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1、围术期口服环氧化酶-2抑制剂对脑脊液前列腺素水平和术后镇痛效果的影响山东省聊城市人民医院麻醉科（252000）张宗旺 贾新权摘要 目的 通过围术期口服选择性环氧化酶（COX）-2抑制剂，观察妇科手术后病人脑脊液中前列腺素浓度的变化和对术后镇痛效果的影响。方法：60例择期行妇科手术的患者，ASA，年龄4567岁，随机分为3组，每组20例。尼美舒利组从麻醉前1h至术后48h内口服选择性COX-2抑制剂尼美舒利100mg，每隔12h一次；布洛芬组从麻醉前1h至术后48h内口服非选择性COX抑制剂布洛芬400mg，每隔6h一次；对照组不服用任何药物。分别于麻醉前、术后24h和48h采取脑脊液2ml和静
2、脉血6ml测定脑脊液中6-酮前列腺素F1、血清中血栓素（TX）B2和前列腺素（PG）E2的浓度。术后采用静脉PCA吗啡进行术后止痛，记录术后2h、6h、12h、24h、48h的视觉模拟评分（VAS）和术后48h累计吗啡需要量。结果：布洛芬可明显抑制血清TXB2生成（P0.05）；尼美舒利可明显抑制脂多糖（LPS）诱导的PGE2的生成（P0.05）；对照组血清TXB2水平和LPS诱导PGE2的生成没有变化。术后48h尼美舒利组脑脊液中6-酮前列腺素F1水平与术前对比无差异，但明显低于对照组和布洛芬组（P0.05）。术后6h、12h和24h，尼美舒利组病人VAS评分和术后48h累计吗啡总需要量都明
3、显低于对照组和布洛芬组（P0.05）。结论：妇科手术创伤可以诱导脊髓表达COX-2，从而增加PGs的合成参与术后疼痛的形成，围术期口服选择性COX-2抑制剂比其他NSAIDs的镇痛效果更好。关键词 前列腺素，环氧化酶，术后止痛The effect of perioperative oral selective cyclooxygenase-2 inhibitor on prostaglandin concentration in cerebral spinal fluid and postoperative analgesia following gynecological surgeryZh
4、ang Zong-wang*, Jia Xin-quan, Chen Yi-qi, Gregory Meredith. *Department of Anaesthesiology, Liaocheng Peoples Hospital, Shandong Province, Liaocheng 252000,ChinaAbstract objective: To observe the effect of perioperative oral selective cyclooxygenase-2 inhibitor on prostaglandin concentration in cere
5、bral spinal fluid(CSF) and postoperative analgesia following gynecological surgery. Methods: Sixty ASApatients aged 4567 yr undergoing gynecological surgery were randomly divided into three groups, each of which included 20 cases: the first group received the selective COX-2 inhibitor nimesulide 100
6、mg orally twice daily from 1h before anaesthesia to 48h postoperatively; the second group received the nonselective COX inhibitor ibuprofen 400mg orally four times daily from 1h before anaesthesia to 48h postoperatively; the third group did not receive any medicine during that period. CSF 2ml and ve
7、nous blood 6ml were collected respectively before anaesthesia, on the first postoperative day and the second postoperative day. CSF was analyzed for 6-keto-PGF1 and venous blood for serum thromboxane (TX) B2 and PGE2 . Postoperative analgesia was attained by intravenous PCA with morphine. The visual
8、 analog scale(VAS) was recorded respectively at 2h、6h、12h、24h、48h postoperatively. The cumulative consumption of morphine during postoperative 48h was also recorded. Results: Comparatively, the serum TX B2 levels were significantly inhibited by ibuprofen (P0.05); the levels of PGE2 induced by LPS we
9、re significantly inhibited by nimesulide (P0.05) ; and both of them did not change in the third group. The concentration of 6-keto-PGF1 in CSF in the first group at 48h postoperatively had no difference with that of before anaesthesia , and was significantly lower than that of the other two groups (
10、P0.05). The VAS and cumulative consumption of morphine during postoperative 48h in the first group were significantly lower than that of the other two groups (P0.05). Conclusion: Spinal COX-2 is induced following gynecological surgery, so increases in spinal PGs synthesis mediate the postoperative p
11、ain. Perioperative oral selective cyclooxygenase-2 inhibitor is better than other NSAIDs for postoperative analgesia.Key words prostaglandin, cyclooxygenase, postoperative analgesia各种化学、物理损伤或生物因子激活磷脂酶A2水解细胞膜磷脂，生成花生四烯酸。后者在COX作用下生成前列腺素（PGs），通过激活外周伤害性感受器而致痛。非甾体类抗炎药（NSAIDs）通过抑制COX减少PGs的合成而减轻手术后疼痛和病人对阿片类
12、药物的需要量1。COX具有COX-1和COX-2两种形式，COX-1存在于大多数细胞中。动物实验表明，外周伤害性刺激可诱导脊髓神经元表达COX-22，鞘内注射COX-2抑制剂可以减轻热刺激引起的大鼠甩尾反射3。但是关于COX-2在人类脊髓部位的分布或疼痛刺激后在脊髓的表达，未见任何报告。为此本研究通过围术期口服选择性COX-2抑制剂，观察妇科手术后病人脑脊液中PGs浓度的变化和对术后镇痛效果的影响。资料与方法临床资料 60例择期行妇科手术的患者，ASA，其中年龄4567岁，体重5278kg。手术种类包括：子宫全切术、卵巢肿瘤切除术、子宫颈癌根治术。研究前征得病人同意并签订协议书。合并消化性溃疡
13、、肝肾功能不全、服用NSAIDs和糖皮质激素者以及患有心理、精神疾病者和不能配合VAS者不列入研究范围之内。实验分组 60例患者随机分成3组，尼美舒利组（n=20）：患者分别于麻醉前1h和麻醉后11h、23h、35h和47h口服选择性COX-2抑制剂尼美舒利100mg（PT Gala 公司，印度尼西亚），麻醉前1h仅用一小口水送下口服药；布洛芬组（n=20）：患者分别于麻醉前1h和麻醉后48h内每隔6h口服非选择性COX抑制剂布洛芬400mg（BASF公司，美国），麻醉前1h仅用一小口水送下口服药，麻醉后应确保病人肠蠕动恢复，能进饮食后再口服药物；对照组（n=20），不服用任何药物。麻醉方法
14、所有病人均在全麻下手术，麻醉诱导前通过L34椎间隙行腰椎穿刺并置入22G鞘内导管（B. Braun公司，德国）。分别于麻醉前、术后24h和48h留取脑脊液2ml。由于鞘内导管死腔量为300l，首次留取的500l脑脊液丢弃不用。留取的2ml脑脊液用于测定其中前列腺素的浓度；同时采取静脉全血6ml测定血中TXB2和PGE2的浓度。麻醉诱导选用异丙酚2mgkg-1，阿曲库胺0.5 mgkg-1，芬太尼0.1mg，利多卡因50mg。术中持续吸入异氟醚，N2O和O2混合气体维持麻醉，间断注射阿曲库胺维持肌肉松弛，根据病人需要间断注射吗啡镇痛。手术完毕，送病人入麻醉恢复室，待病人意识清醒、定向力清楚，各项
15、生命体征稳定，并且疼痛可忍受后，启动病人自控止痛装置（Graseby3300 PCA）。参数设置如下：总量：吗啡1mgml-1，50ml；单次剂量1mg；锁定时间：5min；最大剂量：810mgh-1。分别于术后2h、6h、12h、24h、48h根据VAS评价病人疼痛程度，同时记录手术后48h内累计吗啡需要量。生化分析 通过放射免疫法测定脑脊液中6-酮前列腺素F1的浓度。先取静脉全血1ml加入10U肝素钠和LPS10gml-1，在37条件下孵育24h。其中LPS来自大肠杆菌属（Sigma公司，美国）。孵育24h以上LPS可以诱导全血中单核细胞内COX-2的表达，通过加入阿斯匹林200molL-
16、1以抑制血小板中COX-1的活性4。然后以1000转/min的速率离心10min，将分离的血清-20保存，通过放射免疫法测定PGE2的浓度。其余静脉全血在37非抗凝状态下保存1h，然后以1000转/min的速率离心10min。分离后的血清在-20下保存，通过放射免疫法测定TXB2。统计学处理 计量资料以均数标准差（s）表示，采用SPSS10.0统计软件进行分析。组间比较采用单因素方差分析，组内比较采用配对t检验；P0.05认为差异有统计学意义。结 果一般资料 三组病人年龄、体重、手术时间、术中失血量无差异（表1）。表1三组病人一般资料比较（n=20,s）组别年龄（y）体重（kg）手术时间（min）手术失血量（ml）对照组548.95914.91293111218尼美舒利组567.85810.613424
