摘要
研究目的
氯胺酮相关性泌尿系统损害(Ketamine-associated urinary system dysfunction, KUD)是氯胺酮滥用所导致的诸多疾病之一,主要临床表现为下尿路症状和尿路损害,其致病机理目前仍不清楚。近年来的文献报道主要集中在临床病例观察和临床诊断,尚未见关于KUD的影像尿流动力学研究、上尿路扩张积水的危险因素探讨、治疗药物和大鼠模型的建立等研究报道。因此,本研究旨在通过建立KUD大鼠模型和临床初步研究达到以下目的：1、建立氯胺酮泌尿系统损害的大鼠模型并对其行尿流动力学评估；2、分析氯胺酮相关性泌尿系统损害的影像尿动力学特点；3、探讨氯胺酮相关性泌尿系统损害患者上尿路扩张积水的相关危险因素分析；4、观察透明质酸钠、托特罗定治疗轻、中度氯胺酮相关性泌尿系统损害的疗效。
研究方法
1.实验一采用雌性SD鼠,随机分为实验A组(n=15),对照A组(n=15)；实验B组(n=12),对照B组(n=12)；实验C组(n=12),对照C组(n=12)。实验A、实验B、实验C组分别按120mg/kg-d剂量予以氯胺酮处理,建立氯胺酮滥用动物模型,将每日总量均分2次行腹腔注射,每12小时1次,共12周。对照A、B、C组分别予以2.4mL/kg-d生理盐水注射,每日总量均分2次行腹腔注射,每12小时1次,共12周。分别在第4、8、12周,随机取实验A组、对照A组两组4只大鼠处死,取肾脏及膀胱病理检查。实验B组、对照B组分别于实验前、实验后第2、4、8、12个周予以内眦取血制备血清,测定ALP、ALT、SCr、BUN。实验C、对照C组分别在实验前、第2、4、8周分别进行一次尿流动力学检测,记录尿动力曲线及重要参数。
2.实验二采用影像尿动力学对66例氯胺酮相关性泌尿系统损害患者进行检查,收集尿流动力学参数并分析结果。
3.实验三共收集到245例KUD患者临床资料,包括每周吸食量(g/周)、发病时间(月)、每周吸食频率(次／周)、吸毒累计时间(月)、O'Leary Saint症状指数+问题指数(IC指数)、血生化检查(肾功能、肝功能)、血沉、血清C反应蛋白、超声影像学检查提示上尿路扩张积水(肾盂分离)情况、尿流动力学、膀胱排尿造影。将患者按照肾积水程度分为4组(无、轻、中、重度),并对各个潜在影响因素进行单因素分析,对各独立影响因素以及肾积水之间进行Spearman相关因素分析。
4.实验四根据入组标准,将患者随机分成三组,对照组(n=37)、实验1组(n=35)和实验2组(n=35)；所有患者一经确诊,立即进行至少12周强制戒毒。实验1组在戒毒期间口服托特罗定缓释片(舍尼亭(?),4mg/片)4mg/日；实验2组行透明质酸钠40mg(西施泰⑧,40mg/瓶)膀胱内灌注治疗,保留时间大于30分钟,每周1次,共12次。分别于治疗前、治疗第4、8、12周记录O'Leary-Sant症状评分及问题评分(IC指数)并行尿动力学检查。
研究结果
1.实验一病理结果提示,与对照A组相比,实验A组SD大鼠第8、12周肾小球和肾小管周围及膀胱粘膜下层周围单核细胞浸润,膀胱尿路上皮层数明显较少。病理证实第8周大鼠建模成功率达78.6%(11/14)。实验B组较对照B组ALP、ALT在第4、8、12周显著升高(P均<0.01),SCr、BUN值在第8、12周显著升高(P均<0.01)。实验C组膀胱容量、膀胱排尿间隔时间、排尿前膀胱压阈值与实验前比较均有统计学差异(P均0.01),对照C组无统计学差异(p均>0.05)；实验C与对照C组比较,在第8周,膀胱容量、膀胱排尿间隔时间、排尿前膀胱压阈值两组间均有统计学差异(P均<0.01)。
2.实验二影像尿动力学提示：本研究中的KUD患者初始尿意容量为48.33±26.52ml:膀胱最大测压容量为102.88±48.03ml,膀胱顺应性为11.86·6.31ml/cm:最大尿流率时逼尿肌压力分别为：男性(53.71±10.08)cm H20,女性(20.8±7.32)cm H2O。其中,发现膀胱输尿管返流23例(34.8%),充盈期出现逼尿肌不稳定46例(69.7%),排尿末期不可抑制收缩致排尿(急迫性尿失禁)20例(30.3%)。
3.实验三膀胱顺应性、膀胱最大测压容量、初始尿意容量、IC指数、每周吸食量、发病时间、每周吸食频率与肾积水程度密切相关(P值均<0.01)；性别、膀胱输尿管返流、丙氨酸转氨酶(ALT)、碱性磷酸酶(ALP)、血沉(ESR)、C反应蛋白(CRP)、储尿期逼尿肌无抑制性收缩次数,在肾积水程度各组间比较差异无显著性(P值均>0.05)。Spearman相关因素分析提示：膀胱顺应性、每周吸食量、膀胱最大测压容量、发病时间、IC指数是肾积水重要的危险因素(P值均<0.01)。
4.实验四三组第12周数据与治疗前比较,差异均有统计学意义(P均<0.01)；实验2组与对照组、实验1组比较,在第4、8、12周,IC指数、FDV、SDV及MCC各组间差异有显著性(P均<0.01)。实验2组治疗有效率77.1%(27/35),无效22.9%(8/35)；与对照组比较有显著差异(P=0.013)。实验1组有效率48.6%(17/35),无效51.4%(18/35)；与对照组比较无显著差异(P=0.650)。
研究结论
1.肾脏及膀胱病理证实,以120mg/kg·d氯胺酮剂量腹腔内注射SD大鼠在第8周可成功建立氯胺酮泌尿系统损害的大鼠模型。氯胺酮滥用会导致大鼠肝肾功能的损害。KUD大鼠模型尿流动力学表现为膀胱容量下降,膀胱排尿间隔时间缩短和排尿前膀胱压阈值增高,这与人类KUD患者症状相似。
2.KUD影像尿动力学主要表现为膀胱顺应性、最大膀胱容量和最大尿流率下降,膀胱高度敏感,逼尿肌不稳定,可伴有膀胱输尿管返流。
3.膀胱顺应性、膀胱最大测压容量、初始排尿感容量、每周吸食量、发病时间、IC指数、每周吸食频率是上尿路扩张积水的相关危险因素,并与上尿路扩张积水严重程度密切相关；其中膀胱顺应性、每周吸食量是最为重要的危险因素。
4.随访12周的疗效观察发现,透明质酸钠膀胱灌注治疗能有效缓解轻、中度氯胺酮相关性泌尿系统损害的下尿路症状,改善其储尿功能。其治疗有效率为77.1%(27/35),无效22.9%(8/35)。托特罗定治疗KUD效果与对照组比较无显著差异。
Ketamine-associated urinary system dysfunction (KUD), one of the diseases caused by ketamine abuse, is characterized by severe lower urinary tract symptoms and all urinary tract damage. Different with recent literatures' focusing on the observation of clinical cases and diagnosis, this study will further evaluate the related clinical features of Ketamine-associated urinary system dysfunction and firstly attempt the trail establishment and evaluation of a KUD animal model. Through this study, we intend:
1. to create a short-term and reliable rat model of Ketamine-associated urinary system dysfunction and assess it by urodynamics.
2. to assess the lower urinary tract function and its characteristics of Ketamine-associated urinary system dysfunction (KUD) patients by video-urodynamics.
3. to identify the risk factors for upper urinary tract deterioration in patients with Ketamine-associated urinary system dysfunction.
4. to evaluate the efficacy of hyaluronan and Tolterodine for the treatment of Ketamine-associated urinary system dysfunction. Methods
1.All SD rats(female)were randomly divided into6groups:experimental group A(n=15),control group A(n=15),experimental group B(n=12),control group B (n=12),experimental group C(n=12),control group C(n.12).Rats of experimental groups A,B,C were injected with ketamine(120mg/kg·d)for12weeks and rats of control group were injected with the same menstruum.Then4rats were chosen randomly from both control group A and experimental group A at the4th,8th and12th week respectively,and the kidneys and urinary bladders of the rats were harvested for histology.The serum ALP,ALT of the rats from experimental group B and control group B were detected before and after the experiment,and at the2th,4th,8th and12th week respectively. Rats from experimental group C and control group C received urodynamic tests before the experiment and at the2th,4th,8thand12th week,urodynamic curve and other important parameters were recorded.
2.All66patients suffered Ketamine-associated urinary system dysfunction underwent video-urodynamic study,data from that were collected and analyzed.
3.A total of245patients with KUD were enrolled.Clinical data were collected, including drug-abusing dose (g/w), duration of disease (month), abusing frequency(times/w),accumulated drug-abusing time(months), O'Leary Saint symptom index and problem index(IC Index), blood biochemistry analysis(ALT,ALP),erythrocyte sedimentation rate(ESR),serum C-reactive protein(CRP),urodynamic result,the degree of hydronephrosis in ultrasound imaging tests,and cystography.All patients were divided into f.our groups(adsence singns group,mild group,moderate group and severe group)in accordance with the degree of hydronephrosis.Variables as potential risk factors were compared between groups using single factor analysis. After that,the correlation between each independent risk factor and the degree of hydronephrosis,was analyzed with the Spearman correlation analysis.
4.All patients with Ketamine-associated urinary system dysfunction were randomly divided into3groups:control group (n=37), treattment group1(n=35) and treatment group2(n=35). Once diagnosed definitly, the patient would receive a compulsory drug treatment immediately for12weeks at least. Patients of treattment group1underwent oral tolterodine sustained-release tablets (S, ting;4mg/d), and treatment group2intravesical hyaluronan therapy(cystistat;40mg, once a week for12weeks). O'Leary-Sant symptom, problem Index (IC Index) and urodynamics studies were carried out before treatment, and at the4th,8th and12th week during treatment in each group respectively.
Results
1. When compared experimental group A with control group A, in the8th and12th week, all addicted rats showed monocyte invasion in bladder submucosa, around glomerular and peritubular, accompanied by a decrease in the number of layers of the bladder transitional epithelium. The repeated measure analysis of variance(ANOVA) showed significant differences, when compared experimental group B with control group B, in ALP、ALT of at the4th,8th,12th week, and SCr、 BUN at the8th and12th week (P<0.01). The repeated measure analysis of variance(ANOVA of repeated measure data) showed significant difference in the bladder capacity, intercontraction interval and pressure threshold for voiding in the experimental group C compared with that of pre-experiment (P<0.01), however, no significant difference was found in control group C. When comparing with both groups, there appeared a significant difference in bladder capacity, intercontraction interval and pressure threshold at the8th and12th week(P<0.01).
2.In66cases, the mean value of first desire to void, maximum cystometric capacity, bladder compliance, were48.33±26.52ml,102.88±48.03ml, 11.86±6.31ml/cm, respectively. And the mean value of Pdet at Qmax was53.71±10.08cm H20in males, and20.8±7.32cmH20in females. Of the66patients,23(34.8%) had got vesicoureteric reflux,46(69.7%) got detrusor instability in the filling phase, and20got (30.3%) incontinence caused by non-inhibited contraction in late urine.
3. The Mono-factor analysis showed:of all variables tested, vesical compliance, maximum cystometric capacity, first desire to void, IC index, weekly abusing dose, duration of disease and weekly abusing frequency, were independent risk factors for the degree of hydronephrosis(P<0.01); sexuality, vesicoureteric reflux, ALT, ALP, ESR and CRP were not significantly different among patients grouped by the degree of hydronephrosis(P>0.05for all). Spearman correlation analysis demonstrated that vesical compliance, maximum cystometric capacity, weekly abusing dose、duration of disease and IC index were significant risk factors(P<0.01).
4. The repeated measure analysis of variance(ANOVA of repeated measure data) showed that all variables, in comparison to bofore treatment, differed significantly in three groups at the12th week (P<0.01) respectively. IC Index, FDV, SDV and MCC differed significantly at the4th,8th and12th week when compared treatment group2with control group and treatment group1respectively (P<0.01). The response rate and inefficiency rate were48.6%(17/35) and22.9%(18/35) in treatment group1, and were77.1%(27/35) and22.9%(8/35) in treatment group2. When compared with control group,the response rate of treatment group2showed a significant diffenence(P=0.013), while didn't of treatment group1.
Conclusion
1. Ketamine intraperitoneal injection at a dose of120mg/Kg-d can establish a short-term and reliable rat model of Ketamine-associated urinary system dysfunction. Blood biochemical tests confirmed that ketamine abuse can lead to hepar and renal functional lesion in rats. Urodynamic study of the KUD model rats revealed functional changes including lower cystometric capacity, shortened intercontraction interval and increased pressure threshold for voiding after drug abuse. These symptoms are similar to that of humans'after long-term ketamine abuse.
2.The video-urodynamics fingings of KUD patients usually present with severe sensitive bladder, decreased cystometric capacity, unstable bladder,and part of them may present with vesicoureteric reflux.
3. Vesical compliance, maximum cystometric capacity, first desire to void, IC index, weekly abusing dose, duration of disease are associated with increased risk of hydronephrosis and the extent of damage. Furthermore, vesical compliance and weekly abusing dose are the most important risk factors.
4. After a12-week treatment, intravesical hyaluronan therapy could effectively release mild or moderate lower urinary tract symptoms caused by Ketamine-associated urinary system dysfunction, and improve lower urinary tract function either. The response rate and inefficiency rate of intravesical hyaluronan therapy were77.1%(27/35) and22.9%(8/35). While the response rate of tolterodine therapy wasn't better than that of control group.
引文
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[1]Middela S, Pearce I. Ketamine-induced vesicopathy:a literature review[J]. Int J Clin Pract,2011,65(1):27-30.
[2]Lai Y, Wu S, Ni L, et al. Ketamine-associated urinary tract dysfunction:an underrecognized clinical entity[J]. Urol Int,2012,89(1):93-96.
[3]Shahani R, Streutker C, Dickson B, et al. Ketamine-associated ulcerative cystitis:a new clinical entity[J]. Urology,2007,69(5):810-812.
[4]Muetzelfeldt L, Kamboj S K, Rees H, et al. Journey through the K-hole: phenomenological aspects of ketamine use[J]. Drug Alcohol Depend, 2008,95(3):219-229.
[5]Chu P S, Ma W K, Wong S C, et al. The destruction of the lower urinary tract by ketamine abuse:a new syndrome?[J]. BJU Int,2008,102(11):1616-1622.
[6]Ng S H, Tse M L, Ng H W, et al. Emergency department presentation of ketamine abusers in Hong Kong:a review of 233 cases[J]. Hong Kong Med J, 2010,16(1):6-11.
[7]Tsai T H, Cha T L, Lin C M, et al. Ketamine-associated bladder dysfunction[J]. Int J Urol,2009,16(10):826-829.
[8]吴苋,朱秀群,姚铭广,等.氯胺酮相关性泌尿系统损害[J].中华泌尿外科杂志,2008,29(7)：489-492.
[9]Yeung L Y, Rudd J A, Lam W P, et al. Mice are prone to kidney pathology after prolonged ketamine addiction[J]. Toxicol Lett,2009,191 (2-3):275-278.
[10]Oxley J D, Cottrell A M, Adams S, et al. Ketamine cystitis as a mimic of carcinoma in situ[J]. Histopathology,2009,55(6):705-708.
[11]Selby N M, Anderson J, Bungay P, et al. Obstructive nephropathy and kidney injury associated with ketamine abuse[J]. NDT plus,2008,1(5):310-312.
[12]吴芃；陈烨；成官迅,等.氯胺酮相关性胆管扩张[J].现代消化及介入诊疗.2010,15(4)：247-249.
[13]Craven R. Ketamine[J]. Anaesthesia,2007,62 Suppl 1:48-53.
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[1]Middela S, Pearce I. Ketamine-induced vesicopathy:a literature review[J]. Int J Clin Pract,2011,65(1):27-30.
[2]Shahani R, Streutker C, Dickson B, et al. Ketamine-associated ulcerative cystitis:a new clinical entity[J]. Urology,2007,69(5):810-812
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