右美托咪定复合羟考酮用于胸腔镜手术后病人自控静脉镇痛的研究

发布时间：2018-05-03 18:10

本文选题：盐酸右美托咪定 + 羟考酮　；参考：《山东大学》2017年博士论文

【摘要】：研究背景和目的:肺癌是全世界高发病率恶性肿瘤之一,手术是重要治疗方法。传统开胸手术,创伤大,术后疼痛严重。目前肺癌手术在胸腔镜下即可完成,切除病变同时,还可进行淋巴结切除。相对而言,胸腔镜手术具有很多优点,如缩小手术切口,减轻术后疼痛,缩短平均住院时间等。但是手术创伤依然会导致应激反应,术后疼痛仍然存在,严重者形成慢性疼痛,时间长达术后数月。急性术后疼痛引起交感神经兴奋,增加心脑血管意外,导致肺炎、肺不张等多种并发症,延长住院时间,延迟病人恢复。因此,有效的术后镇痛仍然必不可少。虽然我们在术后疼痛管理方面已经有了许多方法和药物,但是术后镇痛不充分的情况依然存在。所以,研究胸腔镜肺癌手术后病人有效镇痛方法和药物,对临床治疗有重要意义。术后镇痛药物选择,国内外大多以阿片类药物为主导。但是阿片类药物的副作用,如:恶心、呕吐、瘙痒、尿潴留、便秘,严重者甚至发生呼吸抑制,常常引起更多干预性治疗而令人担忧。因此,最新的疼痛管理方法提出少用甚至不用阿片类药。对恶性肿瘤病人来说,免疫功能至关重要。减少促炎因子的产生,保持机体促炎与抑炎的正平衡对于长期预后有积极意义。手术创伤和术后疼痛均可引起机体细胞因子的变化,细胞因子与免疫系统相互调节,通过信号转导通路,产生级联放大反应,对机体的免疫功能产生影响,进而影响预后和转归。高迁移率族蛋白1(high mobility group box 1,HMGB1)是重要的炎症介质,参与机体多种炎性反应,引起促炎细胞因子释放。研究显示,HMGB1作为炎症反应的上游因子,其释放后与受体结合,激活多种信号通路,导致基因转录、修复,产生细胞和组织损伤。而抑制HMGB1相关信号激活,能够减轻炎症细胞聚集,减少炎性细胞因子释放。TNF-α和IL-6是重要的促炎性细胞因子,两者的升高常预示过高的炎症和应激,预后不良。IL-10是重要的抗炎细胞因子,能够调节机体免疫功能,在炎症过程中具有重要作用。盐酸右美托咪定为α2-肾上腺素能受体(α2-adrenergic receptor,α2AR)激动剂,对受体亲和力α2:α1比例为1620:1。除具有镇痛、镇静作用外,还具有抑制交感神经和抗炎、脏器保护的作用。通过作用于中枢和外周的α2AR受体,右美托咪定发挥药理作用。研究认为右美托咪定持续输注能够减少所用阿片类药物的剂量,降低术后镇痛药用量;应用右美托咪定能够降低促炎因子的释放,减轻术中、术后炎症反应。羟考酮是半合成的阿片类药物,能选择性地激动μ和κ阿片受体,特点是快速起效和作用时间短,具有良好的术后镇痛效果,相对其他阿片类药物,呼吸抑制发生率低。其与吗啡效能相似,但比吗啡副作用低,临床广泛用于治疗中到重度疼痛。但是右美托咪定复合羟考酮用于胸腔镜术后镇痛效果,临床相关报道不多。并且二者联合应用于术后镇痛时,对血清细胞因子水平的影响,未见报道。病人静脉自控镇痛,能够提供稳定的血药浓度,还可自主给药,是多种手术后镇痛选择之一。本研究基于此,以肺癌病人为研究对象,将右美托咪定复合羟考酮用于电视胸腔镜下肺叶切除术后病人自控静脉镇痛,观察其镇痛效果,并观察副作用发生情况,以及血清中HMGB1、TNF-α、IL-6和IL-10水平的变化,与单纯羟考酮用药作对比。研究方法和内容:选择2014年6月至2015年12月入住我院胸外科病人,ASA分级为Ⅰ-Ⅲ,年龄18～75岁,确诊为肺癌需行胸腔镜下肺叶切除手术者,采用随机数字表法将病人分为两组:单纯羟考酮组(oxycodone,O)和右美托咪定复合羟考酮组(dexmedetomidine and oxycodone,DO)。所有病人均选择静脉复合吸入双腔气管插管全身麻醉,诱导前右美托咪定复合羟考酮组给予右美托咪定0.5μg/kg,稀释于20ml生理盐水中,持续输注1Omin;单纯羟考酮组给予等量生理药水。两组麻醉诱导均选用咪达唑仑、丙泊酚、芬太尼和罗库溴铵;麻醉维持药物选用丙泊酚和七氟醚,间断静脉推注芬太尼镇痛,罗库溴铵维持肌肉松弛。所有病人均作中心静脉穿刺和有创桡动脉测压,术中监测包括心电图(electrocardiogram,ECG)、血压(blood pressure,BP)、心率(heart rate,HR)、脉搏氧饱和度(pulse oxygen saturation,SpO2)、呼气末二氧化碳分压(partial pressure of carbon dioxide at end-tidal,PetCO2)、脑电双频谱指数(bispectral index,BIS)。术后两组均使用病人自控静脉镇痛(patient-controlled intravenous analgesia PCIA)泵。其中,单纯羟考酮组给予羟考酮50mg,稀释于100ml生理盐水中;右美托咪定复合羟考酮组给药剂量为右美托咪定2.5μg/kg+羟考酮50mg,稀释于100ml生理盐水中。术后镇痛泵设定参数如下:持续背景输注剂量为1ml/h,单次按压剂量2ml,锁定时间为15分钟。如果病人感到疼痛,首先推荐按压镇痛泵,如果无效,肌肉注射哌替啶50mg补救镇痛。观测指标包括:评估病人术后4h、6h、24h和48h视觉模拟镇痛评分(visual analogue scale,VAS)和Ramsay镇静评分,镇痛泵按压次数,羟考酮的消耗量,副作用发生情况。记录不同时间点的平均动脉压(mean arterial pressure,MAP)和心率(heart rate,HR):到达手术室(T0);插管前(TT);插管后(T2);切皮后30min(T3);拔管时(T4);到达PACU(T5);术后1天(T6);以及术后2天(T7)。病人对疼痛控制满意度的评估于术后48小时镇痛泵撤除后进行。分别于术前1天、术后第1、2日晨抽取中心静脉血用ELISA法检测HMGB1、TNF-α、IL-6和IL-10水平的变化。本研究设计遵守1975年《赫尔辛基宣言》中规定的伦理标准。研究结果:1.两组病人术前一般情况如年龄、性别组成、身高、体重指数相比无统计学差异(P0.05);两组手术时间相比,P=0.883;术中芬太尼用量相比,P=0.327。2.两组病人术中及术后不同时间MAP和HR变化无统计学差异(P0.05)。3.O组病人静息时视觉模拟镇痛评分在术后4h、6h和24h显著高于 DO组(P0.001);术后48h时,两组相比无显著统计学差异(P=0.087);O组病人运动时视觉模拟镇痛评分在术后4h、6h和24h显著高于DO组(P≤0.001);术后48h时,两组病人静息和运动时视觉模拟镇痛评分相比均无统计学差异(P0.05);没有病人需要补救镇痛;两组Ramsay镇静评分在不同时间点相比差异无统计学意义(P0.05)。4.术后6h,O组有50%病人发生恶心反应,而DO组仅有7.5%病人发生恶心,两组相比差异显著(P0.001);呕吐发生率在O组为12.5%,DO组为0,有统计学差异(P=0.027);6h后两组均无恶心、呕吐发生。5.O组病人镇痛泵中羟考酮的消耗量在不同时间点均高于DO组(P0.01);O组病人按压镇痛泵的次数显著高于DO组(P0.01)。6.与O组相比,DO组病人取得更高的疼痛控制满意度,完全满意的病人在O组为5%,DO组为15%;对疼痛控制满意的病人在O组为17.5%,DO组为75%,差异有统计学意义(P0.001)。7.术前两组血清中HMGB1水平相比,无统计学差异(P=0.668);术后第一天,两组HMGB1水平均较术前显著升高(P0.01);O组与DO组相比,升高更显著(P=0.008);术后第二天,DO组HMGB1水平回降,与术前相比,差异不显著(P=0.407);O组HMGB1水平术后第二天稍有回降,但与术前相比,仍然升高(P0.01);与DO组相比,亦升高(P0.01)。8.两组病人术前血清中TNF-α和IL-6水平无统计学差异;术后第一天,两组TNF-α和IL-6水平与术前相比,均显著升高(P0.05);O组与DO组相比,升高更显著(P0.05)。术后第二天,O组病人血清中TNF-α和IL-6水平稍有回落,但与术前相比,仍较高(P0.05);DO组病人TNF-α和IL-6水平回落,与术前相比,差异不显著(P0.05);其中,O组术后第二天TNF-α水平与DO组相比,仍然显著升高(P=0.008)。9.术前两组病人血清中IL-10水平无统计学差异(P=0.132);术后第一天,与术前相比,两组IL-10水平均升高(P0.05),两组之间相比,无统计学差异;术后第二天,O组水平回降,与术前相比,差异不显著(P=0.609),DO组仍高于术前水平(P0.01),两组之间相比,无统计学差异(P0.05)。研究结论:右美托咪定复合羟考酮用于胸腔镜下肺叶切除术后病人自控静脉镇痛,与单纯羟考酮用药相比,镇痛效果更好,阿片类药物用量降低,副作用发生率更低,病人对疼痛控制满意度更高,术后早期炎性反应更轻。
[Abstract]:Background and purpose: lung cancer is one of the world's high incidence of malignant tumors. Surgery is an important treatment. Traditional thoracotomy, large trauma, and severe postoperative pain. At present, lung cancer surgery can be performed under thoracoscopy, resection of the lesion and lymph node excision. The surgical incision can reduce the postoperative pain and shorten the average time of hospitalization. However, the surgical trauma still leads to the stress reaction, the postoperative pain still exists, the severe pain is still existed, the serious person forms the chronic pain, the time is long after a few months. The acute postoperative pain causes the sympathetic nerve excitement, the increase of heart and brain vascular accident, the pneumonia, the atelectasis and so on. Therefore, effective postoperative analgesia is still essential. Although we have many methods and drugs in the management of postoperative pain, the condition of postoperative analgesia still exists. Therefore, it is of great significance to study the effective analgesic methods and drugs of patients with thoracoscopic lung cancer after operation. The choice of postoperative analgesic drugs is dominated by opioids at home and abroad. But the side effects of opioids, such as nausea, vomiting, itching, urinary retention, constipation, and even respiratory depression, are often caused by more intervention treatment. Therefore, the latest pain management methods are less or even opioid. For patients with malignant tumor, immune function is very important. Reducing the production of pro-inflammatory factors and maintaining the positive balance of inflammatory and anti inflammation is positive for long-term prognosis. Surgical trauma and postoperative pain can cause changes in the body's cytokines, cytokines and immune systems are regulated by each other, and cascade through signal transduction pathways to produce cascade. The amplification reaction affects the immune function of the body and affects the prognosis and prognosis. High mobility group protein 1 (high mobility group box 1, HMGB1) is an important inflammatory mediator. It participates in various inflammatory reactions and causes the release of proinflammatory cytokines. The study shows that HMGB1 is the upstream factor of inflammatory reaction and is combined with the receptor after release. Activation of a variety of signaling pathways leads to gene transcription, repair, and cell damage. Inhibition of HMGB1 related signal activation, reducing inflammatory cell aggregation, and reducing inflammatory cytokines release.TNF- alpha and IL-6 are important proinflammatory cytokines, which often predict excessive inflammation and stress, and poor prognosis is important for.IL-10. Anti inflammatory cytokines, which can regulate the immune function of the body, play an important role in the process of inflammation. Dexmedetomidine hydrochloride is an alpha 2- adrenergic receptor (alpha 2-adrenergic receptor, alpha 2AR) agonist, and the receptor affinity alpha 2: alpha 1 is 1620:1., except for analgesic and sedative, it also has the inhibition of sympathetic and anti-inflammatory and visceral protection. The effect of right metoimidine on the central and peripheral levels of the alpha 2AR receptor, dexmedetomidin, can reduce the dosage of opioid drugs and reduce the amount of postoperative analgesics; dexmedetomidine can reduce the release of proinflammatory factors and reduce the postoperative inflammatory response. It is a semi synthetic opioid, selectively excited and kappa opioid receptor, characterized by rapid onset and short action time, good postoperative analgesic effect, low incidence of respiratory inhibition compared with other opioids. It is similar to morphine but is lower than morphine and is widely used in the treatment of moderate to severe pain. The effect of dexmedetomidine combined with oxycodone on analgesia after thoracoscopic surgery is not much reported, and the effect of the combination of the two in postoperative analgesia on serum cytokine levels is not reported. The patient controlled intravenous analgesia, which can provide stable blood concentration, and can be administered independently, is one of the choice of postoperative analgesia. Based on this, this study took the patients with lung cancer as the research object, using dexmedetomidine compound oxycodone used for patient-controlled intravenous analgesia after video-assisted thoracoscopic lobectomy, observe the analgesic effect, observe the occurrence of side effects, and change the level of HMGB1, TNF- a, IL-6 and IL-10 in serum, and compare with the use of simple oxycodone. Methods and contents: select the patients in Department of thoracic surgery of our hospital from June 2014 to December 2015. ASA was classified as I - III, 18~75 years old. The patients were diagnosed as lung cancer with thoracoscopic lobectomy. The patients were divided into two groups by random digital table method: the simple oxycodone group (oxycodone, O) and right metomomidin group (dexmedetomidine a) Nd oxycodone, DO). All patients were treated with intravenous combined inhalation of double lumen tracheal intubation for general anesthesia, and right metodetomidin group was induced to give right metomomidin 0.5 u g/kg, diluted in 20ml physiological saline, continuous infusion of 1Omin; simple oxycodone group was given equal amount of physiological water. Midazolam and propofol were selected for the two groups. Fentanyl and rocuronium; anesthesia maintenance drug propofol and sevoflurane, intermittent intravenous fentanyl analgesia, rocuronium to maintain muscle relaxation. All patients were performed central venous puncture and radial artery pressure measurement, including electrocardiogram (ECG), blood pressure (blood pressure, BP), heart rate (heart rate, HR). The pulse oxygen saturation (pulse oxygen saturation, SpO2), the partial pressure of the end expiratory carbon dioxide (partial pressure of carbon dioxide at end-tidal, PetCO2), the EEG bispectral index were used in the two groups after the operation. The dose of oxycodone 50mg was diluted in 100ml saline; right metomomimido compound oxycodone group was given a dose of right metodetone 2.5 g/kg+ ha 50mg, diluted in 100ml physiological saline. The parameters of the postoperative analgesia pump were as follows: continuous background infusion dose 1ml/h, single press dose 2ml, locking time for 15 minutes. If patient felt it was felt. Pain, first recommended pressure analgesia pump, if ineffective, intramuscular injection of piperidine 50mg to remedy analgesia. Observation indexes include: evaluate patients' postoperative 4h, 6h, 24h and 48h visual analogue analgesic score (visual analogue scale, VAS) and Ramsay sedation score, analgesic pump press times, oxycodone consumption, side effects. Record different time points. The average arterial pressure (mean arterial pressure, MAP) and heart rate (heart rate, HR): arriving in the operation room (T0); before intubation (TT); after intubation (T2); 30min (T3) after cutting skin; extubation; 1 days after operation; and 2 days after the operation. The patient's pain control satisfaction assessment was carried out after the 48 hour postoperative analgesia pump. In the 1 day, central venous blood was extracted on the morning of the 1,2 day after the operation. The changes in the level of HMGB1, TNF-, IL-6 and IL-10 were detected by ELISA. The study was designed to comply with the ethical standards stipulated in the 1975 < Helsinki declaration. The results of study: 1. the two groups of patients had no statistical difference before operation, such as age, gender composition, height, and body mass index (P0.05); two Compared with P=0.883, there was no significant difference in MAP and HR during and after operation (P0.05) in group P=0.327.2. two, and in group.3.O, the visual analogue analgesic score was significantly higher in 4h, 6h and 24h than in DO group (P0.001) in group.3.O, and there was no significant difference between the two groups after the operation. Group 4h, 6h and 24h were significantly higher than those in group DO (P < 0.001) after operation (P < < 0.001). There was no significant difference in the visual analogue analgesia score between the two groups after the operation (P0.05), and no patients needed remedial analgesia (P0), and the two groups of Ramsay sedation score had no significant difference at different time points (P0). .05) after.4., 50% patients in group O had nausea, but only 7.5% patients in group DO had nausea, and the difference between the two groups was significant (P0.001); the incidence of vomiting in the O group was 12.5% and the DO group was 0 (P=0.027); the two groups after 6h were all nausea, and the consumption of oxycodone in the vomiting pump was higher in different time points than in the.5.O group. Group DO (P0.01); the number of patients in group O was significantly higher than that of group DO (P0.01).6. and O group, DO patients had higher pain control satisfaction. The patients with complete satisfaction were 5% in O group and 15% in DO group, 17.5% in O group and 75% in DO group for pain control. The difference was statistically significant in the two groups before the operation. The level of B1 was not statistically significant (P=0.668). The level of HMGB1 in the two groups was significantly higher on the first day after operation than before the operation (P0.01), and in the O group, the increase was more significant (P=0.008) than that in the DO group (P=0.008); the level of HMGB1 in DO group was not significant (P=0.407) at the second day after operation (P=0.407), while the HMGB1 level in the O group was slightly descended at second days after the operation, but still compared with that before the operation. Ran Shenggao (P0.01); compared with group DO, there was no significant difference in the level of TNF- alpha and IL-6 in serum before operation (P0.01).8. two. The level of TNF- alpha and IL-6 in the two groups increased significantly on the first day after the operation (P0.05), and the O group was higher than that in the DO group (P0.05). Second days after the operation, the levels of the serum in the patients' serum were slightly higher than that in the DO group. Compared with pre operation, it was still higher (P0.05); the level of TNF- alpha and IL-6 decreased in group DO, and the difference was not significant compared with that before operation (P0.05). In group O, the level of TNF- alpha at second days after operation was still significantly higher than that in DO group (P=0.008), there was no statistical difference between the serum IL-10 levels in the two groups of patients before operation (P=0.132); the first day after operation, compared with preoperative. The level of IL-10 in the two groups increased (P0.05), and there was no statistical difference between the two groups. The level of O in group O was not significant compared with that before operation (P=0.609), and the DO group was still higher than the preoperative level (P0.01). There was no statistical difference between groups (P0.05). Conclusion: right metodetone compound oxycodone was used for thoracoscopic lobectomy. The patient controlled intravenous analgesia after the operation. Compared with the simple oxycodone, the analgesic effect was better, the dosage of opioid drugs was lower, the incidence of side effects was lower, the patient was more satisfied with the pain control, and the early postoperative inflammatory reaction was lighter.

【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R614

【参考文献】