Voiding Function and Dysfunction, Bladder Physiology and Pharmacology, and Female Urology

Urological Survey VOIDING FUNCTION AND DYSFUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY Bladder Diary Measurements in Asymptomatic Females: Functional Bladder Capacity, Frequency, and 24-Hr Volume C. L. Amundsen, M. Parsons, B. Tissot, L. Cardozo, A. Diokno and A. C. Coats, Department of Obstetrics and Gynecology, Division of Urogynecology, Duke University Medical Center, Durham, North Carolina Neurourol Urodyn 2007; 26: 341–349. Aims: To study the effects of age and 24-h volume (V(24)) on bladder diary measurements of voiding frequency (F(24)) and functional bladder capacity (FBC) from an asymptomatic female population. Also, to use these data to develop clinical reference values. (We use FBC as a generic term for bladder diary volume-per-void measurements.) Materials and Methods: Computer-processed 3-day bladder diaries were collected from 161 females (median age: 46.6 years; range ⫽ 19.6 – 81.8 years) claiming no urological symptoms, previous pelvic surgery and diseases and medications effecting urologic function. Regression analysis was used to investigate relationships among age, FBC and V(24). Results: Both FBC and F(24) increase as V(24) increases (P ⬍ 0.0005). With aging, F(24) increases (P ⫽ 0.026) and FBC may decrease slightly (P ⫽ 0.02– 0.08). There is a concave downward, curvilinear relationship between age and V(24). We used multiple regression to generate tables of FBC and F(24) “normal limits” adjusted for these simultaneous influences of V(24) and age. Removing their relationships to age reduces the variability of FBC and F(24) reference values by 50% and 20%, respectively. Conclusions: Our finding, supported by others, that, with increasing V(24), FBC increases more than F(24) suggests an adaptive mechanism that adjusts FBC to urine production to minimize changes in voiding frequency. We illustrate adjustment of reference values for age and V(24) by calculating traditional clinical “normal limits”. However, the probable large overlap between “normal” and “abnormal” suggests that it may be more useful to report bladder diary measurements as reference population percentiles rather than to designate them “normal” or “abnormal”. Editorial Comment: Nicely collected data. Table IX is especially useful, relating 24-hour urine volume and age to 24-hour urinary frequency, average voided volume and maximum voided volume. Data such as these will doubtless result in a revision of some of our “normative” values. For instance in the female population given, at age 50 with a 24-hour urine volume of 1,500 and 2,000 ml, the 24-hour urinary frequency and 96th percentiles are 9.7 and 10.4, respectively—not the usually reported 8 —and so on. Interestingly, in the same journal there is a very small series detailing parameters of bladder function in continent women without detrusor overactivity but divided among premenopausal, perimenopausal and postmenopausal status.1 This includes diary and urodynamic data. Unfortunately, that particular article suffers badly from a very small number of patients in each group but the diaries reported are different from the article summarized above. Alan J. Wein, M.D., Ph.D. (Hon.) 1. Pfisterer MH, Griffiths DJ, Rosenberg L, Schaefer W and Resnick NM: Parameters of bladder function in pre-, peri-, and postmenopausal continent women without detrusor overactivity. Neurourol Urodyn 2007; 26: 356.

Reference Urodynamic Values for Stress Incontinent Women C. W. Nager, M. E. Albo, M. P. Fitzgerald, S. McDermott, L. Wruck, S. Kraus, N. Howden, P. Norton, L. Sirls, E. Varner and P. Zimmern; Urinary Incontinence Treatment Network, University of California, San Diego Women’s Pelvic Medicine Center, La Jolla, California Neurourol Urodyn 2007; 26: 333–340. 0022-5347/08/1794-1480/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION

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Vol. 179, 1480-1487, April 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.12.029

VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY Objective: To determine reference urodynamic values for preoperative urodynamic studies in women undergoing surgery for pure or predominant stress urinary incontinence (SUI). Materials and Methods: Six hundred fifty-five women with pure or predominant SUI were enrolled in a multicenter surgical trial and were randomized to undergo a Burch or autologous fascia sling procedure as part of the Urinary Incontinence Treatment Network (UITN) Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr). Preoperative free uroflowmetry, filling cystometry, and pressure flow studies were performed in all women using a standardized research protocol and standardized urodynamic interpretation guidelines. We define the normal range of urodynamic values in this population as the values that encompass 95% of the results. Results: In 655 women undergoing filling cystometry in the standing position, baseline vesical and abdominal pressures were between 12 and 60 cm H(2)O. The upper limit of detrusor pressure increase during bladder filling to maximum cystometric capacity was 16 cm H(2)O. Ten percent of women who qualified for stress incontinence surgery with a positive cough stress test on physical exam did not demonstrate urodynamic stress incontinence (USI) and less than 10% of subjects in this study demonstrated detrusor overactivity. Conclusions: Results from a large cohort of women with SUI are now available for quantitative plausibility assessments or as reference values when interpreting urodynamic studies. Editorial Comment: Although there are no real surprises here, this article documents expertly collected data in a large number of women with pure or predominant stress urinary incontinence enrolled in a multicenter surgical trial, as detailed in the abstract. For free uroflowmetry it should be noted that only those whose voided volume was 150 ml or greater were included. The fact that less than 10% of the patients in this study demonstrated detrusor overactivity likely reflects “our selection of patients with pure or predominant SUI and our other strict inclusion criteria.” The authors comment that “it also suggests that screening for detrusor overactivity or mixed incontinence as a rationale for preoperative urodynamics in all SUI women may not be necessary since it has low yield in women with predominant SUI symptoms.” It must be remembered that the values published here are valid only for this strictly defined population in this randomized study. However, certain generalized conclusions are applicable to all women, such as, “Our data suggests that the median first desire to void should be expected at 1/3 of maximal cystometric capacity (MCC) and the strong desire to void is typically found at 2/3 MCC. We found that the median MCC in 645 women is 362 ml. This data may be useful to any urodynamic testing center; filling the bladder to volumes less than this may not be assessing true MCC.” Relevant values, including Valsalva leak point pressure, are expressed both in tabular and histogram form, with mean, median and percentile data being displayed. Alan J. Wein, M.D., Ph.D. (Hon.)

Does Urodynamic Investigation Improve Outcome in Patients Undergoing Prolapse Surgery? J. P. Roovers, J. O. van Laar, C. Loffeld, G. L. Bremer, B. W. Mol and M. Y. Bongers, Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands Neurourol Urodyn 2007; 26: 170 –175. Aims: Without solid evidence, it has been advocated to perform urodynamic investigation in all patients scheduled for prolapse surgery. If urodynamic investigations were to be valuable in the diagnostic work-up, patients with normal and abnormal findings would have different treatment results. Our policy to never combine prolapse surgery and stress-incontinence surgery allowed us to study whether incontinence after surgery can be predicted from urodynamic investigation results. Methods: A retrospective study was performed in consecutive patients undergoing vaginal prolapse surgery (anterior colporraphy and/or posterior colporraphy, and/or vaginal hysterectomy) between 2002 and 2004. All patients underwent preoperative urodynamic investigation, including filling cystometry, urethral pressure profile measurement, and free flow cystometry. Data were collected from the files about medical history, findings at pelvic examination, findings at urodynamic investigation and presence of stress- and/or urge-incontinence after surgery. Results: We studied 76 patients, of whom 5 (7%) patients reported stress-incontinence and 5 (7%) patients reported urge-incontinence after surgery. Findings at urodynamic investigation could not predict the presence of stress- or urge-incontinence after surgery. Likelihood ratios (LR) of prior presence of urge and stress-incontinence for the presence of post-operative urge- and stress-incontinence were 4.5 and 1.2, respectively. Of all findings at urodynamic investigation, only negative transmission during cough test was associated with presence of stress-incontinence (LR ⫽ 1.5). Conclusions: The prevalence of incontinence after prolapse surgery is low. None of the investigated parameters of the urodynamic investigation tests was associated with the presence of urinary incontinence after surgery.

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VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY Editorial Comment: These authors point out that according to the recommendations of the International Continence Society, urodynamic investigation should be part of the diagnostic workup in patients with genital prolapse grade 2 or more, and cite the appropriate references for this. They also cite evidence in the literature that “about 40% of all patients with genital prolapse report stress incontinence. In about half of the remaining 60% of these patients, masked stress incontinence will be detected by performing urodynamic investigation.” Later in the same section of the paper (1 sentence later) they then state what seems to be their hypothesis and their supportive conclusion: “There is no evidence that urodynamic testing improves outcome of women undergoing prolapse surgery.” They state up front that their treatment strategy in women with genital prolapse and coexisting (urodynamic) stress incontinence is to correct the prolapse and evaluate afterward whether additional stress incontinence surgery is indicated. They give the following as reasons supporting their strategy: 1) Only a few patients report stress incontinence after surgery—in this study the observed prevalence was 7%. 2) When combining these procedures the patient has an increased risk of developing detrusor overactivity (they cite numbers going from 13% to 27%). They close with the following: “This does not mean that urodynamic investigation should be abandoned. Even though they may not alter clinical management, preoperative tests allow appropriate counseling of the patients, a matter which should not be underestimated in terms of satisfaction and litigation. However, before evidence supporting the diagnostic value of urodynamic investigation has been provided we suggest to discuss with the patient that urodynamic investigation may be informative but not mandatory.” Finally, it should be noted that they did not use mechanical prolapse reduction with subsequent observation as a part of their evaluation strategy. Alan J. Wein, M.D., Ph.D. (Hon.)

What’s a ‘Cure’? Patient-Centred Outcomes of Treatments for Stress Urinary Incontinence R. M. Freeman, Urogynaecology Unit, Directorate of Obstetrics and Gynaecology, Derriford Hospital, Plymouth, United Kingdom Int Urogynecol J Pelvic Floor Dysfunct 2007; 18: 13–18. No Abstract Editorial Comment: This is a short and pithy comment that addresses a significant problem, and the comments are applicable not only to stress urinary incontinence, but also to the evaluation of virtually every intervention, surgical, pharmacological, electrical or behavioral, that we have in our repertoire. The exact mechanics of evaluation will differ from problem to problem (ie surgical treatment of stress urinary incontinence as opposed to behavioral and pharmacological treatment for overactive bladder) but the basic principles are the same. Evaluations fall into 1 of 3 categories: objective (such as urodynamic data); semi-objective (such as questionnaires, pad tests, bladder diaries, specific questions regarding specific symptoms); and subjective. The latter includes patient “satisfaction” indices and scales or questionnaires potentially regarding a large range of subjects: relief of the primary symptoms in qualitative terms, global improvement status and the overall effect on quality of life, with the latter being a combination of relief of the primary symptoms and the development of new symptoms, problems or complications related to these interventions. Patient “satisfaction” is really more of an integration of the factors involved in the subjective category than in the objective or semi-objective data category. Satisfaction depends, as Brubaker and Shull have pointed out,1 on patient expectations at the outset, and this, although frequently unstated, depends a great deal on what we, the treating health care professionals, tell patients when we counsel them about the alternative modalities of treatment available for a given symptom or sign. It really does not do anyone any good to have a pharmaceutical or equipment company come up with yet another “scale” that has been “validated” (meaning in most instances that if the condition improves, the score or number changes in a consistent direction, while if it worsens, it goes in the other direction, and if the condition does not change, the score stays the same) if there is not a consensus among “experts” and companies that this scale not only is valid, but should be used by everyone in evaluating their product or procedures. The author recommends that outcome measures endorsed by the International Continence Society or/and the International Consultation on Incontinence include an “independent” (presumably either subject or investigation) assessment. The Groutz-Blaivas system is specifically

VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY recommended for evaluation of incontinence outcomes,2 as well as the National Institutes of Health criteria for cure. Alan J. Wein, M.D., Ph.D. (Hon.) 1. Brubaker L and Shull B: EGGS for patient-centered outcomes. Int Urogynecol J Pelvic Floor Dysfunct 2005; 16: 171. 2. Groutz A, Blaivas JG and Rosenthal JE: A simplified urinary incontinence score for the evaluation of treatment outcomes. Neurourol Urodyn 2000; 19: 127.

Rho Kinase: A Target for Treating Urinary Bladder Dysfunction? S. L. Peters, M. Schmidt and M. C. Michel, Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Trends Pharmacol Sci 2006; 27: 492– 497. No Abstract Editorial Comment: This is a short but all encompassing review of the role of Rho kinase (ROCK) in the regulation of smooth muscle contraction, including the smooth muscle of the bladder. Although the precise role of ROCK in the bladder and the specific effects of inhibitors on bladder function have yet to be definitively determined, a role for ROCK in bladder contraction has been reported, not only for that initiated by muscarinic receptors, but also by purinergic receptors, neurokinin receptors and bradykinin receptors. Whatever the details, the authors state that “the effects of ROCK on bladder tone are likely to involve calcium sensitization” and “it has been proposed that the ROCK mediated part of bladder contraction preferentially involves M2 receptors.” Evidence suggests to the authors that ROCK inhibitors have the potential to treat filling/storage disorders, whether they are associated with muscarinic receptor mediated phenomena or those elicited by other stimuli, without interfering with physiological emptying. This is a tantalizing suggestion for another class of agents to treat disorders of filling/storage but, as the authors point out, even if future studies yield favorable efficacy, “it remains to be determined whether ROCK inhibitors share the side effects of the muscarinic receptor antagonists, particularly those related to smooth muscle tone . . . .” Alan J. Wein, M.D., Ph.D. (Hon.)

The Detrusor Muscle: An Innocent Victim of Bladder Outlet Obstruction V. Mirone, C. Imbimbo, N. Longo and F. Fusco, Urologic Clinic, University Federico II of Naples, Naples, Italy Eur Urol 2007; 51: 57– 66. Objectives: Benign prostatic hyperplasia (BPH) is considered a frequent cause of bladder outlet obstruction (BOO) and lower urinary tract symptoms (LUTS), although the physiopathologic mechanism through which BPH causes LUTS is not clear. Several morphologic and functional modifications of the bladder detrusor have been described in patients with BPH and could play a direct role in determining symptoms. The opinion is spreading that the enlarged prostates in patients with LUTS is nothing more than a mere bystander. Evidence has accumulated, however, supporting the role of BPH-related BOO as the direct cause determining bladder dysfunction and indirectly causing urinary symptoms. The present review addresses the bladder response to BOO, particularly focusing on the physiopathologic cascade that links obstructive BPH to bladder dysfunction. Methods: A literature review of peer-reviewed articles has been performed, including both in vivo and in vitro studies on human tissue and animal model experiments. Results: Epithelial and smooth muscle cells in the bladder wall are mechanosensitive, and in response to mechanical stretch stress caused by BOO, undergo modifications of gene expression and protein synthesis. This process involves several transduction mechanisms and finally alter the ultrastructure and physiology of cell membranes, cytoskeleton, contractile proteins, mitochondria, extracellular matrix, and neuronal networks. Conclusions: BOO is the initiator of a physiopathologic cascade leading to deep changing of bladder structure and function. Before being a direct cause of storing-phase urinary symptoms, the bladder is the first innocent victim of prostatic obstruction. Editorial Comment: This is an excellent summary of the molecular changes which occur in an animal (mostly) with bladder outlet obstruction in models meant to simulate prostatic obstruc-

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SOCIOECONOMIC FACTORS, UROLOGICAL EPIDEMIOLOGY AND PRACTICE PATTERNS tion. The data are observational. The clinical observation is that with bladder obstruction, at least secondary to prostatic enlargement, detrusor hypertrophy occurs and either compensation (an increase in detrusor pressure during contraction), decompensation and/or symptoms of overactive bladder with or without detrusor overactivity occur. What is lacking is the true “connection” and what determines which consequence follows. A link to overactive bladder symptoms would provide clues to prevention or treatment. The items specifically discussed under the category of detrusor alteration which occur through modification of gene expression and protein synthesis are: 1) alterations in the cytoskeleton and contractile proteins; 2) increase in the expression of several growth factors and cyclooxygenase-2; 3) swelling and structural destruction of detrusor mitochondria; 4) augmented extracellular matrix deposition with a significant increase of the type 3-to-type 1 collagen ratio; 5) down-regulation of matrix metalloproteinases and an up-regulation of tissue inhibitors of metalloproteinases; 6) increased afferent neural activity from epithelial cells, perhaps due to a higher density of mechanosensitive epithelial sodium channels; 7) activation of normally silent unmyelinated C fibers. The article also discusses the possible mechanisms by which epithelial cells and smooth muscle cells are able to change gene expression and protein synthesis in response to obstruction. Alan J. Wein, M.D., Ph.D. (Hon.)

SOCIOECONOMIC FACTORS, UROLOGICAL EPIDEMIOLOGY AND PRACTICE PATTERNS Quality of Life in Women With Urinary Stress Incontinence and Evaluation of Tension-Free Vaginal Tape Treatment J. Pozowski, A. Sobanski, D. Dudkiewicz, B. Michalski and I. Ulman-Wlodarz, Clinical Department of Gynecology and Obstetrics, Silesian Medical Academy, Tychy, Poland Gynecol Obstet Invest 2007; 64: 55– 60. Objectives: Assessment of quality of life in women stress urinary incontinence (USI) and evaluation of tension-free vaginal tape (TVT) treatment. Material and Methods: The research included a group of 112 women aged 33–78 years. Before as well as 3 and 6 months after the TVT operation, patients were asked to fill in quality of life questionnaires. Results: After 3 months 87.25% of the women reported full regression of USI symptoms, 7.8% an insignificant improvement, and 4.9% did not observe any change. After 6 months 85.71% reported full regression, 9.18% an insignificant improvement, and 5.1% did not observe any change. USI is responsible for a decrease in physical activity. The most uncomfortable symptom is involuntary urine leakage occurring mainly during an effort or sleep. After the TVT procedure, the majority of women confirmed a significant improvement in quality of life. Conclusions: The TVT procedure is an effective method of treating USI in women: it significantly improves quality of life, with a recovery rate of 85– 87%, and a low rate of complications.

Colpocleisis for Pelvic Organ Prolapse: Patient Goals, Quality of Life, and Satisfaction K. L. Hullfish, V. E. Bovbjerg and W. D. Steers, Departments of Obstetrics and Gynecology, University of Virginia Health System, Charlottesville, Virginia Obstet Gynecol 2007; 110: 341–345. Objective: To assess patient-centered colpocleisis outcomes in women. Methods: This is a prospective cohort study. Between March 2000 and December 2005, 94 patients underwent colpocleisis. Patients completed follow-up questionnaires about their personal postoperative goal attainment satisfaction with care, regrets about surgery, as well as the Incontinence Impact Questionnaire and Urogenital Distress Inventory. Results: Forty patients (42.6% of all patients) returned questionnaires with complete data on study outcomes. Mean age was 75.4 years (⫹/⫺6.8 years), and mean weight was 70.9 kg (⫹/⫺10.8 kg). Mean follow up was 2.75 years (⫹/⫺1.90 years). Most women agreed or strongly agreed that their goals were met for vaginal pressure (100%), urinary incontinence (84.9%), bladder emptying (76.4%), urinary frequency/ urgency (91.2%), physical activity (88.6%), restoration of normal anatomy (95 %), colorectal symptoms (65.0%), and self-image (96.9%). Mean goal attainment (1.4⫹/⫺0.6) was associated with the postsurgery