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通讯作者:

spondingauthor),E-mail:yang_xl_yang@126.com

中图分类号:R614.2

文献标识码:A

文章编号:1007-4368(2022)07-973-06

DOI:10.7655/NYDXBNS20220709

参考文献 1
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参考文献 2
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参考文献 13
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参考文献 14
BOURDEAUX D,SAUTOU⁃MIRANDAA V,MONTAG⁃ NER A,et al.Simple assay of plasma sevoflurane and its metabolite hexafluoroisopropanol by headspace GC ⁃ MS [J].J Chromatogr B Analyt Technol Biomed Life Sci,2010,878(1):45-50
参考文献 15
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目录contents

    摘要

    目的:通过对SD大鼠吸入不同浓度七氟烷麻醉不同时间后血中游离六氟异丙醇(hexafluoro⁃isopropanol,HFIP)浓度的测定,分析血中游离HFIP的生成规律及其与七氟烷麻醉浓度的关系。方法:选择114只健康成年SD大鼠,其中6只用于测定HFIP样品的血/气分配系数,其余108只随机分为3组,每组36只,分别接受1.16%(S1组)、2.32%(S2组)和3.48%(S3组)浓度的七氟烷麻醉。每组内再分为6个麻醉时段,分别麻醉0.5、1.0、1.5、2.0、3.0、4.0 h,每个时段用鼠6只。麻醉结束后立即取腹主动脉血5~10 mL。首先采用顶空二次平衡法测得大鼠HFIP的血/气分配系数,再使用一次平衡法测得大鼠血中实际游离 HFIP浓度。同时使用顶空二次平衡法测定大鼠血中七氟烷浓度及血/气分配系数。分析组内血中游离HFIP浓度与麻醉时间的关系,及组间七氟烷麻醉浓度与血中游离HFIP浓度的关系。结果:3组不同时点SD大鼠血中均能测出游离HFIP,且在麻醉1.0 h时均达峰值,而后随着麻醉时间的延长,其浓度逐渐降低。与S1组相比,S2组各对应时点血中游离HFIP浓度均增高 (P < 0.05);除4.0 h时点外,S3组各对应时点血中游离HFIP浓度与S1组差异无统计学意义(P > 0.05)。与S2组相比,S3组各对应时点血中游离HFIP浓度均显著降低(P < 0.05)。结论:各组大鼠血中游离HFIP浓度均随七氟烷麻醉时间的延长呈先增高后降低的趋势。当七氟烷麻醉浓度增加到3.48%时,血中各时点游离HFIP浓度反而降低,七氟烷代谢受到抑制。

    Abstract

    Objective:Though determining the free hexafluoro ⁃isopropanol(HFIP)concentration in blood of SD rats anesthetized with different sevoflurane concentrations for different time,the change of free HFIP concentration in rats’blood was observed,and the relationship between inhaled sevoflurane concentration and free HFIP concentration in blood was also analyzed among the three groups. Methods:One hundred and fourteen healthy adult SD rats were selected,in which 6 rats were used to determine the blood/gas partition coefficient(B/G)of HFIP,and the rest 108 rats were randomly divided into three groups(S1,S2,and S3)with 36 rats in each group,and anesthetized by sevoflurane with different concentrations(1.16%,2.32%,and 3.48%),respectively. Every 6 rats in each group were accepted anesthesia by inhaled sevoflurane with a preset concentration for 0.5,1.0,1.5,2.0,3.0,and 4.0 h,respectively. First,the blood/gas partition coefficient of HFIP samples was measured by the two⁃stage headspace equilibration,and then the actual free HFIP concentration in the blood of anesthetized rats was measured by the one⁃stage headspace equilibration. At the same time,the sevoflurane concentration and blood/gas partition coefficient in the blood of anesthetized rats were determined by the two ⁃ stage headspace equilibrium method. Both the curves of free HFIP concentration in blood and inhaled sevoflurane concentration vs.anesthesia time were made,and the relationship among them was analyzed. Results:Free HFIP were detected and its peak value occurred at 1.0 hr after inhaled sevoflurane anesthesia in each group,and after that decreased along with the prolong of anesthesia time. Compared with group S1,the free HFIP concentration in group S2 was higher at each corresponding time point(P < 0.05),but except for the time point of 4.0 h,no significant differences were found in group S3 at corresponding time points(P > 0.05). Compared with group S2,the free HFIP concentration in group S3 was significantly lower at each corresponding time point(P < 0.05). Conclusion: The free HFIP concentration in blood shows a tendency from initial increase to subsequent decrease with the prolongation of sevoflurane anesthesia time. When the inhaled sevoflurane concentration increases to 3.48%,the generation of free HFIP is decreased and the metabolism of sevoflurane is inhibited.

  • SEV(sevoflurane,SEV)是目前临床上最常使用的挥发性吸入麻醉药。进入体内的SEV主要以原型经肺泡随呼吸排出体外,仅少部分(约5%)在肝脏经细胞色素P450酶系(尤其是细胞色素P450 2E1 [1]) 作用进行生物转化,生成无机氟离子及六氟异丙醇 (hexafluoro ⁃isopropanol,HFIP)[2]。所生成的HFIP中约85%在葡萄糖醛酸转移酶的作用下与葡萄糖醛酸结合形成结合型HFIP并随尿液排出体外,仅约15%的HFIP仍以游离形式存在于血液中[2-3]。 Eger等[4] 研究发现HFIP具有强大的麻醉效能,其在SD大鼠的最低肺泡有效浓度(minimum alveolar concentration,MAC)仅为0.004 4%,而SD大鼠SEV的MAC值为2.32%[5]。本研究小组在前期研究中发现,HFIP具有极大的血/气分配系数(452.25)[6],提示在使用SEV麻醉过程中所生成的HFIP易在组织中蓄积,并可能影响SEV的麻醉效应。Kharasch等[2]报道游离HFIP在人体具有较长的半衰期 [(20.1 ± 8.2)h],这可能与其极大的血/气分配系数有关。当停止吸入后,体内SEV因其血/气分配系数小[3],能快速排出体外,但HFIP则不易从体内排出,其潜在麻醉作用可能对术后患者的恢复质量产生影响。有研究发现当吸入SEV浓度增加到一定水平时,可使大鼠[7] 和成人[8] 肝细胞的代谢降低。但是,目前SD大鼠吸入SEV麻醉不同时间后血中游离HFIP的生成情况及其与吸入SEV浓度之间的关系尚不十分清楚。本实验针对该问题进行专门研究,现报道如下。

  • 1 材料和方法

  • 1.1 材料

  • 8~10周龄成年SD大鼠,体重180~230g,共114只,雌雄各半,由川北医学院动物实验中心提供。本实验过程符合本单位实验动物福利伦理委员会所制定的伦理学标准,实验操作人员均具备实验动物从业人员资格。SEV(120mL/瓶,上海恒瑞医药有限公司),六氟异丙醇(10mL/瓶,Sigma Aldrich公司,美国)。Ugo动物麻醉机(Ugo Basile,意大利);SEV蒸发器(Vaor 2000,德国);SPH⁃300A氢气发生器(北京中惠普);Agilent Technologies 7890A气相色谱仪;上述实验设备均由川北医学院麻醉学系实验室提供。

  • 1.2 方法

  • 1.2.1 气相色谱仪测定SEV及HFIP浓度

  • 气相色谱仪测定条件:色谱柱(Agilent19091J⁃ 413)325℃,30.00m × 320.00 μm × 0.25 μm,柱箱温度45℃,氢离子火焰检测器温度200℃,后进样口温度100℃,氢气流速30mL/min,空气流速400mL/min,氮气流速20mL/min。

  • 标准曲线方程的建立:用取样针抽取液态SEV或液态HFIP样品1~2mL,称重后注入事先建立了负压的锥形瓶内,吸取空气反复冲洗确保取样针中所有液体SEV或HFIP均进入锥形瓶内,待其完全挥发成气体时,平衡锥形瓶内外压力。根据公式C=W×R×T/(MW×VX[5] 计算出所配标准气浓度(C),式中W为所取液态麻醉药样品重量,R为常数0.082 06,T为绝对温度(273+摄氏温度),MW即麻醉药分子量,VX为锥形瓶实际容积(L)。采用倍比稀释法,经气相色谱仪多次测定稀释标准气浓度所对应的峰面积。当所测理论浓度已涵盖所有待测气体浓度时即停止稀释,根据相应峰面积和浓度建立SEV及HFIP的标准曲线方程。该标准曲线方程用于血中SEV及HFIP实际浓度的计算。

  • 1.2.2 大鼠HFIP血/气分配系数测定

  • 从114只健康成年SD大鼠中随机选取6只(图1),不经SEV麻醉,采用水合氯醛腹腔注射麻醉后,立即开腹经腹主动脉抽血5~10mL转移至头端接三通的密闭注射器内(已肝素水润化)。编号后将该注射器吸取一定体积已知较高浓度的HFIP标准气,在37℃条件下采用顶空二次平衡法[9-10] 测定SD大鼠HFIP的血/气分配系数(B/G),作为3组实验大鼠使用一次平衡法[11] 测定麻醉不同时间后血中游离HFIP浓度时的引用数据。

  • 1.2.3 大鼠血中SEV和HFIP深度测定

  • 控制室内温度为25℃,麻醉装置氧流量开至2L/min,用气相色谱仪校正麻醉挥发罐的SEV浓度。如图1所示,将剩余108只SD大鼠利用随机数字表法分为S1、S2及S3 3组,吸入SEV浓度分别为1.16%、2.32%和3.48%。每组再分为6个麻醉维持时间段,分别接受上述浓度的SEV麻醉0.5、1.0、1.5、 2.0、3.0、4.0h,每时段用鼠6只。

  • 图1 实验流程图

  • Fig.1 Consort diagram for the trail

  • 待大鼠麻醉装置预充所需设置浓度的SEV 5min后,将6只大鼠放入麻醉框开始计时,麻醉过程中用加热毯保温并检测大鼠肛温。待大鼠达到所需麻醉时间后迅速开腹抽取腹主动脉血5~10mL。采用注射器顶空一次平衡法测定血中游离HFIP浓度,二次平衡法测定血中SEV血/气分配系数及浓度,具体测定方法参见本研究小组以前的报道[9-10]

  • 1.3 统计学方法

  • 采用SPSS 26.0软件进行分析,血中游离HFIP浓度、SEV浓度及两者的血/气分配系数以均数±标准差(x-±s)表示,组内各时间点血中游离HFIP浓度比较采用重复测量方差分析,组间对应时间点血中游离HFIP浓度的比较采用单因素方差分析, P< 0.05为差异有统计学意义。

  • 2 结果

  • 2.1 一般资料

  • 共使用成年SD大鼠114只,其中S2组麻醉3.0h及S3组麻醉2.0h时各1只大鼠因呼吸频率过低、 S3组麻醉0.5h 1只大鼠因体温过低以及S3组麻醉4.0h 2只大鼠因中途死亡而退出实验,最终109只大鼠数据纳入统计分析。

  • 测得37℃时SD大鼠HFIP血/气分配系数为453.18 ± 74.20,SEV血/气分配系数为0.73 ± 0.06。

  • 2.2 大鼠血中游离HFIP和SEV浓度变化趋势

  • 3组大鼠血中游离HFIP浓度变化趋势基本一致,均随着麻醉时间的延长先逐渐增加,并于吸入1.0h时达峰值,随后逐渐降低。与S1组相比,S2组各对应时点血中游离HFIP浓度均增高(P< 0.05); 除4.0h时点外,S3组各对应时点血中游离HFIP浓度与S1组差异无统计学意义(P> 0.05)。与S2组相比,S3组各对应时点血中游离HFIP浓度均显著降低 (P< 0.05,表1)。

  • 图2 显示分别接受1.16%、2.32%和3.48%浓度的SEV麻醉后各时点血中游离HFIP和SEV浓度变化。随着SEV麻醉时间的延长,血中游离HFIP浓度呈现先增加后下降的趋势,峰值出现在吸入麻醉1.0h时点处。

  • 3 讨论

  • 本研究小组在前期实验中发现HFIP的血/气分配系数极大,且在血中HFIP浓度极低的情况下,若采用顶空二次平衡法测定其浓度[9-1012-13],则在第二次平衡结束时,溶解在剩余血中的HFIP不易挥发出来,将增大测量误差,影响其准确性。因此,本研究在该实验中联合应用注射器顶空一次平衡法和二次平衡法对大鼠血中游离HFIP浓度进行测定,即先用二次平衡法,使用已知高浓度HFIP样本气测定出未经SEV麻醉的SD大鼠血液的HFIP血/气分配系数,作为在使用一次平衡法测定实验大鼠血样时游离HFIP含量的计算公式中的引用数据,由此算出血中HFIP浓度。而血中SEV浓度的测定仍然使用顶空二次平衡法,这是因为SEV的血/气分配系数较小,在第二次平衡时SEV仍易于从血中挥发出来,可同时测定其分配系数及浓度。

  • 表1 3组SD大鼠血中游离HFIP浓度比较

  • Table1 Comparison of free HFIP concentration in the blood of SD rats among the three groups

  • S1、S2及S3组分别接受1.16%、2.32%和3.48%浓度的SEV麻醉。与S1组比较,a P< 0.05;与S2组比较,b P< 0.05。

  • 图2 3组SD大鼠血中游离HFIP及SEV浓度变化趋势

  • Fig.2 The trend of sevoflurane and free HFIP concen⁃ trations in the blood of SD rats in three groups

  • 本实验在37℃条件下测得SD大鼠HFIP的血/气分配系数为453.18,与本小组在人体血中测得的血/气分配系数极为相似[6],提示SEV无论是在大鼠还是人体代谢所生成的HFIP均极易滞留于血液中而不易从体内排出。当停止给予SEV时,由于SEV血/气分配系数较小,血中浓度因SEV迅速排出体外而下降,但因HFIP血/气分配系数很大,部分游离HFIP易滞留在体内,其潜在的麻醉作用[414] 可能导致患者苏醒延迟或苏醒期躁动的发生。因此,本研究对吸入不同浓度SEV麻醉后血中游离HFIP生成规律进行探讨,对指导临床合理使用SEV麻醉,减少或避免苏醒期躁动的发生具有一定参考意义。

  • 本研究结果显示,成年SD大鼠在接受不同浓度SEV麻醉后,各时点均能在血中测得一定含量的游离HFIP,随着SEV麻醉时间的延长,血中游离HFIP浓度呈现先增加后下降的趋势。推测其上升时段内SEV在肝脏转化生成的HFIP量多于其排出量,但当吸入SEV麻醉时间继续延长,血中游离HFIP浓度则逐渐下降,这可能与代谢所生成的HFIP大部分在肝脏与葡萄糖醛酸结合生成结合型HFIP并经肾脏排出体外有关。尽管本研究并未对吸入SEV麻醉30min内血中所生成的HFIP进行测定,但Kharasch等[2] 研究报道,在接受SEV麻醉5min后,血中便能检测出游离HFIP,说明SEV在体内代谢迅速。值得注意的是,本研究发现吸入不同浓度SEV麻醉,游离HFIP的生成高峰均在吸入麻醉后1.0h左右。由于HFIP本身具有强大的麻醉效能,可能在体内产生麻醉效应,从而降低SEV的MAC值。推测在进行1.0h左右的手术,若采用SEV吸入麻醉,可能其术后躁动发生率要高于更长时间的手术,并且特别可能发生在使用中等浓度SEV(2.32%)麻醉的小儿患者,但此推论尚需进一步的研究证实。

  • 本研究发现3组各时点血中游离HFIP浓度最高出现在吸入SEV2.32%组,而并非出现在吸入SEV浓度最大组(3.48%)。这表明SEV代谢所生成的HFIP并不一直随着吸入SEV浓度的增大而增加,当SEV吸入浓度超过某一范围时,血中SEV的代谢产物HFIP含量反而减少,这与本小组前期在体外实验中采用小鼠肝脏及脑组织匀浆孵育不同浓度SEV (0.5%、1.0%、3.0%)一定时间后,测得的HFIP生成规律一致[15]。这一现象可能与以下因素有关:一方面,随着吸入SEV浓度的增大,体内蓄积的SEV不断增加,当达到一定浓度时,肝脏代谢相关酶系受到抑制,酶活性降低,SEV的代谢率相应降低,生成的HFIP量减少;另一方面,吸入高浓度的SEV同时会降低肝脏的血流量[16],使肝脏对SEV的摄取量减少,从而经肝脏代谢生成的HFIP量亦减少。该现象提示使用较高浓度SEV麻醉会使自身代谢受到抑制,当患者肝、肾功能受损时,可导致HFIP生成及排出障碍,可能会对患者造成一定的危害[17]。但使用较高浓度SEV麻醉后,苏醒期躁动的发生率是否会低于使用中低浓度SEV麻醉者,有待进一步研究。

  • 本实验的不足之处在于:①各组内每个时间点观察的SD大鼠数量较少,可能会影响实验结果的准确性;②使用一次平衡法时,因引用了已测得的HFIP血/气分配系数值,可能会存在个体差异;③本实验只观察了4.0h内大鼠血中游离HFIP的生成情况,检测时间偏短,不能完全反映HFIP在体内的代谢趋势;④每组各时点未预留部分大鼠观察HFIP的消除及麻醉后恢复情况。

  • 综上所述,SD大鼠血中游离HFIP浓度随着SEV麻醉时间的延长呈先增加后降低的趋势。当SEV吸入浓度增加到一定程度时(3.48%),大鼠体内SEV的代谢会受到抑制。

  • 参考文献

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    • [2] KHARASCH E D,KAROL M D,LANNI C,et al.Clinical sevoflurane metabolism and disposition.I.Sevoflurane and metabolite pharmacokinetics[J].Anesthesiology,1995,82(6):1369-1378

    • [3] KHARASCH E D.Biotransformation of sevoflurane[J].Anesth Analg,1995,81(6 Suppl):S27-S38

    • [4] EGERE I,IONESCU P,LASTER M J,et al.Minimum al⁃ veolar anesthetic concentration of fluorinated alkanols in rats:relevance to theories of narcosis[J].Anesth Analg,1999,88(4):867-876

    • [5] 黄艳,杨小霖,黄三.新生及成年大鼠七氟醚MAC值的测定[J].临床麻醉学杂志,2016,32(8):803-805

    • [6] FENG Y,CHEN X B,YUAN W G,et al.Comparison of the level of free hexafluoro ⁃isopropanol in adults’blood and the incidence of emergence agitation after anesthesia with different concentrations of sevoflurane in laparoscop⁃ ic gastrointestinal surgery:a randomized controlled clini⁃ cal trial[J].Clin Ther,2019,41(11):2263-2272

    • [7] ARAKI M,INABA H,KON S,et al.Effects of volatile an⁃ esthetics on the calcium ionophore A23187⁃mediated al⁃ terations in hepatic flow and metabolism in the perfused liver in fasted rats[J].Acta Anaesthesiol Scand,1997,41(1 Pt 1):55-61

    • [8] SOLIMAN R,YACOUB A,ABDELLATIF M.Compara⁃ tive effect of desflurane and sevoflurane on liver function tests of patients with impaired hepatic function undergo⁃ ing cholecystectomy:a randomized clinical study[J].In⁃ dian J Anaesth,2020,64(5):383-390

    • [9] ZHOU J X,LUO N F,LIANG X M,et al.The efficacy and safety of intravenous emulsified isoflurane in rats[J].Anesth Analg,2006,102(1):129-134

    • [10] YANG X L,ZHANG W S,LIU J,et al.Pharmacokinetics of intravenous emulsified isoflurane in beagle dogs[J].Br J Anaesth,2013,110(1):128-136

    • [11] 杨小霖.静脉应用乳化异氟醚的药代动力学研究[D].成都:四川大学,2005:14-17

    • [12] YU R G,ZHOU J X,LIU J.Prediction of volatile anaes⁃ thetic solubility in blood and priming fluids for extracor⁃ poreal circulation[J].Br J Anaesth,2001,86(3):338-344

    • [13] YANG X L,MA H X,YANG Z B,et al.Comparison of minimum alveolar concentration between intravenous iso⁃ flurane lipid emulsion and inhaled isoflurane in dogs[J].Anesthesiology,2006,104(3):482-487

    • [14] BOURDEAUX D,SAUTOU⁃MIRANDAA V,MONTAG⁃ NER A,et al.Simple assay of plasma sevoflurane and its metabolite hexafluoroisopropanol by headspace GC ⁃ MS [J].J Chromatogr B Analyt Technol Biomed Life Sci,2010,878(1):45-50

    • [15] 杨小霖,EGER E,SHARMA M.SEV在小鼠中的代谢研究[J].四川医学,2012,33(11):1884-1886

    • [16] XU Z,YU J,WU J,et al.The effects of two anesthetics,propofol and sevoflurane,on liver ischemia/reperfusion injury[J].Cell Physiol Biochem,2016,38(4):1631-1642

    • [17] FRINK E J,MORGAN S E,COETZEE A,et al.The ef⁃ fects of sevoflurane,halothane,enflurane,and isoflurane on hepatic blood flow and oxygenation in chronically in⁃ strumented greyhound dogs[J].Anesthesiology,1992,76(1):85-90

  • 参考文献

    • [1] KHARASCH E D,ARMSTRONG A S,GUNN K,et al.Clinical sevoflurane metabolism and disposition.II.The role of cytochrome P450 2E1 in fluoride and hexafluo⁃ roisopropanol formation[J].Anesthesiology,1995,82(6):1379-1388

    • [2] KHARASCH E D,KAROL M D,LANNI C,et al.Clinical sevoflurane metabolism and disposition.I.Sevoflurane and metabolite pharmacokinetics[J].Anesthesiology,1995,82(6):1369-1378

    • [3] KHARASCH E D.Biotransformation of sevoflurane[J].Anesth Analg,1995,81(6 Suppl):S27-S38

    • [4] EGERE I,IONESCU P,LASTER M J,et al.Minimum al⁃ veolar anesthetic concentration of fluorinated alkanols in rats:relevance to theories of narcosis[J].Anesth Analg,1999,88(4):867-876

    • [5] 黄艳,杨小霖,黄三.新生及成年大鼠七氟醚MAC值的测定[J].临床麻醉学杂志,2016,32(8):803-805

    • [6] FENG Y,CHEN X B,YUAN W G,et al.Comparison of the level of free hexafluoro ⁃isopropanol in adults’blood and the incidence of emergence agitation after anesthesia with different concentrations of sevoflurane in laparoscop⁃ ic gastrointestinal surgery:a randomized controlled clini⁃ cal trial[J].Clin Ther,2019,41(11):2263-2272

    • [7] ARAKI M,INABA H,KON S,et al.Effects of volatile an⁃ esthetics on the calcium ionophore A23187⁃mediated al⁃ terations in hepatic flow and metabolism in the perfused liver in fasted rats[J].Acta Anaesthesiol Scand,1997,41(1 Pt 1):55-61

    • [8] SOLIMAN R,YACOUB A,ABDELLATIF M.Compara⁃ tive effect of desflurane and sevoflurane on liver function tests of patients with impaired hepatic function undergo⁃ ing cholecystectomy:a randomized clinical study[J].In⁃ dian J Anaesth,2020,64(5):383-390

    • [9] ZHOU J X,LUO N F,LIANG X M,et al.The efficacy and safety of intravenous emulsified isoflurane in rats[J].Anesth Analg,2006,102(1):129-134

    • [10] YANG X L,ZHANG W S,LIU J,et al.Pharmacokinetics of intravenous emulsified isoflurane in beagle dogs[J].Br J Anaesth,2013,110(1):128-136

    • [11] 杨小霖.静脉应用乳化异氟醚的药代动力学研究[D].成都:四川大学,2005:14-17

    • [12] YU R G,ZHOU J X,LIU J.Prediction of volatile anaes⁃ thetic solubility in blood and priming fluids for extracor⁃ poreal circulation[J].Br J Anaesth,2001,86(3):338-344

    • [13] YANG X L,MA H X,YANG Z B,et al.Comparison of minimum alveolar concentration between intravenous iso⁃ flurane lipid emulsion and inhaled isoflurane in dogs[J].Anesthesiology,2006,104(3):482-487

    • [14] BOURDEAUX D,SAUTOU⁃MIRANDAA V,MONTAG⁃ NER A,et al.Simple assay of plasma sevoflurane and its metabolite hexafluoroisopropanol by headspace GC ⁃ MS [J].J Chromatogr B Analyt Technol Biomed Life Sci,2010,878(1):45-50

    • [15] 杨小霖,EGER E,SHARMA M.SEV在小鼠中的代谢研究[J].四川医学,2012,33(11):1884-1886

    • [16] XU Z,YU J,WU J,et al.The effects of two anesthetics,propofol and sevoflurane,on liver ischemia/reperfusion injury[J].Cell Physiol Biochem,2016,38(4):1631-1642

    • [17] FRINK E J,MORGAN S E,COETZEE A,et al.The ef⁃ fects of sevoflurane,halothane,enflurane,and isoflurane on hepatic blood flow and oxygenation in chronically in⁃ strumented greyhound dogs[J].Anesthesiology,1992,76(1):85-90