周煦燕，孔敏，姜黎珊，沈徐，陆雅萍，姚明，黄兵

(浙江嘉兴市第一医院麻醉科，314000)

·论著·

术前应用氯胺酮对乳腺癌患者术后慢性疼痛发生率的影响

周煦燕，孔敏，姜黎珊，沈徐，陆雅萍，姚明，黄兵

(浙江嘉兴市第一医院麻醉科，314000)

目的观察超前应用NMDA受体拮抗剂氯胺酮对乳腺癌术后慢性疼痛发生率的影响。方法ASA I或Ⅱ级全身麻醉下乳腺癌改良根治手术患者160例，采用随机数字表法将患者随机均分为N组(单纯全身麻醉组)和K组(全身麻醉+氯胺酮组)。记录患者术前1天、麻醉苏醒后即刻、术后24 h、48 h机械痛敏程度；采用视觉模拟评分法(VAS)评估患者术前1天、麻醉苏醒后即刻、术后24 h、48 h、2个月疼痛程度并统计两组慢性疼痛发生率；根据患者自行按压的患者自控镇痛(PCA)次数，计算术后芬太尼需要量。结果术前两组健患侧痛阈及VAS评分测定差异无统计学意义，N组苏醒即刻健侧及患侧痛阈较术前明显降低，术后24 h及48 h健侧痛阈与术前无显著差异，K组健侧术后各时间点痛阈较术前无明显差异，两组患者苏醒即刻及术后24 h患侧痛阈虽然较术前都降低，但K组痛阈明显比N组高，差异有统计学意义(Plt;0.05)，术后48 h两组患侧痛阈差异无统计学意义(Pgt;0.05)；患者术前VAS 评分均为0分，术后即刻及术后24 h K组比N组低，差异有统计学意义(Plt;0.05)，术后PCIA的按压次数及芬太尼使用量K组比N组明显减少，差异有统计学意义(Plt;0.05)；术后K组慢性疼痛发生率比N组明显降低，差异有统计学意义(Plt;0.05)。结论麻醉诱导期给予氯胺酮能有效提高术中应用瑞芬太尼乳腺癌改良根治患者术后痛阈，降低了乳腺癌患者的慢性疼痛的发生率。

乳腺肿瘤；氯胺酮；慢性疼痛；痛阈

慢性疼痛是一个世界范围的恶性疾病。是慢性病患者自杀和致残的主要原因之一[1-3]。尽管近年来镇痛药物和方法都在不断改进，但乳腺癌根治术后一年内慢性疼痛的发生率仍高达30%～55%。此外还伴随麻木，肢体僵硬无力等其他症状。术后慢性疼痛所致的应激与负性情绪反应可对患者造成严重的身心伤害，但目前其发生机制尚不清楚，治疗效果亦不理想，因此改善术后慢性疼痛的治疗现状，对于改善预后、提高患者术后的生活质量具有积极意义。

1 对象与方法

1.1 研究对象 连续纳入2014年6 月1 日至2016年11月30 日在我院行择期乳腺癌改良根治手术患者160例作为研究对象，采用随机数字表法将患者平均分为两组：单纯全身麻醉组(N组)、全身麻醉+氯胺酮组(K组)。纳入标准：全身麻醉下行择期手术患者，年龄18～60岁，ASA分级Ⅰ-Ⅱ级。排除标准为：术前检查发现肝、胰腺、肾功能异常；体质量指数gt;28 kg/m2的肥胖患者；合并糖尿病、甲亢等代谢性疾病；有严重的心血管病史；酗酒或吸毒史以及精神疾病或癫痫史；近1个月内接受过全身麻醉者；无法根据患者提供的联系方式与之取得联系的患者；未获得知情同意患者；认知功能异常患者；无法用语言准确沟通患者；恶性肿瘤术后已明确诊断复发或转移者，不能充分理解问卷内容致调查不能完成及病历资料不全者。本研究经医院伦理委员会批准同意。

1.2 方法 所有患者术前禁饮食8 h，入手术室后常规监测无创血压、血氧饱和度、心电图、脉搏与脑电双频指数(BIS)。开放静脉后，静脉注射丙泊酚(江苏海慈生物药业有限公司生产)2 mg/kg，瑞芬太尼(江苏恩华药业股份有限公司生产)1.5 μg/kg，罗库溴铵(浙江仙琚制药股份有限公司生产)0.6 mg/kg。静脉注射罗库溴铵1.5 min后行气管插管。插管后FiO250%机械通气，维持ETCO235～45 mm Hg，行桡动脉或足背动脉穿刺监测血流动力学指标。术中持续输注瑞芬太尼与吸入七氟烷(上海恒瑞医药有限公司生产)维持麻醉。七氟烷初始呼气末浓度为2%，根据BIS值与血流动力学参数调节七氟烷吸入浓度，当BIS值大于60、平均动脉压较诱导前升高超过20%或心率上升超过15%提高七氟烷吸入浓度，每次调节幅度为0.5%；当平均动脉压低于70 mm Hg或BIS值小于30时降低七氟烷吸入浓度；当出现持续低血压降低七氟烷浓度无法纠正或BIS值大于60时给予去氧肾上腺素维持循环稳定。每间隔40 min追加罗库溴铵0.1 mg/kg维持肌松。术中静滴乳酸钠林格液(陕西济生制药有限公司生产)与羟乙基淀粉130/0.4氯化钠注射液(连云港润众制药有限公司生产)补充血容量，血红蛋白含量小于80 g/L时输注浓缩红细胞。K组在全身麻醉诱导前静脉注射氯胺酮(江苏恒瑞医药股份有限公司生产)1 mg/kg，其余K组与N组相同。手术结束时停用瑞芬太尼与七氟烷，送麻醉恢复室，术后常规使用电子泵，行枸橼酸芬太尼(江苏恩华药业股份有限公司生产)PCIA(10 μg/mL，100 mL)，待患者清醒后拔除气管导管送返病房。

1.3 观察指标 采用电刺激仪(日本光电公司，MEB-5100型)测定记录患者术前1 d、麻醉苏醒后即刻、术后24 h、48 h机械痛敏程度；测定部位：手术切口旁3 cm与手术切口对侧胸壁。采用视觉模拟评分法(VAS)评估患者术前1 d、麻醉苏醒后即刻、术后24 h、48 h、2个月疼痛程度与慢性疼痛发生率。根据患者自行按压的患者自控镇痛(PCA)次数，计算术后芬太尼需要量。

2 结果

本研究由于部分病例收集资料不全，实际共纳入150例患者，N组77例，K组73例，两组患者性别、年龄、身高、体质量和ASA分级等一般资料差异均无统计学意义。结果显示术前两组健患侧痛阈及VAS评分测定差异无统计学意义，N组苏醒即刻健侧及患侧痛阈较术前明显降低，术后24 h及48 h健侧痛阈与术前差异无统计学意义，K组健侧术后各时间点痛阈较术前差异无统计学意义，两组患者苏醒即刻及术后24 h患侧痛阈虽然较术前都降低，但K组痛阈明显比N组高，差异有统计学意义(Plt;0.05)，术后48 h两组患侧痛阈差异无统计学意义(Pgt;0.05)(见表1)；患者术前VAS 评分均为0分，术后即刻及术后24 h K组评分比N组低，差异有统计学意义(Plt;0.05)(见表2)，术后PCIA的按压次数及芬太尼使用量K组比N组明显减少，差异有统计学意义(Plt;0.05)(见表2)；术后两组患者慢性疼痛发生率，差异有统计学意义(Plt;0.05)(见表3)。

表1 两组电刺激痛阈测定结果

注：与组内术前同侧比较，aPlt;0.05

表2 两组术后VAS评分、PCIA按压次数及芬太尼用量

表3 两组术后2个月慢性疼痛发生例数及发生率

3 讨论

阿片类药物已成为现代麻醉中必不可少的组成部分，但在临床中，患者使用该类药物一段时间后，有时会出现痛阈下降、疼痛范围扩大甚至出现接触痛的情况，这就是近年来被药理和麻醉专家广泛关注的阿片诱发痛觉过敏(OIH)现象，该现象可出现在术中应用阿片类药物瑞芬太尼的围手术期[4-6]。

OIH涉及的分子生物学机制复杂，尚无明确定论。现比较公认的机制包括中枢谷氨酸通路激活、脊髓下行易化、脊髓强啡肽浓度增加和遗传因素等。氯胺酮作为谷氨酸受体通道亚型N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂，具有超前镇痛的作用[7-8]，可减轻急性术后痛，减少术后镇痛药用量[9],本研究通过麻醉诱导给予氯胺酮与常规麻醉用药相比较，结果显示术前两组健患侧痛阈及VAS评分测定差异无统计学意义，N组苏醒即刻健测及患测痛阈较术前明显降低，术后24 h及48 h健侧痛阈与术前差异无统计学意义，这与以往研究[10-11]基本相似，瑞芬太尼引起的痛觉过敏一般发生在术后12 h内，K组健侧术后各时间点痛阈较术前差异无统计学意义，两组患者苏醒即刻及术后24 h患侧痛阈虽然较术前都降低，但K组痛阈明显比N组高，差异有统计学意义，这可能与氯胺酮可以阻断中枢谷氨酸能诱发OIH通路的激活有关[12-14]，术后48 h两组患侧痛阈差异无统计学意义。患者术前VAS 评分均为0分，术后即刻及术后24 h K组评分比N组低，差异有统计学意义，此结果与痛阈测定结果一致，同时同时也发现，术后48 h K组VAS评分比N组低，差异有统计学意义，但术后48 h痛阈测定两者差异无统计学意义，存在主观与客观数据的矛盾，本研究可能由于病例数还不充足导致数据分析误差，除此以外，影响患者对疼痛认知的能力受多种因素的影响，如遗传因素、社会经历、教育水平、精神状态等。术后PCIA的按压次数及芬太尼使用量K组比N组明显减少，差异有统计学意义，与术后VAS评分结果一致，也能发现本研究术后疼痛管理及用药的不足，尚需改进。术后慢性疼痛发生率，K组较N组明显降低，这可能与氯胺酮提高了患者术后痛阈，以及作为NMDA受体拮抗剂能阻断中枢谷氨酸通路激活有关，尚需更多数据进行论证。

综上所述，麻醉诱导期给予氯胺酮能有效提高术中应用瑞芬太尼乳腺癌改良根治患者术后痛阈，从而降低了乳腺癌患者术后慢性疼痛的发生率。

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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

浙江嘉兴市科学技术局计划(2014AY21024)

周煦燕，主任医师，Email：zxy43529@163.com

孔敏，主治医师，Email：sdjx10666@163.com

R737.9

A

10.3969/J.issn.1672-6790.2017.06.024

2017-08-10)