以尿路動力學評估抗毒蕈鹼藥物對膀胱過動症婦女下泌尿道功能的影響

Abstract

一、中文摘要 背景與目的 膀胱過動症(overactive bladder)是指急尿症狀的存在，合併或不合併急尿性尿失禁的發生，這類患者通常也有頻尿和夜尿的症狀，而沒有任何病理或代謝的因素可以解釋這些症狀。膀胱過動症的盛行率，依照國外文獻大約佔百分之十七的人口比例，而且比率隨著人口年紀增長而增加。台灣本地的狀況，陳等人於2003年進行國人膀胱過動症盛行率之調查，佔有百分之十八點六的人口比例，而超過六十五歲者，其比率更高達百分之三十九點三。 膀胱過動症的發生雖不至於明顯地妨害到患者的身體健康或威脅到患者生命，但卻嚴重地影響患者的生活品質產生焦慮不安、不願外出，或對社交卻步，然而患者去尋求醫療協助的卻不多。 膀胱過動症的確實致病機轉有許多理論，推論可能是各種原因造成膀胱在儲尿時期其副交感神經的乙醯膽鹼分泌過多且作用在毒蕈鹼接受器上，造成膀胱的感覺變的較為敏感或引發膀胱無法被抑制的收縮，患者於是出現急尿、急尿性尿失禁、頻尿或夜尿等症狀。 抗毒蕈鹼類藥物由於能抑制毒蕈鹼受體進而抑制膀胱的收縮和降低膀胱的敏感性，因此可以用來治療膀胱過動症。臨床上使用這類藥物來治療膀胱過動症確實可以得到一定的療效，但是由於毒蕈鹼接受器廣泛的分佈在全身，因此傳統的抗毒蕈鹼類藥物會出現一些令人不悅的副作用，如口乾、便秘等。新一代的抗毒蕈鹼類藥物(Tolterodine L-tartrate)由於對於膀胱的高度選擇性及低副作用，目前已成為治療膀胱過動症的最佳選擇藥物。 然而抗毒蕈鹼藥物雖可抑制膀胱在儲尿時期副交感神經分泌的乙醯膽鹼透過毒蕈鹼接受器所刺激的逼尿肌不自主收縮，以達到減少急尿、頻尿及夜尿的效果。然而在排尿時期，副交感神經分泌乙醯膽鹼透過毒蕈鹼接受器所刺激的逼尿肌收縮卻是膀胱正常排尿功能所必須的機轉。抗毒蕈鹼藥物是否會在排尿時期抑制了正常的逼尿肌收縮，導致逼尿肌的功能低下，使得排尿量減少而殘尿量的增加，造成下泌尿道症狀的惡化，因為文獻上並沒有這方面的報告，我們希望對這一問題做進一步探討。 另外在臨床上的觀察，可發現在膀胱過動症的患者中，其實隱藏了一部份排尿功能障礙的患者。這些膀胱過動症再加上排尿功能障礙的患者，他們再接受抗毒蕈鹼藥物治療，是否會雪上加霜更加惡化其排尿功能障礙，這也是我們想探討之處。 本研究的目的希望能藉由尿路動力學的測量，來得知膀胱過動症患者經由抗毒蕈鹼藥物治療後，其下泌尿道功能參數在尿路動力學上的變化，特別是逼尿肌的功能有無受影響，殘尿量有無增多等。 材料與方法 預計自本院婦女泌尿門診收集三十位以上膀胱過動症患者參與此次研究。臨床症狀符合膀胱過動症者，安排接受尿路動力學檢查。然後開始服用抗毒蕈鹼藥物。抗毒蕈鹼藥物我們選擇現今治療膀胱過動症的首選藥物Tolterodine L-tartrate(商品名Detrusitol®)，劑量為一顆兩毫克，一天服用兩次。請患者於服用六個月後再做一次尿路動力學檢查，運用Stata電腦統計軟體第八版來做統計分析，使用配對t檢定(paired t-test)，檢定各個尿路動力學變項在治療前及治療後是否有統計學上的差異。 結果 膀胱過動症婦女經過六個月的治療後，膀胱灌注初感覺、第一次感覺排尿感、強烈排尿感、急迫感，這些尿路動力學的參數代表膀胱的感覺與容量，數值上皆有增加，而且在統計上有顯著的意義，代表Tolterodine L-tartrate確實可以增加膀胱容積，以減少膀胱過動症者頻尿、急尿的發生。 另外，最大尿流速之逼尿肌壓力、最大尿流速、平均尿流速、排尿時間等在統計學上均沒有顯著的差異，代表Tolterodine L-tartrate並不會影響膀胱排尿的功能。而排尿後殘尿雖然在統計學上有顯著的差異，但是在臨床上，50毫升左右的殘餘尿量是屬於正常可接受的範圍內，患者本身不會有殘尿的感覺，也不會增加尿道感染的機率。護墊測漏試驗的比較雖然在統計上有顯著的意義，但是在臨床上護墊測漏試驗小於兩公克是屬於正常範圍，故在臨床上不具有特別意義。 膀胱過動症合併排尿功能障礙婦女經過六個月的治療後，結果也相似，代表膀胱的感覺與容量的尿路動力學參數，數值上皆有增加，而且在統計上有顯著的意義，代表Tolterodine L-tartrate確實可以增加膀胱容積，以減少膀胱過動症者頻尿、急尿的發生。另外，最大尿流速之逼尿肌壓力、最大尿流速、平均尿流速、排尿時間、排尿後殘尿等在統計學上均沒有顯著的差異，代表Tolterodine L-tartrate既使在膀胱過動症合併排尿功能障礙婦女身上使用，也不會影響膀胱排尿的功能。 結論 本研究顯示膀胱過動症婦女經由抗毒蕈鹼藥物治療後，確實可以增加膀胱容積，以減少頻尿、急尿的發生，並且不會影響膀胱排尿的功能。

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.