罗哌卡因单独或复合肾上腺素用于高胸段硬膜外麻醉的药效学和药代动力学
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摘要
罗哌卡因(Ropivacaine，RP)是一种新型、长效的酰胺类局麻药，为一纯S-对映异构体的盐酸水化物，其化学结构类似布比卡因和甲哌卡因，只是在六氢吡啶的氮原子上连一丙基，而甲哌卡因和布比卡因分别为甲基、丁基，且后两者为外消旋异构体；RP的理化特性类似布比卡因；作用强度约等于布比卡因，起效时间短，作用时间长；对心血管和中枢神经系统毒性低于布比卡因，低浓度对感觉、运动阻滞分离的显著特点，并且在低浓度时有收缩血管的特性。对罗哌卡因用于腰段硬膜外麻醉和臂丛神经阻滞的药效学和药代动力学研究，国内外均有一些报道，而且罗哌卡因合用肾上腺素对其药效学和药代动力学影响的报道也不尽相同；目前国内外对罗哌卡因用于高胸段硬膜外麻醉的药效学与药代动力学的研究尚未见报道。本研究的目的在于了解罗哌卡因用于乳腺肿瘤病人高胸段硬膜外麻醉的药效学与药代动力学特性，并进一步验证RP与肾上腺素合用的必要性，以便为临床麻醉中合理应用RP，减少局麻药物毒性反应提供理论依据。
1．材料和方法
1．1材料 本试验选取择期乳腺肿瘤患者20例，均为女性，年龄20～47岁，体重50～70kg，身高155～173cm，ASA分级Ⅰ～Ⅱ级。术前血常规，出、凝血时间，心、肺、肝、肾功能均正常。随机将其分为RP单用组(RP组)及其与肾上腺素(Adrenaline，AD)合用组(RP+AD组)，每组10例，均采用连续高胸段硬膜外麻醉。穿刺部位选T_(3-4)，常规硬膜外穿刺成功后向头端置入硬膜外导管3.5cm，且经导管回吸无脑脊液和血液后，2min内经导管注药，RP组注入0.5％罗哌卡因溶液1.3 mg·kg~(-1)，RP+AD组注入加1：200 000肾上腺素(5 μg·ml~(-1))的0.5％罗哌卡因1.3mg·kg~(-1)。
郑州大学2003届硕士学位论文罗呱卡因单独或复合肾上腺素用于高脚段硬膜外麻醉的药效学与药代动力学
1.2药效学
1.2.1感觉阻滞以平头针刺法，硬膜外腔注药后每lmin测定一次感觉消失平面，
10min后每3min测定一次感觉消失平面，直至平面固定。阻滞效果的评价:优:阻
滞平面满意，术中无痛;良:术中有轻微疼痛或不适感，需少量镇痛药或镇静药;差:
术中需加局麻药或改用全麻。运动阻滞:注药后每3min测定一次运动阻滞，运动阻
滞程度采用上肢肌力O~5级六级分级法。
1.2.2麻醉期间循环、呼吸监测所有病人入室均连接惠普多功能监测仪连续测定并
记录注药前、注药后10、20、30、60、90、120min时的收缩压(SBP)、舒张压(DBP)、
平均动脉压(MAp)、心率(HR)、脉搏血氧饱和度(spoZ)和心电图(Eeo);以人
工计数和肺活量计测定并记录上述各时间点仰卧位呼吸频率(RR)和用力肺活量
(FVC)。同时记录麻醉期间不良反应的发生情况。
1.3药代动力学
1.3.1血浆罗呱卡因浓度HPLC测定方法
色谱条件:分析柱为E沙omasilc;:色谱柱，柱温:32℃，柱压:100一1 1 okg. cm.’;
流动相采用0.olmol一’磷酸二氢钾(pH3.4)和乙睛(体积比为3:l)，流速1.2 ml.min-l;
检测波长为206nxn;灵敏度0.08 AUFS;内标物:布比卡因;定量方法:峰面积法。
HPLC测定中血浆的内源性物质对测定无干扰。罗呱卡因的保留时间约为6.5 min，内
标布比卡因保留时间约为10.5 min。
1.3.2血浆样品的采集
硬膜外腔注入全量RP后即刻、10、20、30、40、50、60、90、120、150、180、
240、360、72Omin分别取静脉血4ml，肝素抗凝后离心，分离血浆，置一20℃冰箱保
存待测。
1.3.3数据处理
本研究所得”血药浓度一时间数据，用中国药理学会数学药理委员会编制的3p97
药动学软件经微机处理，选择最佳房室模型，绘出药一时曲线，并求出药动学参数，血
药浓度峰值(Cmax)由实测值计算得到，梯形法计算血药浓度，时间曲线下面积。
1.4统计学处理
，
犷
所得数据以均数士标准差(x士S)表示，采用t检验或卡方检验处理，P蕊0.05
尹
、嗯
郑州大学2003届硕士学位论文罗呱卡因单独或复合肾上腺素用于高胸段硬膜外麻醉的药效学与药代动力学
为差异有显著性。
2.结果
2.1两组病人药效学比较
即和即+AD组感觉阻滞起效时间(3 .8士0.6 vs 3.6士0.7) min，感觉阻滞完善时
间(28.3士4.3 vs 29.0士3.4)min，脊神经阻滞节段数(15.4士2.5 vs 16.8士1.8)节，运动阻滞
起效时间(19.0士1.8 vs x9.0士2.9)min，上肢肌力分级111/IV例数(5/5 vs4/6)级均相似，
统计学上均无显著性差异(P>0.05)，感觉阻滞维持时间和运动阻滞恢复时间即+AD
组比砂组似有延长(173.5士23.4 vs 151.6士31.98)min和(78.32士34.35 vs 67.60士
42.74)min，但统计学上无显著性差异。
麻醉期间循环、呼吸变化:即和即+AD组注药后10，20，3Omin内，SBP:两
组与注药前比较变化不明显印>0.05)(121.3士12，8，117.6士12.2，112.5士15·7 vs 125·0
士13.3mmHg)和(120.5士17.8，115.9士10.4，110.8士17.8 vs 124.8士17.gmmHg);DBP
和MAP:即组均有所下降但与注药前比较无显著性差异(p>0.05)(76.5士10.5，73.7
士10.9，71.4士12.6vs80.4士12.snunHg)和(91.4士11.1，88.4士10.4，86.8士12.6vs95.2
士12.2mmHg)，即+AD组下降明显，与注药前比较有显著性差异(p<0.01)(66.6士11.4，
60.5士9.8，62.8士13.2 vs 76
Ropivacaine (RP) is a new, long-acting aminoamide local anesthetic. It is a pure S-(-) enantiomer monohydrate of the hydrochloride salt. It is close to bupivacaine and mepivacaine in that it has a propyl group on the piperidine nitrogen atom, whereas mepivacaine has a methyl group and bupivacaine has a butyl group. Both mepivacaine and bupivacaine are the racemic mixtures of the enantiomers. The physicochemical properties of ropivacaine and bupivacaine apper are similar. Ropivacaine is slightly less potent compared with bupivacaine. The onset time is short and the duration of action is long. The central nervous system toxicity and cardiotoxicity of ropivacaine is lower than that of bupivacaine. Ropivacaine produces markedly sensory motor separation and has an intrinsic vasoconstricting property when used in low concentration. The pharmacodynemics and pharmacokinetics of ropivacaine used for lumber epidural or brachial plexus had been studied in some countries. This study is to investigate the pharmacodynemic
s and pharmacokinetics of ropivacaine, to confirm the necessity of ropivacaine with adrenaline for upper thoracic epidural anesthesia (UTEA). Material and Method
This study included 20 female patients scheduled to undergo breast surgery under continuous UTEA(ASA I ~ II, aged 20~47 years). They were randomly divided into two groups: Group RP (ropivacaine group, n=10)and Group RP+AD (ropivacaine with
adrenaline group, n=10). UTEA was performed at the T3-4 interspace by using epidural catherter. Patients of Group RP and RP+AD received 5mg ?L-1 RP 1.3mg ?kg-1 and 5mg ?L-1 RP 1.3mg ?kg-1 plus adrenaline 5 g . kg epidurally in 2 min, respectively. Sensory block was determined using a blunt point needle to test for loss and return of sensation to pin-prick. Motor block was assessed using a myodymamia scale (0 V). Assessments of sensory and motor block were performed at 1 min or 3 min intervals in first 30 min after
injection of total dose, and thereafter at 30 min intervals until normal sensation and motor
function had been reestablished. During anesthesia, SBP, DBP, MAP, HR, ECG and SpO were continuously recorded by automatic monitor. RR were counted by anesthetist and FVC was measured by spivometer. The adverse reactions were recorded during anesthesia. Twenty patients had peripheral venous blood samples (4mL) collected for assay of the total plasma concentration of RP. Samples were taken immediately prior to the start of epidural administration(time 0 )and 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 360 and 720 min after injection.The samples were drawn into heparinized tubre, centrifuged and frozen at -20 癈 until drug assay. The total plasma concentration of RP was determined by high performance liquid chromatography. The pharmacokinetic parameters were determined from plasma concentration-time data with 3P97 software package. Results
1. Comparison of pharmacodynemic index between groups: the Group RP and RP+AD were similar with respect to epidural block characteristics. No significant difference in onset time, time to maximum spread, segment of spinal nerve blocked and onset time of motor block were observed between two groups (p>0.05). The number of patients with different degrees of motor block was similar in the two groups (p>0.05). Compared with
Group RP, the duration of sensory and motor block prolonged slightly, and no significant
difference observed (see Tab. 3).
2. The changes of index for circulation and respiration: At 10,20,30 min after injection, there was a little decreased in SBP relative to baseline (p>0.05) in two groups; DBP and MAP decreased slightly and had no significant difference than the baseline (p>0.05) in Group RP; the DBP and MAP decreased markedly and had significant differences than the baseline
(p<0.01) (DBP:66.611.4, 60.5 9.8, 62.8 ?3.2 vs 76.1 ?.7mmHg and MAP:
82.9?.7,75.5?.7,78.2?.2 vs 90.15.7mmHg);HR had a larger decreased c
1．材料和方法
1．1材料 本试验选取择期乳腺肿瘤患者20例，均为女性，年龄20～47岁，体重50～70kg，身高155～173cm，ASA分级Ⅰ～Ⅱ级。术前血常规，出、凝血时间，心、肺、肝、肾功能均正常。随机将其分为RP单用组(RP组)及其与肾上腺素(Adrenaline，AD)合用组(RP+AD组)，每组10例，均采用连续高胸段硬膜外麻醉。穿刺部位选T_(3-4)，常规硬膜外穿刺成功后向头端置入硬膜外导管3.5cm，且经导管回吸无脑脊液和血液后，2min内经导管注药，RP组注入0.5％罗哌卡因溶液1.3 mg·kg~(-1)，RP+AD组注入加1：200 000肾上腺素(5 μg·ml~(-1))的0.5％罗哌卡因1.3mg·kg~(-1)。
郑州大学2003届硕士学位论文罗呱卡因单独或复合肾上腺素用于高脚段硬膜外麻醉的药效学与药代动力学
1.2药效学
1.2.1感觉阻滞以平头针刺法，硬膜外腔注药后每lmin测定一次感觉消失平面，
10min后每3min测定一次感觉消失平面，直至平面固定。阻滞效果的评价:优:阻
滞平面满意，术中无痛;良:术中有轻微疼痛或不适感，需少量镇痛药或镇静药;差:
术中需加局麻药或改用全麻。运动阻滞:注药后每3min测定一次运动阻滞，运动阻
滞程度采用上肢肌力O~5级六级分级法。
1.2.2麻醉期间循环、呼吸监测所有病人入室均连接惠普多功能监测仪连续测定并
记录注药前、注药后10、20、30、60、90、120min时的收缩压(SBP)、舒张压(DBP)、
平均动脉压(MAp)、心率(HR)、脉搏血氧饱和度(spoZ)和心电图(Eeo);以人
工计数和肺活量计测定并记录上述各时间点仰卧位呼吸频率(RR)和用力肺活量
(FVC)。同时记录麻醉期间不良反应的发生情况。
1.3药代动力学
1.3.1血浆罗呱卡因浓度HPLC测定方法
色谱条件:分析柱为E沙omasilc;:色谱柱，柱温:32℃，柱压:100一1 1 okg. cm.’;
流动相采用0.olmol一’磷酸二氢钾(pH3.4)和乙睛(体积比为3:l)，流速1.2 ml.min-l;
检测波长为206nxn;灵敏度0.08 AUFS;内标物:布比卡因;定量方法:峰面积法。
HPLC测定中血浆的内源性物质对测定无干扰。罗呱卡因的保留时间约为6.5 min，内
标布比卡因保留时间约为10.5 min。
1.3.2血浆样品的采集
硬膜外腔注入全量RP后即刻、10、20、30、40、50、60、90、120、150、180、
240、360、72Omin分别取静脉血4ml，肝素抗凝后离心，分离血浆，置一20℃冰箱保
存待测。
1.3.3数据处理
本研究所得”血药浓度一时间数据，用中国药理学会数学药理委员会编制的3p97
药动学软件经微机处理，选择最佳房室模型，绘出药一时曲线，并求出药动学参数，血
药浓度峰值(Cmax)由实测值计算得到，梯形法计算血药浓度，时间曲线下面积。
1.4统计学处理
，
犷
所得数据以均数士标准差(x士S)表示，采用t检验或卡方检验处理，P蕊0.05
尹
、嗯
郑州大学2003届硕士学位论文罗呱卡因单独或复合肾上腺素用于高胸段硬膜外麻醉的药效学与药代动力学
为差异有显著性。
2.结果
2.1两组病人药效学比较
即和即+AD组感觉阻滞起效时间(3 .8士0.6 vs 3.6士0.7) min，感觉阻滞完善时
间(28.3士4.3 vs 29.0士3.4)min，脊神经阻滞节段数(15.4士2.5 vs 16.8士1.8)节，运动阻滞
起效时间(19.0士1.8 vs x9.0士2.9)min，上肢肌力分级111/IV例数(5/5 vs4/6)级均相似，
统计学上均无显著性差异(P>0.05)，感觉阻滞维持时间和运动阻滞恢复时间即+AD
组比砂组似有延长(173.5士23.4 vs 151.6士31.98)min和(78.32士34.35 vs 67.60士
42.74)min，但统计学上无显著性差异。
麻醉期间循环、呼吸变化:即和即+AD组注药后10，20，3Omin内，SBP:两
组与注药前比较变化不明显印>0.05)(121.3士12，8，117.6士12.2，112.5士15·7 vs 125·0
士13.3mmHg)和(120.5士17.8，115.9士10.4，110.8士17.8 vs 124.8士17.gmmHg);DBP
和MAP:即组均有所下降但与注药前比较无显著性差异(p>0.05)(76.5士10.5，73.7
士10.9，71.4士12.6vs80.4士12.snunHg)和(91.4士11.1，88.4士10.4，86.8士12.6vs95.2
士12.2mmHg)，即+AD组下降明显，与注药前比较有显著性差异(p<0.01)(66.6士11.4，
60.5士9.8，62.8士13.2 vs 76
Ropivacaine (RP) is a new, long-acting aminoamide local anesthetic. It is a pure S-(-) enantiomer monohydrate of the hydrochloride salt. It is close to bupivacaine and mepivacaine in that it has a propyl group on the piperidine nitrogen atom, whereas mepivacaine has a methyl group and bupivacaine has a butyl group. Both mepivacaine and bupivacaine are the racemic mixtures of the enantiomers. The physicochemical properties of ropivacaine and bupivacaine apper are similar. Ropivacaine is slightly less potent compared with bupivacaine. The onset time is short and the duration of action is long. The central nervous system toxicity and cardiotoxicity of ropivacaine is lower than that of bupivacaine. Ropivacaine produces markedly sensory motor separation and has an intrinsic vasoconstricting property when used in low concentration. The pharmacodynemics and pharmacokinetics of ropivacaine used for lumber epidural or brachial plexus had been studied in some countries. This study is to investigate the pharmacodynemic
s and pharmacokinetics of ropivacaine, to confirm the necessity of ropivacaine with adrenaline for upper thoracic epidural anesthesia (UTEA). Material and Method
This study included 20 female patients scheduled to undergo breast surgery under continuous UTEA(ASA I ~ II, aged 20~47 years). They were randomly divided into two groups: Group RP (ropivacaine group, n=10)and Group RP+AD (ropivacaine with
adrenaline group, n=10). UTEA was performed at the T3-4 interspace by using epidural catherter. Patients of Group RP and RP+AD received 5mg ?L-1 RP 1.3mg ?kg-1 and 5mg ?L-1 RP 1.3mg ?kg-1 plus adrenaline 5 g . kg epidurally in 2 min, respectively. Sensory block was determined using a blunt point needle to test for loss and return of sensation to pin-prick. Motor block was assessed using a myodymamia scale (0 V). Assessments of sensory and motor block were performed at 1 min or 3 min intervals in first 30 min after
injection of total dose, and thereafter at 30 min intervals until normal sensation and motor
function had been reestablished. During anesthesia, SBP, DBP, MAP, HR, ECG and SpO were continuously recorded by automatic monitor. RR were counted by anesthetist and FVC was measured by spivometer. The adverse reactions were recorded during anesthesia. Twenty patients had peripheral venous blood samples (4mL) collected for assay of the total plasma concentration of RP. Samples were taken immediately prior to the start of epidural administration(time 0 )and 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 360 and 720 min after injection.The samples were drawn into heparinized tubre, centrifuged and frozen at -20 癈 until drug assay. The total plasma concentration of RP was determined by high performance liquid chromatography. The pharmacokinetic parameters were determined from plasma concentration-time data with 3P97 software package. Results
1. Comparison of pharmacodynemic index between groups: the Group RP and RP+AD were similar with respect to epidural block characteristics. No significant difference in onset time, time to maximum spread, segment of spinal nerve blocked and onset time of motor block were observed between two groups (p>0.05). The number of patients with different degrees of motor block was similar in the two groups (p>0.05). Compared with
Group RP, the duration of sensory and motor block prolonged slightly, and no significant
difference observed (see Tab. 3).
2. The changes of index for circulation and respiration: At 10,20,30 min after injection, there was a little decreased in SBP relative to baseline (p>0.05) in two groups; DBP and MAP decreased slightly and had no significant difference than the baseline (p>0.05) in Group RP; the DBP and MAP decreased markedly and had significant differences than the baseline
(p<0.01) (DBP:66.611.4, 60.5 9.8, 62.8 ?3.2 vs 76.1 ?.7mmHg and MAP:
82.9?.7,75.5?.7,78.2?.2 vs 90.15.7mmHg);HR had a larger decreased c
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2. Arthur GK, et al, Comparative phamacokinetics of bupivacaine and ropivacaine, a new local anesthetic.Anesth Analg,1998,67(11):1053-8
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4. Akerman B, Hellkerg IB, Trossvikc C, et al. Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA 103). Acta Anaesthesol Stand, 1988,32:571-578
5．张富军，邓小明．罗哌卡因的实验与临床研究进展．中国新药与临床研究，2000，19(4)：317-319
6. Dony P, Dewinde V,Vanderich B,et al.The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats. Anesth Analg, 2000,91:1489-92
7. Knudsen K,Bechman Saurkiila M,Blomberg S,et al.Central nervous and cardiovascular effects of i.v.infusions of ropivacaine, Bupivacaine and placebo in volunteers. Br J Anaesth, 1997;78:507-14
8. Morrison SG, Dominguez JJ, Frascardo P, et al.A comparioson of the eletrocardiographic cardiotoxic effects or racemic bupivacaine, Levobupivacaine, and ropivacaine in anesthetized swine. Anesth Analg, 2000, 90:130-14
9. Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg, 1989, 69: 563-569
10. Lee A, Fagan D, Lamont M, et al. Disposition Kinetics of ropivacaine in humans. Anesth Analg, 1989, 69: 736-738
11．罗爱伦．新型局部麻醉药罗哌卡因．见：黄宇光，罗爱伦主编．21世纪医师丛书：麻醉科分册．北京：中国协和医科大学出版社，2000．1—11
12. Ekstrom G. Gunnarsson UB. Ropivacaine, a new amide-type local anesthetic agent is metabolized by cytochromes P450 1 A and 3 A in human liver mircrosomes. Drug Metab Dispos, 1996, 24: 955-961
13. Halldin MM, Bredberg E, Angelin B, et al. Metabolsm and excretion of ropivacaine in humans. Drng Metab Dispos, 1996,24(9):962-968
14．徐惠青，冯艺，杨拔贤，等．肾移植术硬膜外罗哌卡因的药效学和药代动力学研究．中华麻醉学杂志，2002，22(3)：133-135
15. Hickey R, Candido KD, Ramamurthy S. A comparison of ropivacaine 0.5％ and bupivacaine 0.5％ for brachial plexus block. Anesthesiotogy, 1991,74:639-642.
16. Hickey R, Blanchard J, Hoffman J, sjovall J, et al. Rlasma concentrations of ropivacaine given with or withont epinephrine for brachial plexus block. Can J anaesth, 1990, 37(8):878-82.
17．郭艳辉，冯婉玉，蔡爽，等．罗哌卡因单独或复合肾上腺素用于臂丛麻醉的药代动力学比较．中华麻醉学杂志，2001，21(4)：202-203。
18．涂恩平，吴新民，解大建，等．罗哌卡因含或不含肾上腺素硬膜外麻醉的药效学和药代动力学．中华麻醉学杂志，1999，19(12)：714-715。
19．陈文彬．主编，诊断学．第五版，北京：人民卫生出版社，2001，191-2
20．张春燕，顾健，段金菊，等．反相高效液相色谱法测定人血清中的罗哌卡因．色谱，2002，20(1)：56-58。
21．谢文钦，吴伟平，丁志荣，等．罗哌卡因用于高位硬膜外麻醉的临床观察．临床麻醉杂志，2001，17(9)：501-502
22．候文杰，王双燕，关键，等．0.5％罗哌卡因硬膜外麻醉乳腺癌根治术的临床观察．中国妇幼保健，2001，16(9)：570-571。
23. Cederholm I,Anskav S, Bengtsson M, et al. Sensory, Motor, and stmpathetic block during epidural analgesia with and 0.75％ ropivacaint with and withont epinephrine. Reg Anesth, 1994.19:18-33
24. Charles E, Pther, Britt-Marie Emanuelsson,Hakan Reventlid, et al. A Comparison of the dynamics and pharmacokinetics of ropivacaine 7.5mg/ml with and without epinephrine used for epidural anaesthesia in urological surgery. Cli Drag Invest,2003,23(4):245-253.
25. Germishugs PJ.Hyperresponders and adrenaline in local anaesthetic solutions. SAD J,2001;56:175-177.
26．解大建，吴新民，许幸，等．硬膜外阻滞时罗哌卡因和布此卡因的药代动力学．中华麻醉学杂志，1999，19(8)：459-460
27．易三平，姚尚龙，孟庆新，等．罗哌卡因在硬膜外阻滞时的药代动力学研究．中华麻醉学杂志，2001，21(8)：500
28. Lee BB, Ngan kee, Plummer JL, et al. The effect of addition of epinephrine on early systemic absorption of epidural ropivacaine in humans. Anesth Analg, 2002, 95(5): 1402-1407
29. Roelants FA,Veyckemans F,Verbeeck RK, et al.Pharmacokinetics of caudal ropivacaine and with without epinephrine in Chitdren Anesthesiology. 2000, 3A:A 1269.
30. Emanuelsson BM, Persson J, Alm C, et al. Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers. Anesthesiology, 1997, 87(6): 1039-1317
2. Arthur GK, et al, Comparative phamacokinetics of bupivacaine and ropivacaine, a new local anesthetic.Anesth Analg,1998,67(11):1053-8
3．杨拔贤．局部麻醉药．见：赵俊主编．新编麻醉学．北京：人民军医出版社，2000，319
4. Akerman B, Hellkerg IB, Trossvikc C, et al. Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA 103). Acta Anaesthesol Stand, 1988,32:571-578
5．张富军，邓小明．罗哌卡因的实验与临床研究进展．中国新药与临床研究，2000，19(4)：317-319
6. Dony P, Dewinde V,Vanderich B,et al.The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats. Anesth Analg, 2000,91:1489-92
7. Knudsen K,Bechman Saurkiila M,Blomberg S,et al.Central nervous and cardiovascular effects of i.v.infusions of ropivacaine, Bupivacaine and placebo in volunteers. Br J Anaesth, 1997;78:507-14
8. Morrison SG, Dominguez JJ, Frascardo P, et al.A comparioson of the eletrocardiographic cardiotoxic effects or racemic bupivacaine, Levobupivacaine, and ropivacaine in anesthetized swine. Anesth Analg, 2000, 90:130-14
9. Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg, 1989, 69: 563-569
10. Lee A, Fagan D, Lamont M, et al. Disposition Kinetics of ropivacaine in humans. Anesth Analg, 1989, 69: 736-738
11．罗爱伦．新型局部麻醉药罗哌卡因．见：黄宇光，罗爱伦主编．21世纪医师丛书：麻醉科分册．北京：中国协和医科大学出版社，2000．1—11
12. Ekstrom G. Gunnarsson UB. Ropivacaine, a new amide-type local anesthetic agent is metabolized by cytochromes P450 1 A and 3 A in human liver mircrosomes. Drug Metab Dispos, 1996, 24: 955-961
13. Halldin MM, Bredberg E, Angelin B, et al. Metabolsm and excretion of ropivacaine in humans. Drng Metab Dispos, 1996,24(9):962-968
14．徐惠青，冯艺，杨拔贤，等．肾移植术硬膜外罗哌卡因的药效学和药代动力学研究．中华麻醉学杂志，2002，22(3)：133-135
15. Hickey R, Candido KD, Ramamurthy S. A comparison of ropivacaine 0.5％ and bupivacaine 0.5％ for brachial plexus block. Anesthesiotogy, 1991,74:639-642.
16. Hickey R, Blanchard J, Hoffman J, sjovall J, et al. Rlasma concentrations of ropivacaine given with or withont epinephrine for brachial plexus block. Can J anaesth, 1990, 37(8):878-82.
17．郭艳辉，冯婉玉，蔡爽，等．罗哌卡因单独或复合肾上腺素用于臂丛麻醉的药代动力学比较．中华麻醉学杂志，2001，21(4)：202-203。
18．涂恩平，吴新民，解大建，等．罗哌卡因含或不含肾上腺素硬膜外麻醉的药效学和药代动力学．中华麻醉学杂志，1999，19(12)：714-715。
19．陈文彬．主编，诊断学．第五版，北京：人民卫生出版社，2001，191-2
20．张春燕，顾健，段金菊，等．反相高效液相色谱法测定人血清中的罗哌卡因．色谱，2002，20(1)：56-58。
21．谢文钦，吴伟平，丁志荣，等．罗哌卡因用于高位硬膜外麻醉的临床观察．临床麻醉杂志，2001，17(9)：501-502
22．候文杰，王双燕，关键，等．0.5％罗哌卡因硬膜外麻醉乳腺癌根治术的临床观察．中国妇幼保健，2001，16(9)：570-571。
23. Cederholm I,Anskav S, Bengtsson M, et al. Sensory, Motor, and stmpathetic block during epidural analgesia with and 0.75％ ropivacaint with and withont epinephrine. Reg Anesth, 1994.19:18-33
24. Charles E, Pther, Britt-Marie Emanuelsson,Hakan Reventlid, et al. A Comparison of the dynamics and pharmacokinetics of ropivacaine 7.5mg/ml with and without epinephrine used for epidural anaesthesia in urological surgery. Cli Drag Invest,2003,23(4):245-253.
25. Germishugs PJ.Hyperresponders and adrenaline in local anaesthetic solutions. SAD J,2001;56:175-177.
26．解大建，吴新民，许幸，等．硬膜外阻滞时罗哌卡因和布此卡因的药代动力学．中华麻醉学杂志，1999，19(8)：459-460
27．易三平，姚尚龙，孟庆新，等．罗哌卡因在硬膜外阻滞时的药代动力学研究．中华麻醉学杂志，2001，21(8)：500
28. Lee BB, Ngan kee, Plummer JL, et al. The effect of addition of epinephrine on early systemic absorption of epidural ropivacaine in humans. Anesth Analg, 2002, 95(5): 1402-1407
29. Roelants FA,Veyckemans F,Verbeeck RK, et al.Pharmacokinetics of caudal ropivacaine and with without epinephrine in Chitdren Anesthesiology. 2000, 3A:A 1269.
30. Emanuelsson BM, Persson J, Alm C, et al. Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers. Anesthesiology, 1997, 87(6): 1039-1317
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