郭怡,謝澎,王鵬
(陜西省西安兵器工業(yè)五二一醫(yī)院 1.麻醉科;2.肝膽血管外科;3.重癥醫(yī)學科,陜西 西安 710065)
B超引導腹橫肌平面阻滯應用于老年患者腹腔鏡直腸癌根治術后鎮(zhèn)痛效果及對機體免疫功能的影響研究
郭怡1,謝澎2,王鵬3
(陜西省西安兵器工業(yè)五二一醫(yī)院 1.麻醉科;2.肝膽血管外科;3.重癥醫(yī)學科,陜西 西安 710065)
目的 觀察B超引導腹橫肌平面阻滯應用于老年患者腹腔鏡直腸癌根治術后鎮(zhèn)痛效果及對機體免疫功能的影響。方法 60例需行腹腔鏡直腸癌根治術的老年患者,按照入院順序編號采取數(shù)字隨機法分為腹橫肌平面阻滯組及生理鹽水對照組。腹橫肌平面阻滯組于全麻誘導后行B超引導腹橫肌平面阻滯,靜注0.25%鹽酸羅哌卡因30 ml;生理鹽水對照組靜注等容量生理鹽水。術后均給予靜脈鎮(zhèn)痛泵:舒芬太尼1.00μg/kg+昂丹司瓊16.00 mg+地佐辛10.00 mg+生理鹽水配置成100 ml,設置2 ml/h,自控時間15 min。觀察兩組麻醉前(T0)、術后 1 h(T1)、術后 12 h(T2)、術后 24 h(T3)及術后 48 h(T4)的視覺模擬評分(VAS)及血流動力學相關指標;記錄術后24 h鎮(zhèn)痛泵按壓次數(shù)及舒芬太尼使用總量;并抽取靜脈血采取流式細胞儀測定CD4+%、CD8+%水平,應用酶聯(lián)免疫吸附法測定γ干擾素(IFN-γ)水平;比較兩組術后不良反應。結(jié)果 與生理鹽水對照組比較,腹橫肌平面阻滯組于T1和T2時點平均動脈壓(MAP)降低,T1、T2及T3時點心率(HR)降低(均P <0.05);腹橫肌平面阻滯組組內(nèi)比較,T1時點MAP高于T0時點,T1和T2時點HR高于T0時點(均P <0.05)。與生理鹽水對照組比較,腹橫肌平面阻滯組于T1、T2、T3和T4時點VAS評分均更低,且術后24 h按壓次數(shù)及舒芬太尼總量均降低(均P <0.05),CD4+%水平均升高,IFN-γ水平T2和T3時點均升高(均P <0.05);不良反應發(fā)生率降低(P <0.05)。結(jié)論 B超引導腹橫肌平面阻滯應用于老年患者腹腔鏡直腸癌根治術后鎮(zhèn)痛效果較佳,血流動力學平穩(wěn),術后疼痛程度更低,對機體免疫能力具有一定保護作用,且不良反應發(fā)生率低,臨床應用安全。
B超;腹橫肌平面阻滯;腹腔鏡;直腸癌根治術;老年;免疫功能
腹腔鏡直腸癌根治術對機體創(chuàng)傷大,術后切口疼痛發(fā)生率高,于術后數(shù)小時程度最為劇烈,逐步減輕至術后2或3 d,而2.00%~56.00%患者還可發(fā)生術后慢性疼痛,嚴重影響患者預后及生活質(zhì)量[1-2]。術后疼痛可引起血流動力學劇烈波動,老年患者常伴有眾多慢性疾病,心血管系統(tǒng)、呼吸系統(tǒng)等儲備能力顯著降低,耐受能力降低,圍術期并發(fā)癥及風險增加。此外,有研究證實,老年患者因多器官功能衰退,機體免疫能力降低,而術后疼痛可進一步降低免疫能力,延緩切口愈合,延長住院時間[3]。目前,臨床主要的鎮(zhèn)痛方式為靜脈鎮(zhèn)痛或者硬膜外鎮(zhèn)痛,靜脈鎮(zhèn)痛泵通常以阿片類藥物為主體,呼吸抑制發(fā)生率較高;而硬膜外鎮(zhèn)痛雖效果較佳,但硬膜外導管脫落、感染發(fā)生率較高。B超引導腹橫肌平面阻滯于超聲顯像下腹內(nèi)斜肌、腹橫肌之間筋膜層注射局麻藥,阻斷前腹壁痛覺神經(jīng)傳導,獲得良好鎮(zhèn)痛效果。本研究旨在觀察B超引導腹橫肌平面阻滯應用于老年患者腹腔鏡直腸癌根治術后鎮(zhèn)痛效果及對機體免疫功能影響,探討其臨床價值?,F(xiàn)報道如下:
選擇2014年1月-2016年8月需行腹腔鏡直腸癌根治術老年患者60例,均符合直腸癌診斷標準[4]及腹腔鏡直腸癌根治術手術指征[5],凝血功能正常且腹壁皮膚無傷口及感染,均未合并嚴重心臟、肝、腎、腦等疾病及精神類疾病。60例患者隨機分為兩組,腹橫肌平面阻滯組(n =30),男19例,女11例,平均年齡(69.5±4.5)歲,體質(zhì)指數(shù)(body mass index,BMI)(21.6±3.9)kg/m2,美國麻醉醫(yī)師協(xié)會(American Society of Anesthesiologists,ASA)分級Ⅰ級11例,Ⅱ級12例,Ⅲ級7例;合并高血壓12例,高血脂癥10例。生理鹽水對照組(n =30),男20例,女10例,平均年齡(68.6±5.2)歲,BMI(22.3±4.1)kg/m2,ASA分級Ⅰ級12例,Ⅱ級10例,Ⅲ級8例;合并高血壓11例,高血脂癥9例。兩組患者一般資料比較差異無統(tǒng)計學意義(P >0.05),具有可比性。本研究均經(jīng)醫(yī)院倫理委員會批準,且患者及監(jiān)護人均簽署知情同意。
60例患者入室后均監(jiān)測血壓、心率(heart rate,HR)、血氧飽和度等生命體征,局麻下行左側(cè)橈動脈穿刺監(jiān)測有創(chuàng)動脈壓,局麻下行右側(cè)頸內(nèi)靜脈穿刺監(jiān)測中心靜脈壓。兩組均靜注長托寧0.50 mg、咪達唑侖0.05 mg/kg、芬太尼4.00μg/kg、丙泊酚1.50~2.00 mg/kg、順-阿曲庫銨10.00 mg行麻醉誘導,待意識消失、肌松滿意后行氣管內(nèi)導管插管。誘導后患者仰臥位,腹壁常規(guī)消毒、鋪巾,采取便攜式超聲儀(英國SONATEST SiteScan 240)及超聲高頻探頭掃描患者髂嵴與12肋之間腹壁,從淺至深辨別皮下脂肪、腹外斜肌、腹內(nèi)斜肌及腹橫肌、腹膜、腹膜內(nèi)組織,將局麻針沿著探頭縱軸線進針至腹內(nèi)斜肌、腹橫肌之間筋膜(進針過程中保持針與探頭縱軸中位線位于同一平面,即平面內(nèi)阻滯),回抽無血無氣后,腹橫肌平面阻滯組靜注0.25%鹽酸羅哌卡因30 ml;生理鹽水對照組全麻后靜注等容量生理鹽水。術中兩組均泵注瑞芬太尼10.00μg/(kg·h)、丙泊酚6.00~10.00 mg/(kg·h)及間斷靜注順-阿曲庫銨維持麻醉深度,術中采取Aspect Medical腦電雙頻指數(shù)(bispect ral index,BIS)監(jiān)護儀進行麻醉深度監(jiān)測,維持BIS于40~60范圍內(nèi)。兩組手術均由同一組醫(yī)生,嚴格按照腹腔鏡直腸癌根治術步驟進行手術治療。兩組均于縫皮時停止藥物泵注,連接靜脈鎮(zhèn)痛泵(一次性使用輸注泵,100 ml;廠家:新鄉(xiāng)市鴻潤醫(yī)療器械有限公司),鎮(zhèn)痛泵藥物配置舒芬太尼1.00μg/kg+昂丹司瓊16.00 mg+地佐辛10.00 mg配置成100 ml,設置2 ml/h,自控時間15 min。
記錄兩組麻醉前(T0)、術后1 h(T1)、術后12 h(T2)、術后 24 h(T3)及術后 48 h(T4)時刻平均動脈壓(mean arterial pressure,MAP)、HR及視覺模擬評分(visual analogue scale,VAS);記錄兩組術后24 h內(nèi)鎮(zhèn)痛泵按壓次數(shù)及舒芬太尼使用總量;測定兩組靜脈血CD4+%、CD8+%及γ干擾素(interferon-γ,IFN-γ)水平,其中CD4+%、CD8+%水平采取流式細胞儀測定,IFN-γ水平應用酶聯(lián)免疫吸附法測定;記錄兩組不良反應發(fā)生率,如惡心、嘔吐和呼吸抑制等。
于10 cm長標尺上標注10個刻度,兩端分別為0分端及10分端,0代表無痛,10分代表最劇烈的疼痛,由患者根據(jù)疼痛程度評估疼痛程度[6]。
采用SPSS 19.0統(tǒng)計軟件進行統(tǒng)計分析,計數(shù)資料采用χ2檢驗,計量資料以均數(shù)±標準差(±s)表示,采取重復測量方差分析,兩兩比較采取LSD-t檢驗,P <0.05為差異有統(tǒng)計學意義。
與生理鹽水對照組比較,腹橫肌平面阻滯組于T1和T2時點MAP降低,T1、T2及T3時點 HR 降低(均P <0.05);腹橫肌平面阻滯組組內(nèi)比較,T1時點MAP高于T0時點,T1和T2時點HR高于T0時點(均P <0.05);生理鹽水對照組組組內(nèi)比較,T1和T2時點MAP 高于 T0時點,T1、T2及 T3時點 HR 高于 T0時點(均P <0.05)。見表 1。
表1 兩組不同時點MAP和HR比較 (±s)Table 1 Comparison of MAP and HR at different time points between the two groups (±s)
表1 兩組不同時點MAP和HR比較 (±s)Table 1 Comparison of MAP and HR at different time points between the two groups (±s)
注:1)與生理鹽水對照組比較,P <0.05;2)與同組T0比較,P <0.05
組別 T0 T1 T2 T3 T4 F值時點 P值時點腹橫肌平面阻滯組(n =30)MAP/mmHg 71.2±6.9 77.9±7.11)2) 72.9±6.51) 73.1±6.8 72.4±6.7 22.68 0.000 HR/(次/min) 66.5±5.7 71.9±6.51)2) 70.4±6.31)2) 68.7±5.91) 67.4±6.3 31.42 0.000生理鹽水對照組(n =30)MAP/mmHg 72.5±6.3 86.5±7.22) 79.8±6.82) 75.4±6.3 74.5±6.2 16.78 0.000 HR/(次/min) 67.9±6.2 77.8±6.92) 76.4±5.12) 74.5±6.32) 68.9±6.8 18.53 0.000 F值組間·MAP 0.48 14.20 21.39 17.65 0.14 P值組間·MAP 0.323 0.000 0.000 0.000 0.441 F值組間·HR 1.50 19.32 28.52 23.67 0.39 P值組間·HR 0.196 0.000 0.000 0.000 0.348
與生理鹽水對照組比較,腹橫肌平面阻滯組于T1、T2、T3和 T4時點 VAS評分分別為(2.1±0.6)、(1.7±0.5)、(1.1±0.4)和(0.7±0.3)分,均低于對照組(均P <0.05)。見表 2。
表2 兩組不同時點VAS評分比較 (分,±s)Table 2 Comparison of VAS scores at different time points between the two groups (score,±s)
表2 兩組不同時點VAS評分比較 (分,±s)Table 2 Comparison of VAS scores at different time points between the two groups (score,±s)
組別 T1 T2T3T4腹橫肌平面阻滯組(n =30) 2.1±0.6 1.7±0.5 1.1±0.4 0.7±0.3生理鹽水對照組(n =30) 4.2±0.7 3.6±0.8 2.4±0.9 1.9±0.7 t值 12.48 11.03 7.23 8.63 P值 0.000 0.000 0.021 0.016
與生理鹽水對照組比較,腹橫肌平面阻滯組術后24 h按壓次數(shù)及舒芬太尼總量分別為(1.3±0.3)次和(52.1±1.3)μg,均低于對照組(4.5±1.1)次和(62.5±3.7)μg。腹橫肌平面阻滯組有效按壓次數(shù)/總按壓次數(shù)為(0.8±0.1)明顯高于生理鹽水對照組(0.6±0.2),差異有統(tǒng)計學意義(均P <0.05)。見表3。
表3 兩組鎮(zhèn)痛泵按壓次數(shù)及舒芬太尼總量比較 (±s)Table 3 Comparison of number of analgesic pump press and the total amount of Sufentanil between the two groups (±s)
表3 兩組鎮(zhèn)痛泵按壓次數(shù)及舒芬太尼總量比較 (±s)Table 3 Comparison of number of analgesic pump press and the total amount of Sufentanil between the two groups (±s)
按壓次數(shù)次/24 d 舒芬太尼總量/μg 有效按壓次數(shù)/總按壓次數(shù)腹橫肌平面阻滯組(n =30) 1.3±0.3 52.1±1.3 0.8±0.1生理鹽水對照組(n =30) 4.5±1.1 62.5±3.7 0.6±0.2 t值 15.37 14.53 4.90 P值 0.000 0.000 0.036組別
與生理鹽水對照組比較,腹橫肌平面阻滯組T1、T2、T3及T4時點CD4+%水平均升高,IFN-γ水平T2和T3時點均升高(均P <0.05);腹橫肌平面阻滯組組內(nèi)比較,T2、T3及T4時點CD4+%水平均低于T0時點,T2、T3及T4時點IFN-γ均高于T0時點(均P <0.05);生理鹽水對照組組內(nèi)比較,T1、T2、T3及 T4時點CD4+%水平均低于T0時點(均P <0.05)。見表4。
表4 兩組CD4+%、CD8+%及IFN-γ水平不同時點比較 (±s)Table 4 Comparison of CD4+%,CD8+% and IFN-γ levels at different time points between the two groups (±s)
表4 兩組CD4+%、CD8+%及IFN-γ水平不同時點比較 (±s)Table 4 Comparison of CD4+%,CD8+% and IFN-γ levels at different time points between the two groups (±s)
注:1)與生理鹽水對照組比較,P <0.05;2)與同組T0比較,P <0.05
組別 T0 T1 T2 T3 T4 F值時點 P值時點腹橫肌平面阻滯組(n =30)CD4+% 30.8±2.7 29.3±2.51) 28.9±2.71)2) 28.5±2.91)2) 28.4±2.41)2) 26.82 0.000 CD8+% 25.2±5.6 23.3±5.5 22.1±4.6 21.4±5.3 20.5±5.7 1.51 0.484 IFN-γ/(pg/ml) 396.5±42.5 406.3±45.7 452.6±41.91)2) 468.9±43.21)2) 432.6±44.71)2) 15.74 0.000生理鹽水對照組(n =30)CD4+% 30.4±2.9 26.4±3.12) 26.1±2.52) 26.3±2.62) 26.2±2.32) 21.67 0.000 CD8+% 25.5±6.2 24.5±5.6 24.9±5.1 24.2±6.4 25.3±5.4 0.32 0.378 IFN-γ/(pg/ml) 399.5±42.7 394.5±41.5 402.6±46.5 404.6±46.1 411.2±47.6 36.47 0.000 F值組間·CD4+ 0.67 14.23 20.75 17.65 25.81 P值組間·CD4+ 0.247 0.000 0.000 0.000 0.000 F值組間·CD8+ 0.13 0.26 0.78 1.44 0.78 P值組間·CD8+ 0.448 0.397 0.223 0.079 0.212 F值組間·IFN-γ 1.05 1.35 13.02 14.23 10.72 P值組間·IFN-γ 0.151 0.092 0.000 0.000 0.000
與生理鹽水對照組比較,腹橫肌平面阻滯組不良反應發(fā)生率2例(6.66%),明顯低于對照組7例(23.32%)(P <0.05)。見表 5。
表5 兩組不良反應的比較 例(%)Table 5 Comparison of adverse reactions between the two groups n(%)
術后早期疼痛增加患者痛苦,可引起機體發(fā)生生理及心理一系列反應。有研究證實[7-9],術后疼痛可刺激交感神經(jīng),引起全身氧耗增加,進而增加缺血臟器損傷;還可引起HR增快、血壓升高,增強心臟做功,增加心肌缺血風險,尤對老年患者影響更為顯著;此外,術后疼痛還可降低機體呼吸功能,使呼吸淺快,潮氣量降低,增加肺不張及術后感染發(fā)生率等。術后疼痛可帶來眾多不良影響,完善鎮(zhèn)痛對緩解患者痛苦、增加圍術期舒適度及降低疼痛所致不良反應均具有重要意義。
腹壁肌肉由腹直肌、腹外斜肌、腹內(nèi)斜肌及腹橫肌組成,腹側(cè)壁由腹外斜肌、腹內(nèi)斜肌、腹橫肌及筋膜鞘組成,而前腹壁皮膚及肌肉等由下胸部6對神經(jīng)及第1對腰神經(jīng)支配,神經(jīng)前支于椎間隙間走形穿入側(cè)腹壁肌肉組織,經(jīng)過腹內(nèi)斜肌、腹橫肌間的腹橫肌前面,而感覺神經(jīng)于腋中線發(fā)出皮神經(jīng)側(cè)支后也于此平面向前支配皮膚[10-11]。基于以上解剖學分析,腹橫肌平面阻滯可使前腹壁感覺阻滯更為完善,降低疼痛感覺,以解決術后疼痛所帶來的一系列不良后果。隨著超聲顯像技術逐步應用于臨床,超聲引導下行腹橫肌平面阻滯取得較佳鎮(zhèn)痛效果。操作過程中探頭沿著腹壁掃描可見背闊肌及腹橫肌起點,還可直接觀察側(cè)腹壁腹橫肌平面,而平面內(nèi)阻滯技術可直視進針方向及部位,提高穿刺成功準確率;且超聲條件下可直接觀察麻醉藥物注射部位及擴散方向,及時調(diào)整針尖方向,可使藥液較好地擴散至整個腹壁,完善阻滯效果,獲得更加好的鎮(zhèn)痛效果[12-14]。與臨床較常應用的單純靜脈鎮(zhèn)痛泵相比,聯(lián)合應用B超引導腹橫肌平面阻滯,患者術后血流動力學更為平穩(wěn),且術后不同時點VAS評分降低,表明鎮(zhèn)痛效果更佳,而劇烈疼痛所引起的血壓劇烈波動更不明顯。本研究經(jīng)分析,與生理鹽水對照組比較,腹橫肌平面阻滯組于T1和T2時點MAP降低,T1、T2及T3時點HR降低(均P <0.05);腹橫肌平面阻滯組組內(nèi)比較,T1時點MAP高于T0時點,T1和T2時點HR高于T0時點(均P <0.05),與前述較為一致。此外,本研究觀察到,與生理鹽水對照組比較,腹橫肌平面阻滯組術后24 h按壓次數(shù)及舒芬太尼總量均降低(均P <0.05),表明腹橫肌平面阻滯組獲得更佳鎮(zhèn)痛效果,降低了舒芬太尼使用總量。
機體免疫應答包括體液免疫及致敏T淋巴細胞介導的細胞免疫,而T細胞不僅為細胞免疫的重要效應細胞,還是重要的免疫調(diào)節(jié)細胞,其數(shù)量及功能狀態(tài)一定程度上可反應機體免疫能力[15-17]。疼痛可降低機體免疫能力已得到研究證實,而有文獻報道[18-20],術后靜脈鎮(zhèn)痛泵也可降低免疫能力,認為阿片類藥物可抑制NK細胞活性及T淋巴細胞亞群數(shù)量及功能。T淋巴細胞亞群可分為CD4+及CD8+,CD4+T具有介導免疫反應功能,而CD8+T可特異性殺滅靶細胞,被稱為殺傷性T細胞,故認為CD4+T細胞數(shù)量升高、CD8+T數(shù)量降低表明機體細胞免疫功能增強,反則相反。IFN-γ由活化T細胞或者NK細胞產(chǎn)生,具有抑制腫瘤增殖及抗腫瘤作用,其數(shù)量增加表明機體抗腫瘤活性增加,免疫功能增強[21-22]。本研究結(jié)果分析,與生理鹽水對照組比較,腹橫肌平面阻滯組T1、T2、T3及T4時點CD4+%水平均升高,IFN-γ水平T2和T3時點均升高(均P <0.05),表明腹橫肌平面阻滯組術后機體免疫能力優(yōu)于生理鹽水對照組,對術后疼痛、阿片類藥物所引起的免疫能力降低具有一定保護作用。究其原因,筆者認為可能與腹橫肌平面阻滯鎮(zhèn)痛效果更優(yōu),且降低舒芬太尼使用總量相關。
臨床常用術后靜脈自控鎮(zhèn)痛泵通常以阿片類藥物為主體,設置自控時間15 min,患者常因劇烈疼痛而按壓次數(shù)增加,導致阿片類藥物使用總量增加,而芬太尼、舒芬太尼等均可引起呼吸抑制、嗜睡等不良反應發(fā)生,增加圍術期風險[23-25]。聯(lián)合腹橫肌平面阻滯不僅可達到理想術后鎮(zhèn)痛效果,VAS評分更低,且可降低阿片類藥物使用總量,不良反應更少。本研究經(jīng)統(tǒng)計,與生理鹽水對照組比較,腹橫肌平面阻滯組不良反應發(fā)生率降低(P <0.05),與前述較為一致,臨床應用更為安全。
綜上所述,B超引導腹橫肌平面阻滯應用于老年患者腹腔鏡直腸癌根治術可取得較好的術后鎮(zhèn)痛效果,血流動力學平穩(wěn),且對機體免疫功能具有一定保護作用,不良反應發(fā)生率低,臨床應用安全。
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Postoperative analgesic effect and impact on immune function of ultrasound guided transversus abdominis plane block used in elderly patients after laparoscopic radical resection of rectal cancer
Yi Guo1, Peng Xie2, Peng Wang3
(1.Department of Anesthesiology; 2. Department of Hepatobiliary Surgery; 3. Department of Intensive Care Medicine, Xi’an Medical College, Xi’an, Shaanxi 710065, China)
Objective To observe the effect of ultrasound guided transversus abdominis plane block used in laparoscopic radical resection of rectal cancer in elderly patients on postoperative analgesic and impact on immune function. Methods Sixty cases need laparoscopic radical resection of rectal cancer in elderly patients with admission order number to take the digital randomized method was divided into abdominal transverse muscle block group and saline control group. The transversus abdominis plane block group underwent ultrasound guided transversusabdominis plane block after induction of general anesthesia while accepted intravenous injection of 0.25%ropivacaine hydrochloride of 30 ml; Saline control group took equal volume intravenous saline. After operation all were given analgesia pump: Sufentanil 1.00 μg/kg + Ondansetron 16.00 mg + Dezocine 10.00 mg + saline to con fi gure for 100 ml, and set 2 ml/h and 15 min of automatic control time. To observe visual analogue score (VAS)and related indexes of hemodynamics before anesthesia (T0), 1 h after operation (T1), 12 h after operation (T2), 24 h after operation (T3) and 48 h after operation (T4) between two groups; Record 24 h analgesia pressing times and total postoperative Sufentanil; And take venous blood to measure CD4+%, CD8+% level by fl ow cytometry and determinate interferon gamma (IFN-γ) by enzyme-linked immunosorbent assay; Then compare postoperative adverse reactions of two groups. Results Compared with saline control group,transversus abdominis plane block group’ MAP decreased in T1, T2, and HR decreased in T2and T3(P < 0.05). Transversus abdominis plane block groups’ MAP in T1was higher than T0, and HR in T1, T2was higher than that of T0(P < 0.05). Compared with saline control group, transversus abdominis plane block group’ VAS scores were lower at the T1, T2, T3, T4, else postoperative 24 h pressing times and amount of Sufentanil were decreased (P < 0.05). Compared with saline control group, transversus abdominis plane block group’ CD4+% levels increased in T1, T2, T3and T4, IFN-γ levels in T2, T3points were higher (P < 0.05).Compared with the saline control group, transversus abdominis plane block group’ rate of adverse reactions was lower (P < 0.05). Conclusion Ultrasound guided transversus abdominis plane block used in laparoscopic radical resection of rectal cancer in elderly patients has better postoperative analgesic effect, stable hemodynamics and less postoperative pain, and it has protective effect on immune function and lower incidence of adverse reactions, so clinical application is safety.
ultrasonography; transversus abdominis plane block; laparoscopy; rectal cancer; elderly; immune function
R619
A
10.3969/j.issn.1007-1989.2017.10.016
1007-1989(2017)10-0076-07
2017-03-02
(曾文軍 編輯)