盐酸右美托咪啶联合乌司他丁对腹腔镜下结直肠癌手术老年患者术后早期认知功能障碍的影响

发布时间：2018-06-08 13:20

本文选题：右美托咪定 + 乌司他丁　；参考：《南方医科大学》2014年硕士论文

【摘要】：术后认知功能障碍(Postoperative Cognitive Dysfunction, POCD)是指患者术后出现中枢神经系统并发症,主要表现为术后出现定向力、记忆力、注意力、语言理解力等中枢神经功能改变。 POCD患者精神和人格的改变,会导致术后社交能力及认知能力等改变,康复延迟,增加患者住院医疗总费用,影响术后生活质量,甚至会进展成为永久性认知障碍,失去生活自理能力,进而影响到患者的社会活动以及工作。造成严重后果。据文献报道,60岁以上的非心脏手术老年患者,术后早期POCD的发生率高达3%～61%。导致POCD的因素很多,但尚缺乏明确和统一的金标准。到目前为止,比较公认的高危因素为高龄及比较严重的外科创伤。既往研究表明,手术创伤、术后疼痛及机体应激引起全身炎性反应综合征及不同类型细胞因子释放,在患者POCD的发生中起到至关重要的作用。随着微创技术的进步,腹腔镜下直结肠癌手术已成为临床中较为常见的手术。研究发现,腔镜手术患者术中C02气腹后,会导致脑组织代谢存在不同程度的障碍,术中大脑氧合情况的变化,加上气腹造成不同程度的神经损伤,使血浆S100β蛋白和NSE浓度有所增高,可能会诱发POCD。开腹手术组患者相比,腹腔镜手术组患者术后认知功能评分的下降幅度较小,可能是由于腹腔镜手术创伤相对小,手术及麻醉时间较短,对患者神经功能影响也较小,所以术后认知功能评分优于开腹组。但目前研究缺乏足够证据证明腹腔镜手术是否能够降低老年患者POCD的发生率。麻醉方式的选择对POCD的影响存在争议。研究发现：全麻药物通过影响机体神经突触的可塑性,导致记忆受损,进而改变或损害大脑而引起POCD。老龄化社会的到来,POCD引发的各种医学以及社会问题正越来越受到医学界的重视。如何降低老年患者围术期POCD的发生率,改善其晚年的生活质量尤为重要。盐酸右美托咪定(dexmedetomidine,Dex)是一种特异性α2-肾上腺素能受体激动剂,具有镇静、睡眠、抗焦虑等效应,在产生抗交感及抗寒战等作用的同时,还具有一定的镇痛作用,用于手术中辅助麻醉,对中枢神经有保护作用,并能改善患者术后认知功能。研究证明,Dex具有不同程度的神经保护作用。也有研究发现Dex应用于传统开腹手术结直肠癌手术老年患者中,能降低其POCD发生率。但Dex对腹腔镜下结直肠癌手术老年患者POCD的影响,还缺少相关研究报道。乌司他丁(ulinastatin, urinary trypsin inhibitor。UTI)是一种从我们人体的尿液中进行分离纯化出来的药物,具有较为广谱的酶的抑制作用而被广泛使用。研究证明,乌司他丁能够对机体的炎症反应产生抑制,通过减少机体神经细胞的凋亡,从而对机体的学习记忆功能障碍产生改善作用,因而降低老年患者POCD的发生率。研究发现,单独应用乌司他丁或地塞米松,对内毒素所致的兔肺损伤,均有不同程度的保护作用,联合应用乌司他丁与地塞米松可能强化此作用,从而起到更好效果。而乌司他丁复合其他药物对降低老年患者的POCD发生率的影响,目前国内外还缺少相关研究报道。综上所述,由于麻醉药本身对POCD发病影响尚存争议,POCD发病机制尚不明确,临床研究工作中的伦理问题、研究方法、诊断标准并未统一、主观性较强等问题,造成报道的结论并不一致。本研究借鉴国际POCD研究小组的研究方案,通过建立空白对照组,从而达到判断患者术后认知功能变化是否为正常变异的目的,使POCD诊断方法较为合理。研究表明,乌司他丁与盐酸右美托咪啶均可一定程度减少应激反应,减少炎症介质等对手术患者脏器的损伤,从而降低老年患者POCD的发生率。但是,两者联合应用是否具有协同或强化作用,从而进一步降低患者术后POCD的发生率,起到更好的脏器保护目的鲜见报道。因此,本研究探讨在相同麻醉深度,根据患者术后第1天和术后第3天MMSE的神经精神测试结果,评估并比较单独应用盐酸右美托咪啶或乌司他丁,及两者联合应用对腹腔镜下直结肠癌手术老年患者POCD的影响,为预防老年患者POCD的发生提供新思路和方法,进而改善老年患者晚年的生活质量。方法选取择期全麻下行腹腔镜下结直肠癌手术老年患者80例为研究对象,患者ASA Ⅰ～Ⅱ级,年龄65岁以上。随机数字表法分为0.9%氯化钠注射液空白对照组(A组),盐酸右美托咪定组(D组),乌司他丁组(U组),盐酸右美托咪定+乌司他丁组(D+U组),每组20例。四组患者一般资料差异无统计学意义(P0.05),具有可比性。患者进入手术室前均不给予术前用药。所有患者均采用全凭静脉麻醉。其中D组在麻醉诱导前15min采用微量输注泵在15mmin内输注0.5μg/kg盐酸右美托咪定预注负荷剂量,后以0.3μg/kg/h的速度持续泵注(生理盐水将盐酸右美托咪定配制成4μg/mL),手术结束前30min停止输注；U组在相同时点予2ku/kg乌司他丁,随后以1ku/(kg·h)泵注至术毕；D+U组按上述两种方法同时给予盐酸右美托咪定和乌司他丁持续泵注；A组于相同时点予等量0.9%氯化钠注射液持续泵注。麻醉诱导：静脉注射咪达唑仑0.02～0.04mg/kg,依托咪酯0.1～0.3mg/kg,枸橼酸舒芬太尼0.2～0.3μg/kg,维库溴铵0.1mg/kg,气管插管后接麻醉机行机械通气。麻醉维持采用丙泊酚和瑞芬太尼全凭静脉维持麻醉,采用微量输注泵持续泵入瑞芬太尼0.05～0.2μ g/kg/min,并根据手术情况间断追加枸橼酸舒芬太尼及维库溴铵。术中保持血压波动在基础值的10%以内,维持术中血氧饱和度(SP02)98%。维持NI值在D1-E1级,NI目标值在45～55间。手术结束前半小时给予舒芬太尼5-10μ g,氟比洛芬脂50mg进行超前镇痛。患者术毕不给予拮抗肌松,待患者恢复自主呼吸,潮气量6mL/kg,呼吸频率30次/min, PETCO2维持35～45mmHg,患者呼之能睁眼,握拳有力时拔除气管导管。术后给予经静脉自控镇痛(PCIA),药物配方为舒芬太尼1.5～2.0μg/kg,氟比洛芬脂1.5～2.0mg/kg,雷莫司琼3mg,用生理盐水稀释至150m1,背景输注速率为3ml/h,自控镇痛(PCA)量为3m1,锁定时间15mim,维持患者术后VAS评分≤3分。观察指标术中常规监测血压、心电图、SP02,记录术中出血量、胶体及晶体输液量、尿量、手术时间、恢复自主呼吸时间(从术毕到患者恢复自主呼吸)、睁眼时间(从患者恢复自主呼吸到睁眼时间)、拔除气管导管时间(从患者睁眼到拔除气管导管时间)；记录术中使用舒芬太尼,瑞芬太尼,维库溴铵,丙泊酚的用量情况；记录恢复期不良反应,包括高血压、心动过速、躁动、恶心、呕吐发生率的发生情况。观察术后伤口疼痛情况,并行VAS评分。分别在手术前1天和手术后第1天和术后第3天进行简易智力状态检查法(MMSE)的神经精神测试。如果术后得分对比术前基础值降低≥2分,认为发生POCD。计算出手术后患者第1天和术后第3天的POCD的发生率。统计学处理研究数据采用SPSS13.0统计学软件进行处理。计量资料采用均数±标准差(x±s)表示,组间比较采用单因素方差分析,计数资料采用x2检验。P0.05为差异有统计学意义。结果1)一般情况和术中液体出入量、手术时间、恢复自主呼吸时间、拔除气管导管时间,以及术中使用舒芬太尼、瑞芬太尼、维库溴铵的总量比较,差异无统计学意义(P0.05)；与对照组、乌司他丁组比较,盐酸右美托咪定组和盐酸右美托咪定+乌司他丁组睁眼时间延长,术中使用丙泊酚的量明显减少,恢复期高血压、心动过速、躁动、恶心、呕吐发生率均下降,差异有统计学意义(P0.05)。 2)术前MMSE评分组间比较差异无统计学意义(P0.05)；对照组术后第1天和术后第3天的MMSE评分均明显下降,与术前MMSE评分相比较,差异有统计学意义(P0.05)；盐酸右美托咪定组、乌司他丁组和盐酸右美托咪定+乌司他丁组患者术后第1天和术后第3天的MMSE评分均无明显下降,与术前MMSE评分相比较,差异无统计学意义(P0.05)。 3)对照组患者术后第一天和第三天POCD的发生率比较差异无统计学意义(P0.05)；与对照组比较,盐酸右美托咪定组、乌司他丁组和盐酸右美托咪定+乌司他丁组患者术后认知功能障碍的发生率均明显下降,差异有统计学意义(P0.05)；与盐酸右美托咪定组、乌司他丁组比较,盐酸右美托咪定+乌司他丁组患者术后认知功能障碍的发生率无明显进一步下降,差异无统计学意义(P0.05)。结论1)麻醉诱导前给予盐酸右美托咪啶0.5μg/kg,术中以0.3μg/kg/h的输注速率输注能使腹腔镜下结直肠癌手术老年患者术后早期认知功能障碍的发生率下降,并减少患者恢复期不良反应。 2)麻醉诱导前给予乌司他丁2ku/kg,术中以1ku/(kg·h)的输注速率输注能降低腹腔镜下结直肠癌手术老年患者术后早期认知功能障碍的发生率。 3)与单独应用盐酸右美托咪啶或乌司他丁相比,联合应用盐酸右美托咪啶与乌司他丁,并不能进一步降低腹腔镜下结直肠癌手术老年患者术后早期认知功能障碍的发生率。
[Abstract]:Postoperative cognitive dysfunction (Postoperative Cognitive Dysfunction, POCD) refers to the postoperative complications of the central nervous system, mainly manifested in the changes of central nervous function, such as orientation, memory, attention, and language comprehension.
Changes in the spirit and personality of POCD patients will lead to changes in social and cognitive abilities after operation, delay in rehabilitation, increase the total cost of hospitalization, affect the quality of life, even become permanent cognitive impairment, lose the ability to take care of life, and then affect the social activities and work of the patient. It is reported that the incidence of POCD in the elderly patients over 60 years old is 3% to 61%. after operation.
There are many factors leading to POCD, but there is still a lack of clear and unified gold standards. Up to now, the relatively recognized high risk factors are older and more severe surgical trauma. Previous studies have shown that surgical trauma, postoperative pain and body stress cause systemic inflammatory response syndrome and different types of cytokines release, and the occurrence of POCD in patients. With the progress of minimally invasive technique, laparoscopic colon cancer surgery has become a more common operation in the clinic. It is found that the C02 pneumoperitoneum in patients undergoing endoscopic surgery can lead to different degrees of disturbance in the brain tissue metabolism, changes in cerebral oxygenation in the operation, and the effects of pneumoperitoneum on different degrees. Nerve injury, which makes the plasma S100 beta protein and the concentration of NSE increase, may induce the decrease in the cognitive function score of the patients in the laparotomy group and the laparoscopic operation group, which may be due to the relatively small trauma of the laparoscopic operation, the shorter operation and the anesthesia time, and the less influence on the patient's nerve function. The posterior cognitive function score is better than the laparotomy group. However, there is insufficient evidence to prove that laparoscopic surgery can reduce the incidence of POCD in elderly patients.
The effect of the selection of anesthetic methods on POCD is controversial. The study found that general anesthesia drugs can cause impairment of memory by affecting the plasticity of the body's synapses, and then change or damage the brain and cause POCD..
With the advent of the aging society, various medical and social problems caused by POCD are being paid more and more attention by the medical community. It is particularly important to reduce the incidence of POCD in the perioperative period of the elderly and improve the quality of life in his later years.
Dexmedetomidine (Dex) is a specific alpha 2- adrenergic receptor agonist, which has sedative, sleep and anti anxiety effects. It also has a certain analgesic effect while producing anti sympathetic and anti cold action. It can be used to assist anesthesia during operation, protect the central nervous system and improve the postoperative patients' operation. Cognitive function.
Studies have shown that Dex has different degrees of neuroprotective effect. There are also studies found that Dex can reduce the incidence of POCD in elderly patients with colorectal cancer surgery, but the impact of Dex on POCD in elderly patients with colorectal cancer surgery is still lack of relevant research reports.
Ulinastatin (urinary trypsin inhibitor.UTI) is a drug that is isolated and purified from the urine of our human body and is widely used in the inhibition of broad-spectrum enzymes.
Studies have shown that Ulinastatin can inhibit the inflammatory response of the body and reduce the body's learning and memory dysfunction by reducing the apoptosis of the body's nerve cells, thus reducing the incidence of POCD in the elderly patients.
The study found that Ulinastatin or dexamethasone have different protective effects on endotoxin induced lung injury in rabbits. Combined use of ulinastatin and dexamethasone may enhance the effect, and the effect of ulinastatin combined with other drugs on the incidence of POCD in elderly patients is currently in the country. There is also a lack of relevant research reports.
In summary, because the effect of the anesthetic on the incidence of POCD remains controversial, the pathogenesis of POCD is not clear, the ethical problems in the clinical research work, the research methods, the diagnostic criteria are not unified, the subjectivity is strong and so on, and the results of the report are not consistent. This study borrows from the research program of the international POCD research group and through the establishment of the empty space. White control group, so as to determine whether the postoperative cognitive function changes are normal changes, so that the POCD diagnosis method is more reasonable.
Studies have shown that Ulinastatin and dexmeimidine hydrochloride can reduce the stress response to a certain extent, reduce the damage of the inflammatory mediators to the viscera of the patients and reduce the incidence of POCD in the elderly patients. However, the combination of the two combinations has a synergistic or enhanced effect to further reduce the incidence of postoperative POCD in patients. Good viscera protection is rarely reported. Therefore, this study was to evaluate and compare the effects of right metoimidine or ulinastatin on the same anesthetic depth at the first day after first days and third days after the operation, and the combination of them on POCD in elderly patients with colon cancer surgery under abdominal endoscopy. To provide new ideas and methods to prevent the occurrence of POCD in elderly patients, and to improve the quality of life of elderly patients in their later years.
Methods 80 elderly patients with laparoscopic colorectal cancer surgery under general anesthesia were selected as the subjects. The patients were ASA I to grade II, aged over 65 years. The random digital table method was divided into 0.9% Sodium Chloride Injection blank control group (group A), right metoimidin group (group D), ulinastatin group (Group U), right metomomidin + Ulinastatin group (group D+U). There were 20 cases in each group. There was no statistical difference in the general data of the four groups (P0.05), which was comparable. All patients were not given preoperative medication before entering the operation room. All patients were treated with total intravenous anesthesia. In group D, before induction of anesthesia, 15min was injected into the 15mmin infusion of 0.5 mu g/kg dexmeimidin. At the speed of 0.3 mu g/kg/h (normal saline was prepared by right metomomidine hydrochloride to 4 g/mL), 30min stopped infusion before the end of the operation; group U was given 2ku/kg Ulinastatin at the same time, followed by 1ku/ (kg h) pump, and the D+U group was given a continuous infusion of right metomomidin and Ulinastatin by these two methods; A group 0.9% Sodium Chloride Injection continuous pumps were given at the same time. Anesthesia induction: intravenous midazolam 0.02 ~ 0.04mg/kg, etomidate 0.1 ~ 0.3mg/kg, sufentanil citrate 0.2 ~ 0.3 u g/kg, vecuronium 0.1mg/kg, endotracheal intubation machine for mechanical ventilation. Anesthesia was maintained by propofol and remifentanil by intravenous Maintenance anesthesia, using a microinfusion pump continuously pumped into remifentanil 0.05 ~ 0.2 g/kg/min, and adding sufentanil and vecuronium citrate intermittently according to the operation conditions. During the operation, the blood pressure fluctuated within 10% of the basic value. The maintenance of blood oxygen saturation (SP02) 98%. maintained NI value at D1-E1, NI target value at 45~55. After half an hour, sufentanil was given 5-10 mu g and flurbiprofen 50mg for preemptive analgesia. The patients did not give antagonistic muscle relaxants, the patients recovered their spontaneous breathing, the moisture content was 6mL/kg, the respiratory rate was 30 times /min, the PETCO2 was maintained 35 to 45mmHg, the patients were able to open their eyes, and the tracheal catheter was removed when the fist was forceful. The patients were given intravenous self-control analgesia (PCIA) after the operation. The formula was sufentanil 1.5 ~ 2 mu g/kg, flurbiprofen fat 1.5 ~ 2.0mg/kg, Lei Mo Si Qiong 3mg, diluted to 150m1 with saline, background infusion rate 3ml/h, 3M1 for controlled analgesia (PCA), locking time 15mim, and maintaining patients' postoperative VAS score less than 3 points.
Routine monitoring of blood pressure, electrocardiogram, SP02, recorded intraoperative bleeding, colloid and crystal infusion volume, urine volume, operation time, recovery of spontaneous breathing time (from the surgery to the patient's spontaneous breathing), open eye time (recovering from the patient to the eye opening time from the patient), and pulling out the tracheal catheter time (from the patient's open eyes to the extraction of the trachea from the patient). Guan Shijian); records the use of sufentanil, remifentanil, vecuronium, and propofol; records the occurrence of adverse reactions in the recovery period, including the incidence of hypertension, tachycardia, agitation, nausea and vomiting. Observation of postoperative wound pain and VAS score. 1 days before the operation and first days after the operation and after the operation, respectively. The neuropsychiatric test of the simple intelligence state examination (MMSE) was performed on the 3 day. If the baseline score was reduced more than 2 points before the operation, the incidence of POCD after first days after the operation and third days after the operation was calculated by POCD..
The statistics processing data were processed with SPSS13.0 statistics software. The measurement data were expressed by mean mean standard deviation (x + s). The single factor variance analysis was used in the group, and the count data using the x2 test.P0.05 was statistically significant.
Results 1) the general situation and the amount of liquid in the operation, the time of operation, the recovery of the time of spontaneous breathing, the time of removal of the tracheal tube, and the total comparison of sufentanil, remifentanil and vecuronium (P0.05), compared with the control group, the right metomomidin group and right metomomidine hydrochloride + The opening time of the Ulinastatin group was prolonged, the amount of propofol used in the operation decreased significantly, and the incidence of hypertension, tachycardia, agitation, nausea and vomiting decreased in the recovery period, and the difference was statistically significant (P0.05).
2) there was no significant difference between the MMSE scores before operation (P0.05); the MMSE scores of the control group first days after the operation and the third day after the operation were significantly decreased, compared with the preoperative MMSE score, the difference was statistically significant (P0.05); the right metoamidine group, the Ulinastatin group and the right metomomidin + Ulinastatin group were performed first days after operation and operation. There was no significant decrease in MMSE scores on the third day after operation, and there was no significant difference compared with preoperative MMSE score (P0.05).
3) there was no significant difference in the incidence of POCD in the first and third days after operation in the control group (P0.05). Compared with the control group, the incidence of postoperative cognitive impairment in right metoimidin group, ulinastatin group and right metomomidin + Ulinastatin group were significantly decreased (P0.05); There was no significant reduction in the incidence of cognitive impairment in the patients with dexmetamidine group and ulinastatin group. There was no significant difference in the incidence of postoperative cognitive impairment in the patients with dexmedetomidin + ulinastatin (P0.05).
Conclusion 1) right metodetidine hydrochloride was given 0.5 g/kg before induction of anesthesia, and the infusion rate of 0.3 mu g/kg/h during the operation could reduce the incidence of early cognitive impairment in the elderly patients with colorectal cancer surgery and reduce the adverse reaction in the recovery period of the patients.
2) ulinastatin 2ku/kg was given before anesthesia induction, and the infusion rate of 1ku/ (kg. H) during the operation could reduce the incidence of early cognitive impairment in elderly patients with laparoscopic colorectal cancer surgery.
3) in comparison with dexmeimidine or Ulinastatin, a combination of right metoimidine and ulinastatin, the incidence of early cognitive impairment in elderly patients with colorectal cancer surgery could not be further reduced.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R735.34

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