發(fā)布時間：2018-05-03 18:10

  本文選題：鹽酸右美托咪定 + 羥考酮��； 參考：《山東大學》2017年博士論文

【摘要】：研究背景和目的:肺癌是全世界高發(fā)病率惡性腫瘤之一,手術是重要治療方法。傳統(tǒng)開胸手術,創(chuàng)傷大,術后疼痛嚴重。目前肺癌手術在胸腔鏡下即可完成,切除病變同時,還可進行淋巴結切除。相對而言,胸腔鏡手術具有很多優(yōu)點,如縮小手術切口,減輕術后疼痛,縮短平均住院時間等。但是手術創(chuàng)傷依然會導致應激反應,術后疼痛仍然存在,嚴重者形成慢性疼痛,時間長達術后數月。急性術后疼痛引起交感神經興奮,增加心腦血管意外,導致肺炎、肺不張等多種并發(fā)癥,延長住院時間,延遲病人恢復。因此,有效的術后鎮(zhèn)痛仍然必不可少。雖然我們在術后疼痛管理方面已經有了許多方法和藥物,但是術后鎮(zhèn)痛不充分的情況依然存在。所以,研究胸腔鏡肺癌手術后病人有效鎮(zhèn)痛方法和藥物,對臨床治療有重要意義。術后鎮(zhèn)痛藥物選擇,國內外大多以阿片類藥物為主導。但是阿片類藥物的副作用,如:惡心、嘔吐、瘙癢、尿潴留、便秘,嚴重者甚至發(fā)生呼吸抑制,常常引起更多干預性治療而令人擔憂。因此,最新的疼痛管理方法提出少用甚至不用阿片類藥。對惡性腫瘤病人來說,免疫功能至關重要。減少促炎因子的產生,保持機體促炎與抑炎的正平衡對于長期預后有積極意義。手術創(chuàng)傷和術后疼痛均可引起機體細胞因子的變化,細胞因子與免疫系統(tǒng)相互調節(jié),通過信號轉導通路,產生級聯(lián)放大反應,對機體的免疫功能產生影響,進而影響預后和轉歸。高遷移率族蛋白1(high mobility group box 1,HMGB1)是重要的炎癥介質,參與機體多種炎性反應,引起促炎細胞因子釋放。研究顯示,HMGB1作為炎癥反應的上游因子,其釋放后與受體結合,激活多種信號通路,導致基因轉錄、修復,產生細胞和組織損傷。而抑制HMGB1相關信號激活,能夠減輕炎癥細胞聚集,減少炎性細胞因子釋放。TNF-α和IL-6是重要的促炎性細胞因子,兩者的升高常預示過高的炎癥和應激,預后不良。IL-10是重要的抗炎細胞因子,能夠調節(jié)機體免疫功能,在炎癥過程中具有重要作用。鹽酸右美托咪定為α2-腎上腺素能受體(α2-adrenergic receptor,α2AR)激動劑,對受體親和力α2:α1比例為1620:1。除具有鎮(zhèn)痛、鎮(zhèn)靜作用外,還具有抑制交感神經和抗炎、臟器保護的作用。通過作用于中樞和外周的α2AR受體,右美托咪定發(fā)揮藥理作用。研究認為右美托咪定持續(xù)輸注能夠減少所用阿片類藥物的劑量,降低術后鎮(zhèn)痛藥用量;應用右美托咪定能夠降低促炎因子的釋放,減輕術中、術后炎癥反應。羥考酮是半合成的阿片類藥物,能選擇性地激動μ和κ阿片受體,特點是快速起效和作用時間短,具有良好的術后鎮(zhèn)痛效果,相對其他阿片類藥物,呼吸抑制發(fā)生率低。其與嗎啡效能相似,但比嗎啡副作用低,臨床廣泛用于治療中到重度疼痛。但是右美托咪定復合羥考酮用于胸腔鏡術后鎮(zhèn)痛效果,臨床相關報道不多。并且二者聯(lián)合應用于術后鎮(zhèn)痛時,對血清細胞因子水平的影響,未見報道。病人靜脈自控鎮(zhèn)痛,能夠提供穩(wěn)定的血藥濃度,還可自主給藥,是多種手術后鎮(zhèn)痛選擇之一。本研究基于此,以肺癌病人為研究對象,將右美托咪定復合羥考酮用于電視胸腔鏡下肺葉切除術后病人自控靜脈鎮(zhèn)痛,觀察其鎮(zhèn)痛效果,并觀察副作用發(fā)生情況,以及血清中HMGB1、TNF-α、IL-6和IL-10水平的變化,與單純羥考酮用藥作對比。研究方法和內容:選擇2014年6月至2015年12月入住我院胸外科病人,ASA分級為Ⅰ-Ⅲ,年齡18～75歲,確診為肺癌需行胸腔鏡下肺葉切除手術者,采用隨機數字表法將病人分為兩組:單純羥考酮組(oxycodone,O)和右美托咪定復合羥考酮組(dexmedetomidine and oxycodone,DO)。所有病人均選擇靜脈復合吸入雙腔氣管插管全身麻醉,誘導前右美托咪定復合羥考酮組給予右美托咪定0.5μg/kg,稀釋于20ml生理鹽水中,持續(xù)輸注1Omin;單純羥考酮組給予等量生理藥水。兩組麻醉誘導均選用咪達唑侖、丙泊酚、芬太尼和羅庫溴銨;麻醉維持藥物選用丙泊酚和七氟醚,間斷靜脈推注芬太尼鎮(zhèn)痛,羅庫溴銨維持肌肉松弛。所有病人均作中心靜脈穿刺和有創(chuàng)橈動脈測壓,術中監(jiān)測包括心電圖(electrocardiogram,ECG)、血壓(blood pressure,BP)、心率(heart rate,HR)、脈搏氧飽和度(pulse oxygen saturation,SpO2)、呼氣末二氧化碳分壓(partial pressure of carbon dioxide at end-tidal,PetCO2)、腦電雙頻譜指數(bispectral index,BIS)。術后兩組均使用病人自控靜脈鎮(zhèn)痛(patient-controlled intravenous analgesia PCIA)泵。其中,單純羥考酮組給予羥考酮50mg,稀釋于100ml生理鹽水中;右美托咪定復合羥考酮組給藥劑量為右美托咪定2.5μg/kg+羥考酮50mg,稀釋于100ml生理鹽水中。術后鎮(zhèn)痛泵設定參數如下:持續(xù)背景輸注劑量為1ml/h,單次按壓劑量2ml,鎖定時間為15分鐘。如果病人感到疼痛,首先推薦按壓鎮(zhèn)痛泵,如果無效,肌肉注射哌替啶50mg補救鎮(zhèn)痛。觀測指標包括:評估病人術后4h、6h、24h和48h視覺模擬鎮(zhèn)痛評分(visual analogue scale,VAS)和Ramsay鎮(zhèn)靜評分,鎮(zhèn)痛泵按壓次數,羥考酮的消耗量,副作用發(fā)生情況。記錄不同時間點的平均動脈壓(mean arterial pressure,MAP)和心率(heart rate,HR):到達手術室(T0);插管前(TT);插管后(T2);切皮后30min(T3);拔管時(T4);到達PACU(T5);術后1天(T6);以及術后2天(T7)。病人對疼痛控制滿意度的評估于術后48小時鎮(zhèn)痛泵撤除后進行。分別于術前1天、術后第1、2日晨抽取中心靜脈血用ELISA法檢測HMGB1、TNF-α、IL-6和IL-10水平的變化。本研究設計遵守1975年《赫爾辛基宣言》中規(guī)定的倫理標準。研究結果:1.兩組病人術前一般情況如年齡、性別組成、身高、體重指數相比無統(tǒng)計學差異(P0.05);兩組手術時間相比,P=0.883;術中芬太尼用量相比,P=0.327。2.兩組病人術中及術后不同時間MAP和HR變化無統(tǒng)計學差異(P0.05)。3.O組病人靜息時視覺模擬鎮(zhèn)痛評分在術后4h、6h和24h顯著高于 DO組(P0.001);術后48h時,兩組相比無顯著統(tǒng)計學差異(P=0.087);O組病人運動時視覺模擬鎮(zhèn)痛評分在術后4h、6h和24h顯著高于DO組(P≤0.001);術后48h時,兩組病人靜息和運動時視覺模擬鎮(zhèn)痛評分相比均無統(tǒng)計學差異(P0.05);沒有病人需要補救鎮(zhèn)痛;兩組Ramsay鎮(zhèn)靜評分在不同時間點相比差異無統(tǒng)計學意義(P0.05)。4.術后6h,O組有50%病人發(fā)生惡心反應,而DO組僅有7.5%病人發(fā)生惡心,兩組相比差異顯著(P0.001);嘔吐發(fā)生率在O組為12.5%,DO組為0,有統(tǒng)計學差異(P=0.027);6h后兩組均無惡心、嘔吐發(fā)生。5.O組病人鎮(zhèn)痛泵中羥考酮的消耗量在不同時間點均高于DO組(P0.01);O組病人按壓鎮(zhèn)痛泵的次數顯著高于DO組(P0.01)。6.與O組相比,DO組病人取得更高的疼痛控制滿意度,完全滿意的病人在O組為5%,DO組為15%;對疼痛控制滿意的病人在O組為17.5%,DO組為75%,差異有統(tǒng)計學意義(P0.001)。7.術前兩組血清中HMGB1水平相比,無統(tǒng)計學差異(P=0.668);術后第一天,兩組HMGB1水平均較術前顯著升高(P0.01);O組與DO組相比,升高更顯著(P=0.008);術后第二天,DO組HMGB1水平回降,與術前相比,差異不顯著(P=0.407);O組HMGB1水平術后第二天稍有回降,但與術前相比,仍然升高(P0.01);與DO組相比,亦升高(P0.01)。8.兩組病人術前血清中TNF-α和IL-6水平無統(tǒng)計學差異;術后第一天,兩組TNF-α和IL-6水平與術前相比,均顯著升高(P0.05);O組與DO組相比,升高更顯著(P0.05)。術后第二天,O組病人血清中TNF-α和IL-6水平稍有回落,但與術前相比,仍較高(P0.05);DO組病人TNF-α和IL-6水平回落,與術前相比,差異不顯著(P0.05);其中,O組術后第二天TNF-α水平與DO組相比,仍然顯著升高(P=0.008)。9.術前兩組病人血清中IL-10水平無統(tǒng)計學差異(P=0.132);術后第一天,與術前相比,兩組IL-10水平均升高(P0.05),兩組之間相比,無統(tǒng)計學差異;術后第二天,O組水平回降,與術前相比,差異不顯著(P=0.609),DO組仍高于術前水平(P0.01),兩組之間相比,無統(tǒng)計學差異(P0.05)。研究結論:右美托咪定復合羥考酮用于胸腔鏡下肺葉切除術后病人自控靜脈鎮(zhèn)痛,與單純羥考酮用藥相比,鎮(zhèn)痛效果更好,阿片類藥物用量降低,副作用發(fā)生率更低,病人對疼痛控制滿意度更高,術后早期炎性反應更輕。
[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.

【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R614

【參考文獻】

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6 鄭勇萍;郭偉;張宗澤;王焱林;彭勉;王成夭;;右美托咪定、地佐辛單獨或復合用藥對開胸術患者蘇醒期躁動的影響[J];中華麻醉學雜志;2013年06期

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