电针结合济生肾气丸治疗脊髓损伤后神经源性膀胱的研究

发布时间：2018-07-28 06:42

【摘要】：正常的排尿反射是沿从脑、脊髓到膀胱、尿道平滑肌这样一条协调完整的通路进行。由交感、副交感、躯体周围神经共同参与,任何与排尿有关的神经受到损害后,引起的排尿功能障碍称为神经源性膀胱(neurogenic bladder,NB)。NB是一类由神经病变或损害引起的膀胱和(或)尿道的功能障碍性疾病,常同时伴有膀胱尿道功能的协调性失常。可产生复杂的排尿症状,而排尿不畅或尿潴留是其中最常见的症状之一。NB是脊髓损伤(spinal cord injury,SCI)后的常见并发症,是SCI患者最常见的临床问题,症状根据脊髓损伤平面的不同可以分为不同类型,常见为:①逼尿肌反射亢进;②逼尿肌无反射。而之后伴随的肾功能衰竭、肾和膀胱结石、膀胱癌症、尿路感染(UTI)和输尿管返流(VUR)将增加患者死亡风险。因此,对于瘫痪的SCI患者,恢复膀胱功能甚至比恢复运动功能更加重要。现代研究SCI后NB缺乏安全有效的治疗方案,电针能阻止或减轻SCI后的继发性的损害,促进脊髓的修复和再生。但是电针刺激治疗脊髓损伤的机理还未完全揭开,刺激强度也不好把握,而且电针不是上下神经元的电生理恢复和传导束的功能性重建,故还不能做到损伤部位的功能性替代,不能完全重建膀胱功能。SCI后NB属中医"癃闭"范畴。现代基础研究证实:济生肾气丸具有良性调节膀胱内压力及调节代谢、神经和免疫的功能,因此我们选用电针刺激骶神经治疗SCI后NB的同时,结合祖国医学的优势,辨证选用中药济生肾气丸治疗SCI后NB,旨在降低膀胱感染保护膀胱及肾功能,促进膀胱功能的重建。本文通过SCI后NB的文献研究、动物实验及临床尿动力学分析三部分探讨了 SCI后NB动物模型的建立及评估、电针结合济生肾气丸济生肾气丸治疗SCI后NB的疗效及初步探讨其改善SCI后NB大鼠膀胱功能的分子机制,为临床治疗SCI后NB提供新的方法和思路。1文献综述从西医和中医两个方面对SCI后NB的流行病学、病理生理、分型、诊断和治疗及中医理论基础、中药治疗、针灸治疗和中医其它疗法等方面的现状进展进行阐述,并总结SCI后NB的中西医治疗上的优缺点。2实验研究2.1实验一目的:建立理想的脊髓损伤后神经源性膀胱动物模型并评估脊髓及膀胱状态。方法:16只SD大鼠分为对照组(假手术)6只,实验组(T9脊髓全横断损伤大鼠模型)10只,记录每日实验组大鼠手法排尿量等情况以评估脊髓损伤后神经源性膀胱恢复情况,术后2周使用尿流动力学方法检测并比较两组大鼠膀胱内压以评估大鼠膀胱状态。结果:术后一周内,大鼠手法辅助排尿量逐渐增加并达到最大。术后一周后,大鼠辅助排尿量逐渐减低并于两周时渐渐稳定。对照组及实验组大鼠在最大膀胱压、膀胱基础压、排尿阈、收缩间隔、膀胱容量、排尿效率的参数值分别为(26.60±4.31)mmH2O、(21.66±2.56)mmH20;(11.66±1.33)mmH20、(14.72±2.65)mmH20;(20.46±0.52)mmH20、(16.99±0.81)mmH20;(1.36±1.58)min、(2.02±0.36)min;(0.82±0.15)ml、(2.20±0.24)ml;(92.67±1.97)%、(25.33±4.46)%。差异均具有统计学意义(P0.05)。结论:采用T9水平脊髓全横断损伤制作的神经源性膀胱大鼠模型可操作性强,易量化、可重复,在正确积极的术后护理下并发症少、死亡率低。使用术后SCI大鼠手法排尿量的变化判断脊髓恢复情况,并以尿流动力学方法检测大鼠在膀胱连续灌注下的膀胱压力变化来评价其膀胱状态客观可行。2.2实验二目的:探讨电针结合济生肾气丸对于SCI后NB大鼠膀胱功能、肾功能的干预作用及初步探讨对损伤修复的分子机制。方法:SD雌性大鼠50只,随机挑选8只作为A组(假手术组),其余42只大鼠进行T9脊髓全横断损伤造模,2周后对确定神经源性膀胱成模的存活大鼠39只随机挑选8只作为B组(对照组),其余31只采用随机数字表法分为:C组(中药组)、D组(电针组)、E组(中药+电针组)分别为11只、10只、10只。A组不予任何干预。B组造模后不予任何干预。C组给予自制济生肾气丸水煎剂灌胃和骶2神经处体表肌肉电针。D组予蒸馏水灌胃和骼2神经电针刺激。E组自制济生肾气丸水煎剂灌胃和骶2神经电针刺激。实验期间观察并记录实验动物的死亡情况;分别在造模前、干预4天后、干预2周后、干预4周后称取实验动物的体重;在处死实验动物后,称取膀胱重量。干预2周后,眼眶取血测定血肌酐、尿素氮、尿微量白蛋白。并取T8-T10脊髓及S2双侧神经根用于Western blot 检测。结果:动物共死亡9只,其中造模过程死亡3只;干预及取标本过程死亡6只,分别是C组3只、D组1只、E组2只。①一般情况:E组的电针结合济生肾气丸的干预方式能够明显改善SCI后大鼠的体重下降的情况,差异具有统计学意义(P0.05)。干预大鼠与对照组比较,在膀胱重量和最后一次手法排尿量方面差异不具有统计学意义(P0.05)。②血清肌酐、尿素氮和尿微量白蛋白检查:血清肌酐各干预组同对照组比较差异不具有统计学意义(P0.05);干预2周后,E组电针结合济生肾气丸的干预方式能够明显降低SCI后大鼠尿素氮水平,与对照组比较差异具有统计学意义(P0.05);C组、D组、E组大鼠的尿微量白蛋白检测结果较对照组均显著降低,差异具有统计学意义(P0.05)。③膀胱HE染色:C组、D组、E组均能显著改善SCI后NB大鼠的膀胱形态:减轻膀胱壁肌层和黏膜层的水肿、充血及炎性细胞的浸润,降低肌层增生的程度,而其中E组改善情况最明显。④充盈性膀胱内压测定:D组、E组能够显著降低SCI后NB大鼠的膀胱容量,与对照组比较,差异具有统计学意义(P0.05)。⑤Western Blot检测相关因子蛋白表达:C组中药治疗以及E组电针结合中药的治疗方式能够提高SCI后NB大鼠脊髓组织中神经生长因子NGF及其受体TrkA表达同时降低神经根组织中神经生长因子NGF及其受体TrkA表达,D组电针的方式能够提高SCI后NB大鼠脊髓组织中TrkA表达同时降低神经根组织中TrkA表达,与对照组比较,差异均具有统计学意义(P0.05)。结论:①电针结合济生肾气丸治疗能够改善SCI后NB大鼠的体重下降情况、肾功能、膀胱组织病理学改变及膀胱容量。②电针结合济生肾气丸的治疗方式能够提高SCI后NB大鼠脊髓组织中神经生长因子NGF及其受体TrkA表达同时降低神经根组织中神经生长因子NGF及其受体TrkA表达,这可能是其改善SCI后NB大鼠膀胱功能的机制之一。3临床分析目的:分析临床不同损伤节段SCI后NB患者的尿动力学检查的特点。方法:收集2014年10月-2016年12月中国康复研究中心北京博爱医院影像尿动力学检查中心检查的门诊或病房病人113例。根据患者损伤情况分为骶上脊髓损伤组和骶髓损伤组,分析比较两组患者尿动力检查指标最大膀胱容量、残余尿量及通过影像尿动力检查观测两组患者逼尿肌无反射、逼尿肌过度活动、顺应性增加、顺应性降低、膀胱感觉异常、膀胱-输尿管返流的情况。结果:两组患者尿动力检查指标最大膀胱容量、残余尿量比较均无明显差异,差异不具有统计学意义(P0.05);骶上脊髓损伤患者的逼尿肌无反射、逼尿肌过度活动、膀胱顺应性增加、膀胱顺应性降低、膀胱感觉异常及膀胱-输尿管返流的发生率分别是34.7%、36.8%、9.5%、44.2%、55.8%、63.2%,而骶髓损伤患者的发生率则分别是85.7%、21.4%、21.4%、35.7%、28.6%、71.4%。骶髓损伤患者比骶上脊髓损伤患者的逼尿肌无反射的表现较明显,并且膀胱-输尿管返流的发生率更高,但膀胱感觉异常的发生率明显低于骶上脊髓损伤患者,差异均具有统计学意义(P0.05)。结论:骶上脊髓损伤患者主要表现为膀胱感觉异常,而骶髓损伤患者主要表现为逼尿肌无反射和膀胱-输尿管返流。
[Abstract]:Normal urination reflex is a coordinated and complete pathway from the brain, the spinal cord to the bladder, and the smooth muscle of the urethra. It is involved in the sympathetic, parasympathetic, and peripheral nerves. After any injury to the urination, the urinary dysfunction (neurogenic bladder, NB).NB is a type of nerve. Dysfunction of the bladder and / or urethra caused by lesion or damage, often accompanied by a coordinated disorder of the urinary bladder and urethra, can produce complicated urination symptoms, and urinary retention or retention of urine is one of the most common symptoms,.NB is a common complication after spinal cord injury (SCI) and is the most common SCI patient. Clinical problems can be divided into different types according to the different plane of spinal cord injury, which are common as: (1) detrusor hyperreflexiism; (2) detrusor reflex; and subsequent renal failure, kidney and bladder stones, bladder cancer, urinary tract infection (UTI) and ureteral reflux (VUR) will increase the risk of death in patients. Therefore, for paralyzed SCI patients The restoration of bladder function is even more important than restoring the function of the motor. After the modern study of SCI, NB lacks a safe and effective treatment. Electroacupuncture can prevent or reduce secondary damage after SCI and promote the repair and regeneration of the spinal cord. However, the mechanism of electroacupuncture therapy for spinal cord injury has not been completely uncovered, and the intensity of stimulation is not well understood, and The electroacupuncture is not the electrophysiological recovery of the upper and lower neurons and the functional reconstruction of the conduction beam. Therefore, the functional replacement of the injured part can not be achieved, and the NB belongs to the category of "long closed" in Chinese medicine after the complete reconstruction of the bladder function.SCI. Modern basic research has confirmed that Jisan Shenqi Pill has a benign intravesical pressure regulating and regulating metabolism, nerve and immunity. Yes, so we choose the electroacupuncture stimulation of the sacral nerve to treat the NB after SCI, combined with the advantages of the Chinese medicine, and select the traditional Chinese medicine Jisan Shenqi Pill for the treatment of NB after SCI, in order to reduce the bladder and renal function of bladder infection and promote the reconstruction of the function of the bladder. This article through the literature study, animal experiment and clinical urodynamic analysis three after SCI. The establishment and evaluation of NB animal model after SCI, the effect of electroacupuncture combined with jiseng Shenqi Pill with Jisan Shenqi Pill in the treatment of NB after SCI and the molecular mechanism of improving the bladder function of NB rats after SCI, provide new methods and ideas for the clinical treatment of SCI after NB, and the.1 literature review from two aspects of Western medicine and traditional Chinese medicine to SCI NB flow The progress in the current status of disease, pathophysiology, typing, diagnosis and treatment and traditional Chinese medicine theory, traditional Chinese medicine treatment, acupuncture and moxibustion treatment and other therapies of traditional Chinese medicine were expounded, and the advantages and disadvantages of traditional Chinese medicine and Western medicine after SCI were summed up by the.2 experimental study 2.1 experiment: to establish an ideal model of neurogenic bladder animal after spinal cord injury and evaluate the neurogenic bladder animal model. Methods: 16 SD rats were divided into 6 rats in the control group (sham operation) and 10 rats in the experimental group (T9 spinal complete transection injury rat model). The urine volume of the rats in the experimental group was recorded in order to evaluate the recovery of neurogenic bladder after spinal cord injury. 2 weeks after the operation, the urine flow kinetics method was used to detect and compare the two groups of rats. Intravesical pressure was used to evaluate the bladder state of rats. Results: during the week after the operation, the amount of manual urination in rats increased gradually and reached the maximum. After one week, the amount of auxiliary urination decreased gradually and gradually stabilized at two weeks. The control and experimental group were in the maximum bladder pressure, bladder base pressure, urination threshold, contraction interval, bladder capacity, urination. The parameters of the efficiency were (26.60 + 4.31) mmH2O, (21.66 + 2.56) mmH20, (11.66 + 1.33) mmH20, (14.72 + 2.65) mmH20, (20.46 + 0.52) mmH20, (16.99 + 0.81) mmH20, (1.36 + 1.58) min, ML, ml; (P0.05 + +)%, (P0.05)%. (P0.05). Conclusion: T9 horizontal spinal cord was used. The neurogenic rat model of neurogenic bladder produced by total transection injury is highly operable, easy to quantify, repeatable, less complications and lower mortality in the correct and active postoperative care. The recovery of spinal cord is judged by the changes in the amount of manipulative urination of SCI rats after operation, and the bladder pressure of rats under continuous bladder perfusion by urinary flow dynamic method is detected. Objective: To evaluate the objective and feasible.2.2 experiment two objective: To explore the effect of the electroacupuncture combined with jisen Shenqi Pill on bladder function, renal function and the molecular mechanism of injury repair in NB rats after SCI. Methods: 50 SD female rats were randomly selected as A group (sham operation group), and the other 42 rats were treated with T9 spinal cord. After 2 weeks, 39 rats were randomly selected as B group (control group), and the other 31 were divided into group C (group of Chinese Medicine), group D (electroacupuncture group), group E (traditional Chinese medicine + acupuncture group) 11, 10 respectively, and 10 group of.A without any intervention in.B group without any interference in.C The group gave the self-made Jisan Shenqi Pill water decoction and the 2 nerve of the sacrum to the body surface muscle electroacupuncture.D group to give the distilled water to irrigate the stomach and the iliac 2 nerve electroacupuncture stimulation to stimulate the.E group with the water decoction of Jisheng Shenqi Pill and the 2 nerve needle stimulation of the sacral nerve. During the experiment, the death situation of the experimental animals was observed and recorded. Before the model, the intervention was 4 days after intervention, and after the intervention for 2 weeks, the dry matter was dried. After 4 weeks, the body weight of the animal was weighed. After the experimental animals were killed, the weight of the bladder was weighed. After 2 weeks of intervention, blood creatinine, urea nitrogen and urine microalbumin were measured in the orbit. The T8-T10 spinal cord and S2 bilateral nerve roots were used for Western blot detection. Results: 9 animals died in the animal model process, and 3 of them died in the process of modeling; the intervention and sample process were taken. There were 6 deaths in group C, 3 in group C, 1 in group D and 2 in group E. (1) the interference of electroacupuncture combined with jiseng kidney qi pill in group E could obviously improve the weight decline of rats after SCI, and the difference was statistically significant (P0.05). Statistical significance (P0.05). (2) serum creatinine, urea nitrogen and urine microalbumin examination: serum creatinine intervention group was not significantly different from the control group (P0.05). After 2 weeks of intervention, the intervention of electroacupuncture combined with jiseng kidney qi pill in group E could significantly reduce the level of urea nitrogen in rats after SCI, and there was a statistical difference between the control group and the control group. The results of urinary microalbuminuria in group C, group D, and group E were significantly lower than those in the control group. The difference was statistically significant (P0.05). (P0.05) bladder HE staining: C group, D group and E group could significantly improve the bladder morphology of NB rats after SCI: reducing the edema of the muscularis and mucous layer of the bladder wall, congestion and infiltration of inflammatory cells, and reducing the muscle layer The degree of proliferation, and the most obvious improvement in group E. (4) filling bladder pressure measurement: group D, E group can significantly reduce the volume of bladder in NB rats after SCI, the difference has statistical significance (P0.05). 5. Western Blot detection related factor protein expression: C group of traditional Chinese medicine treatment and E group electroacupuncture combined with traditional Chinese medicine treatment The expression of nerve growth factor NGF and its receptor TrkA in spinal cord tissue of NB rats can be increased and the expression of nerve growth factor NGF and its receptor TrkA in the nerve root tissue is reduced. The D group electroacupuncture can increase TrkA expression in spinal cord tissue of NB rats after SCI and reduce TrkA expression in the nerve root group. The difference is compared with the control group. The difference is compared with the control group. Statistical significance (P0.05). Conclusion: (1) electroacupuncture combined with Jisan Shenqi Pill can improve the weight loss of NB rats after SCI, renal function, bladder histopathological changes and bladder capacity. 2. The treatment of electroacupuncture combined with jiseng kidney qi pill can improve the neural growth factor NGF and its receptor TrkA in spinal cord of NB rats after SCI To reduce the expression of nerve growth factor NGF and its receptor TrkA in nerve root tissue, which may be one of the mechanisms for improving the bladder function of NB rats after SCI,.3 clinical analysis: the characteristics of urodynamic examination of NB patients after SCI in different segments of the segmental SCI. Methods: to collect the Chinese rehabilitation research center in December -2016 year October 2014 113 patients in the clinic or ward were examined by the imaging urodynamic examination center in Beijing Bo'ai Hospital. The patients were divided into sacral spinal cord injury group and sacromedullary injury group according to the damage of the patients. The maximum bladder capacity, the residual urine volume and the detrusor inreflex in the two groups were observed and compared in the two groups. Excessive activity of detrusor, increased compliance, decreased compliance, abnormality of bladder sensation, bladder ureteral reflux. Results: there was no significant difference in the residual urine volume between the two groups, and the difference was not statistically significant (P0.05); the detrusor was not reflected in the sacral spinal cord injury and detrusor. The incidence of bladder compliance, bladder compliance and bladder ureteral reflux was 34.7%, 36.8%, 9.5%, 44.2%, 55.8%, 63.2%, respectively, while the incidence of sacral injury was 85.7%, 21.4%, 21.4%, 35.7%, 28.6%, respectively, and the 71.4%. sacral injury patients were less detrusor than those with sacral spinal cord injury. The incidence of bladder and ureteral reflux was higher, but the incidence of abnormal bladder sensation was significantly lower than that of the sacral spinal cord injury patients. The difference was statistically significant (P0.05). Conclusion: the patients with upper sacral spinal cord injury were mainly characterized by abnormal bladder sensation, and the main manifestations of sacral injury were detrusor inreflexity. Bladder ureteral reflux.
【学位授予单位】：北京中医药大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R651.2

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