李艷,左欣鷺,秦紅軍,楊立強,武百山,岳劍寧,楊惠婕,倪家驤
C型臂X光機引導(dǎo)穿刺聯(lián)合神經(jīng)電生理分支定位技術(shù)在三叉神經(jīng)半月節(jié)射頻熱凝術(shù)中的應(yīng)用價值
李艷,左欣鷺,秦紅軍,楊立強,武百山,岳劍寧,楊惠婕,倪家驤
目的探討C型臂X光機引導(dǎo)穿刺聯(lián)合神經(jīng)電生理指導(dǎo)三叉神經(jīng)半月節(jié)射頻熱凝術(shù)治療三叉神經(jīng)痛(TN)的效果。方法選取2013年6月—2014年9月于首都醫(yī)科大學(xué)宣武醫(yī)院行C型臂X光機引導(dǎo)穿刺三叉神經(jīng)半月節(jié)射頻熱凝術(shù)治療的TN患者110例。采用隨機數(shù)字表法將患者分為試驗組和對照組,各55例。C型臂X光機掃描下確定卵圓孔,根據(jù)患者疼痛反應(yīng)以及X線影像,調(diào)整射頻針方向與深度,直至達卵圓孔內(nèi)約3 mm。對照組根據(jù)給予電刺激時患者出現(xiàn)病變部位強烈的疼痛或感覺異常、肌肉抽動,確定針尖部位位于病變支。試驗組分別于眶上孔、眶下孔、頦孔連接經(jīng)皮記錄電極,分別給予高、低頻電刺激,多功能電流記錄儀記錄各支電位。以波幅較其他支波幅顯著增高,確定針尖位置位于病變支。記錄術(shù)后即刻、48 h疼痛視覺模擬評分(VAS)、麻木VAS及范圍、并發(fā)癥發(fā)生情況。分別于術(shù)后第1周及第1、3、6個月進行電話隨訪,記錄疼痛VAS評分、麻木范圍及復(fù)發(fā)情況。對照組和試驗組分別完整隨訪53、47例。結(jié)果試驗組術(shù)后即刻疼痛消失患者比例高于對照組,差異有統(tǒng)計學(xué)意義(P<0.05)。兩組術(shù)后48 h、1周及1、3、6個月疼痛消失患者比例比較,差異無統(tǒng)計學(xué)意義(P>0.05)。試驗組和對照組術(shù)后即刻麻木VAS分別為(7.3±1.4)、(8.5±1.5)分,差異有統(tǒng)計學(xué)意義(t=4.120,P<0.001)。對照組術(shù)后即刻、48 h、1周及1、3個月麻木超出預(yù)期范圍患者比例高于試驗組,差異有統(tǒng)計學(xué)意義(P<0.001)。對照組術(shù)后48 h嘔吐發(fā)生率高于試驗組,差異有統(tǒng)計學(xué)意義(P<0.05)。兩組眩暈、惡心、復(fù)視、皮膚麻木及咀嚼肌無力發(fā)生率比較,差異均無統(tǒng)計學(xué)意義(P>0.05)。對照組1例患者于術(shù)后2周復(fù)發(fā),試驗組隨訪期間無復(fù)發(fā)患者。兩組復(fù)發(fā)率比較,差異無統(tǒng)計學(xué)意義(P>0.05)。結(jié)論與電刺激患者反應(yīng)引導(dǎo)穿刺技術(shù)比較,C型臂X光機引導(dǎo)聯(lián)合神經(jīng)電生理指導(dǎo)射頻卵圓孔穿刺,病變支定位準(zhǔn)確性較好,術(shù)后麻木超出預(yù)期范圍的風(fēng)險降低。
三叉神經(jīng)痛;射頻熱凝術(shù);X線;誘發(fā)電位
李艷,左欣鷺,秦紅軍,等.C型臂X光機引導(dǎo)穿刺聯(lián)合神經(jīng)電生理分支定位技術(shù)在三叉神經(jīng)半月節(jié)射頻熱凝術(shù)中的應(yīng)用價值[J].中國全科醫(yī)學(xué),2015,18(32):3926-3931.[www.chinagp.net]
Li Y,Zuo XL,Qin HJ,et al.Application value of puncture guided by C-arm X-ray machine combining nerve electrophysiology branch positioning technique in trigeminal semilunar ganglion radio frequency thermocoagulation[J].Chinese General Practice,2015,18(32):3926-3931.QIN Hong-jun,et al.Department of Pain Medicine,Xuanwu Hospital,Capital Medical University,Beijing 100053,China
三叉神經(jīng)痛(trigeminal neuralgia,TN)是以面部三叉神經(jīng)分布區(qū)內(nèi)出現(xiàn)反復(fù)發(fā)作性、觸電樣、短暫而劇烈疼痛為臨床特征的常見神經(jīng)病理性疼痛。Koopman等[1]對荷蘭調(diào)查顯示TN發(fā)病率為12.6/10萬,吳升平等[2]對我國6大城市調(diào)查顯示TN發(fā)病率為4.3/10萬。TN多發(fā)生于中老年人,女性多于男性[1]。原發(fā)性TN的發(fā)病機制尚不明確,因此,尚無確切根治性治療方法。目前,TN首選藥物治療,但長期應(yīng)用可發(fā)生耐藥性。射頻熱凝術(shù)最初由Sweet等[3]不斷改進并應(yīng)用于治療TN,因其創(chuàng)傷小、操作相對簡單、并發(fā)癥少而被臨床醫(yī)生及患者廣泛接受,有效率達90%以上[4-7],但也存在咬肌癱瘓、復(fù)視、角膜炎、神經(jīng)麻木性疼痛等術(shù)后并發(fā)癥及復(fù)發(fā)的風(fēng)險[5]。術(shù)中準(zhǔn)確定位病變支是確保術(shù)后療效及避免并發(fā)癥的關(guān)鍵。目前臨床TN病變支的定位主要依據(jù)電刺激及患者主訴,該方法主觀性強,對于高度緊張、聽力或語言溝通障礙等患者,術(shù)中判斷可能會導(dǎo)致偏差,從而使療效不佳或出現(xiàn)嚴(yán)重并發(fā)癥。而神經(jīng)電生理技術(shù)客觀判斷針尖位置,可較準(zhǔn)確定位病變支。本研究探討C型臂X光機引導(dǎo)下半月節(jié)穿刺,神經(jīng)電生理輔助三叉神經(jīng)分支定位的準(zhǔn)確性,并分析術(shù)后療效。
1.1病例納入與排除標(biāo)準(zhǔn)納入標(biāo)準(zhǔn):(1)符合《國際頭痛紊亂分類診斷》第2版[8]中TN診斷標(biāo)準(zhǔn):突發(fā)性疼痛,持續(xù)數(shù)秒至2 min,涉及三叉神經(jīng)一支或多支支配區(qū),且疼痛特征為強烈的、尖銳的、表淺的或刀割樣疼痛或由扳機點、誘發(fā)因素誘發(fā),患者疼痛性質(zhì)、發(fā)作形式不變,并排除神經(jīng)損傷及其他疾病引起的疼痛; (2)年齡≥18歲;(3)疼痛程度為中重度;(4)藥物治療3個月以上仍有劇烈疼痛或不能耐受藥物不良反應(yīng),或神經(jīng)外科手術(shù)治療無效或復(fù)發(fā)。排除標(biāo)準(zhǔn):(1)顱腦CT或MRI掃描示顱內(nèi)占位性病變,或顱內(nèi)腫瘤繼發(fā)性TN;(2)接受三叉神經(jīng)感覺根切斷術(shù),面部遺留嚴(yán)重麻木;(3)嚴(yán)重系統(tǒng)性疾病;(4)有出血性疾病或凝血時間明顯延長;(5)穿刺部位有感染病灶;(6)精神障礙或神經(jīng)病變,語言溝通障礙,不能合作;(7)拒絕參加本研究。
1.2研究對象選取2013年6月—2014年9月于首都醫(yī)科大學(xué)宣武醫(yī)院行C型臂X光機引導(dǎo)穿刺三叉神經(jīng)半月節(jié)射頻熱凝術(shù)治療的TN患者110例。采用隨機數(shù)字表法將患者分為試驗組和對照組,各55例?;颊吆喜⒙约膊≈饕獮楦哐獕?、心臟病及糖尿病,入組前藥物控制良好。
1.3方法
1.3.1手術(shù)方法患者入手術(shù)室后,監(jiān)測心電圖、無創(chuàng)血壓、血氧飽和度,建立外周靜脈通路,術(shù)前半小時靜脈給予阿托品0.25 mg,氟哌利多2.5 mg?;颊呷⊙雠P位,肩稍墊高,頭后仰,穿刺點為患側(cè)口角延線與同側(cè)眼眶中線垂直線的交叉點,局部常規(guī)消毒鋪巾,局部給予局部麻醉藥浸潤麻醉。
C型臂X光機掃描下確定卵圓孔,依據(jù)Hartel穿刺方法,采用長150 mm、針尖裸露端直徑5 mm的射頻穿刺針進行穿刺,直達卵圓孔[9-10],針尖深度不能達到X線側(cè)位顱底高密度疊加線。根據(jù)患者疼痛反應(yīng)以及X線影像,不斷調(diào)整進針方向與深度,直至達卵圓孔內(nèi)約3 mm。
對照組患者給予高頻電刺激(50 Hz,0.1 ms,0.1~0.5 V),從0.1 V逐漸增加,在此范圍內(nèi)如出現(xiàn)病變部位強烈的疼痛或感覺異常,確定針尖部位位于病變支;再以低頻電刺激(2 Hz,1 ms,0.3~1.0 V),從1.0 V逐漸降低,在此范圍誘發(fā)病變神經(jīng)支配肌肉抽動,確定針尖部位位于病變支。針尖位置根據(jù)患者對神經(jīng)系統(tǒng)電刺激反應(yīng)進行微調(diào)至滿足上述理想狀態(tài)。
試驗組針尖位置根據(jù)多功能電流記錄儀(DAVINCI,Mogliano Veneto,意大利)行電刺激-分支皮區(qū)記錄進行微調(diào)。第Ⅰ支經(jīng)皮記錄電極置于眶上孔,第Ⅱ支為眶下孔,第Ⅲ支為頦孔(見圖1)。95%乙醇局部去脂,每一記錄部位為正負(fù)一對盤狀電極(正極在內(nèi),負(fù)極在外,兩者間距為0.5 cm,且保證兩電極間電阻≤5Ω,地線夾于病變同側(cè)耳垂)。分別給予高頻電刺激(50 Hz,0.1 ms,0.1~0.5 V)和低頻電刺激(2 Hz,1 ms,0.3~1.0 V),多功能電流記錄儀記錄各支電位。以波幅較其他支波幅顯著增高,確定針尖位置位于病變支(見圖2)。
圖1 體表記錄電極固定位置Figure 1 Body surface records of electrode fixed positions
圖2 高頻電刺激三叉神經(jīng)分支電位變化Figure 2 Trigeminal nerve branch potential changes by high-frequency electrical stimulation
射頻針微調(diào)成功后,給予至少5 min面罩吸氧,靜脈給予異丙酚(2 mg/kg)進行全身麻醉,70~75℃行射頻熱凝。
1.3.2藥物治療術(shù)后患者如無疼痛,可停用術(shù)前止痛藥物,如有疼痛(需排除復(fù)發(fā)),繼續(xù)服用術(shù)前止痛藥物,依疼痛程度劑量可減半。術(shù)后麻木嚴(yán)重者可口服甲鈷胺0.5 mg/次,3次/d,術(shù)后1個月停用。
1.3.3評估方法記錄術(shù)后即刻、48 h疼痛視覺模擬評分(VAS)、麻木VAS及范圍、并發(fā)癥發(fā)生情況。如TN病變支定位準(zhǔn)確以及限制熱凝溫度、時間的情況下,術(shù)后麻木范圍應(yīng)與術(shù)前病變支累及范圍一致,否則判定麻木超出預(yù)期范圍。分別于術(shù)后第1周及第1、3、6個月進行電話隨訪,記錄疼痛VAS、麻木范圍及復(fù)發(fā)情況。疼痛VAS評價前,患者需停藥24 h。研究對象中9例因聯(lián)系方式變更、錯誤,1例拒絕隨訪而失訪,對照組和試驗組分別完整隨訪53、47例。
1.4統(tǒng)計學(xué)方法采用SPSS 17.0統(tǒng)計軟件進行統(tǒng)計分析,正態(tài)分布的計量資料以(±s)表示,組間比較采用t檢驗;非正態(tài)分布的計量資料以M(QR)表示,組間比較采用非參數(shù)檢驗;計數(shù)資料以相對數(shù)表示,組間比較采用χ2檢驗。以P<0.05為差異有統(tǒng)計學(xué)意義。
2.1一般資料比較兩組性別、年齡、病程、疼痛VAS、患側(cè)及病變支分布比較,差異均無統(tǒng)計學(xué)意義(P>0.05,見表1)。
表1 兩組一般資料比較Table 1 Comparison of general data between the two groups
2.2術(shù)后疼痛試驗組術(shù)后即刻疼痛消失患者比例高于對照組,差異有統(tǒng)計學(xué)意義(P<0.05)。兩組術(shù)后48 h、1周及1、3、6個月疼痛消失患者比例比較,差異無統(tǒng)計學(xué)意義(P>0.05,見表2)。
表2 兩組術(shù)后各時間疼痛消失患者比例比較〔n(%)〕Table 2 Comparison of proportions of patients with postoperative pain disappearing at each time point after surgery between the two groups
2.3術(shù)后麻木試驗組和對照組術(shù)后即刻麻木VAS分別為(7.3±1.4)、(8.5±1.5)分,差異有統(tǒng)計學(xué)意義(t=4.120,P<0.001)。對照組術(shù)后即刻、48 h、1周及1、3個月麻木超出預(yù)期范圍患者比例高于試驗組,差異有統(tǒng)計學(xué)意義(P<0.001)。兩組術(shù)后6個月麻木超出預(yù)期范圍患者比例比較,差異無統(tǒng)計學(xué)意義(P>0.05,見表3)。
表3 兩組術(shù)后各時間麻木超出預(yù)期范圍患者比例比較〔n(%)〕Table 3 Comparison of proportions of patients with postoperative numbness outreaching range at each time point after surgery between the two groups
2.4并發(fā)癥對照組術(shù)后48 h嘔吐發(fā)生率高于試驗組,差異有統(tǒng)計學(xué)意義(P<0.05)。兩組眩暈、惡心、復(fù)視、皮膚麻木及咀嚼肌無力發(fā)生率比較,差異均無統(tǒng)計學(xué)意義(P>0.05,見表4)。
表4 兩組術(shù)后48 h并發(fā)癥發(fā)生率比較〔n(%)〕Table 4 Comparison of the incidence rates of complications 48 hours after surgery between the two groups
2.5復(fù)發(fā)情況對照組1例患者于術(shù)后2周復(fù)發(fā),試驗組隨訪期間無復(fù)發(fā)患者。兩組復(fù)發(fā)率比較,差異無統(tǒng)計學(xué)意義(P>0.05)。
TN為一典型的、反復(fù)發(fā)作的、頑固的、非自愈性的神經(jīng)病理性疼痛,治療方法主要有藥物、微創(chuàng)及開放手術(shù)。藥物長期使用療效不佳,且患者無法耐受其不良反應(yīng)。經(jīng)皮三叉神經(jīng)半月節(jié)射頻熱凝術(shù)是被臨床醫(yī)生及患者普遍接受的微創(chuàng)治療,該方法操作簡單、安全、療效較好,但仍存在發(fā)生術(shù)后麻木、角膜/結(jié)膜炎等并發(fā)癥的風(fēng)險。如何提高TN病變支定位準(zhǔn)確性、避免或減少術(shù)后并發(fā)癥的發(fā)生已成為臨床亟待解決的問題。
早在1974年Sweet等[3]將射頻熱凝術(shù)用于TN的治療。經(jīng)皮三叉神經(jīng)半月節(jié)射頻熱凝術(shù)治療TN可有效控制溫度和維持射頻時間,選擇性破壞半月神經(jīng)節(jié)后無髓鞘的A-δ和C細(xì)神經(jīng)纖維(司傳導(dǎo)痛溫覺),保留有髓鞘的A-α和β粗神經(jīng)纖維(司傳導(dǎo)觸覺)。動物研究顯示,A-δ和C細(xì)神經(jīng)纖維在70℃和75℃時發(fā)生變性,而A-α和β粗神經(jīng)纖維可耐受較高的溫度[11]。因此,選擇合適的射頻熱凝溫度既可緩解TN,又可保留顏面部觸覺,療效達90%以上[4-7]。
在臨床工作中,影響射頻熱凝術(shù)后療效與并發(fā)癥的關(guān)鍵為射頻針穿刺和病變支定位。Lopez等[12]報道,徒手穿刺失敗率約10%。若穿刺方向錯誤可導(dǎo)致顱神經(jīng)損傷相關(guān)并發(fā)癥,如角膜潰瘍、失明、聽力障礙、聲音嘶啞和吞咽障礙等,甚至損傷大血管,刺入頸靜脈孔刺激迷走神經(jīng),則引起心律失常[13-14]。反復(fù)穿刺可引發(fā)顱底血腫,進針深度不當(dāng)則是術(shù)后頭昏、惡心、嘔吐的主要原因[15]。另外,TN也存在復(fù)發(fā)的風(fēng)險,Tronnier等[16]報道射頻熱凝術(shù)治療TN術(shù)后復(fù)發(fā)率約20%。
CT引導(dǎo)下可清晰識別卵圓孔,三維成像可指導(dǎo)穿刺方向,是目前多數(shù)臨床醫(yī)生所認(rèn)可的穿刺引導(dǎo)方法[17-24]。但其費用高,且難以在基層醫(yī)院普及。而X線也是引導(dǎo)穿刺到達卵圓孔的良好方法[25-28]。
上世紀(jì)80年代,有研究[29-31]開始探討三叉神經(jīng)半月節(jié)電刺激,于三叉神經(jīng)三支皮膚分布區(qū)安置電極進行記錄,觀察波的潛伏期及峰值。在此基礎(chǔ)上,有學(xué)者[32-33]將逆向電刺激應(yīng)用到三叉神經(jīng)半月節(jié)射頻熱凝術(shù)中分支定位。其中Li等[32]采用逆向電刺激行三叉神經(jīng)熱凝術(shù)中分支定位,結(jié)果顯示電刺激分支記錄陽性出現(xiàn)率與患者感知一致性較高,并且第Ⅲ支靈敏度高于第Ⅰ、Ⅱ支。
本研究為進一步探討C型臂X光機引導(dǎo)下聯(lián)合三叉神經(jīng)半月節(jié)電刺激指導(dǎo)三叉神經(jīng)半月節(jié)射頻熱凝術(shù)中分支定位準(zhǔn)確性,設(shè)立以患者主訴定位為依據(jù)的對照組,比較兩者術(shù)后療效及并發(fā)癥。若術(shù)中針尖位置不準(zhǔn)確,遺留未處理神經(jīng)纖維較多,而非病變支神經(jīng)纖維處理較多,則出現(xiàn)復(fù)發(fā)或麻木超出預(yù)期范圍[34-35]。本研究結(jié)果發(fā)現(xiàn),對照組術(shù)后即刻、48 h、1周及1、3個月麻木超出預(yù)期范圍的患者比例高于試驗組,而兩者術(shù)后6個月麻木超出預(yù)期范圍的患者比例差異無統(tǒng)計學(xué)意義。分析原因可能為對照組患者術(shù)中損傷了部分非病變支,但在術(shù)后一定時間可自行修復(fù)。部分患者在術(shù)后即刻疼痛消失后再次出現(xiàn)疼痛,在術(shù)后6個月可恢復(fù)。其主要原因為部分患者射頻熱凝術(shù)后1~2周出現(xiàn)神經(jīng)水腫,從而出現(xiàn)疼痛,待水腫恢復(fù)后疼痛即消失[36]。部分患者可能由于部分神經(jīng)纖維未處理,射頻熱凝術(shù)后仍遺留疼痛,而術(shù)后神經(jīng)修復(fù)或通過藥物控制后疼痛消失。本研究兩組患者術(shù)后即刻疼痛消失患者比例近90%,并可短期內(nèi)維持療效,且大部分患者術(shù)后無需服用鎮(zhèn)痛藥。麻木VAS超過8分者有50%服用甲鈷胺,持續(xù)1個月。
與電刺激患者反應(yīng)引導(dǎo)穿刺技術(shù)比較,C型臂X光機引導(dǎo)聯(lián)合神經(jīng)電生理指導(dǎo)射頻卵圓孔穿刺,病變支定位準(zhǔn)確性較好,術(shù)后麻木超出預(yù)期范圍的風(fēng)險降低。該技術(shù)避免了患者主觀因素對確定針尖位置的影響,并降低由CT帶來的醫(yī)療費用,尤其適于在高齡、有語言溝通障礙或聽力障礙等不能合作的患者中進行推廣。本研究隨訪時間短,患者長期療效及復(fù)發(fā)風(fēng)險可能存在一定偏倚,本研究結(jié)論尚需大樣本、長期隨訪進一步證實。
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(本文編輯:吳立波)
App lication Value of Puncture Guided by C-arm X-ray M achine Com bining Nerve Electrophysiology Branch Positioning Technique in Trigem inal Sem ilunar Ganglion Radio Frequency Thermocoagulation
LIYan,ZUO Xin-lu,QIN Hong-jun,et al.Department of Pain Medicine,Xuanwu Hospital,Capital Medical University,Beijing 100053,China
Objective To investigate the effect of puncture guided by C-arm X-ray machine combining nerve electrophysiology in the treatment of trigeminal neuralgia(TN)by trigeminal semilunar ganglion radio frequency thermocoagulation.M ethods We enrolled 110 TN patients who underwent trigeminal semilunar ganglion radio frequency thermocoagulation with puncture guided by C-arm X-raymachine in Xuanwu Hospital,Capital Medical University from June 2013 to September 2014.By random number tablemethod,the subjectswere divided into trialgroup and controlgroup,with 55 patients in each group.Oval foramen was confirmed by the scan of C-arm X-raymachine,and the direction and depth of radio frequency needle were adjusted according to patients'pain reaction and X-ray image until the needle reached 3 mm inside ovalforamen.For control group,whether the needle tip was positioned in lesion branch was determined by whether strong pain or paresthesia appeared and muscle twitch when electrical stimulation was given.For trial group,percutaneous recording electrodes were connected at supraorbital foramen,infraorbital foramen and mental foramen,after which high-frequency electrical stimulation and low-frequency electrical stimulation given,and electric potential of each branch was recorded by multifunctional galvo-recorder;whether the needle tip was located in lesion branch was determined by whether the wave amplitude of a branch was evidently higher than other branches.The VAS pain score,the VAS numbness score,the range of numbness and the incidence rates of complicationswere recorded immediately and 48 hoursafter surgery.Telephone follow-up was conducted 1 week,1 month,3 months and 6 months after surgery,during which the VAS pain score,range of numbness and relapse were recorded.The number of patients who completed the follow-up was 53 for control group and 47 for trial group.Results Trial group was higher(P<0.05)than control group in the proportion of patients whose pain disappeared immediately after surgery.The two groups were not significantly different(P>0.05)in the proportions of patients whose pain disappeared 48 hours,1 week,1 month,3 months and 6 months after surgery.The VAS score of immediate numbness was(7.3±1.4)for trial group and(8.5±1.5)for control group(t=4.120,P<0.001).Control group was higher than trial group in the proportions of patients whose numbness outreached the expected range immediately,48 hours,1 week,1 month and 3 months after surgery were higher than trial group(P<0.001).Control group was higher(P<0.05)than trial in the incidence of emesis 48 hours after surgery.The two groups were not significantly different(P>0.05)in the incidence of dizziness,nausea,diplopia,skin numbness and masticatorymuscle weakness.One patient in control group relapsed after surgery,and no patient relapsed during follow-up in trialgroup.The two groupswere notsignificantly different in recurrence rate(P>0.05).Conclusion Compared with puncture guided by patients'response to electric stimulation,oval foramen puncture guided by C-arm X-ray machine combining nerve electrophysiology is more accurate in the positioning of lesion branch and leads to lower risk in numbness outreaching expected range after surgery.
Trigeminal neuralgia;Radiofrequency thermocoagulation;X-ray;Evoked potentials
R 745.11
A
10.3969/j.issn.1007-9572.2015.32.008
北京市科技計劃課題(Z131107002213154)
100053北京市,首都醫(yī)科大學(xué)宣武醫(yī)院疼痛科(李艷,楊立強,武百山,岳劍寧,楊惠婕,倪家驤);承德護理職業(yè)學(xué)院(左欣鷺);北京電力醫(yī)院放射科(秦紅軍)
倪家驤,100053北京市,首都醫(yī)科大學(xué)宣武醫(yī)院疼痛科;E-mail:nijiaxiang@263.net
2015-01-11;
2015-09-18)