three groups. Alternatively, when appropriate, the Kruskall–Wallis test or Friedman test were used to compare groups with nonparametric values. Data for incidence of UTI and AUASI symptom score were analyzed by Cochran’s Q-test. Tests were considered significant for P < 0.05. Statistical analysis was carried out using the SPSS 15.0 software (SPSS, Chicago, IL, USA).
Results Of the 155 patients initially enrolled, 128 women aged 18–34 years (mean age 25.3 years) completed the study and were finally evaluated; 35 were included in group 1, 38 in group 2, 37 in group 3 and 18 in group 4 (patients of group 4 who did not complete all the scheduled investigations were excluded from the final evaluation; Fig. 1). The baseline characteristics of the patients are not significantly different among the four groups for each of the considered parameters. At enrolment, storage symptoms (consisting mainly in frequency and urgency) were recorded respectively in 27 (77.1%) patients of group 1, 27 (71%) of group 2, 29 (78.4%) of group 3 and 11 (61.1%) of group 4; emptying symptoms (consisting mainly of decreased force of stream, hesitancy, need to strain and a feeling of incomplete bladder emptying) were observed respectively in 27 (77.1%) patients of group 1, 24 (63.1%) of group 2, 25 (65.7%) of group 3, and in 11 (61.1%) of group 4 (Table 1). In Table 1, we can also observe the urodynamic parameters of the four groups of patients at enrolment and after treatment. 3
110 ± 11.2 60 ± 12 88.7 ± 15 73 ± 13 NA 60 ± 15
Uroflowmetry biofeedback (group 1), α1-AR antagonists (group 2), uroflowmetry biofeedback combined to α1-AR antagonists (group 3), no treatment (group 4).
78.4 ± 20 71 ± 15 NA 62 + 15 84 ± 18 112.6 ± 13.7 116 ± 16 106.5 ± 20 118 ± 25
75 ± 19
91 ± 11.6 43.7 ± 13 68.2 ± 11 52.1 ± 9 NA 38 ± 17 47.8 ± 11 50 ± 15 NA 46 ± 16 64 ± 12 90.8 ± 13.4 85.8 ± 17 89.9 ± 11 93.2 ± 19
58.9 ± 15
47 ± 6.5 16.2 + 8 26 + 9 25 + 8 NA 16 + 8 21 + 12 25.2 + 8 NA 19.2 + 5 28 + 11 45.9 ± 7.8 39.2 ± 9 42 ± 12 46.3 ± 9
26.3 + 9
52 ± 4.4 17 ± 5 20 ± 4 16 ± 5 NA 14 ± 6 22 ± 11 19 ± 7 NA 16 ± 5 18 ± 12 49.3 ± 5.1 48 ± 5 45 ± 12
Mean post-void residual urine (mL) Mean opening detrusor pressure (cm/H2O) Mean detrusor pressure at maximum flow (cm/H2O) Mean urethral closure pressure (cm/H2O) Max urethral closure pressure (cm/H2O)
60 ± 15
52.3 ± 8
19 ± 7
26.1 ± 2.2 377 ± 3.3 58.6 ± 9.9
13.7 ± 2.3 20.2 ± 4.9
18 ± 4 469 ± 50 18 ± 10 20 ± 8 462 ± 55 18 ± 11
17.1 ± 7.0 17.8 ± 6.9
20 ± 3 460 ± 37 15 ± 10 NA NA NA
NA 19.4 ± 5.3
16 ± 4 498 ± 49 20 ± 12 19 ± 7 458 ± 49 30 ± 15
16.7 ± 7.1 16.2 ± 7.2
19 ± 5 472 ± 48 22 ± 10 NA NA NA
NA 19.5 ± 5.1
16 ± 5 492 ± 58 15 ± 11 18 ± 5 459 ± 70 30 ± 15
16.4 ± 7.2
24.9 ± 6.3 387.2 ± 50 59.5 ± 0.3 25 ± 5 395 ± 85 64 ± 12 22 ± 6 389 ± 88 55 ± 15 24 ± 5 397 ± 45
19 ± 5 473 ± 44 20 ± 12
14.2 ± 4.9 12.5 ± 5.7 13.1 ± 6.2 13.4 ± 5.9
Mean flow time (s) Mean voiding volume (mL)
16.7 ± 7.1
11 (61.1%) 11 (61.1%) 11 (39.2%)
11 (39.2%)
20 (66.6%)
19 (63.3%)
16 (59.2%)
15 (55.5%)
11 (61.1%) 11 (61.1%) 12 (42.8%) 10 (35.7%) 18 (60.0%) 18 (60.0%) 15 (55.5%) 16 (59.2%) 11 (61.1%) 11 (61.1%) 15 (40.5%) 15 (40.5%) 25 (65.7%) 21 (55.2%)
At 1 year At 6 months At 3 months
18 (51.4%) 20 (57.1%) 11 (61.1%) 11 (61.1%) 29 (78.4%) 25 (65.7%) 27 (77.1%) 27 (77.1%)
27 (71%) 24 (63.1%)
Storage symptoms (no. patients) Emptying symptoms (no. patients) Mean flow rate (mL/s)
Group 4 Group 3 Group 2 Group 1
Baseline
Patients’ characteristics and study results Table 1
4
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
D MINARDI ET AL.
The incidence of storage and emptying symptoms decreased significantly at 3, 6 and 12 months after treatment in all the three treated groups (P < 0.05), and remained stable during the study period; decrease of storage and emptying symptoms were not observed in the untreated patients (Fig. 2). We could observe that mean flow rate and voiding volume increased significantly after treatment in all the three treated groups (with a better outcome in patients of group 3), with an overall better voiding pattern, whereas flow time and PVR urine decreased (P < 0.05); the results remained stable up to 12 months (Fig. 3). By the analysis of the urodynamic parameters, we could observe that mean opening detrusor pressure and detrusor pressure at maximum flow decreased significantly after treatment in all the three groups (with a better outcome in patients of group 3; P < 0.05), and remained stable during the follow-up period, whereas they did not change significantly in the untreated patients. By the analysis of mean urethral closure pressure and maximum urethral closure pressure, we could observe that they decreased significantly after treatment in the treated groups, but not in the untreated patients. However, in group 3; that is, in those patients receiving uroflowmetry biofeedback combined with α1-AR antagonists, the decrease was significantly higher than for patients of groups 1 and 2; that is, those patients who received uroflowmetry biofeedback or α1-AR antagonists as a single treatment (P < 0.05; Fig. 4). The prevalence of UTI decreased significantly in all groups after treatment (P < 0.05), and the results remained stable in the follow-up period. There were no significant differences between UTI success rates in the three groups, and the prevalence of UTI remained unchanged in the untreated group (Table 2). At month 24 after study beginning, by AUASI it was possible to observe that storage and emptying symptoms were similar to the baseline values in 45% of patients. The mean flow rate was 14.2 ± 5.4 mL/s, mean flow time 22 ± 6 s, voiding volume 385 ± 70 mL, PVR urine 66 ± 20 mL, mean opening detrusor pressure 49 ± 7 cmH2O, detrusor pressure at maximum flow 39 ± 5 cmH2O, mean urethral closure pressure 86 ± 8 cmH2O and maximum urethral closure pressure 107 ± 15 cmH2O. The incidence of UTI was similar to baseline values in 35% of patients of groups 1, 2 and 3. No adverse effects were recorded in our patients during the treatment with each modality.
Discussion Dysfunctional voiding is an abnormally learned spectrum of voiding behavior, different from the true detrusor-external sphincter dyssynergia;2,4,6 it can result in various lower urinary tract symptoms, and also be responsible for recurrent urinary tract infections.5,12,18 Biofeedback therapy is a recognized treatment option for children with dysfunctional voiding and inadequate pelvic floor relaxation during voiding.12,15 In the adult population, success with biofeedback as a treatment modality for several pelvic floor disorders is promising. The principal disadvantage of biofeedback is that success depends on patients’ motivation and dedication to the program.19–22 For women with predominately voiding symptoms, there is a relative paucity of appropriate treatment options; few © 2014 The Japanese Urological Association
α1-Blockers and dysfunctional voiding
Fig. 2 Baseline (a) storage and (b) emptying symp, toms, and during and after treatment. (a) , group 3; , group 4; , group 1. Group 2; , Group 1; , group 2; , group 3; (b) , group 4.
Storage symptoms 90 80 70 60 50 40 30 20 10 0 Baseline
(a)
Mean flow rate
Baseline
(b) 30
20
25 20
15 10
5 0 Baseline
(c)
3 Months 6 Months 12 Months
Voided volume
Baseline
(d)
3 Months 6 Months 12 Months
Postvoid residual
60
70
50
60 50 ml
40 ml
15 10
0
30
40 30
20
20
10
10
0
0 Baseline
3 Months 6 Months 12 Months
treatments have been adequately studied. α1-AR blockers are considered the first-line treatment in male patients with moderate to severe LUTS;23 because of evidence of receptor level similarities between men and women in the lower urinary tract, α1-AR blockers could function to reduce LUTS in both men and women by improving voiding symptoms and storage symptoms.24–28 In a prospective, open-label, multicenter study, a total of 106 female patients with at least 3 months of voiding dysfunction symptoms were initiated on tamsulosin and evaluated after 8 weeks of treatment.6 The mean International Prostate Symptom Score were decreased significantly with improvements in both storage and voiding symptom scores; urodynamic parameters also improved from baseline. Pummangura et al. carried out a prospective, randomized double-blind placebo controlled trial to evaluate the efficacy of tamsulosin versus placebo for the treatment of LUTS in 140 women; after 4 weeks of treatment, a statistically significant difference was found for the mean change in International Prostate Symptom Score and flow rate from baseline in the tamsulosin group.29 Constantini et al. © 2014 The Japanese Urological Association
3 Months 6 Months 12 Months
Flow time
25
5
Fig. 3 Baseline voiding parameters, and during and after treatment. (a) Mean flow rate. (b) Flow , time. (c) Voided volume. (d) Post-void residual. , group 2; , group 3; , group 4. Group 1;
Emptying symptoms 90 80 70 60 50 40 30 20 10 0
3 Months 6 Months 12 Months
sec
ml/sec
(b)
Incidence (%)
Incidence (%)
(a)
Baseline
3 Months 6 Months 12 Months
evaluated the effect of tamsulosin on recurrent UTI; 63 women with predominant voiding symptoms and functional bladder outlet obstruction were enrolled and given tamsulosin 0.4 mg daily for at least 30 days, 65% of patients experienced improvements in urodynamic parameters (peak flow rate and PVR) and 81% of patients had a 50% reduction in recurrent UTI.30 The results in the present study were comparatively good. We could observe that mean flow rate, flow time and voiding volume were significantly better in patients of group 3; that is, in those patients receiving uroflowmetry biofeedback combined with α1-AR antagonists, whereas PVR urine was lower in the same group. The mean urethral closure pressure and maximum urethral closure pressure were significantly lower in patients of group 3. The training program in the present study was effective in treating recurrent UTI in most of the women; therefore, pelvic floor therapy seems to be a reasonable and meaningful component in the treatment of recurrent UTI in which dysfunctional voiding plays a role. Therapy was continued during the whole observation period (although at low frequency in the end), and 5
D MINARDI ET AL.
(a)
Mean detrusor opening pressure
(b)
Detrusor pressure at maximum flow
60
40
cmH2O
cmH2O
50
30 20 10 0 Baseline
(c)
3 Months 6 Months 12 Months
Mean urethral closure pressure 100 90 80 70 60 50 40 30 20 100 0
(d)
3 Months 6 Months 12 Months
Max urethral closure pressure 120
cmH2O
100 80 60 40 20 0 Baseline
3 Months 6 Months 12 Months
Table 2 Incidence of episodes of UTI (over a 12-month period) before and after treatment
Group 1 Group 2 Group 3 Group 4
Baseline
140
cmH2O
Fig. 4 Baseline urodynamic parameters, and during and after treatment. (a) Mean detrusor opening pressure. (b) Detrusor pressure at maximum flow. (c) Mean urethral closure pressure. , (d) Maximum urethral closure pressure. , group 2; , group 3; , group 4. Group 1;
50 45 40 35 30 25 20 15 10 5 0
Baseline
At 12 months
100% (27 patients) 100% (30 patients) 100% (28 patients) 100% (18 patients)
25.9% (7 patients) 23.3% (7 patients) 21.4% (6 patients) 94.4% (17 patients)
Baseline
3 Months 6 Months 12 Months
The consistent positive findings of the present study suggest that in women with dysfunctional voiding and recurrent urinary tract infection, tamsulosin associated with uroflowmetry biofeedback could be an effective and safe treatment option for improving urinary symptoms and quality of life.
Conflict of interest None declared.
References we believe that this is an important issue to ensure long-term results of the treatment, and a valid predictive factor for success. For women with primarily voiding dysfunction, there is a relative paucity of appropriate treatment options; the use of α1-AR antagonists on women with dysfunctional voiding can be a treatment option, with improvement of symptom scores and urodynamic parameters.10 The good results obtained in the present study not only on emptying, but also on storage symptoms are interesting. We can suppose that they are partly due to patients being aware of the condition, and voiding frequency and liquid intake being adjusted and measuring voided volume; but pelvic floor therapy probably also has an indirect effect on storage symptoms. Further studies will be necessary to elucidate this issue. The involvement and motivation of the patient is very important for success. Using simple rules, they were taught how to contribute each day to remedy their bladder problems. In all patients, the scheduled treatment program at hospital was maintained, and patients attended monthly sessions of uroflowmetry biofeedback. We believe that this is the reason for success in our patients, and that any treatment protocol should take into consideration the possibility of extending treatment in the long term. 6
1 Groutz A, Blaivas JG. Non-neurogenic female voiding dysfunction. Curr. Opin. Urol. 2002; 12: 311–16. 2 Carlson KV, Rome S, Nitti VW. Dysfunctional voiding in women. J. Urol. 2001; 165: 143–8. 3 Messelink B, Benson T, Berghmans B et al. Standardization of terminology of pelvic floor muscle function and dysfunction: report from the pelvic floor assessment group of the International Continence Society. Neurourol. Urodyn. 2005; 24: 374–80. 4 Yagci S, Kibar Y, Akay O et al. The effect of biofeedback treatment on voiding and urodynamic parameters in children with voiding dysfunction. J. Urol. 2005; 174: 1994–8. 5 Minardi D, Parri G, d’Anzeo G, Fabiani A, El Asmar Z, Muzzonigro G. Perineal ultrasound evaluation of dysfunctional voiding in women with recurrent urinary tract infections. J. Urol. 2008; 179: 947–51. 6 Lee KS, Han DH, Lee YS et al. Efficacy and safety of tamsulosin for the treatment of non-neurogenic voiding dysfunction in females: a 8-week prospective study. J. Korean Med. Sci. 2010; 25: 117–22. 7 Kessler TM, Studer UE, Burkhard FC. The effect of terazosin on functional bladder outlet obstruction in women: a pilot study. J. Urol. 2006; 176: 1487–92. 8 Pischedda A, Pirozzi Farina F, Madonia M, Cimino S, Morgia G. Use of alpha1-blockers in female functional bladder neck obstruction. Urol. Int. 2005; 74: 256–61. 9 Hajebrahimi S, Asrbadr YA, Azaripour A, Sadeghi-Bazargani H. Effect of tamsulosin versus prazosin on clinical and urodynamic parameters in women with voiding difficulty: a randomized clinical trial. Int. J. Gen. Med. 2011; 4: 35–9. 10 Meyer LE, Brown JN. Tamsulosin for voiding dysfunction in women. Int. Urol. Nephrol. 2012; 44: 1649–56. © 2014 The Japanese Urological Association
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11 Mazzola B, von Vigier RO, Marchand S, Tönz M, Bianchetti MG. Behavioral and functional abnormalities linked with recurrent urinary tract infections in girls. J. Nephrol. 2003; 16: 133–8. 12 de Paepe H, Renson C, van Laecke E, Raes A, Vande Walle J, Hoebeke P. Pelvic-floor therapy and toilet training in young children with dysfunctional voiding and obstipation. BJU Int. 2000; 85: 889–93. 13 Scarpero HM, Fiske J, Xue X, Nitti VW. American Urological Association Symptom index for lower urinary tract symptoms in women: correlation with degree of bother and impact on quality of life. Urology 2003; 61: 1118–22. 14 Schäfer W, Abrams P, Liao L et al. Good urodynamic practices: uroflowmetry, filling cystometry and pressure-flow studies. Neurourol. Urodyn. 2002; 21: 261–74. 15 Deindl FM, Vodusek DB, Bishoff CH, Hofmann R, Hartung R. Dysfunctional voiding in women: which muscles are responsible? Br. J. Urol. 1998; 82: 814–19. 16 Chin-Peuckert L, Salle JL. A modified biofeedback program for children with detrusor-sphincter dyssinergia: a 5-year experience. J. Urol. 2001; 166: 1470–5. 17 Nelson JD, Cooper CS, Boyt MA, Hawtrey CE, Austin JC. Improved uroflow parameters and post-void residual following biofeedback therapy in pediatric patients with dysfunctional voiding does not correspond to outcome. J. Urol. 2004; 172: 1653–6. 18 Schwinn DA, Michelotti GA. A1-adrenergic receptors in the lower urinary tract and vascular bed: potential role for the a1d subtype in filling symptoms and effects of aging on vascular expression. BJU Int. 2000; 85 (Suppl 2): 6–11. 19 Vasconcelos M, Lima E, Caiafa L et al. Voiding dysfunction in children. Pelvic floor excercises or biofeedback therapy: a randomized study. Pediatr. Nephrol. 2006; 21: 1858–64. 20 de Paepe H, Hoebecke P, Rensons C et al. Pelvic-floor therapy in girls with recurrent urinary tract infections and dysfunctional voiding. Br. J. Urol. 1998; 81: 109–13.
© 2014 The Japanese Urological Association
21 Soresen K, Lose G, Nathan E. Urinary tract infections and diurnal incontinence in girls. Eur. J. Pediatr. 1998; 148: 146–7. 22 McKenna PH, Herndon CD, Connery S, Ferrer FA. Pelvic floor muscle retraining for pediatric voiding dysfunction using interactive computer games. J. Urol. 1999; 162: 1056–63. 23 Abrams P, Chapple C, Khoury S, Roehrborn C, de la Rosette J, International Consultation on New Developments in Prostate Cancer and Prostate Diseases. Evaluation and treatment of lower urinary tract symptoms in older men. J. Urol. 2009; 181: 1779–87. 24 Fitzpatrick JM. Facts and future lines of research in lower urinary tract symptoms in men and women: an overview of the role of the a1-adrenoreceptor antagonists. BJU Int. 2000; 85 (Suppl 2): 1–5. 25 Meyer LE, Brown JB. Tamsulosin for voiding dysfunction in women. Int. Urol. Nephrol. 2012; 44: 1649–56. 26 Low BY, Liong M, Yuen KH et al. Terazosin therapy for patients with female lower urinary tract symptoms: a randomized, double-blind, placebo controlled trial. J. Urol. 2008; 179: 1461–9. 27 Kessler TM, Studer U, Burkhard FC. The effect of terazosin in functional bladder outlet obstruction in women:a pilot study. J. Urol. 2006; 176: 1487–92. 28 Lepor H, Theune C. Randomized double-blind study comparing the efficacy of terazosin versus placebo in women with prostatism-like symptoms. J. Urol. 1995; 154: 116–18. 29 Pummangura N, Kochakarn W. Efficacy of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) in women. Asian J. Surg. 2007; 30: 131–7. 30 Costantini E, Lazzeri M, Bini V et al. Open-label, longitudinal study of tamsulosin for functional bladder outlet obstruction in women. Urol. Int. 2009; 83: 311–15.
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International Journal of Urology (2014)
doi: 10.1111/iju.12601
Original Article
α1-Blockers for the treatment of recurrent urinary tract infections in women with dysfunctional voiding: A prospective randomized study Daniele Minardi, Francesco Pellegrinelli, Alessandro Conti, Donatella Fontana, Michela Mattia, Giulio Milanese and Giovanni Muzzonigro Department of Clinic and Specialistic Sciences, Institute of Urology, Polytechnic University of the Marche Region, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy
Abbreviations & Acronyms α1-AR = α1-adrenoceptor AUASI = American Urological Association Symptom Index ITT = intention to treat PVR = post-void residual urine UTI = urinary tract infection Correspondence: Daniele Minardi M.D., Ph.D., Clinica Urologica, Università Politecnica delle Marche, A.O. Ospedali Riuniti, Via Conca 71, 60020 Ancona, Italy. Email: [email protected] Received 2 May 2014; accepted 18 July 2014.
Objectives: To evaluate the therapeutic effects of tamsulosin on recurrent urinary tract infections in women with dysfunctional voiding. Methods: A total of 155 women with recurrent urinary tract infections and dysfunctional voiding were included and randomly assigned to the following groups: uroflowmetry biofeedback (group 1), α1-adrenoceptor antagonists (group 2), uroflowmetry biofeedback combined with α1-adrenoceptor antagonists (group 3) and no treatment (group 4). Patients were evaluated by the American Urological Association Symptom Index at 3, 6 and 12 months. Urodynamics was carried out in patients of groups 1, 2, and 3 at 3, 6 and 12 months, whereas urodynamics was only carried out at 12 months in group 4. All patients were followed up for 1 year with monthly urine cultures. Results: The incidence of storage and emptying symptoms decreased significantly at 3, 6 and 12 months. Mean flow rate, flow time and voiding volume increased significantly (with a better outcome in patients of group 3), whereas post-void residual urine decreased. Mean opening detrusor pressure and detrusor pressure at maximum flow decreased significantly (with a better outcome in patients of group 3). Mean urethral closure pressure and maximum urethral closure pressure decreased significantly with a more significant decrease for patients in group 3. The prevalence of urinary tract infection decreased significantly in all groups after treatment, and this decrease remained stable during the follow up. Conclusions: In women with dysfunctional voiding and recurrent urinary tract infection, tamsulosin associated with uroflowmetry biofeedback might be an effective and safe treatment option for improving urinary symptoms and quality of life.
Key words: α1-blockers, dysfunctional voiding, recurrent urinary tract infection, uroflowmetry biofeedback.
Introduction The prevalence of voiding dysfunction in women has been reported to be 2–25.5% among those referred for evaluation of lower urinary tract symptoms;1 recurrent UTI can occur in up to 42% in patients with dysfunctional voiding.2 This is an abnormality of bladder emptying in neurologically normal individuals in whom there is increased external sphincter activity during voluntary voiding; it is thought to be a learned behavior.2,3 There are reports of this condition in children, but in adults much less has been written.4 The main objective of treatment of dysfunctional voiding is restoration of a normal micturition pattern, reduction of excess detrusor and pelvic floor activity, and elimination of storage symptoms, emptying symptoms and urinary tract infections. Biofeedback therapy is a recognized treatment option for children with dysfunctional voiding, but has been applied to a lesser extent in adult women.5 Reduction of urethral resistance by α-blockers might provide a therapeutic rationale. α1-AR antagonists were first used to treat patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia; however, very little is known about its effects in women. Some studies have shown that α1-AR antagonists effectively improve symptoms and voiding parameters in women with functional bladder outlet obstruction.6–10 Because α1-AR appear to play roles in lower urinary tract function, it seems logical that α1-AR antagonists can be used in female patients with voiding dysfunction. However, little clinical evidence is available to show that α1-AR antagonists are effective in female patients with dysfunctional voiding. © 2014 The Japanese Urological Association
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In the present study, we evaluated the therapeutic effects of α1-AR antagonists (using tamsulosin) on recurrent urinary tract infections in women with dysfunctional voiding, with particular regard on lower urinary tract symptoms, and urodynamic and voiding parameters.
Methods A prospective study was carried out at the Institute of Urology, Ancona, Italy, between 2008 and 2012. The study population comprised women referred to our department with more than a 3-year history of recurrent UTI, with at least three or more symptomatic episodes over a 12-month period, and the diagnosis of UTI being made using clean catch urine specimens sent for urinalysis and culture.5 The population included only nulliparous patients aged younger than 40 years without genital prolapse, previous surgery for incontinence or other pelvic procedures, or behavioral causes of recurrent UTI.11,12 The institutional review board approved the study design. All the patients provided informed consent to adhere to the study protocol. They provided history, and underwent physical examination, abdominal ultrasound, cystoscopy and neurological investigation as necessary. Those with morphological abnormalities and/or neurological disease were excluded from the study. The selected patients completed the AUASI before further testing.13 The index was divided into a total score (sum of all seven questions), a voiding score (sum of questions 1, 3, 5 and 6) and a storage symptom score (sum of questions 2, 4 and 7).12,13 For the purpose of the present study, only patients with recurrent UTI and dysfunctional voiding were considered. The diagnosis of dysfunctional voiding was made by multichannel video urodynamic investigation and perineal ultrasound as described.5 Multichannel video urodynamic investigation was then carried out in all the patients by one operator (DM), according to International Continence Society criteria,14 using a Duet multi-P Medtronic (Medtronic, Brescia, Italy). Patients had negative urine cultures at the time of investigation, or antibiotic treatment was started at least 10 days before urodynamics in those with positive urine cultures. Free urine flow measurement preceded the conventional fluid-fill pressure-flow studies, which were carried out using a 7-Fr dual lumen catheter for bladder filling, with simultaneous measurement of intravesical pressure, a 6-Fr vented rectal catheter for recording of intra-abdominal pressure, and needle electrodes for electromyography of the pelvic floor.15 Simultaneous fluoroscopic images were obtained. The fill rate was 20 mL/min with X-ray contrast material.2,5 Attention was given to the fluoroscopic appearance of the bladder outlet during voiding, including the bladder neck, and urethral and external sphincter. Urethral pressure profilometry was carried out using the perfusion catheter technique with a 7-Fr urethral catheter.5 Patients with anatomical abnormalities were excluded from further investigations. The others were sent for perineal ultrasound at the same session.5 A total of 297 patients were referred to our institution for recurrent UTI during the study period, including 155 who fulfilled the selection criteria and were enrolled. 2
The patients were then randomly assigned by a randomization table to receive a treatment schedule as follows: (i) uroflowmetry biofeedback (group 1); (ii) α1-AR antagonists (group 2); (iii) uroflowmetry biofeedback combined to α1-AR antagonists (group 3); or (iv) no treatment (group 4) – these patients received only antibiotics in case of symptomatic UTI (Fig. 1). The training programs began with the recording of a voiding and drinking chart; the patients were asked to record for 5 days their voiding frequency, urine volume and liquid intake. To achieve an increase of the bladder capacity, the recognition of the feeling of a full bladder and eventually remedying wet and/or dirty underpants during the day and night, the voiding frequency and liquid intake were adjusted and further supervised.12 During treatment, all patients received antibiotics, as necessary, in case of UTI.
Uroflowmetry biofeedback Patients were instructed to drink liquid and arrive with a full bladder. Biofeedback was carried out by two operators (FD, MM), using a Duet multi-P Medtronic urodynamic system, which enabled simultaneous recording of urine flow and electromyography, and visual display of flow-electromyography activity. The procedure was discussed clearly with the patients before starting. Surface electromyography patches were placed at the 3 and 9 o’clock positions on the perineum to measure electrical activity of the pelvic floor muscle group. An additional surface electrode patch was placed on the rectus abdominis to measure muscle activity. The muscle activity was presented to the patients as a visual signal (a red line) on a display unit; in this way the patients were aware of the grade of relaxation and tone of the pelvic floor muscles, as the shape of the red line changed proportionally with contraction and relaxation. The urinary flow rate was measured regularly to quantify the woman’s ability to relax the pelvic floor; once voided into the flowmeter, she was asked to predict the shape of the voiding curve, the amount of urine and the PVR. This prediction was then compared with the curve produced, again as a form of biofeedback. The true PVR was then assessed by ultrasonography. At the beginning of the study, biofeedback training was carried out weekly for 10 weeks. The results of each session were compared with those of previous sessions. After the patients understood the concept, sessions were scheduled at 4-week intervals and continued for 12 months. Between sessions, patients were reminded about exercises, periodically mentioning the need to relax during voiding.16,17
α1-AR antagonists Tamsulosin 0.4 mg once daily was given for 3 months and then stopped. Patients were evaluated by AUASI also at month 3 and 6 after study beginning, and at year 1; urodynamic investigation was carried out in patients of group 1, 2, and 3 at month 3 and 6 after study beginning and at 1 year, and in patients of group 4 at 12 months. All of the patients were followed up for 1 year with monthly urine cultures and clinical assessment. Patients of © 2014 The Japanese Urological Association
α1-Blockers and dysfunctional voiding
Assessed for eligibility (n = 297)
Excluded (n = 142) because • Not meeting inclusion criteria (n = 99) • Refused to participate (n = 43) Randomized (n = 155)
Fig. 1
Group 1 n = 38
Group 2 n = 42
Group 3 n = 39
Group 4 n = 36
ITT population n = 35 (92%)
ITT population n = 38 (90.5%)
ITT population n = 37 (94.9%)
ITT population n = 18 (50%)
Lost to follow-up n = 3 (0.9%) Discontinued intervention n = 8 (2.1%)
Lost to follow-up n = 4 (0.9%) Discontinued intervention n = 8 (1.9%)
Lost to follow-up n = 2 (0.5%) Discontinued intervention n = 9 (2.3%)
Lost to follow-up n = 18 (50%)
The Consolidated Standards of Reporting Trials diagram of the study protocol.
group 4 received therapy as necessary after 1 year, and therefore were not followed up any further. Patients of group 1, 2, and 3 did not receive uroflowmetry biofeedback and/or α1-AR antagonists in the period between months 12 and 24, but continued to carry out urine cultures every second month up to 24 months. A further evaluation was carried out in these patients at month 24 by AUASI and free uroflowmetry with measurement of residual urine. Treatment results were documented as subjective and objective improvements; the subjective improvement was assessed by the reported changes in urinary symptoms (storage and emptying symptoms), the objective improvement was defined by changes in flow pattern, decrease of bladder outlet obstruction and incidence of urinary tract infections; the following parameters were analyzed: mean flow rate, flow time, voiding volume and PVR volume, mean opening detrusor pressure, detrusor pressure at maximum flow, and mean and maximum urethral closure pressure; therapy was considered successful when the patients stayed free of infection during a follow up of at least 6 months.3 People who administered the questionnaires and those who carried out urodynamics were blinded to the treatment groups; personnel who carried out uroflowmetry biofeedback were blinded to the results of questionnaires and of urodynamics. For the analysis of the subjective and objective variables, differences between each treatment were tested in the ITT population (all participants who had a baseline assessment and at least one valid post-baseline assessment). The normality of the numeric variables was evaluated by Kolmogorov–Smirnov test. Data were then analyzed by ANOVA, using the Bonferroni © 2014 The Japanese Urological Association
post-hoc test for repeated measures, for differences of parameters in each group and then comparing the three groups. Alternatively, when appropriate, the Kruskall–Wallis test or Friedman test were used to compare groups with nonparametric values. Data for incidence of UTI and AUASI symptom score were analyzed by Cochran’s Q-test. Tests were considered significant for P < 0.05. Statistical analysis was carried out using the SPSS 15.0 software (SPSS, Chicago, IL, USA).
Results Of the 155 patients initially enrolled, 128 women aged 18–34 years (mean age 25.3 years) completed the study and were finally evaluated; 35 were included in group 1, 38 in group 2, 37 in group 3 and 18 in group 4 (patients of group 4 who did not complete all the scheduled investigations were excluded from the final evaluation; Fig. 1). The baseline characteristics of the patients are not significantly different among the four groups for each of the considered parameters. At enrolment, storage symptoms (consisting mainly in frequency and urgency) were recorded respectively in 27 (77.1%) patients of group 1, 27 (71%) of group 2, 29 (78.4%) of group 3 and 11 (61.1%) of group 4; emptying symptoms (consisting mainly of decreased force of stream, hesitancy, need to strain and a feeling of incomplete bladder emptying) were observed respectively in 27 (77.1%) patients of group 1, 24 (63.1%) of group 2, 25 (65.7%) of group 3, and in 11 (61.1%) of group 4 (Table 1). In Table 1, we can also observe the urodynamic parameters of the four groups of patients at enrolment and after treatment. 3
110 ± 11.2 60 ± 12 88.7 ± 15 73 ± 13 NA 60 ± 15
Uroflowmetry biofeedback (group 1), α1-AR antagonists (group 2), uroflowmetry biofeedback combined to α1-AR antagonists (group 3), no treatment (group 4).
78.4 ± 20 71 ± 15 NA 62 + 15 84 ± 18 112.6 ± 13.7 116 ± 16 106.5 ± 20 118 ± 25
75 ± 19
91 ± 11.6 43.7 ± 13 68.2 ± 11 52.1 ± 9 NA 38 ± 17 47.8 ± 11 50 ± 15 NA 46 ± 16 64 ± 12 90.8 ± 13.4 85.8 ± 17 89.9 ± 11 93.2 ± 19
58.9 ± 15
47 ± 6.5 16.2 + 8 26 + 9 25 + 8 NA 16 + 8 21 + 12 25.2 + 8 NA 19.2 + 5 28 + 11 45.9 ± 7.8 39.2 ± 9 42 ± 12 46.3 ± 9
26.3 + 9
52 ± 4.4 17 ± 5 20 ± 4 16 ± 5 NA 14 ± 6 22 ± 11 19 ± 7 NA 16 ± 5 18 ± 12 49.3 ± 5.1 48 ± 5 45 ± 12
Mean post-void residual urine (mL) Mean opening detrusor pressure (cm/H2O) Mean detrusor pressure at maximum flow (cm/H2O) Mean urethral closure pressure (cm/H2O) Max urethral closure pressure (cm/H2O)
60 ± 15
52.3 ± 8
19 ± 7
26.1 ± 2.2 377 ± 3.3 58.6 ± 9.9
13.7 ± 2.3 20.2 ± 4.9
18 ± 4 469 ± 50 18 ± 10 20 ± 8 462 ± 55 18 ± 11
17.1 ± 7.0 17.8 ± 6.9
20 ± 3 460 ± 37 15 ± 10 NA NA NA
NA 19.4 ± 5.3
16 ± 4 498 ± 49 20 ± 12 19 ± 7 458 ± 49 30 ± 15
16.7 ± 7.1 16.2 ± 7.2
19 ± 5 472 ± 48 22 ± 10 NA NA NA
NA 19.5 ± 5.1
16 ± 5 492 ± 58 15 ± 11 18 ± 5 459 ± 70 30 ± 15
16.4 ± 7.2
24.9 ± 6.3 387.2 ± 50 59.5 ± 0.3 25 ± 5 395 ± 85 64 ± 12 22 ± 6 389 ± 88 55 ± 15 24 ± 5 397 ± 45
19 ± 5 473 ± 44 20 ± 12
14.2 ± 4.9 12.5 ± 5.7 13.1 ± 6.2 13.4 ± 5.9
Mean flow time (s) Mean voiding volume (mL)
16.7 ± 7.1
11 (61.1%) 11 (61.1%) 11 (39.2%)
11 (39.2%)
20 (66.6%)
19 (63.3%)
16 (59.2%)
15 (55.5%)
11 (61.1%) 11 (61.1%) 12 (42.8%) 10 (35.7%) 18 (60.0%) 18 (60.0%) 15 (55.5%) 16 (59.2%) 11 (61.1%) 11 (61.1%) 15 (40.5%) 15 (40.5%) 25 (65.7%) 21 (55.2%)
At 1 year At 6 months At 3 months
18 (51.4%) 20 (57.1%) 11 (61.1%) 11 (61.1%) 29 (78.4%) 25 (65.7%) 27 (77.1%) 27 (77.1%)
27 (71%) 24 (63.1%)
Storage symptoms (no. patients) Emptying symptoms (no. patients) Mean flow rate (mL/s)
Group 4 Group 3 Group 2 Group 1
Baseline
Patients’ characteristics and study results Table 1
4
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
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The incidence of storage and emptying symptoms decreased significantly at 3, 6 and 12 months after treatment in all the three treated groups (P < 0.05), and remained stable during the study period; decrease of storage and emptying symptoms were not observed in the untreated patients (Fig. 2). We could observe that mean flow rate and voiding volume increased significantly after treatment in all the three treated groups (with a better outcome in patients of group 3), with an overall better voiding pattern, whereas flow time and PVR urine decreased (P < 0.05); the results remained stable up to 12 months (Fig. 3). By the analysis of the urodynamic parameters, we could observe that mean opening detrusor pressure and detrusor pressure at maximum flow decreased significantly after treatment in all the three groups (with a better outcome in patients of group 3; P < 0.05), and remained stable during the follow-up period, whereas they did not change significantly in the untreated patients. By the analysis of mean urethral closure pressure and maximum urethral closure pressure, we could observe that they decreased significantly after treatment in the treated groups, but not in the untreated patients. However, in group 3; that is, in those patients receiving uroflowmetry biofeedback combined with α1-AR antagonists, the decrease was significantly higher than for patients of groups 1 and 2; that is, those patients who received uroflowmetry biofeedback or α1-AR antagonists as a single treatment (P < 0.05; Fig. 4). The prevalence of UTI decreased significantly in all groups after treatment (P < 0.05), and the results remained stable in the follow-up period. There were no significant differences between UTI success rates in the three groups, and the prevalence of UTI remained unchanged in the untreated group (Table 2). At month 24 after study beginning, by AUASI it was possible to observe that storage and emptying symptoms were similar to the baseline values in 45% of patients. The mean flow rate was 14.2 ± 5.4 mL/s, mean flow time 22 ± 6 s, voiding volume 385 ± 70 mL, PVR urine 66 ± 20 mL, mean opening detrusor pressure 49 ± 7 cmH2O, detrusor pressure at maximum flow 39 ± 5 cmH2O, mean urethral closure pressure 86 ± 8 cmH2O and maximum urethral closure pressure 107 ± 15 cmH2O. The incidence of UTI was similar to baseline values in 35% of patients of groups 1, 2 and 3. No adverse effects were recorded in our patients during the treatment with each modality.
Discussion Dysfunctional voiding is an abnormally learned spectrum of voiding behavior, different from the true detrusor-external sphincter dyssynergia;2,4,6 it can result in various lower urinary tract symptoms, and also be responsible for recurrent urinary tract infections.5,12,18 Biofeedback therapy is a recognized treatment option for children with dysfunctional voiding and inadequate pelvic floor relaxation during voiding.12,15 In the adult population, success with biofeedback as a treatment modality for several pelvic floor disorders is promising. The principal disadvantage of biofeedback is that success depends on patients’ motivation and dedication to the program.19–22 For women with predominately voiding symptoms, there is a relative paucity of appropriate treatment options; few © 2014 The Japanese Urological Association
α1-Blockers and dysfunctional voiding
Fig. 2 Baseline (a) storage and (b) emptying symp, toms, and during and after treatment. (a) , group 3; , group 4; , group 1. Group 2; , Group 1; , group 2; , group 3; (b) , group 4.
Storage symptoms 90 80 70 60 50 40 30 20 10 0 Baseline
(a)
Mean flow rate
Baseline
(b) 30
20
25 20
15 10
5 0 Baseline
(c)
3 Months 6 Months 12 Months
Voided volume
Baseline
(d)
3 Months 6 Months 12 Months
Postvoid residual
60
70
50
60 50 ml
40 ml
15 10
0
30
40 30
20
20
10
10
0
0 Baseline
3 Months 6 Months 12 Months
treatments have been adequately studied. α1-AR blockers are considered the first-line treatment in male patients with moderate to severe LUTS;23 because of evidence of receptor level similarities between men and women in the lower urinary tract, α1-AR blockers could function to reduce LUTS in both men and women by improving voiding symptoms and storage symptoms.24–28 In a prospective, open-label, multicenter study, a total of 106 female patients with at least 3 months of voiding dysfunction symptoms were initiated on tamsulosin and evaluated after 8 weeks of treatment.6 The mean International Prostate Symptom Score were decreased significantly with improvements in both storage and voiding symptom scores; urodynamic parameters also improved from baseline. Pummangura et al. carried out a prospective, randomized double-blind placebo controlled trial to evaluate the efficacy of tamsulosin versus placebo for the treatment of LUTS in 140 women; after 4 weeks of treatment, a statistically significant difference was found for the mean change in International Prostate Symptom Score and flow rate from baseline in the tamsulosin group.29 Constantini et al. © 2014 The Japanese Urological Association
3 Months 6 Months 12 Months
Flow time
25
5
Fig. 3 Baseline voiding parameters, and during and after treatment. (a) Mean flow rate. (b) Flow , time. (c) Voided volume. (d) Post-void residual. , group 2; , group 3; , group 4. Group 1;
Emptying symptoms 90 80 70 60 50 40 30 20 10 0
3 Months 6 Months 12 Months
sec
ml/sec
(b)
Incidence (%)
Incidence (%)
(a)
Baseline
3 Months 6 Months 12 Months
evaluated the effect of tamsulosin on recurrent UTI; 63 women with predominant voiding symptoms and functional bladder outlet obstruction were enrolled and given tamsulosin 0.4 mg daily for at least 30 days, 65% of patients experienced improvements in urodynamic parameters (peak flow rate and PVR) and 81% of patients had a 50% reduction in recurrent UTI.30 The results in the present study were comparatively good. We could observe that mean flow rate, flow time and voiding volume were significantly better in patients of group 3; that is, in those patients receiving uroflowmetry biofeedback combined with α1-AR antagonists, whereas PVR urine was lower in the same group. The mean urethral closure pressure and maximum urethral closure pressure were significantly lower in patients of group 3. The training program in the present study was effective in treating recurrent UTI in most of the women; therefore, pelvic floor therapy seems to be a reasonable and meaningful component in the treatment of recurrent UTI in which dysfunctional voiding plays a role. Therapy was continued during the whole observation period (although at low frequency in the end), and 5
D MINARDI ET AL.
(a)
Mean detrusor opening pressure
(b)
Detrusor pressure at maximum flow
60
40
cmH2O
cmH2O
50
30 20 10 0 Baseline
(c)
3 Months 6 Months 12 Months
Mean urethral closure pressure 100 90 80 70 60 50 40 30 20 100 0
(d)
3 Months 6 Months 12 Months
Max urethral closure pressure 120
cmH2O
100 80 60 40 20 0 Baseline
3 Months 6 Months 12 Months
Table 2 Incidence of episodes of UTI (over a 12-month period) before and after treatment
Group 1 Group 2 Group 3 Group 4
Baseline
140
cmH2O
Fig. 4 Baseline urodynamic parameters, and during and after treatment. (a) Mean detrusor opening pressure. (b) Detrusor pressure at maximum flow. (c) Mean urethral closure pressure. , (d) Maximum urethral closure pressure. , group 2; , group 3; , group 4. Group 1;
50 45 40 35 30 25 20 15 10 5 0
Baseline
At 12 months
100% (27 patients) 100% (30 patients) 100% (28 patients) 100% (18 patients)
25.9% (7 patients) 23.3% (7 patients) 21.4% (6 patients) 94.4% (17 patients)
Baseline
3 Months 6 Months 12 Months
The consistent positive findings of the present study suggest that in women with dysfunctional voiding and recurrent urinary tract infection, tamsulosin associated with uroflowmetry biofeedback could be an effective and safe treatment option for improving urinary symptoms and quality of life.
Conflict of interest None declared.
References we believe that this is an important issue to ensure long-term results of the treatment, and a valid predictive factor for success. For women with primarily voiding dysfunction, there is a relative paucity of appropriate treatment options; the use of α1-AR antagonists on women with dysfunctional voiding can be a treatment option, with improvement of symptom scores and urodynamic parameters.10 The good results obtained in the present study not only on emptying, but also on storage symptoms are interesting. We can suppose that they are partly due to patients being aware of the condition, and voiding frequency and liquid intake being adjusted and measuring voided volume; but pelvic floor therapy probably also has an indirect effect on storage symptoms. Further studies will be necessary to elucidate this issue. The involvement and motivation of the patient is very important for success. Using simple rules, they were taught how to contribute each day to remedy their bladder problems. In all patients, the scheduled treatment program at hospital was maintained, and patients attended monthly sessions of uroflowmetry biofeedback. We believe that this is the reason for success in our patients, and that any treatment protocol should take into consideration the possibility of extending treatment in the long term. 6
1 Groutz A, Blaivas JG. Non-neurogenic female voiding dysfunction. Curr. Opin. Urol. 2002; 12: 311–16. 2 Carlson KV, Rome S, Nitti VW. Dysfunctional voiding in women. J. Urol. 2001; 165: 143–8. 3 Messelink B, Benson T, Berghmans B et al. Standardization of terminology of pelvic floor muscle function and dysfunction: report from the pelvic floor assessment group of the International Continence Society. Neurourol. Urodyn. 2005; 24: 374–80. 4 Yagci S, Kibar Y, Akay O et al. The effect of biofeedback treatment on voiding and urodynamic parameters in children with voiding dysfunction. J. Urol. 2005; 174: 1994–8. 5 Minardi D, Parri G, d’Anzeo G, Fabiani A, El Asmar Z, Muzzonigro G. Perineal ultrasound evaluation of dysfunctional voiding in women with recurrent urinary tract infections. J. Urol. 2008; 179: 947–51. 6 Lee KS, Han DH, Lee YS et al. Efficacy and safety of tamsulosin for the treatment of non-neurogenic voiding dysfunction in females: a 8-week prospective study. J. Korean Med. Sci. 2010; 25: 117–22. 7 Kessler TM, Studer UE, Burkhard FC. The effect of terazosin on functional bladder outlet obstruction in women: a pilot study. J. Urol. 2006; 176: 1487–92. 8 Pischedda A, Pirozzi Farina F, Madonia M, Cimino S, Morgia G. Use of alpha1-blockers in female functional bladder neck obstruction. Urol. Int. 2005; 74: 256–61. 9 Hajebrahimi S, Asrbadr YA, Azaripour A, Sadeghi-Bazargani H. Effect of tamsulosin versus prazosin on clinical and urodynamic parameters in women with voiding difficulty: a randomized clinical trial. Int. J. Gen. Med. 2011; 4: 35–9. 10 Meyer LE, Brown JN. Tamsulosin for voiding dysfunction in women. Int. Urol. Nephrol. 2012; 44: 1649–56. © 2014 The Japanese Urological Association
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11 Mazzola B, von Vigier RO, Marchand S, Tönz M, Bianchetti MG. Behavioral and functional abnormalities linked with recurrent urinary tract infections in girls. J. Nephrol. 2003; 16: 133–8. 12 de Paepe H, Renson C, van Laecke E, Raes A, Vande Walle J, Hoebeke P. Pelvic-floor therapy and toilet training in young children with dysfunctional voiding and obstipation. BJU Int. 2000; 85: 889–93. 13 Scarpero HM, Fiske J, Xue X, Nitti VW. American Urological Association Symptom index for lower urinary tract symptoms in women: correlation with degree of bother and impact on quality of life. Urology 2003; 61: 1118–22. 14 Schäfer W, Abrams P, Liao L et al. Good urodynamic practices: uroflowmetry, filling cystometry and pressure-flow studies. Neurourol. Urodyn. 2002; 21: 261–74. 15 Deindl FM, Vodusek DB, Bishoff CH, Hofmann R, Hartung R. Dysfunctional voiding in women: which muscles are responsible? Br. J. Urol. 1998; 82: 814–19. 16 Chin-Peuckert L, Salle JL. A modified biofeedback program for children with detrusor-sphincter dyssinergia: a 5-year experience. J. Urol. 2001; 166: 1470–5. 17 Nelson JD, Cooper CS, Boyt MA, Hawtrey CE, Austin JC. Improved uroflow parameters and post-void residual following biofeedback therapy in pediatric patients with dysfunctional voiding does not correspond to outcome. J. Urol. 2004; 172: 1653–6. 18 Schwinn DA, Michelotti GA. A1-adrenergic receptors in the lower urinary tract and vascular bed: potential role for the a1d subtype in filling symptoms and effects of aging on vascular expression. BJU Int. 2000; 85 (Suppl 2): 6–11. 19 Vasconcelos M, Lima E, Caiafa L et al. Voiding dysfunction in children. Pelvic floor excercises or biofeedback therapy: a randomized study. Pediatr. Nephrol. 2006; 21: 1858–64. 20 de Paepe H, Hoebecke P, Rensons C et al. Pelvic-floor therapy in girls with recurrent urinary tract infections and dysfunctional voiding. Br. J. Urol. 1998; 81: 109–13.
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21 Soresen K, Lose G, Nathan E. Urinary tract infections and diurnal incontinence in girls. Eur. J. Pediatr. 1998; 148: 146–7. 22 McKenna PH, Herndon CD, Connery S, Ferrer FA. Pelvic floor muscle retraining for pediatric voiding dysfunction using interactive computer games. J. Urol. 1999; 162: 1056–63. 23 Abrams P, Chapple C, Khoury S, Roehrborn C, de la Rosette J, International Consultation on New Developments in Prostate Cancer and Prostate Diseases. Evaluation and treatment of lower urinary tract symptoms in older men. J. Urol. 2009; 181: 1779–87. 24 Fitzpatrick JM. Facts and future lines of research in lower urinary tract symptoms in men and women: an overview of the role of the a1-adrenoreceptor antagonists. BJU Int. 2000; 85 (Suppl 2): 1–5. 25 Meyer LE, Brown JB. Tamsulosin for voiding dysfunction in women. Int. Urol. Nephrol. 2012; 44: 1649–56. 26 Low BY, Liong M, Yuen KH et al. Terazosin therapy for patients with female lower urinary tract symptoms: a randomized, double-blind, placebo controlled trial. J. Urol. 2008; 179: 1461–9. 27 Kessler TM, Studer U, Burkhard FC. The effect of terazosin in functional bladder outlet obstruction in women:a pilot study. J. Urol. 2006; 176: 1487–92. 28 Lepor H, Theune C. Randomized double-blind study comparing the efficacy of terazosin versus placebo in women with prostatism-like symptoms. J. Urol. 1995; 154: 116–18. 29 Pummangura N, Kochakarn W. Efficacy of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) in women. Asian J. Surg. 2007; 30: 131–7. 30 Costantini E, Lazzeri M, Bini V et al. Open-label, longitudinal study of tamsulosin for functional bladder outlet obstruction in women. Urol. Int. 2009; 83: 311–15.
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