Urodynamic evaluation of antimuscarinic drug effect on lower urinary tract function in women with overactive bladder

Summary
Background
The International Continence Society (ICS) in 2002 derived a consensus for symptomatic definition of overactive bladder (OAB) as urinary urgency, with or without urge incontinence, usually with urinary frequency (voiding eight or more times in a 24-hour period), and nocturia (awakening two or more times at night to void), in the absence of pathologic or metabolic factors that would explain these symptoms (Abrams, 2002).
OAB occurs in an estimated 17% of the population, and the frequency increases with age in the United States (Stewart, 2003)and 18.6% in Taiwan (Chen, 2003). In European countries, the overall prevalence of OAB symptoms in individuals aged 40 years and more was 16.6%. The prevalence of OAB is similar to or higher than the rates of most other chronic diseases, including asthma, coronary-artery disease, and peptic-ulcer disease (Milsom, 2001).
The potential risk factors that might predispose women to the occurrence of OAB were elderly, menopausal, vaginal deliveries, higher BMIs (≧75 percentile), parities >2, symptoms of uterovaginal prolapse, a history of diabetes or hypertension (Chen, 2003; Teleman, 2004).
Overall, the effects of OAB on quality of life are profound (Stewart, 2003), but many affected individuals do not seek help from professionals (Milsom, 2001). In the aspect of lower urinary tract symptoms, the symptoms of OAB impair quality of life much more than the symptoms of stress urinary incontinence. The reason is the unpredictable nature of the urinary symptoms associated with detrusor instability (Kelleher, 1997). Patients with symptoms of OAB tend to curtail their participation in social activities and to isolate themselves and are predisposed to depression (Dugan, 2000). Nocturia is associated with sleep disruption, which decreases the quality of life. Postmenopausal women with urge incontinence have a substantially higher risk of falling and sustaining a fracture than women without urge incontinence (Brown, 2000). People with OAB have a greater risk of being injured in a fall (Wagner, 2002). Besides, nocturia is also a risk factor for falls in the elderly (Stewart, 1992). Nocturia also makes the hypertension poor control.
The pathophysiology of OAB is very complicated. The common view is that in OAB which is stimulated by acetylcholine released from activated cholinergic (parasympathetic) nerves and this phenomenon may make patient suffer from urgency, frequency and nocturia (Chapple, 2000). OAB is associated with the effects on neurologic control or myogenic activity by a variety of conditions, including :
(1) Neurologic illness or injury, most commonly spinal cord injury, stroke, Parkinson disease, Alzheimer disease, diabetes, spinal stenosis, and multiple sclerosis and similar demyelinating diseases;
(2) Bladder outlet obstruction that affects sensory and motor aspects of voiding reflexes and leads to changes in bladder muscle structure and function;
(3) Urethral weakness associated with intrinsic sphincter deficiency and pelvic relaxation in middle-aged and elderly women;
(4) Detrusor hyperactivity and impaired contractility in elderly patients;
(5) Emergence of new voiding reflexes mediated by unmyelinated capsaicin-sensitive C-afferents, leading to hypersensitivity-induced overactivity; and
(6) So-called idiopathic bladder overactivity, which may be caused by some parts of all these categories or factors not yet discovered(Staskin, 2002).
Currently, it is difficult to consolidate our knowledge about OAB and its causes into a single theory. There are simply too many observations that do not easily fit together. It has also been difficult to integrate experimental results on changes in bladder muscle with changes seen in afferent nerve activity after bladder outlet obstruction. Although these changes may occur concurrently in humans and other animals, it is not clear how to integrate our knowledge about them. Additional research into the etiology of OAB is needed.
The treatment of OAB includes behavioral treatment, pelvic floor muscle rehabilitation, biofeedback treatment, pharmacologic treatment, neurostimulatory, or surgical modalities. Pelvic floor muscle rehabilitation focuses more on altering the physiologic responses of the bladder and pelvic floor muscles. Biofeedback can help patients learn to inhibit bladder contraction using pelvic floor muscle contraction and other urge suppression strategies (Rovner, 2002).
The first-line pharmacological treatment of OAB has been and still is antimuscarinic (anticholinergic) drugs (Andersson, 2004). There is much evidence that the treatment is associated with side-effects that limit its clinical use because of widespread of many types of muscarinic receptor over the whole body. A recent meta-analysis of randomized controlled trials on antimuscarinic treatment (Tolterodine) of OAB concluded that the drugs produce significant improvements in OAB symptoms compared with placebo (Chapple, 2005). Due to its high selectivity to bladder and less side effect of dry mouth and constipation, Tolterodine has become the first choice for patient with OAB.
However, in normal physiological state, there is a massive release of acetylcholine during voiding phase of bladder contraction. Does Tolterodine inhibit detrusor contraction during voiding phase of bladder which induces voiding dysfunction due to hypoactive detrusor and increases residual urine amount or decreases urinary flow rate?
This study was to evaluate effects of antimuscarinic drug on lower urinary tract function by urodynamic assessment in female patients with OAB, especially focused on detrusor function and residual urine amount.
Women with OAB symptoms can show variable findings on filling cystometry. The bladder may show unstable phasic contractions (of any amplitude) that cannot be suppressed (detrusor instability), a tonic rise in bladder pressure (reduced bladder compliance), or a stable but low capacity as a result of pain or urgency (Dwyer, 2002).
In clinical observation, some patients with OAB revealed voiding dysfunction in the urodynamic study. The definition of voiding dysfunction is maximal flow rate < 15 ml/sec or post void residual > 150ml (Stanton, 1983; Dwyer, 1994; Everaert, 2000). We also want to know whether the voiding function will deteriorate or not after antimuscarinic drug treatment in these OAB with voiding dysfunction patients.

Material and methods

We planned to collect at least 30 subjects with OAB from our urogynecology outpatient department. After urodynamic study and pad test screening, subject will be prescribed Tolterodine 2mg 1# BID for six months continuously. After six-month treatment, each subject will perform urodynamic study and pad test again. Paired t-test will be used to evaluate whether there is statistical difference between pre- and post-treatment urodynamic variables by computer statistical soft ware (Stata, 8th version). A p value < 0.05 was considered statistically significant.

Results

There were forty-four patients enrolled in this study. Three patients (6.9%) dropped out of the study due to side effect (dry mouth). Four patients (9%) lost follow-up. Four patients (9%) completed the six-month treatment but did not undergo the second urodynamic study. Totally thirty-three (70%) women who completed the six-month treatment were evaluated before and after treatment. The average age was 51.9 yeas old. Seventeen (51.5%) patients were menopausal.
Among 33 patients, the urodynamic reports of the 30 patients revealed low capacity and hypersensitive bladder. The urodynamic reports of the remaining 3 patients revealed detrusor instability or idiopathic detrusor overactivity (Abrams, 2002). No patient had low compliance bladder.
Besides, maximal flow rate in 12 patients with OAB was smaller than 15 ml/sec. They were OAB with voiding dysfunction patients. Among the 12 patients, the urodynamic reports of 11 patients showed hypersensitive bladder with voiding dysfunction and remaining one patient showed idiopathic detrusor overactivity with voiding dysfunction. The average age of this group was 54.3 years old.
In total 33 patients, the amounts of first-sensation, first-desire, strong-desire and urgency showed statistically significant increases after Tolterodine treatment. Detrusor pressure at maximal flow rate, maximal flow rate, average flow rate and voiding time showed no statistically significant differences. The residual urine amount had statistically significant increase after treatment but the average amount was within normal range and had no clinical significance. The pad weight results had statistically significant decrease but had no clinical significance. Besides, the 12 patients with OAB and voiding dysfunction revealed the similar results mentioned above.

Discussion

The side effects of antimuscarinic drug should be notified to patients due to some patients could not tolerate it. According to our study, antimuscarinic drug is effective to distend bladder volume in hypersensitive bladder patients and to stabilize detrusor activity in patients with detrusor overactivity.
The parameters of voiding function except post void residual showed no statistical difference in total 33 patients. However, post void residual just increased from the average amount of 38 ml to 56.5 ml. Clinically, post void residual around 50 ml is normal. Post void residual larger than 100 ml is just a suspicious voiding problem. Detrusor pressure at maximal flow rate decreased from average pressure of 32.1 cmH2O to 29.8 cmH2O but was still within normal limit. These data revealed that Tolterodine treatment for patients with OAB is safe and effective.
The storage parameters revealed statistically significant increase which means Tolterodine treatment could enlarge bladder capacity and relieved the frequency and urgency symptoms of OAB.
The continent parameters except functional profile length did not show statistical change after treatment. The fact that muscarinic receptors distributed not only bladder but also urethra could explain this effect (Mutoh, 1997).
Patients with OAB and voiding dysfunction treated with Tolterodine still could benefit from the increase of bladder capacity and stability of detrusor muscle, but the low maximal flow rate still kept the same condition. However, we need a study of larger sample size to support this point.