夜尿癥研究與治療進(jìn)展

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同濟(jì)大學(xué)附屬同濟(jì)醫(yī)院泌尿外科,上海 200065

夜尿癥研究與治療進(jìn)展

錢多成(綜述),吳登龍(審校)

同濟(jì)大學(xué)附屬同濟(jì)醫(yī)院泌尿外科,上海200065

夜尿癥是一種非常普遍但常被忽視的疾病,發(fā)病率高；以往研究證明其與抑郁、睡眠障礙、情緒障礙、摔倒等有相關(guān)性。夜尿癥病理生理機(jī)制復(fù)雜，病因多樣,定義存有爭(zhēng)議,其臨床表現(xiàn)與夜間尿頻、遺尿癥、尿失禁癥狀相似,概念很容易混淆。單一藥物治療夜尿癥往往不能取得理想的效果,多種藥物聯(lián)合應(yīng)用可能成為一種新的治療方向。本研究對(duì)夜尿的定義、病因?qū)W、鑒別診斷及治療的現(xiàn)狀和進(jìn)展進(jìn)行綜述。

夜尿癥; 下尿路癥狀; 睪酮; 診斷; 治療

根據(jù)國(guó)際尿控協(xié)會(huì)(ICS)的定義，夜尿癥是指患者迫于夜間尿意需要起床排尿1次或 1次以上,并且每次均中斷睡眠。夜尿量是指入睡后到第2天起床期間的總尿量,包括清晨起床第1次排尿量[1]。但是,ICS對(duì)夜尿癥的定義沒(méi)有考慮尿量等一些具體指標(biāo),過(guò)去WHO 和很多研究人員都以每晚≥2次排尿作為夜尿癥的診斷標(biāo)準(zhǔn)。目前,很多學(xué)者以>1 mL/min作為夜尿癥的標(biāo)準(zhǔn)[2]。

1 夜尿癥的流行病學(xué)

夜尿癥是臨床上較常見(jiàn)的疾病,有70%的中年人受影響,目前夜尿癥已經(jīng)成為老年人常見(jiàn)的一種癥狀,同時(shí)也是泌尿外科的比較常見(jiàn)的疾病[3]。有研究表明,夜尿增多將會(huì)導(dǎo)致老年人死亡率增加[4],隨著夜尿癥患者增多,也引起了很多學(xué)者的重視。在過(guò)去,很多學(xué)者認(rèn)為,夜尿癥是一種簡(jiǎn)單的下尿路癥狀(LUTS),現(xiàn)研究表明,一般來(lái)說(shuō),夜尿癥隨著年齡的增長(zhǎng)而變得越來(lái)越普遍,這是社會(huì)老齡化的特征性疾病,夜尿癥嚴(yán)重影響老年人身體健康和生活質(zhì)量,與抑郁、認(rèn)知功能障礙、情緒障礙、摔倒和骨折等密切相關(guān),隨著現(xiàn)代社會(huì)生活質(zhì)量的提高,夜尿癥對(duì)人類健康的影響越來(lái)越受重視。在芬蘭,研究人員發(fā)現(xiàn)在18～79歲的人群中,在夜間排尿>1次的人群中,男性與女性的比例分別為43%、37%,如果夜間排尿≥2次,男女比例為12%、13%[5-6]。研究發(fā)現(xiàn),夜尿癥會(huì)隨著年齡增長(zhǎng),發(fā)病率呈現(xiàn)上升趨勢(shì),最新研究顯示,每晚≥2次排尿的夜尿癥患者,在20～40歲人群中的發(fā)病率為2%～18%[7],70歲以上老年人中,夜尿癥的患病率超過(guò)60%[8]。

2 夜尿癥的病因及分類

2.1 多尿癥

多尿癥的定義為24 h產(chǎn)尿>2 500 mL,有些研究人員定義為尿量>40 mL/kg[9],多尿癥有夜間尿液增多和全天多尿,夜間多尿多見(jiàn)于夜間抗利尿激素分泌減少、心房利鈉肽分泌增加、充血性心力衰竭、阻塞性睡眠呼吸暫停綜合征、腎病、高蛋白血癥、夜間煩渴及酗酒患者[10];全天多尿的常見(jiàn)病因?yàn)樘悄虿?、尿崩癥、習(xí)慣性煩渴、腎功能不全、高鈣血癥和尿鈣增多等疾病;但引起多尿癥最常見(jiàn)的原因有糖尿病、尿崩癥和原發(fā)性煩渴癥[11]。

2.2 夜間膀胱容量減少

夜間膀胱容量減少是指夜間排尿時(shí)膀胱容量小于膀胱容量。夜間排尿次數(shù)=夜間尿量/功能性膀胱容量-1,在臨床分為兩種類型:解剖性膀胱容量減少或者功能性夜間膀胱容量減少。兩種情況的條件均為夜間的尿量超出膀胱承載的最大容量,當(dāng)夜間尿量大于膀胱容量過(guò)度活動(dòng)、膀胱出口梗阻殘余尿量增多、膀胱過(guò)度敏感、膀胱占位、膀胱壁纖維化及外科術(shù)后膀胱功能障礙引起;抑郁、焦慮、激動(dòng)劑的使用以及年齡相關(guān)的褪黑素不足誘發(fā)睡眠障礙[12]。

2.3 混合型夜尿癥

許多患者并不是表現(xiàn)為單一的夜尿增多或者膀胱有效容量減少,而表現(xiàn)為二者兼有的混合性夜癥。一項(xiàng)近期對(duì)850例膀胱過(guò)度活躍的患者的調(diào)查顯示,年輕人主要是由于夜間膀胱容量減少,老年人多與夜間多尿密切相關(guān)[13]。對(duì)194例患有夜尿癥調(diào)查顯示:由于夜間多尿引起的夜尿癥占7%,低夜間膀胱容量占57%,解剖性膀胱容量減少引起的多尿占23%,夜間多尿和低夜間膀胱容量混合性夜尿癥的比例達(dá)到36%[14]。

2.4 夜尿癥與睪酮

在男性中,下尿路癥狀(LUTS)是一種常見(jiàn)的男性疾病,會(huì)隨著前列腺體積的增加,癥狀更加明顯。50歲以后,LUTS的發(fā)病率隨之增加,據(jù)統(tǒng)計(jì),隨著老齡化加重,男性總體發(fā)病率>50%。老年男性血清中睪酮水平逐漸下降,其降低與晚發(fā)性性腺功能減退癥(LOH)綜合征的癥狀有關(guān)[15]。LOH綜合征包括一系列臨床癥狀,其中包括性欲減少,肌無(wú)力,內(nèi)臟脂肪增加,肥胖,骨質(zhì)疏松癥,貧血和胰島素敏感性降低等[15-18]。最近的研究表明,睪酮缺乏也與LUTS發(fā)展有關(guān)[19]。多項(xiàng)研究認(rèn)為,睪酮缺乏癥對(duì)整體睡眠質(zhì)量有負(fù)面影響。這些發(fā)現(xiàn)表明睪丸激素與老年男性夜尿癥的發(fā)展具有直接或間接的關(guān)系。

3 夜尿癥的鑒別診斷

由于夜間多尿癥、夜間尿頻、夜間遺尿癥、尿失禁與夜尿癥癥狀相似,須注意鑒別。(1)夜尿癥與夜間多尿癥的鑒別:夜間多尿癥指夜間尿量占24 h尿量的比例升高。青年人夜間尿量≥24 h尿量的20%,中年人夜間尿量≥24 h尿量的20%～30%,老年人夜間尿量≥24 h尿量的3%。(2)夜尿癥與夜間尿頻的鑒別:夜間尿頻指夜間從以睡覺(jué)為目的的上床休息開(kāi)始到醒來(lái)后起床為止這段時(shí)間內(nèi)排尿次數(shù)增多。夜尿癥是在夜間睡眠中醒來(lái)排尿,排尿前后均為睡眠狀態(tài),不包含上床至入睡以及睡眠中醒來(lái)至起床這兩個(gè)時(shí)間段[20]。(3)夜尿癥與夜間遺尿癥的鑒別:夜間遺尿癥指年齡≥5歲的患者夜間睡眠中尿液非自主性漏出。夜間遺尿癥患者睡眠中不能意識(shí)到膀胱充盈憋脹感,而非自主性尿液漏出。夜尿癥患者睡眠中可以意識(shí)到膀胱充盈憋脹感,并從睡眠中醒來(lái)排尿。(4)夜尿癥與尿失禁的鑒別:尿失禁指尿液非自主的漏出,與睡眠無(wú)關(guān)。尿失禁常見(jiàn)有充盈性尿失禁和急迫性尿失禁。尿失禁患者可以感知膀胱充盈,從睡眠中醒來(lái),但醒來(lái)后不能抑制尿液排出,出現(xiàn)尿液非自主的漏出。而夜尿癥患者醒來(lái)后可以控制尿液排出。

4 夜尿癥的治療

4.1 行為干預(yù)治療

調(diào)整日常飲食,減少飲用酒精和咖啡類飲料,睡前限制液體攝入;睡前穿長(zhǎng)筒襪及下午提升腿部可減少水腫,加強(qiáng)鍛煉,增強(qiáng)體質(zhì)。膀胱過(guò)度活動(dòng)癥(OAB)患者加強(qiáng)膀胱功能訓(xùn)練,逐漸減少排尿次數(shù),加強(qiáng)盆底功能鍛煉,增強(qiáng)盆底肌收縮力;睡前排尿;尿流率低、殘余尿量增多的患者,建議睡覺(jué)前排尿采用2次或多次排尿法盡可能排空尿液,減少殘余尿量;重癥患者常需聯(lián)合藥物治療。Soda等[21]研究發(fā)現(xiàn),鍛煉身體與夜尿癥負(fù)相關(guān),在男性中,每周活動(dòng)≥1 h,夜尿癥的發(fā)生率減少13%,重度夜尿癥的發(fā)生率減少34%,Hashim等[22]研究發(fā)現(xiàn),行為治療下超過(guò)50%的患者夜尿癥狀改善。而OAB患者液體攝入量減少25%,夜尿癥患者夜尿次數(shù)減少,限制前后依次為1.4次和1.3次(P<0.05),當(dāng)液體攝入量減少32%時(shí),夜尿癥的發(fā)生由2.3次/晚減少至1.8次/晚[23],行為干預(yù)聯(lián)合特拉唑嗪、扎來(lái)普隆治療,平均夜尿次數(shù)由2.6次/晚減少至1.9次[24]。

4.2 藥物治療

BPH是夜尿癥最常見(jiàn)的病因,治療BPH常見(jiàn)藥物有 α-受體阻滯劑、5α-還原酶抑制劑、磷酸二酯酶抑制劑和植物制劑等。文獻(xiàn)報(bào)道,藥物治療后BPH平均改善為9.5%～33%,但藥物干預(yù)組和安慰劑組夜間排尿次數(shù)改變僅差0.2次[24]。多沙唑嗪、非那雄胺聯(lián)合治療,治療組較安慰劑組夜間排尿次數(shù)明顯減少,但與多沙唑嗪?jiǎn)嗡幹委熛啾?聯(lián)合用藥并未出現(xiàn)協(xié)同效應(yīng)[25],α-受體阻滯劑聯(lián)合磷酸二酯酶抑制劑同樣未發(fā)現(xiàn)協(xié)同效應(yīng)[26]。Kawahara等[27]聯(lián)合催眠藥雷美替胺和 α1-受體阻滯劑治療的夜尿癥伴BPH中發(fā)現(xiàn),雷美替胺聯(lián)合 α1-受體阻滯劑治療4周,IPSS夜尿癥得分由2.88減小到2.41,OABSS夜尿癥得分2.63減少到2.13 。Shin等[28]報(bào)道氯索洛芬、α-受體阻滯劑及5α-還原酶抑制劑聯(lián)合治療夜尿癥伴BPH患者較α-受體阻滯劑聯(lián)合5α-還原酶抑制劑治療效果顯著,治療3個(gè)月后兩組夜尿發(fā)生次數(shù)較基線及夜尿減少次數(shù)之間均存在顯著性差異。其他研究發(fā)現(xiàn),鎮(zhèn)靜催眠藥奧沙西泮可以使夜尿發(fā)生次數(shù)減少63%[29]。

4.3 去氨加壓素的治療

抗利尿激素是一種人類合成類似物,醋酸去氨加壓素自1974年上市以來(lái)就開(kāi)始在治療尿崩癥和夜尿癥中被廣泛應(yīng)用。大量的臨床研究已證明醋酸加壓素在治療夜尿癥中療效顯著[30]。抗利尿激素能調(diào)節(jié)人體內(nèi)液體總量和滲透平衡。血漿滲透壓的升高會(huì)刺激腦下垂體分泌精氨酸抗利尿激素,從而促進(jìn)腎重吸收水分,減少尿量。去氨加壓素可以模擬精氨酸抗利尿激素與腎遠(yuǎn)端集合小管上V2受體結(jié)合,濃縮尿液,降低總尿量[31]。而去氨加壓素比生理性精氨酸加壓素作用更強(qiáng)。針對(duì)不同年齡、不同性別患者的長(zhǎng)期和短期研究已經(jīng)證實(shí)去氨加壓素在治療夜尿癥中的功效[31-32]。研究發(fā)現(xiàn)與安慰劑對(duì)比,去氨加壓素能顯著減少夜間尿量,減少夜尿次數(shù),提高患者生活質(zhì)量。但值得注意的是,該藥也存在腹痛、頭痛、失眠和低鈉血癥等多種不良反應(yīng)。其中低鈉血癥是藥物相關(guān)的唯一嚴(yán)重并發(fā)癥,低鈉血癥的風(fēng)險(xiǎn)隨著年齡的增加而增大[33],多數(shù)發(fā)生在65歲以上老年人。存在低鈉血癥的65歲以上的高齡患者,應(yīng)避免使用去氨加壓素[34]。

4.4 抗毒蕈堿劑

抗毒蕈堿劑是一類被廣泛應(yīng)用于治療膀胱過(guò)度活動(dòng)癥(OAB)的藥物。包括酒石酸托特羅定、琥珀索利那新等。乙酰膽堿通過(guò)與毒蕈堿受體結(jié)合介導(dǎo)膀胱收縮和排尿,抗毒蕈堿劑可直接通過(guò)與毒蕈堿受體結(jié)合抑制逼尿肌收縮從而緩解尿頻。研究表明,抗毒蕈堿劑還可能通過(guò)抑制傳人神經(jīng)發(fā)揮作用,從而緩解尿急癥[35-36]。毒蕈堿受體在人體內(nèi)分布廣泛,全身用藥可能引起便秘、口干、頭痛和頭暈等不良反應(yīng),發(fā)生率<10%[37]。在臨床應(yīng)用中發(fā)現(xiàn)抗毒蕈堿劑可以通過(guò)抑制膀胱不穩(wěn)定收縮,降低膀胱敏感性,增加功能膀胱容量,適用于夜間膀胱容量縮小的患者。目前有關(guān)于抗毒蕈堿在治療夜尿癥中療效的理論基礎(chǔ)還較少,需要進(jìn)一步驗(yàn)證。

4.5 睪酮替代治療

睪酮替代療法(TRT)是目前比較熱的新技術(shù),一項(xiàng)在509例年齡40歲至79歲男子的研究發(fā)現(xiàn)，血清睪酮激素水平與夜尿癥顯著相關(guān),而上四分位數(shù)血清睪酮水平的男性為44%,在最低四分位數(shù)中,發(fā)生夜尿的風(fēng)險(xiǎn)降低[38],另一項(xiàng)涉及2 180例患者的研究表明,每當(dāng)晚上患者醒來(lái)時(shí),睪酮激素下降0.142 μg / L,特別是夜尿多尿的患者,均伴有血清睪酮的下降[39],Kim等[40]指出,血清總睪酮水平可能對(duì)下尿路癥狀的發(fā)展有一定作用,并表明它們?cè)诨加?次或更多次患者中夜尿水平顯著降低,在一組632例患者中,患者平均總睪酮激素水平為(2.21±0.51) μg/mL,夜尿癥患病率較高[41],經(jīng)過(guò)TURP手術(shù)，睪酮水平較低的患者中也經(jīng)常觀察到夜尿癥狀[42]。血清睪酮水平降低,男性夜尿癥狀明顯增加,經(jīng)過(guò)12周的去氨加壓素治療,可明顯改善低睪酮水平。睡眠障礙是夜尿發(fā)生的一個(gè)重要原因,最近的研究表明內(nèi)源性睪酮激素產(chǎn)生依賴于睡前3小時(shí)不間斷的深度睡眠,并且各種睡眠障礙,包括異常睡眠質(zhì)量和持續(xù)時(shí)間,晝夜節(jié)律紊亂,睡眠呼吸暫停綜合征(SAS)均可降低睪酮水平[43-44]。最近的一項(xiàng)隨機(jī)臨床試驗(yàn)發(fā)現(xiàn)TRT改善男性夜尿癥,睡眠狀況和生活質(zhì)量[45]。Yassin等[46]報(bào)道,TRT可以改善夜尿癥患者的IPSS評(píng)分,殘余尿和膀胱壁厚度,并且TRT中斷導(dǎo)致這些臨床狀況惡化?；趬毫α鲃?dòng)研究,TRT被發(fā)現(xiàn)有助于前列腺體積的顯著增加和改善,在IPSS評(píng)分中,并且顯著增加最大膀胱容量和依從性,改善儲(chǔ)尿癥狀。

5 結(jié)論

夜尿癥近年來(lái)一直備受關(guān)注,嚴(yán)重影響身體健康和生活質(zhì)量,目前定義存在一定爭(zhēng)議,缺少量化指標(biāo),缺乏統(tǒng)一規(guī)范,給相關(guān)研究人員帶來(lái)極大困擾。夜尿癥不是一種單一的疾病,而是多因素導(dǎo)致的一大類年齡相關(guān)性疾病,隨著現(xiàn)代社會(huì)的發(fā)展和老齡化社會(huì)的到來(lái),夜尿癥逐漸引起醫(yī)務(wù)人員及患者的重視,夜間多尿、全天多尿、膀胱容量減少和睡眠障礙是主要原因。詳細(xì)詢問(wèn)病史、體格檢查和輔助檢查,記錄72 h排尿日記,全面評(píng)估病情是診斷夜尿癥的基本流程。由于夜尿癥病情復(fù)雜,單一藥物的治療往往不能取得理想的效果,常需個(gè)體化、聯(lián)合用藥。使用去氨加壓素、利尿劑等夜尿癥狀明顯緩解。目前夜尿癥對(duì)聯(lián)合治療的研究較少,TRT治療是一種最新方法,還沒(méi)有被推廣,隨著研究的深入,必將成為一種新的治療方法。

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Advancesonresearchandtreatmentofnocturia

QIANDuocheng,WUDenglong

DepartmentofUrology,TongjiHospitalAffiliatedtoTongjiUniversity,Shanghai200065,China

Nocturia is a very common but often overlooked disease,with a high morbidity.Previous studies have shown a correlation with depression,sleep disorder,mood disorder,and fall.The pathophysiological mechanism of nocturia is diverse and the definition is controversial.Its clinical manifestations are similar to nocturnal urination,enuresis,and urinary incontinence.The treatment for nocturia using a single medicine often fails to achieve desired effects,whereas combinations of drugs may be a new direction.This article reviewed the definition,etiology,differential diagnosis,and treatment of nocturia.

Nocturia; Symptom of lower urinary tract; Testosterone; Diagnosis; Treatment

R656

A

2095-378X(2017)03-0198-05

2017-07-04)

錢多成(1989—),男,碩士研究生,從事泌尿外科

吳登龍,電子信箱:wudenglong@163.com

10.3969/j.issn.2095-378X.2017.03.015