不同脂质含量的脂肪乳对局部麻醉药物的吸附作用

胡惠静, 吉红梅, 陈云, 宋丰宇

西安力邦肇新生物科技有限公司制剂研发部,西安 710077

HU Huijing^,, JI Hongmei, CHEN Yun, SONG Fengyu

Department of Targeted Pharmaceutical Preparations,Xi'an Libang Zhaoxin Biological Technology Co.,Ltd,Xi'an 710077,China

作者简介胡惠静(1982-),女,河南濮阳人,工程师,硕士,研究方向:药物靶向制剂及药效药理学。电话:029-88338890,E-mail:huhuijing0505@163.com。

中图分类号: R971.2;R969 文献标识码: A 文章编号: 1004-0781(2018)01-0035-05

摘要:

目的观察不同脂质含量的脂肪乳对局部麻醉药物的吸附效果,探讨脂肪乳救治局部麻醉药物中毒的机制。方法定量的盐酸布比卡因、盐酸罗哌卡因溶液中分别加入10%,20%,30%脂肪乳,漩涡10 min后,37 ℃下恒温水浴振荡15 h,离心后取下清液采用高效液相色谱(HPLC)检测。色谱柱为Agilent HC-C₁₈(4.6 mm×250 mm,5 μm),流动相为乙腈-10 mmol·L^-1磷酸二氢钠缓冲溶液(25:75),用磷酸溶液调节pH值=3.5,流速1 mL·min^-1,柱温30 ℃,检测波长210 nm。结果盐酸布比卡因在0.3~3.0 μg·mL^-1浓度范围内线性关系良好,线性方程为Y=0.093 6X-0.017 3,r=0.999 6,最低检测限为0.05 μg·mL^-1(S/N>3);盐酸罗哌卡因在0.3~3.0 μg·mL^-1浓度范围内线性关系良好,线性方程为Y=0.086 6X-0.022 3,r=0.999 1,最低检测限为0.05 μg·mL^-1(S/N>3)。两种供试样品均在5 h内稳定,样品重复性良好。10%,20%,30%脂肪乳对等量盐酸布比卡因的吸附率分别为46.0%,70.4%,89.2%,对等量盐酸罗哌卡因的吸附率分别为51.3%,76.1%,90.7%。结论 10%,20%,30%脂肪乳电位、pH值相近,粒径略微增加,可以吸附游离盐酸布比卡因、盐酸罗哌卡因,且随着脂质含量的增加,其提取量增加。脂肪乳可提供脂质,使过量的或已经分布到组织的局部麻醉药物重新分散在油相中,从而降低局部麻醉药物毒性。

关键词: 脂肪乳 ; 中毒,局部麻醉药物 ; 布比卡因,盐酸 ; 罗哌卡因,盐酸 ; 吸附作用

Abstract:

Objective To research sorption of local anesthetic by fat emulsion with different content of lipid in vitro and then to discuss the mechanism of action of fat emulsion for treatment of local anesthetic toxicity. Methods 10%,20%,30% fat emulsion was added to the bupivacaine hydrochloride and ropivacaine hydrochloride.After the mixture was vortexed for 10 mins,it was vibrated in thermostatic water bath at 37 ℃ for 15 h ,then centrifugated and got the aqueous phase to HPLC test.The chromatography was carried on a C₁₈ column(4.6 mm×250 mm,5 μm ),the mobile phase was composed of acetonitrile-natrium biphosphoricum(25:75),the flow rate was 1 mL·min^-1,the column temperature was 30 ℃ and the detection wavelength was set at 210 nm. Results Under the condition of this test,the linear ranges and linear equations for bupivacaine hydrochloride and ropivacaine hydrochloride were 0.3-3.0 μg·mL^-1,Y=0.093 6X-0.017 3(r=0.999 6) ,and 0.3-3.0 μg·mL^-1,Y=0.086 6X-0.022 3(r=0.999 1) respectively.The lowest limit of quantitation were both 0.05 μg·mL^-1(S/N>3),and the ingredients showed good relationships between the peak area and the concentration.Sample reproducibility was good because the test sample was stable in 5 h.The extraction rates of bupivacaine hydrochloride by 10%,20%,30% fat emulsion were 46.0%,70.4%,89.2% respectively.The extraction rates of ropivacaine hydrochloride by 10%,20%,30% fat emulsion were 51.3%,71.6%,90.7% respectively. Conclusion Electric potential and the pH value of the 10%,20%,30% fat emulsion are similar,while the particle size increase slightly.Free bupivacaine hydrochloride and ropivacaine hydrochloride can be absorbed and with the increase of fat content,the extraction of local anesthetic is increased.The mechanism of action of fat for the treatment of local anesthetic toxicity maybe related to that fat emulsions can provided lipid,so that the excessive local anesthetic or those which had already distributesd in tissue can re-dispersed in lipid,and then the plasma concentration of local anesthetic is reduced,the toxicity is also reduced.

Key words: Fat emulsion ; Toxicity, drug, local anesthetic ; Bupivacaine,hydrochloride ; Ropivacaine ,hydrochloride ; Sorption

临床上局部麻醉药物应用广泛,其常见并发症为局部麻醉药物中毒。至今局部麻醉药物中毒仍是一个悬而未决的问题,这也限制了局部麻醉药物在临床的使用^[1-2]。避免局部麻醉药物中毒仍应以预防为主,若中毒一旦发生可采用常规救治措施,如停止注射局部麻醉药物、吸氧并进行辅助呼吸、静脉注射肌松药后气管内插管、机械通气、开放静脉等,临床数据表明这些措施收效甚微^[3]。最近10年,静脉注射脂肪乳对局部麻醉药物中毒的解毒作用逐渐引起人们的关注。大量动物和临床试验证明^[4-5],合理地采用脂肪乳可以救治局部麻醉药物中毒。

脂肪乳救治局部麻醉药物中毒的机制尚不清楚,人们根据大量的实验研究把解毒机制归结为三点:脂质槽机制、代谢与分布机制、脂肪酸补充理论^[6]。其中脂质槽理论研究最多,因此,本实验通过体外实验,初步研究不同脂质含量的脂肪乳对局部麻醉药物的吸附效果,以期为脂肪乳体内解毒机制的研究奠定基础,从而指导临床如何合理使用脂肪乳救治局部麻醉药物中毒,同时也为脂肪乳救治其他药物中毒或寻找其他局部麻醉药物解毒剂提供研究方向。

1 试药与仪器

1.1 试药

盐酸布比卡因(批号:C053-070801);盐酸罗哌卡因(批号:C013-060602);10%脂肪乳(批号:1003171)、20%脂肪乳(批号:1003083)、30%脂肪乳(批号:0910093)均购自西安力邦制药有限公司;乙腈为色谱纯;磷酸二氢钠为分析纯。

1.2 仪器

高效液相色谱仪(Waters Alliance 2695 System);Waters2996二极管阵列检测器;赛特湘仪台式高速离心机(湖南赛特湘仪离心机仪器有限公司,TG16A-WS);马尔文Zeta 激光粒度和ZETA电位仪;漩涡混合器(宁波新芝生物科技股份有限公司,XW-80A);恒温水浴振荡器(上海智城分析仪器制造有限公司,ZHWY-110X30)。

2 方法与结果

2.1 局部麻醉药物的选择

临床上常用的局部麻醉药物为酰胺类局部麻醉药物,尤其以布比卡因、罗哌卡因、普鲁卡因使用较多。布比卡因使用最多,脂溶性较大,作用时间较长,可带来较大的毒性,因此大部分实验在研究使用脂肪乳用于救治局部麻醉药物中毒时通常采用布比卡因。本实验同时选用罗哌卡因与布比卡因进行对比,以研究脂肪乳在提取引起中高毒性的局部麻醉药物的效果。

2.2 脂肪乳样品表征

局部麻醉药物在溶剂环境中的解离程度、脂肪乳脂质含量、脂肪乳乳滴大小及脂肪乳稳定性均影响到脂肪乳对局部麻醉药物的提取效果。故本实验先考察了3种规格脂肪乳的粒径、电位和pH值。动态光散射仪分别测定10%,20%,30%脂肪乳的粒径和电位。pH计测定不同脂质含量脂肪乳的pH值。表征结果见表1,粒径分布见图1。

图1 10%,20%,30%脂肪乳粒径分布图

Fig.1 Distribution of partical size of 10%,20% and 30% lipid emulsion

样品名称	pH值	粒径/nm	Zeta电位/mV
10%脂肪乳	8.4	346.2	-22.2±3.92
20%脂肪乳	8.4	380.5	-19.4±4.22
30%脂肪乳	9.1	402.5	-28.1±4.58

表1 10%,20%,30%脂肪乳的表征结果

Tab.1 Physical properties of 10%,20% and 30% lipid emulsion

由以上结果可见,10%,20%,30%脂肪乳均呈现弱碱性,对局部麻醉药物解离程度的影响相近。3种规格脂肪乳的粒径随着脂质含量的增加略微增加。脂肪乳电位的大小直接影响脂肪乳的稳定性,从而影响脂肪乳是否能以乳滴形式存在起到脂质槽的作用,由以上数据可见3种脂肪乳均稳定存在。

2.3 分析方法

2.3.1 色谱条件色谱柱:Agilent HC-C₁₈(4.6 mm×250 mm,5 μm);流动相:乙腈-磷酸二氢钠缓冲溶液10 mmol·L^-1(25:75),用磷酸溶液调节pH值=3.5;流速:1 mL·min^-1;柱温:30 ℃;进样量:20 μL;紫外检测,检测波长210 nm;单次时间20 min。

2.3.2 溶液配制 ①盐酸罗哌卡因溶液的配制:精密称取盐酸罗哌卡因50 mg,置100 mL量瓶中,加超纯水定容制得500 μg·mL^-1的盐酸罗哌卡因溶液。精密量取该溶液1 mL,置10 mL量瓶中,加超纯水定容制得50 μg·mL^-1盐酸罗哌卡因溶液,同样稀释制得5 μg·mL^-1盐酸罗哌卡因溶液,置4 ℃冰箱保存备用。

②盐酸布比卡因溶液的配制:精密称取盐酸布比卡因50 mg,置于100 mL量瓶中,加超纯水定容制得500 μg·mL^-1盐酸布比卡因溶液。精密量取该溶液1 mL至10 mL量瓶中,加超纯水定容制得50 μg·mL^-1的盐酸布比卡因溶液,同样稀释制得5 μg·mL^-1的盐酸布比卡因溶液,置4 ℃冰箱保存备用。

2.4 样品处理

精密量取50 μg·mL^-1盐酸布比卡因溶液1 mL,置10 mL量瓶中,分别用10%,20%,30%脂肪乳定容至10 mL,则得到5 μg·mL^-1盐酸布比卡因脂肪乳样品;取上述制备的脂肪乳样品5 mL置于10 mL离心管中,漩涡混合10 min;漩涡混合后置恒温水浴振荡器中,37 ℃下,200 r·min^-1水浴振荡15h;然后10 000 r·min^-1离心30 min,下清液逐滴滴出,记录下清液体积;取全部的脂肪乳样品离心下清液至5 mL量瓶中,用超纯水定容,高效液相色谱(HPLC)分析检测。盐酸罗哌卡因提取实验处理过程同盐酸布比卡因。每种浓度脂肪乳样品平行6个。空白样品的制备过程中把局部麻醉药物溶液换成1 mL的超纯水,其他步骤同上。

2.5 方法专属性考查

盐酸布比卡因、盐酸罗哌卡因出峰时间分别为15.8,9.6 min,见图2。离心下清液中其他成分不干扰局部麻醉药物的测定,本方法具有较强的专属性。

图2 脂肪乳提取局部麻醉药物色谱图 A.空白脂肪乳离心下清液;B.盐酸布比卡因脂肪乳下清液;C.盐酸罗哌卡因脂肪乳下清液;1.盐酸布比卡因;2.盐酸罗哌卡因

Fig.2 Chromatogram of local anesthetic extracted by fat emulsion A.centrifugal liquid below blank fat emulsion;B.centrifugal liquid below fat emulsion containing bupivacaine hydrochloride;C.centrifugal liquid below fat emulsion containing ropivacaine hydrochloride;1.bupivacaine hydrochloride;2.ropivacaine hydrochloride

2.6 线性关系考察

精密量取5 μg·mL^-1盐酸布比卡因溶液0.6,1,2,4,6 mL,置10 mL量瓶中,加超纯水至刻度,分别得到0.3,0.5,1,2,3 μg·mL^-1盐酸布比卡因标准液。以样品吸收面积为纵坐标,盐酸布比卡因浓度为横坐标做标准曲线。结果线性方程为Y=0.093 6X-0.017 3,r=0.999 6,盐酸布比卡因在0.3~3.0 μg·mL^-1浓度范围内线性关系良好。最低检测限为0.05 μg·mL^-1(S/N>3)。盐酸罗哌卡因溶液处理过程同盐酸布比卡因,结果盐酸罗哌卡因在0.3~3.0 μg·mL^-1浓度范围内线性关系良好,线性方程为Y=0.086 6X-0.022 3,r=0.999 1,最低检测限为0.05 μg·mL^-1(S/N>3)。

2.7 样品稳定性实验

取同一份样品分别于0,1,2,3,4,5 h时,按上述色谱条件进行,测定峰面积,分别计算出各个时间点游离浓度(μg·mL^-1),结果见表2,RSD值均<2%,说明供试品在5 h内稳定。

表2 样品稳定性实验结果
Tab.2 Results of stability test on sample μg·mL^-1

样品名称	0 h	1 h	2 h	3 h
盐酸布比卡因+
10%脂肪乳	2.70	2.7	2.68	2.71
20%脂肪乳	1.48	1.46	1.50	1.46
30%脂肪乳	0.54	0.55	0.53	0.54
盐酸罗哌卡因+
10%脂肪乳	2.44	2.45	2.42	2.42
20%脂肪乳	1.20	1.23	1.21	1.20
30%脂肪乳	0.46	0.46	0.45	0.46
样品名称	4 h	5 h	RSD/%
盐酸布比卡因+
10%脂肪乳	2.71	2.69	0.43
20%脂肪乳	1.47	1.46	1.09
30%脂肪乳	0.53	0.55	1.65
盐酸罗哌卡因+
10%脂肪乳	2.44	2.44	0.51
20%脂肪乳	1.23	1.21	1.12
30%脂肪乳	0.45	0.45	1.20

表2 样品稳定性实验结果

Tab.2 Results of stability test on sample μg·mL^-1

2.8 样品重复性实验

取同一份样品,平行进行5次,结果见表3,RSD值均<2%,表明本方法重复性良好。

样品名称	1	2	3	4	5	RSD/%
盐酸布比卡因+
10%脂肪乳	2.70	2.72	2.68	2.67	2.71	0.76
20%脂肪乳	1.48	1.48	1.47	1.49	1.47	0.67
30%脂肪乳	0.54	0.54	0.55	0.55	0.54	1.01
盐酸罗哌卡因+
10%脂肪乳	2.44	2.42	2.43	2.45	2.44	0.41
20%脂肪乳	1.20	1.20	1.21	1.22	1.20	0.74
30%脂肪乳	0.46	0.46	0.45	0.45	0.46	1.20

表3 样品重复性实验

Tab.3 Results of reproducibility test on sample μg·mL^-1

2.9 脂肪乳提取盐酸布比卡因、盐酸罗哌卡因的实验结果

HPLC检测下清液中盐酸布比卡因、盐酸罗哌卡因的峰面积记为S1、S2,代入标准曲线,算得游离盐酸布比卡因、盐酸罗哌卡因的含量,从而算得10%,20%,30%脂肪乳对等量盐酸布比卡因的吸附率,每种浓度脂肪乳样品制备6个,结果见表4。

样品名称	游离局部麻醉药物的含量/ μg	游离局部麻醉药物含量比例	吸附率
盐酸布比卡因+
10%脂肪乳	13.5	54.0	46.0±4.1
20%脂肪乳	7.4	29.6	70.4±2.7
30%脂肪乳	2.7	10.8	89.2±3.3
盐酸罗哌卡因+
10%脂肪乳	12.2	48.7	51.3±3.7
20%脂肪乳	6.0	23.9	76.1±1.6
30%脂肪乳	2.3	9.3	90.7±2.4

表4 不同脂质含量的脂肪乳对局部麻醉药物的吸附结果

Tab.4 Abosorption of local anesthetic by lipid emulsions with different lipid content x¯±s,n=6

由以上结果可见,随着脂肪乳脂质含量的增加,对盐酸布比卡因、盐酸罗哌卡因的吸附均呈增加趋势,游离呈递减趋势。

3 讨论

自1998年WEINBERG等^[7]首次报道了脂肪乳可成功救治大鼠局部麻醉药物过量使用后,2003年他们又报道了脂肪乳也可成功用于救治犬类局部麻醉药物过量使用^[8]。2004年首次发表了脂肪乳可用于人体局部麻醉药物引起的心搏停止的治疗,并命名为“脂质救治”。ROSENBLATT等^[9]2006年首次报道了1例腋路神经阻滞时发生局部麻醉药物中毒所致心搏骤停病例,经常规抢救无效使用脂肪乳剂后成功复苏。此后,一系列临床病例报道支持脂肪乳剂能够有效解救局部麻醉药物中毒所致的心血管毒性。基于这些动物实验和临床报道,2007年8月英国爱尔兰麻醉协会(Association of Anaesthetists of Great Britain and Ireland,AAGBI)发布了脂质救治局部麻醉药物中毒的指导方针,并指出所有的使用中毒剂量局部麻醉药物的部门都应该时刻备有脂肪乳。

脂肪乳是以大豆油为油相、卵磷脂为乳化剂形成的乳剂,人们推测脂肪乳在血液中形成脂质槽,与血液中的局部麻醉药物碰撞而将脂溶性局部麻醉药物吸附,从而能把局部麻醉药物从血浆中提取出来,使得局部麻醉药物不能到达其他易受损组织,或者迫使已经进入组织内的局部麻醉药物与高脂血浆重新分配,从而减少组织中局部麻醉药物的含量,达到解毒的作用。WEINBERG等^[10]用放射线标记研究了20%含量脂肪乳对大鼠和猎犬的布比卡因中毒的救治,当脂肪乳和血浆混合后,布比卡因的体外脂肪乳/血浆分配系数为1.2,即布比卡因交换进入脂肪乳的能力要略微大于其在血浆中的溶解度,由此推测布比卡因完全可以被脂肪乳吸附从而不被组织吸收。并且脂肪乳可以加速大鼠体外心脏组织内的布比卡因的清除,降低布比卡因含量在心脏组织中的含量,解除布比卡因引起的心脏毒性。脂肪乳在解毒过程中以遍布血液的微小“脂肪库”捕捉局部麻醉药物,把脂溶性局部麻醉药物交换出受损组织,缓解甚至逆转其毒副作用。所以脂肪乳的解毒功效必然与血液中的脂肪乳乳滴的密度相关,实验数据显示脂肪乳用量增加,引起心搏暂停的布比卡因用量同比递增^[10-11]。预注射脂肪乳还能提高布比卡因引起的心搏暂停的耐受量和动物苏醒成活率。

本实验采用10%,20%,30%脂肪乳对等量的盐酸布比卡因、盐酸罗哌卡因吸附效果进行了研究。在3种脂肪乳pH值均呈弱碱性、乳滴稳定的情况下,随着脂肪乳中脂质含量的增加,对局部麻醉药物吸附率也增加,但对盐酸布比卡因的吸附率略低于盐酸罗哌卡因。这说明脂肪乳能够吸附局部麻醉药物,且脂质含量越多,吸附能力越强。这也解释了动物与临床试验中脂肪乳可成功救治局部麻醉药物中毒。但是脂肪乳如何解救局部麻醉药物中毒?至今尚无定论,仅仅用脂质槽能捕捉局部麻醉药物来解释尚过于简单,脂肪乳救治局部麻醉药物中毒的效果可能不仅仅与脂质含量有关。体外实验存在缺陷,它是在忽略了体内环境的基础上进行的,但体内环境复杂,脂肪乳进入体内后与局部麻醉药物的作用过程受多方面因素影响。体外实验为体内实验提供了一定的理论基础,但不能代替体内实验,人们仍需进一步进行体内实验研究脂肪乳救治局部麻醉药物中毒的机制,从而很好地指导脂肪乳救治局部麻醉药物中毒,同时也为脂肪乳救治其他药物中毒或寻找其他局部麻醉药物解毒剂提供研究方向。

The authors have declared that no competing interests exist.

参考文献

View Option

[1]	孙建斌,陆阳春,程海涛.急性局麻药中毒三例[J].实用心脑肺血管病杂志,2013,21(6):180. [本文引用:1]
[2]	吴黄辉,陈国忠,王玉同.局麻药神经毒性的研究进展[J].神经解剖学杂志,2013,29(2):214-220. 正自1864年可卡因首次成功应用于眼科手术的表面麻醉以来,局麻药临床应用已超过一个多世纪的历史。局麻药神经传导阻滞麻醉的功效已在临床实践中获得广泛认可,但其所引起的神经功能障碍也引起越来越多麻醉医师的关注。本文就局麻药神经毒性影响因素和机制研究进行综述,为局 URL [本文引用:1]
[3]	李永春. 局麻药应用进展[J].中国实用医药,2011,6(30):229-231. [本文引用:1]
[4]	PICARD J,WARD S C,ZUMPE R,et al.Guidelines and the adoption of ‘lipid rescue’ therapy for local anaesthetic toxicity[J].Anaesthesia,2009,64(2):122-125. Abstract Gathering evidence from animal experiments, an editorial in this journal and published human case reports culminated in the Association of Anaesthetists of Great Britain and Ireland recommending in August 2007 that lipid emulsion be immediately available to all patients given potentially cardiotoxic doses of local anaesthetic drugs. This development offered an opportunity to track the adoption of an innovation by anaesthetists in the UK and to gauge the effects of guidelines. Two surveys, each of 66 NHS hospitals delivering acute care within London and its penumbra, examined the adoption of lipid emulsion therapy. After the publication of the editorial in autumn 2006, the spread of 'lipid rescue' was rapid. The timing of the adoption and the impetus for innovation varied substantially between the sampled hospitals. When the formal guidelines were published, approximately half of the hospitals surveyed did not have lipid rescue. Of those that subsequently adopted it, half attributed their decision to the guidelines. At the end of 2007, there remained a small number of hospitals that had yet to adopt lipid rescue. Lipid rescue's adoption by anaesthetists in the UK offers a rare example of swift uptake of an innovation. National guidelines accelerated the adoption of innovation by some hospitals. DOI:10.1111/j.1365-2044.2008.05816.x PMID:19143686 URL [本文引用:1]
[5]	WONG G K,JOO D T,MCDONNE C.Lipid resuscitation in a carnitine deficient child following intravascular migration of an epidural catheter[J].Anaesthesia,2010,65(2):192-195. Summary Top of page Summary Case report Discussion Acknowledgement References A child with cerebral palsy and carnitine deficiency developed ventricular arrhythmias with loss of cardiac output during elective surgery under general anaesthesia with concomitant epidural analgesia. Sinus rhythm was restored on administration of adrenaline, but hypotension persisted despite resuscitation. Bolus administration of 0.8ml.kg 鈭1 (20ml) lipid emulsion resulted in rapid improvement in cardiac output. Blood samples taken before and after the lipid bolus did not demonstrate toxic concentrations of bupivacaine. This case suggests that carnitine deficiency may increase susceptibility to bupivacaine cardiotoxicity. DOI:10.1111/j.1365-2044.2009.06131.x PMID:19849674 URL [本文引用:1]
[6]	罗中兵,张燕辉,陶军,等.脂肪乳剂对布比卡因药代动力学的影响[J].华南国防医学杂志,2013,27(12):866-869. 目的观察脂肪乳剂对布比卡因药代动力学的影响,探讨脂肪乳剂救治布比卡因中毒的主要机制。方法 14只新西兰大白兔随机分对照组和实验组2组,每组7只(n=7)。2组实验动物均在3 min内静脉持续注射布比卡因2 mg/kg后,对照组在7 min内持续静脉输注生理盐水15 ml/kg,而实验组输注20%英脱利匹特(长链脂肪乳剂)15 ml/kg。布比卡因开始输注后60 min内,使用高效液相技术在第3 min和每10 min测定每组实验动物血浆布比卡因浓度,以及第65 min时的心肌布比卡因的浓度。记录平均动脉压(mean arterial pressure,MAP)、心率(heart rate,HR)和心电图(electrocardiogram,ECG)等的变化,计算药代动力学参数。结果布比卡因开始输注后第10~60 min内,每10 min测定的MAP、HR,组内和基础值比较,以及组间比较差异均无统计学意义(P0.05)。布比卡因开始输注后第3 min时,实验组和对照组血浆布比卡因浓度差异无统计学意义(P0.05),而在其它相同时间点的血浆布比卡因浓度,实验组均显著高于对照组(P0.01)。对照组房室参数t1/2β、V1、CL等均高于实验组,而AUC、K10、K21等均低于实验组(P0.05),t1/2α和K12差异无统计学意义(P0.05);对照组统计矩参数AUC(0-t)和AUC(0-∞)均低于实验组,而Vz和CLz均高于实验组,MRT(0-t)和t1/2z差异无统计学意义(P0.05);对照组心肌布比卡因浓度为(304±61)ng/g显著高于实验组(176±50)ng/g(P0.01)。结论脂肪乳剂输注后提高布比卡因血浆药物浓度,降低心脏组织中的布比卡因药物浓度,"脂肪池机制"可能是脂肪乳剂救治局麻药中毒的主要机制。 URL [本文引用:1]
[7]	WEINBERG G,VADEBONCOUER T,RAMARAJU G,et al.Pretreatment of resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats[J].Anesthesiology,1998,88(4):1071-1075. Abstract BACKGROUND: The authors sought to confirm a chance observation that intravenous lipid treatment increases the dose of bupivacaine required to produce asystole in rats. The authors also measured the partitioning of bupivacaine between the lipid and aqueous phases of a plasma-lipid emulsion mixture. METHODS: Anesthetized Sprague-Dawley rats were used in pretreatment (protocol 1) and resuscitation (protocol 2) experiments. In protocol 1, animals were pretreated with saline or 10%, 20%, or 30% Intralipid (n = 6 for all groups), then received 0.75% bupivacaine hydrochloride at a rate of 10 ml x kg x min(-1) to asystole. In protocol 2, mortality was compared over a range of bolus doses of bupivacaine after resuscitation with either saline or 30% Intralipid (n = 6 for all groups). The lipid:aqueous partitioning of bupivacaine in a mixture of plasma and Intralipid was measured using radiolabeled bupivacaine. RESULTS: Median doses of bupivacaine (in milligrams per kilogram) producing asystole in protocol 1 were for 17.7 for saline, 27.6 for 10% Intralipid, 49.7 for 20% Intralipid, and 82.0 for 30% Intralipid (P < 0.001 for differences between all groups). Differences in mean +/- SE concentrations of bupivacaine in plasma (in micrograms per milliliter) were significant (P < 0.05) for the difference between saline (93.3 +/- 7.6) and 30% Intralipid (212 +/- 45). In protocol 2, lipid infusion increased the dose of bupivacaine required to cause death in 50% of animals by 48%, from 12.5 to 18.5 mg/kg. The mean lipid:aqueous ratio of concentrations of bupivacaine in a plasma-Intralipid mixture was 11.9 +/- 1.77 (n = 3). CONCLUSIONS: Lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Partitioning of bupivacaine into the newly created lipid phase may partially explain this effect. These results suggest a potential application for lipid infusion in treating cardiotoxicity resulting from bupivacaine. DOI:10.1097/00000542-199804000-00028 PMID:9579517 URL [本文引用:1]
[8]	WEINBERG G,RICHARD R,DOUGLAS L,et al.Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity[J].Regi Anesth Pain Med,2003,28(3):198-202. Abstract BACKGROUND AND OBJECTIVES: We previously demonstrated in rats that intravenous infusion of a lipid emulsion increases survival in resuscitation from severe bupivacaine cardiac toxicity. The present studies were undertaken to determine if this method is similarly effective in a non-rodent model using a larger animal. METHODS: Bupivacaine, 10 mg/kg, was administered intravenously over 10 seconds to fasted dogs under isoflurane general anesthesia. Resuscitation included 10 minutes of internal cardiac massage followed with either saline or 20% lipid infusion, administered as a 4-mL/kg bolus followed by continuous infusion at 0.5 mL/kg/min for 10 minutes. Electrocardiogram (EKG), arterial blood pressure (BP), and myocardial pH (pHm) and pO2 (pmO2) were continuously measured. RESULTS: Survival after 10 minutes of unsuccessful cardiac massage was successful for all lipid-treated dogs (n = 6), but with no survivors in the saline controls (n = 6) (P <.01). Hemodynamics, PmO2, and pHm were improved during resuscitation with lipid compared with saline treatment in which dogs did not recover. CONCLUSIONS: We found that infusing a lipid emulsion during resuscitation from bupivacaine-induced cardiac toxicity substantially improved hemodynamics, pmO2, and pHm and increased survival in dogs. DOI:10.1053/rapm.2003.50041 PMID:12772136 URL [本文引用:1]
[9]	ROSENBLATT M A,ABEL M,FISCHER G W,et al.Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-relate cardiac arrest[J].Anesthesiology,2006,105(1):217-218. DOI:10.1097/00000542-200607000-00033 URL [本文引用:1]
[10]	WEINBERG G,GUIDO D,RICHARD R,et al.Resuscita-tion with lipid versus epinephrine in a rat model of bupivacaine overdose[J].Anesthesiology,2008,108(5):907-913. Lipid emulsion infusion reverses cardiovascular compromise due to local anesthetic overdose in laboratory and clinical settings. The authors compared resuscitation with lipid, epinephrine, and saline control in a rat model of bupivacaine-induced cardiac toxicity to determine whether lipid provides a benefit over epinephrine.Bupivacaine, 20 mg/kg, was infused in rats anesthetized with isoflurane, producing asystole in all subjects. Ventilation with 100% oxygen and chest compressions were begun immediately, along with intravenous treatment with 30% lipid emulsion or saline (5-ml/kg bolus plus continuous infusion at 0.5 ml . kg . min) or epinephrine (30 microg/kg). Chest compressions were continued and boluses were repeated at 2.5 and 5 min until the native rate-pressure product was greater than 20% baseline. Electrocardiogram and arterial pressure were monitored continuously and at 10 min, arterial blood gas, central venous oxygen saturation, and blood lactate were measured. Effect size (Cohen d) was determined for comparisons at 10 min.Lipid infusion resulted in higher rate-pressure product (P < 0.001, d = 3.84), pH (P < 0.01, d = 3.78), arterial oxygen tension (P < 0.05, d = 2.8), and central venous oxygen saturation (P < 0.001, d = 4.9) at 10 min than did epinephrine. Epinephrine treatment caused higher lactate (P < 0.01, d = 1.48), persistent ventricular ectopy in all subjects, pulmonary edema in four of five rats, hypoxemia, and a mixed metabolic and respiratory acidosis by 10 min.Hemodynamic and metabolic metrics during resuscitation with lipid surpassed those with epinephrine, which were no better than those seen in the saline control group. Further studies are required to optimize the clinical management of systemic local anesthetic toxicity. DOI:10.1097/ALN.0b013e31816d91d2 PMID:18431127 URL [本文引用:2]
[11]	陆捷,江伟.脂肪乳剂解救局麻药中毒的机制及临床应用进展[J].临床麻醉学杂志,2009,25(5):458-460. 在有关脂肪乳剂能减轻布比卡因所致严重毒性反应的动物试验报道的基础上，Rosenblatt等于2006年首次报道了1例腋路神经阻滞时发生局麻药中毒所致心搏骤停病例，经常规抢救无效使用脂肪乳剂后成功复苏。此后，一系列病例报道支持脂肪乳剂能够有效解救局麻药中毒所致的心血管毒性。本文就脂肪乳剂对局麻药中毒的解救机制及临床应用进展等方面进行综述。 URL [本文引用:1]

急性局麻药中毒三例

2013

... 临床上局部麻醉药物应用广泛,其常见并发症为局部麻醉药物中毒.至今局部麻醉药物中毒仍是一个悬而未决的问题,这也限制了局部麻醉药物在临床的使用^[1-2].避免局部麻醉药物中毒仍应以预防为主,若中毒一旦发生可采用常规救治措施,如停止注射局部麻醉药物、吸氧并进行辅助呼吸、静脉注射肌松药后气管内插管、机械通气、开放静脉等,临床数据表明这些措施收效甚微^[3].最近10年,静脉注射脂肪乳对局部麻醉药物中毒的解毒作用逐渐引起人们的关注.大量动物和临床试验证明^[4-5],合理地采用脂肪乳可以救治局部麻醉药物中毒. ...

局麻药神经毒性的研究进展

2013

局麻药应用进展

2011

Guidelines and the adoption of ‘lipid rescue’ therapy for local anaesthetic toxicity

2009

Lipid resuscitation in a carnitine deficient child following intravascular migration of an epidural catheter

2010

脂肪乳剂对布比卡因药代动力学的影响

2013

... 脂肪乳救治局部麻醉药物中毒的机制尚不清楚,人们根据大量的实验研究把解毒机制归结为三点:脂质槽机制、代谢与分布机制、脂肪酸补充理论^[6].其中脂质槽理论研究最多,因此,本实验通过体外实验,初步研究不同脂质含量的脂肪乳对局部麻醉药物的吸附效果,以期为脂肪乳体内解毒机制的研究奠定基础,从而指导临床如何合理使用脂肪乳救治局部麻醉药物中毒,同时也为脂肪乳救治其他药物中毒或寻找其他局部麻醉药物解毒剂提供研究方向. ...

Pretreatment of resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats

1998

... 自1998年WEINBERG等^[7]首次报道了脂肪乳可成功救治大鼠局部麻醉药物过量使用后,2003年他们又报道了脂肪乳也可成功用于救治犬类局部麻醉药物过量使用^[8].2004年首次发表了脂肪乳可用于人体局部麻醉药物引起的心搏停止的治疗,并命名为“脂质救治”.ROSENBLATT等^[9]2006年首次报道了1例腋路神经阻滞时发生局部麻醉药物中毒所致心搏骤停病例,经常规抢救无效使用脂肪乳剂后成功复苏.此后,一系列临床病例报道支持脂肪乳剂能够有效解救局部麻醉药物中毒所致的心血管毒性.基于这些动物实验和临床报道,2007年8月英国爱尔兰麻醉协会(Association of Anaesthetists of Great Britain and Ireland,AAGBI)发布了脂质救治局部麻醉药物中毒的指导方针,并指出所有的使用中毒剂量局部麻醉药物的部门都应该时刻备有脂肪乳. ...

Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity

2003

Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-relate cardiac arrest

2006

Resuscita-tion with lipid versus epinephrine in a rat model of bupivacaine overdose

2008

... 脂肪乳是以大豆油为油相、卵磷脂为乳化剂形成的乳剂,人们推测脂肪乳在血液中形成脂质槽,与血液中的局部麻醉药物碰撞而将脂溶性局部麻醉药物吸附,从而能把局部麻醉药物从血浆中提取出来,使得局部麻醉药物不能到达其他易受损组织,或者迫使已经进入组织内的局部麻醉药物与高脂血浆重新分配,从而减少组织中局部麻醉药物的含量,达到解毒的作用.WEINBERG等^[10]用放射线标记研究了20%含量脂肪乳对大鼠和猎犬的布比卡因中毒的救治,当脂肪乳和血浆混合后,布比卡因的体外脂肪乳/血浆分配系数为1.2,即布比卡因交换进入脂肪乳的能力要略微大于其在血浆中的溶解度,由此推测布比卡因完全可以被脂肪乳吸附从而不被组织吸收.并且脂肪乳可以加速大鼠体外心脏组织内的布比卡因的清除,降低布比卡因含量在心脏组织中的含量,解除布比卡因引起的心脏毒性.脂肪乳在解毒过程中以遍布血液的微小“脂肪库”捕捉局部麻醉药物,把脂溶性局部麻醉药物交换出受损组织,缓解甚至逆转其毒副作用.所以脂肪乳的解毒功效必然与血液中的脂肪乳乳滴的密度相关,实验数据显示脂肪乳用量增加,引起心搏暂停的布比卡因用量同比递增^[10-11].预注射脂肪乳还能提高布比卡因引起的心搏暂停的耐受量和动物苏醒成活率. ...

... [10-11].预注射脂肪乳还能提高布比卡因引起的心搏暂停的耐受量和动物苏醒成活率. ...

脂肪乳剂解救局麻药中毒的机制及临床应用进展

2009