Clinical symptoms evaluation for ketamine cystitis Reporter: Dr. Liang-Kang Huang R3 Preceptor: Dr. Yu-Chao Hsu M.D. 座長，各位醫師大家好，我是林口長庚泌尿科的R3黃亮鋼，今天很榮幸能為大家present這個study,臨床上看到一些吸食Ｋ他命的病人,在長時間的吸食過後,或產生一些泌尿道的症狀,而我們想針對這些病人的症狀做一個評估

What is Ketamine K他命是一種NMDA的receptor,他最早從1960年代起被用作麻醉藥的用途,他的特色是作用時間短且藥效快，Ｋ他命以許多種形式流通於市面上，有錠劑，膠囊，粉劑等等，最常見的是捲菸的形式，這些吸食者先以信用卡或小紙片將Ｋ他命切成粉末再捲成Ｋ菸後吸食，病人普遍在吸食過後會產生一些分離性的幻覺,從吸入之後,大概十幾分鐘的時間會開始發揮藥效,持續約一個小時後,由肝臟代謝,並且經由尿液排出

What is Ketamine 而病人在長時間的使用過後,會產生如下腹部的疼痛,急尿,頻尿等等的症狀,前一陣子,甚至出現”拉k一時,尿布一世”的警語

What is Ketamine 在台灣，Ｋ他命以經被列為第三及管制藥， 目前僅次於安非他命，因為其較容易取得加上相關的罰則較輕微，在青少年族群中尤其氾濫，以18~24歲這個族群最多

Purpose To identify The risk factors of ketamine abusers developing urological symptoms What is the timing of causing irreversible urological injury 因此，我們所做的這個study便是針對這些吸食Ｋ他命而產生泌尿道症狀的病人，探討他們的risk factor以及在吸食多久之後可能會造成這樣不可逆的情況

Patients and Methods From August 2011 to December 2016 Urological out patient department of Chang Gung Memoral Hospital, Linkou and Keelung distribution Ketamine users with urological problems Total 130 patients 我們的database主要 from August 2011 to December 2016,在這段期間因為長期使用Ｋ他命而有泌尿道方面的症狀並來長庚的泌尿科門診求診的病人，總共有130位病人

Patients and Methods Chart review Symptoms OABSS categories and pain score Bacteriuria was defined as urine culture positive Image finding by CTU, IVP or kidney echo Bladder capacity by urodynamic study Statistics SPSS Ver.22 Calculated by T test, Chi-square and ANOVA 我們主要是根據chart review來收集病人的 OABSS categories, images, urine analysis and urodynamic studies 如果ＵＣ的結果是positive則定義為有baceteruria的情形 而image的部分主要是根據IVP,CTU及kidney echo 另外膀胱容量的部分是以urodynamic study的結果來判斷

Results 接下來是結果的部分

Percentage of Gender Male 69% (90/130) Female 31% (40/30) 在我們的study中,男性大約佔七成

Age distribution Average: 27.89 years old 平均年齡則是28歲，以26~30這個族群人數最多

Drugs usage duration and doses Average: 4.34 years Average: 4.02 g/day 這些病人平均吸食時間是4.3年,吸食量大約是每天4克

Urine analysis High prevalence of hematuria and pyuria Few proved to be bacteriuria 大部分的病人UA驗起來有hematuria及pyuria的情形,大約兩成有baceteruria的狀況

Image study of urinary tract Cystitis were seen in most of the patients Relatively few patients have hydronephrosis Image的部分，在七成的病人身上可以看到一個shrinkage或者有wall thickening的bladder,而大約兩成的病人有hydronephrosis的狀況

Duration vs Symptoms No significant difference between symptoms and duration. Duration < 5 years % or Mean ± SD, N=65 Duration ≧ 5 years % or Mean ± SD, N=54 P value Pain 65% 74% 0.267 Urgency 38% 44% 0.513 Frequency(Mins/Time) 56.14 ± 54.56 55.37 ± 53.24 0.939 Nocturia(Times) 4.02 ± 4.14 3.94 ± 3.84 0.924 Incontinence 11% 17% 0.352 接下來我們想要探討在吸食時間長短的部分,是否會影響到症狀的嚴重程度，我們將病人以五年作為一個cut point，大於五年跟小於五年來做比較，這邊可以看到在症狀各方面兩個族群都是沒有明顯差異的

Duration vs Cystitis No significant difference between cystitis and duration, either. Duration < 5 years % or Mean ± SD, N=62 Duration ≧ 5 years % or Mean ± SD, N=54 P value Urine analysis RBC 55% 54% 0.904 Urine analysis WBC 58% 59% 0.897 Urine culture 17% 22% 0.568 同樣，在UA,UC及image等部份兩個族群也是沒有明顯差異的 Duration < 5 years % or Mean ± SD, N=39 Duration ≧ 5 years % or Mean ± SD, N=44 P value Cystitis 69% 73% 0.73

Duration vs Bladder capacity No matter functional or total capacity, has a significant finding with relationship to duration. Duration < 5 years % or Mean ± SD, N=17 Duration ≧ 5 years % or Mean ± SD, N=18 P value Bladder functional capacity(ml) 144.06 ± 112.33 65.67 ± 95.66 0.033* Bladder total capacity(ml) 157.06 ± 112.67 80.50 ± 103.66 0.047* Bladder functional capacity代表的是在病人自主解尿時所解出的尿液量,而bladder total capacity代表的則是加上解尿後加上餘尿的部分，在這邊可以看到，不論是在bladder functional或total capacity的部分，兩者都是有顯著差異的，也就代表，今天隨著吸食Ｋ他命時間的增加，膀胱的容量會逐漸變小

Duration vs Bladder capacity 做成圖表可以更清楚地看到，在吸食五年以上的這個族群，膀胱的容量大約只有五年以下的二分之一

Discussion 接下來進入discussion的部分

Discussion First case report about ketamine and cystitis at Shahani et al in 2007.(Shahani, Streutker, Dickson, & Stewart, 2007) Symptoms appear after 1 month of starting the usage and became severe by the end of 1 year.(TH, L, & CM, 2009) Ketamine, norketamine, and hydroxynorketamine can be measured in urine, which may cause chronic submucosal inflammatory response in urinary tract system. (Chu et al., 2008) 針對Ｋ他命的病人所產生的一些bladder dysfunction的問題，最早的一篇case report是來自香港在2007所發表 Ｋ他命濫用的情形目前應該是被嚴重低估的，這方面epidermiological study的資料不容易取得,並且,病人除非症狀較嚴重不然通常較少就醫,之前Dr.蔡發現病人在吸食Ｋ他命後大約一個月會逐漸產生一些泌尿道症狀，而在一年後會變得更為嚴重 近年所做的一些study發現由於ketamine以及他的代謝產物norketamine及hydroxynorketamine等等會累積在尿液中，產生一些chronic的 submucosal inflammatory response,造成submucosal edema, vascular ectasia, detrusor muscle inflammation and fibrosis. 使得病人出現dysruia及膀胱容量縮小的狀況

Discussion Pal et al reported a prevalence of LUTS of 30% among recent users.(Pal et al., 2013) Both the lower and upper urinary tract can be involved, either separately or concomitantly.(Chu et al., 2008) 而大部分的病人產生的症狀以下泌尿道為主，但上泌尿道也同樣有可能受到傷害

Discussion Jhang, Hsu, & Kuo, 2015 在image的部分,我們可以看到一個 contracted bladder or bladder wall thickening, ureter dilatation, or ureter wall thickening的情形,在cystoscopy底下,可以看到multiple erythematous patches,K他命及他的代謝產物同樣會對泌尿道的血管產生傷害，使得膀胱在漲尿的過程中會產生一些ischemia的狀況而出現suprapubic pain的情形,隨著時間增加，會慢慢變成interstitial fibrosis and diminished bladder capacity. Jhang, Hsu, & Kuo, 2015

Treatment The only consensus on the effective management is cessation of ketamine.(Jhang, Hsu, & Kuo, 2015) Another large study reported a 51% improvement in urinary symptoms upon cessation, but about 4% of patients endured deteriorating symptoms even after stopping ketamine. (Winstock, Mitcheson, Gillatt, & Cottrell, 2012) Abstinence from ketamine usage and the amount of ketamine consumed have bearings on treatment response and symptom relief.(Yee, Lai, Lee, Tam, & Ng, 2015) 治療的部分，目前認為最有效的治療方式還是停止繼續使用Ｋ他命 在2012的一篇study中發現有一半左右的病人在停止使用之後症狀會有明顯的改善,不過有一部分的病人即使在停止使用之後症狀仍然逐漸變嚴重 而在另一篇study同樣提到,停止使用k他命之後,對治療的反應效果也會比較好

Treatment For patients who failed to improve with cessation of ketamine abuse, anticholinergics could be used with the aim to reduce bladder detrusor muscle contraction.(P, T, C, C, & G, 2009) Cystoscopic hydrodistention Diagnostic value to evaluate maximal bladder (Jhang, Hsu, & Kuo, 2015) Intravesical instillation of hyaluronic acid Intravesical injection of BoNT-A Inhibits the release of neurotransmitters from nerve fibers and urothelium Improves frequency and pain Surgery 而在停止使用K他命之後症狀仍然沒有明顯改善的病人可能會需要一些藥物或者手術治療 常見的藥物包括anticholinergics及pain killer如NSAID and COX-2 inhibitor 都有助於症狀改善 如果在藥物治療仍然沒有效果的這些病人,可能可以考慮一些侵入性的治療,例如hydrodistention, intravesical instillation of hyaluronic acid or Botulinum toxin serotype Ａ來改善frequency及pain的問題 而針對產生acute kidney injury的病人,可以考慮放一個ureter stent或nephrostomy tube來preserve他們的renal function以避免產生irreversible的damage,對於膀胱容量小於100ml的病人,可能可以考慮做augmentation enterocystoplasty

Conclusions The symptoms of ketamine usage for more than 5 years did not differentiate from those less than 5 Cystitis did not show difference in those two groups, either. However, the longer the ketamine usage, the smaller the bladder capacity, no matter functional or total To our acknowledgement, it’s the first article comparing the differences of each items along with duration 結論的部分,我們發現到隨著時間的增加,在症狀以及cystitis的部分並沒有顯著的差異,不過在膀胱的容量的部分,隨著時間的增加,膀胱會逐漸地變小,吸食Ｋ他命五年以上的病人，容量大約只有五年以下的一半

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