| 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. Methods1.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.Results1. 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.Conclusion1. 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. |
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