周煦燕，孔敏，姜黎珊，沈徐，陸雅萍，姚明，黃兵

(浙江嘉興市第一醫(yī)院麻醉科，314000)

·論著·

術(shù)前應(yīng)用氯胺酮對(duì)乳腺癌患者術(shù)后慢性疼痛發(fā)生率的影響

周煦燕，孔敏，姜黎珊，沈徐，陸雅萍，姚明，黃兵

(浙江嘉興市第一醫(yī)院麻醉科，314000)

目的觀察超前應(yīng)用NMDA受體拮抗劑氯胺酮對(duì)乳腺癌術(shù)后慢性疼痛發(fā)生率的影響。方法ASA I或Ⅱ級(jí)全身麻醉下乳腺癌改良根治手術(shù)患者160例，采用隨機(jī)數(shù)字表法將患者隨機(jī)均分為N組(單純?nèi)砺樽斫M)和K組(全身麻醉+氯胺酮組)。記錄患者術(shù)前1天、麻醉蘇醒后即刻、術(shù)后24 h、48 h機(jī)械痛敏程度；采用視覺模擬評(píng)分法(VAS)評(píng)估患者術(shù)前1天、麻醉蘇醒后即刻、術(shù)后24 h、48 h、2個(gè)月疼痛程度并統(tǒng)計(jì)兩組慢性疼痛發(fā)生率；根據(jù)患者自行按壓的患者自控鎮(zhèn)痛(PCA)次數(shù)，計(jì)算術(shù)后芬太尼需要量。結(jié)果術(shù)前兩組健患側(cè)痛閾及VAS評(píng)分測(cè)定差異無統(tǒng)計(jì)學(xué)意義，N組蘇醒即刻健側(cè)及患側(cè)痛閾較術(shù)前明顯降低，術(shù)后24 h及48 h健側(cè)痛閾與術(shù)前無顯著差異，K組健側(cè)術(shù)后各時(shí)間點(diǎn)痛閾較術(shù)前無明顯差異，兩組患者蘇醒即刻及術(shù)后24 h患側(cè)痛閾雖然較術(shù)前都降低，但K組痛閾明顯比N組高，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)，術(shù)后48 h兩組患側(cè)痛閾差異無統(tǒng)計(jì)學(xué)意義(Pgt;0.05)；患者術(shù)前VAS 評(píng)分均為0分，術(shù)后即刻及術(shù)后24 h K組比N組低，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)，術(shù)后PCIA的按壓次數(shù)及芬太尼使用量K組比N組明顯減少，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)；術(shù)后K組慢性疼痛發(fā)生率比N組明顯降低，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)。結(jié)論麻醉誘導(dǎo)期給予氯胺酮能有效提高術(shù)中應(yīng)用瑞芬太尼乳腺癌改良根治患者術(shù)后痛閾，降低了乳腺癌患者的慢性疼痛的發(fā)生率。

乳腺腫瘤；氯胺酮；慢性疼痛；痛閾

慢性疼痛是一個(gè)世界范圍的惡性疾病。是慢性病患者自殺和致殘的主要原因之一[1-3]。盡管近年來鎮(zhèn)痛藥物和方法都在不斷改進(jìn)，但乳腺癌根治術(shù)后一年內(nèi)慢性疼痛的發(fā)生率仍高達(dá)30%～55%。此外還伴隨麻木，肢體僵硬無力等其他癥狀。術(shù)后慢性疼痛所致的應(yīng)激與負(fù)性情緒反應(yīng)可對(duì)患者造成嚴(yán)重的身心傷害，但目前其發(fā)生機(jī)制尚不清楚，治療效果亦不理想，因此改善術(shù)后慢性疼痛的治療現(xiàn)狀，對(duì)于改善預(yù)后、提高患者術(shù)后的生活質(zhì)量具有積極意義。

1 對(duì)象與方法

1.1 研究對(duì)象 連續(xù)納入2014年6 月1 日至2016年11月30 日在我院行擇期乳腺癌改良根治手術(shù)患者160例作為研究對(duì)象，采用隨機(jī)數(shù)字表法將患者平均分為兩組：?jiǎn)渭內(nèi)砺樽斫M(N組)、全身麻醉+氯胺酮組(K組)。納入標(biāo)準(zhǔn)：全身麻醉下行擇期手術(shù)患者，年齡18～60歲，ASA分級(jí)Ⅰ-Ⅱ級(jí)。排除標(biāo)準(zhǔn)為：術(shù)前檢查發(fā)現(xiàn)肝、胰腺、腎功能異常；體質(zhì)量指數(shù)gt;28 kg/m2的肥胖患者；合并糖尿病、甲亢等代謝性疾??；有嚴(yán)重的心血管病史；酗酒或吸毒史以及精神疾病或癲癇史；近1個(gè)月內(nèi)接受過全身麻醉者；無法根據(jù)患者提供的聯(lián)系方式與之取得聯(lián)系的患者；未獲得知情同意患者；認(rèn)知功能異常患者；無法用語言準(zhǔn)確溝通患者；惡性腫瘤術(shù)后已明確診斷復(fù)發(fā)或轉(zhuǎn)移者，不能充分理解問卷內(nèi)容致調(diào)查不能完成及病歷資料不全者。本研究經(jīng)醫(yī)院倫理委員會(huì)批準(zhǔn)同意。

1.2 方法 所有患者術(shù)前禁飲食8 h，入手術(shù)室后常規(guī)監(jiān)測(cè)無創(chuàng)血壓、血氧飽和度、心電圖、脈搏與腦電雙頻指數(shù)(BIS)。開放靜脈后，靜脈注射丙泊酚(江蘇海慈生物藥業(yè)有限公司生產(chǎn))2 mg/kg，瑞芬太尼(江蘇恩華藥業(yè)股份有限公司生產(chǎn))1.5 μg/kg，羅庫溴銨(浙江仙琚制藥股份有限公司生產(chǎn))0.6 mg/kg。靜脈注射羅庫溴銨1.5 min后行氣管插管。插管后FiO250%機(jī)械通氣，維持ETCO235～45 mm Hg，行橈動(dòng)脈或足背動(dòng)脈穿刺監(jiān)測(cè)血流動(dòng)力學(xué)指標(biāo)。術(shù)中持續(xù)輸注瑞芬太尼與吸入七氟烷(上海恒瑞醫(yī)藥有限公司生產(chǎn))維持麻醉。七氟烷初始呼氣末濃度為2%，根據(jù)BIS值與血流動(dòng)力學(xué)參數(shù)調(diào)節(jié)七氟烷吸入濃度，當(dāng)BIS值大于60、平均動(dòng)脈壓較誘導(dǎo)前升高超過20%或心率上升超過15%提高七氟烷吸入濃度，每次調(diào)節(jié)幅度為0.5%；當(dāng)平均動(dòng)脈壓低于70 mm Hg或BIS值小于30時(shí)降低七氟烷吸入濃度；當(dāng)出現(xiàn)持續(xù)低血壓降低七氟烷濃度無法糾正或BIS值大于60時(shí)給予去氧腎上腺素維持循環(huán)穩(wěn)定。每間隔40 min追加羅庫溴銨0.1 mg/kg維持肌松。術(shù)中靜滴乳酸鈉林格液(陜西濟(jì)生制藥有限公司生產(chǎn))與羥乙基淀粉130/0.4氯化鈉注射液(連云港潤眾制藥有限公司生產(chǎn))補(bǔ)充血容量，血紅蛋白含量小于80 g/L時(shí)輸注濃縮紅細(xì)胞。K組在全身麻醉誘導(dǎo)前靜脈注射氯胺酮(江蘇恒瑞醫(yī)藥股份有限公司生產(chǎn))1 mg/kg，其余K組與N組相同。手術(shù)結(jié)束時(shí)停用瑞芬太尼與七氟烷，送麻醉恢復(fù)室，術(shù)后常規(guī)使用電子泵，行枸櫞酸芬太尼(江蘇恩華藥業(yè)股份有限公司生產(chǎn))PCIA(10 μg/mL，100 mL)，待患者清醒后拔除氣管導(dǎo)管送返病房。

1.3 觀察指標(biāo) 采用電刺激儀(日本光電公司，MEB-5100型)測(cè)定記錄患者術(shù)前1 d、麻醉蘇醒后即刻、術(shù)后24 h、48 h機(jī)械痛敏程度；測(cè)定部位：手術(shù)切口旁3 cm與手術(shù)切口對(duì)側(cè)胸壁。采用視覺模擬評(píng)分法(VAS)評(píng)估患者術(shù)前1 d、麻醉蘇醒后即刻、術(shù)后24 h、48 h、2個(gè)月疼痛程度與慢性疼痛發(fā)生率。根據(jù)患者自行按壓的患者自控鎮(zhèn)痛(PCA)次數(shù)，計(jì)算術(shù)后芬太尼需要量。

2 結(jié)果

本研究由于部分病例收集資料不全，實(shí)際共納入150例患者，N組77例，K組73例，兩組患者性別、年齡、身高、體質(zhì)量和ASA分級(jí)等一般資料差異均無統(tǒng)計(jì)學(xué)意義。結(jié)果顯示術(shù)前兩組健患側(cè)痛閾及VAS評(píng)分測(cè)定差異無統(tǒng)計(jì)學(xué)意義，N組蘇醒即刻健側(cè)及患側(cè)痛閾較術(shù)前明顯降低，術(shù)后24 h及48 h健側(cè)痛閾與術(shù)前差異無統(tǒng)計(jì)學(xué)意義，K組健側(cè)術(shù)后各時(shí)間點(diǎn)痛閾較術(shù)前差異無統(tǒng)計(jì)學(xué)意義，兩組患者蘇醒即刻及術(shù)后24 h患側(cè)痛閾雖然較術(shù)前都降低，但K組痛閾明顯比N組高，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)，術(shù)后48 h兩組患側(cè)痛閾差異無統(tǒng)計(jì)學(xué)意義(Pgt;0.05)(見表1)；患者術(shù)前VAS 評(píng)分均為0分，術(shù)后即刻及術(shù)后24 h K組評(píng)分比N組低，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)(見表2)，術(shù)后PCIA的按壓次數(shù)及芬太尼使用量K組比N組明顯減少，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)(見表2)；術(shù)后兩組患者慢性疼痛發(fā)生率，差異有統(tǒng)計(jì)學(xué)意義(Plt;0.05)(見表3)。

表1 兩組電刺激痛閾測(cè)定結(jié)果

注：與組內(nèi)術(shù)前同側(cè)比較，aPlt;0.05

表2 兩組術(shù)后VAS評(píng)分、PCIA按壓次數(shù)及芬太尼用量

表3 兩組術(shù)后2個(gè)月慢性疼痛發(fā)生例數(shù)及發(fā)生率

3 討論

阿片類藥物已成為現(xiàn)代麻醉中必不可少的組成部分，但在臨床中，患者使用該類藥物一段時(shí)間后，有時(shí)會(huì)出現(xiàn)痛閾下降、疼痛范圍擴(kuò)大甚至出現(xiàn)接觸痛的情況，這就是近年來被藥理和麻醉專家廣泛關(guān)注的阿片誘發(fā)痛覺過敏(OIH)現(xiàn)象，該現(xiàn)象可出現(xiàn)在術(shù)中應(yīng)用阿片類藥物瑞芬太尼的圍手術(shù)期[4-6]。

OIH涉及的分子生物學(xué)機(jī)制復(fù)雜，尚無明確定論?，F(xiàn)比較公認(rèn)的機(jī)制包括中樞谷氨酸通路激活、脊髓下行易化、脊髓強(qiáng)啡肽濃度增加和遺傳因素等。氯胺酮作為谷氨酸受體通道亞型N-甲基-D-天門冬氨酸(NMDA)受體拮抗劑，具有超前鎮(zhèn)痛的作用[7-8]，可減輕急性術(shù)后痛，減少術(shù)后鎮(zhèn)痛藥用量[9],本研究通過麻醉誘導(dǎo)給予氯胺酮與常規(guī)麻醉用藥相比較，結(jié)果顯示術(shù)前兩組健患側(cè)痛閾及VAS評(píng)分測(cè)定差異無統(tǒng)計(jì)學(xué)意義，N組蘇醒即刻健測(cè)及患測(cè)痛閾較術(shù)前明顯降低，術(shù)后24 h及48 h健側(cè)痛閾與術(shù)前差異無統(tǒng)計(jì)學(xué)意義，這與以往研究[10-11]基本相似，瑞芬太尼引起的痛覺過敏一般發(fā)生在術(shù)后12 h內(nèi)，K組健側(cè)術(shù)后各時(shí)間點(diǎn)痛閾較術(shù)前差異無統(tǒng)計(jì)學(xué)意義，兩組患者蘇醒即刻及術(shù)后24 h患側(cè)痛閾雖然較術(shù)前都降低，但K組痛閾明顯比N組高，差異有統(tǒng)計(jì)學(xué)意義，這可能與氯胺酮可以阻斷中樞谷氨酸能誘發(fā)OIH通路的激活有關(guān)[12-14]，術(shù)后48 h兩組患側(cè)痛閾差異無統(tǒng)計(jì)學(xué)意義?；颊咝g(shù)前VAS 評(píng)分均為0分，術(shù)后即刻及術(shù)后24 h K組評(píng)分比N組低，差異有統(tǒng)計(jì)學(xué)意義，此結(jié)果與痛閾測(cè)定結(jié)果一致，同時(shí)同時(shí)也發(fā)現(xiàn)，術(shù)后48 h K組VAS評(píng)分比N組低，差異有統(tǒng)計(jì)學(xué)意義，但術(shù)后48 h痛閾測(cè)定兩者差異無統(tǒng)計(jì)學(xué)意義，存在主觀與客觀數(shù)據(jù)的矛盾，本研究可能由于病例數(shù)還不充足導(dǎo)致數(shù)據(jù)分析誤差，除此以外，影響患者對(duì)疼痛認(rèn)知的能力受多種因素的影響，如遺傳因素、社會(huì)經(jīng)歷、教育水平、精神狀態(tài)等。術(shù)后PCIA的按壓次數(shù)及芬太尼使用量K組比N組明顯減少，差異有統(tǒng)計(jì)學(xué)意義，與術(shù)后VAS評(píng)分結(jié)果一致，也能發(fā)現(xiàn)本研究術(shù)后疼痛管理及用藥的不足，尚需改進(jìn)。術(shù)后慢性疼痛發(fā)生率，K組較N組明顯降低，這可能與氯胺酮提高了患者術(shù)后痛閾，以及作為NMDA受體拮抗劑能阻斷中樞谷氨酸通路激活有關(guān)，尚需更多數(shù)據(jù)進(jìn)行論證。

綜上所述，麻醉誘導(dǎo)期給予氯胺酮能有效提高術(shù)中應(yīng)用瑞芬太尼乳腺癌改良根治患者術(shù)后痛閾，從而降低了乳腺癌患者術(shù)后慢性疼痛的發(fā)生率。

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EffectofpreoperaionuseofNMDAreceptorantagonistketamineontheincidenceofchronicpainafterbreastcancersurgery

ZhouXuyan,KongMin,JiangLishan,ShenXu,LuYaping,YaoMing,HuangBing

(DepartmentofAnesthesiology,JiaxingFirstHospital,Jiaxing314000，China)

KongMin,Email：sdjx10666@163.com

ObjectiveTo observe the effect of preoperaion use of NMDA receptor antagonist ketamine on the incidence of chronic pain after breast cancer surgery.Methods160 cases of patients with modified radical mastectomy for breast cancer under ASA Ⅰ or Ⅱ general anesthesia were randomly divided into group N (named as general anesthesia group) and group K (named as general anesthesia + ketamine group) by random number table.Record the mechanical hyperalgesia of postoperative 1 days before anesthesia,immediately after,24 hours and 48 hours after the operation;to evaluate the degree of chronic pain of patients before 1 days,immediately after anesthesia,after 24 hours and 48 hours by the VAS score,and the incidence of two groups patients by February statistics;to calculate the postoperative fentanyl requirement according to press the number of PCA.ResultsThe preoperative health ipsilateral pain threshold and VAS score was no significant difference between the two groups,the immediate ipsilateral and contralateral pain threshold in N group were significantly lower than their preoperative index,the contralateral preoperative pain threshold at postoperative 24 hours and 48 hours had no significant difference compared with operation before.The healthy side at each time point after operation in K group had no obvious differences compared with operation before,the ipsilateral pain threshold after the surgery while and 24 hours decreased compared with preoperative,but pain threshold was higher in the K group than that of N group,the difference was statistically significant (Plt;0.05),lateral pain threshold after 48 hours of operation in the two groups had no significant difference between (Pgt;0.05);the VAS score postoperative in patients was 0,it was lower at immediately after operation and 24 hours after operation in K group than in N group,the difference was statistically significant (Plt;0.05),postoperative PCIA Press Number and fentanyl use in K group was obviously lower than that of N group,the difference was statistically significant (Plt;0.05);the incidence of postoperative pain chronic in K group was statistically significant lower than that of the N group (Plt;0.05).ConclusionKetamine can improve the pain threshold in patients undergoing modified radical mastectomy and reduce the incidence of chronic pain in patients with breast cancer.

Breast neoplasms；Ketamine；Chronic pain；Pain threshold

浙江嘉興市科學(xué)技術(shù)局計(jì)劃(2014AY21024)

周煦燕，主任醫(yī)師，Email：zxy43529@163.com

孔敏，主治醫(yī)師，Email：sdjx10666@163.com

R737.9

A

10.3969/J.issn.1672-6790.2017.06.024

2017-08-10)