丙泊酚对颅内手术患者脑缺血缺氧性损伤的影响
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摘要
目的：颅内手术中对脑组织的牵拉压迫及电凝止血等因素，均可造成术野周边或其供血区不同范围和程度的脑组织缺血/缺氧性损害，机械通气及控制性降压等因素亦可影响脑氧供需平衡。随着颅内动脉瘤夹闭术、颅内占位切除术、体外循环等外科技术的迅猛发展，脑缺血/缺氧性损伤在临床上越来越普遍，加上颅内肿瘤患者常常在术前及术中发生颅内压增高、脑组织缺血、缺氧、水肿、坏死等病理性改变；术中电切、电凝、吸引、自动拉钩压迫及牵拉等操作难免会导致周围正常脑组织的缺血/缺氧性损伤；神经外科手术较为精细，耗时比一般手术时间长，可能会不同程度地影响神经细胞的代谢甚至造成脑组织损伤，并且直接影响到患者的转归与预后。因此，如何减轻和消除这种损伤以及阐明这种损伤的机制有重要的临床实用价值，也是近年来研究的重点和热点之一。
脑缺血缺氧性损伤机制可能与氧自由基及兴奋性氨基酸（EAA）大量产生、钙超载及细胞凋亡等多种因素共同作用的结果有关。生理条件下脑内EAA与抑制性氨基酸水平保持动态平衡，非生理性灌注可导致脑组织缺氧，诱发EAA的异常释放产生神经毒性作用，从而损伤神经细胞。丙泊酚作为一种在临床麻醉中广泛应用的静脉全麻药，既可通过增强中枢抑制性神经传递，也可通过抑制中枢兴奋性神经传递发挥麻醉作用，其主要作用位点是中枢抑制性的γ-氨基丁酸a受体(GABAa)。丙泊酚既可以降低脑血流量、颅内压和脑代谢率并保持脑血流与脑代谢的良好匹配，亦可抑制EAA的释放，使脑缺血组织谷氨酸（Glu）的浓度降低，从而减轻EAA受体的介导的神经毒性作用。丙泊酚可以直接与氧自由基反应，减轻了脂质过氧化反应的级联反应，而且还能保持自由基清除剂的活性，使超氧化物歧化酶（SOD）含量升高。动物实验表明，丙泊酚对动物脑缺血性损伤有保护作用，但其确切机制仍有待进一步研究。
目前，评价脑缺血缺氧性损伤指标包括监测脑氧供需平衡、检测兴奋性氨基酸浓度、SOD活性和丙二醛（MDA）含量等方法，各代表不同的方面：监测脑氧供需平衡不仅反映脑组织氧的摄取与利用，同时也间接反映脑血流与颅内压变化；检测EAA浓度并计算兴奋性毒性指数（excitatorytoxicity index ETI）可反映脑损伤的程度及预后；检测SOD、MDA反映脑组织中自由基的含量及脂质过氧化程度。鉴于此，脑内EAA、MDA、SOD及颈内静脉球部氧饱和度（SjvO2）检测相结合可以很好的反映脑组织的代谢。目前，临床研究也已有报道丙泊酚对急性颅脑损伤的患者具有脑保护作用，但在颅内手术中通过监测EAA及SOD等指标来衡量丙泊酚的脑保护作用的研究鲜有报道。颅内手术应用丙泊酚麻醉使患者不知不觉得到安全平稳的麻醉同时，又可以降低副作用与减少并发症，有较好的临床应用价值，产生较大的社会效益和经济效益，有广阔的应用前景。
方法：
1一般资料择期行颅内脑膜瘤切除术患者28例，ASAⅠ～Ⅱ级，年龄20～65岁。随机分为丙泊酚组（P组）和咪唑安定组（M组）两组，每组14例。所有患者均为首次择期颅内脑膜瘤切除术患者，术前无明显颅内高压，无冠心病、糖尿病、肾脏疾病以及其它合并症。
2麻醉方法术前常规禁饮、禁食8～12h，入手术室前两组患者均肌注阿托品0.5mg，局麻下桡动脉穿刺置管和右颈内静脉逆行穿刺并置管至颈内静脉球部。全麻诱导：P组顺次静注丙泊酚1.5~2.0mg/kg，芬太尼4μg/kg阿曲库铵0.6mg/kg，给氧去氮3min后气管插管，5min后采用丙泊酚-瑞芬太尼-阿曲库铵静脉复合麻醉；M组顺次静注咪达唑仑0.1~0.2mg/kg，芬太尼4μg/kg和阿曲库铵0.6mg/kg，全麻维持采用咪达唑仑-瑞芬太尼-阿曲库铵静脉复合麻醉。术中根据血压心率等因素综合判断麻醉深度并相应调整全麻复合液的输注量。术中输入液体为乳酸林格氏液溶液和羟乙基淀粉（万汶130/0.4），晶:胶体比例为1:1。Datex-ohmedaAestiva/5PSVPro麻醉机控制呼吸，潮气量8~10ml/kg,呼吸频率10~12次/min。根据血气分析调节潮气量。术中不应用吸入性麻醉药，剔除输血病例，术中不应用含糖的液体，以避免对试验的影响。
3标本采集和测定分别于全麻诱导前（T1）、手术开始（T2）、切开硬脑膜即刻（T3）、术毕（T4）、手术后1h（T5）五个时点同步采集颈内静脉球部和桡动脉血进行血气分析，并取血液标本５ml至真空试管。2000r/min离心10min，移液器取血浆0.4ml，加1.2ml无水乙醇，混匀后，12000r/min离心30min，取上清1ml于-80℃冰箱冻存，避免反复冻融。血清EAA采用高效液相色谱法（HPLC法）测定、血清SOD活性采用改良盐酸羟胺法以及MDA含量采用TBA荧光法测定。所有资料使用SPSS16.0软件做统计分析，所有数据以均数±标准差（x±s）表示，组间数据用单因素方差分析，组内数据用t检验进行统计学处理，P＜0.05为差异有统计学意义（经方差齐性检验，方差不齐时用校正后的P值）。
结果：
1两组患者一般情况的比较
两组患者的年龄、体重、手术时间、麻醉时间、瑞芬太尼的用量和输液量均无明显差异（P>0.05）。手术过程中两组患者MAP和HR均无明显差异(P>0.05)。
2两组患者脑氧供需平衡的比较
2.1两组患者SjvO2T4和T5较T1显著升高(P<0.05)；两组组间各时间点SjvO2无显著差异(P>0.05)。
2.2两组患者颈内静脉血氧含量(CjvO2) T4和T5较T1显著升高(P<0.05)；两组组间各时间点CjvO2无显著差异(P>0.05)。
2.3两组患者动静脉血氧含量差(Ca-jvO2)组内T2、T3、T4和T5较T1显著降低(P<0.05)；两组组间各时间点无显著差异(P>0.05)。
2.4两组组内脑氧摄取率(CERO2) T2、T3、T4和T5较T1显著降低(P<0.05)；两组组间各时间点无显著差异(P>0.05)。
3两组患者血清Glu、Gly、GABA浓度及兴奋性毒性指数（ETI）的比较
3.1两组患者Glu浓度T4和T5较T1显著升高(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著低于M组(P<0.05)。
3.2两组患者Gly浓度T4和T5较T1显著升高(P<0.05)；两组组间各时间点无显著差异(P>0.05)。
3.3两组患者GABA浓度组内进行比较， P组T5较T1显著降低(P<0.05)，M组T4和T5较T1显著降低(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著高于M组(P<0.05)。
3.4两组患者ETI组内进行比较，P组T5较T1显著升高(P<0.05)，M组T4和T5较T1显著升高(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著低于M组(P<0.05)。
4两组患者血清SOD活性和MDA含量的比较
4.1两组组内比较SOD活性有显著差异，T4和T5时点较T1显著降低(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著高于M组(P<0.05)。
4.2两组组内比较MDA含量有显著差异，T4和T5时点较T1显著升高(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著低于M组(P<0.05)。
结论：
1在颅内肿瘤切除术应用丙泊酚全静脉麻醉，通过降低颅内手术患者EAA的浓度、提高GABA的浓度及降低兴奋性毒性指数，可起到显著的脑保护作用。
2丙泊酚静脉麻醉能增加患者血清SOD活性，降低MDA含量，具有显著的脑保护作用。
3丙泊酚全静脉麻醉与咪达唑仑全静脉麻醉相比在改善患者脑氧供需平衡方面优势不明显，可能与本研究所观察的病例数偏少有关，有待进一步研究。
Objective: On brain tissue distraction, compression, electrocoagulationand other factors can cause the surgical field surrounding or its supply areadifferent scope and degree of brain ischemia hypoxia injury in surgicaloperation. Mechanical ventilation and controlled hypotension may also affectthe balance of cerebral oxygen supply and demand. With the development ofintracranial aneurysm, intracranial mass resection, cardiopulmonary bypasssurgery technology swift and violent, cerebral ischemia hypoxia injuries inclinical are more and more prevalent. And intracranial tumor patients oftenlead to intracranial hypertension, cerebral ischemia, hypoxia, edema, necrosisand pathological changes. Intraoperative electrical cutting, coagulation,suction, automatic retractor oppression and pulling operation could inevitablylead to the surrounding normal brain tissue ischemia hypoxia injury. Theneurosurgeries are relatively elaborate and time consuming than the averageoperation, may affect neural cell metabolism and even damage the brain tissue.Therefore, how to reduce and eliminate this injury and to illustrate themechanism of this injury are very important in the clinical application andalso are one of the important and hot spots in recent years.
Hypoxic-ischemic brain injury mechanisms may be related to oxygenfree radicals and excitatory amino acid produced in great quantities and theresult of the role of calcium overload and apoptosis factors. Underphysiological conditions, EAA and inhibitory amino acid level maintainhomeostasis. Non-physiological perfusion can lead to cerebral hypoxia andEAA abnormal release of neurotoxicity, damage the nerve cells.
As a widely used intravenous anesthetics, propofol can enhance centralinhibition of neurotransmitter, but also through inhibition of central excitatoryneurotransmission play a narcotic effect. The main role of propofol is the central inhibitory GABAa receptors. Propofol can reduce cerebral blood flow,intracranial pressure and cerebral metabolic rate and maintain a good match ofthe cerebral blood flow and cerebral metabolism, can also inhibit the releaseof EAA, and reduce the concentration of cerebral ischemia glutamate (Glu),thereby reducing the EAA receptor-mediated neurotoxicity. Propofol canreduce cerebral blood flow, intracranial pressure and cerebral metabolic rateand maintain a good match of the cerebral blood flow and cerebralmetabolism, can also inhibit the release of EAA. So that the cerebralischemia glutamate (Glu) concentration is reduced, thereby reducing theEAA receptor mediated neurotoxicity. Animal experiments show that theprotective effect of propofol on ischemic injury of the animal brain. But itsexact mechanism remains to be studied.
At present, the evaluation of cerebral hypoxic-ischemic injuryindicators include monitoring of cerebral oxygen supply and demand balance,detection of excitatory amino acid concentrations, superoxide dismutase(SOD), malondialdehyde (MDA) and other methods. Each represents adifferent aspect: Monitor the balance of cerebral oxygen and energymetabolism reflects not only the brain tissue oxygen uptake and utilization,but also indirectly reflect changes in cerebral blood flow and intracranialpressure. Detection of excitatory amino acid concentrations calculatedexcitatory toxicity index can reflect the degree of brain injury and prognosis;detection of SOD, MDA in brain tissue reflect the degree of brain tissue thecontent of free radicals and lipid peroxidation. In view of this, the brain EAA,MDA, SOD and SjvO2combined with testing can be a good reflection of brainmetabolism. At present, clinical studies have also reported the effects ofpropofol on acute brain injury patients with cerebral protection effect, but insurgical operation by monitoring the EAA and SOD indexes to measure thecerebral protective effect of propofol are rarely reported. Patients underanesthesia in a benefit, there is some clinical value, has a broad applicationprospect.
Methods:
1. We selected28patients for resection of intracranial meningioma,ASA I~II, age20~55.They were randomly divided into propofol group (groupP) and midazolam group (group M),14cases in each. All patients were firstelective intracranial tumor surgery patients with preoperative non-obviousintracranial pressure, coronary heart disease, diabetes, kidney disease andother complications.
2. Patient before surgery by the provisions of regulation forbidden todrink, fasting for8~12h. They must in both groups inject intramuscularatropine0.5mg, the radial artery catheterization in local anesthesia, the jugularvein puncture and retrograde catheter to the internal jugular venous bulbdepartment. Induction of general anesthesia：group P sequential intravenouspropofol1.5~2.0mg/kg, fentanyl4.0ug/kg atracurium0.8mg/kg induction ofgeneral anesthesia, the oxygen nitrogen removal3min after tracheal intubation,and5minutes after using propofol-remifentanil-atracurium compoundintravenous anesthesia; group M sequential intravenous midazolam0.1~0.2mg/kg fentanyl4.0ug/kg atracurium0.8mg/kg, anesthesia was maintainedwith midazolam-remifentanil-atracurium compound intravenous anesthesia.Intraoperative input liquid as lactated Ringer's solution, hydroxyethyl starchinjection. The ratio of crystal colloidalis1:1. GE Aespire-7100anesthesiamachine control of breathing, tidal volume8~10ml/kg respiratory rate of10to12times per minute, according to blood gas analysis to adjust the tidalvolume. Should not be used inhaled anesthetics, transfusion volume of morethan2unit cases culling; Should not be used of sugar containing liquid, inorder to avoid the impact on the experiment.
3. Respectively before general anesthesia induced by intubationimmmediate(T1), began operation (T2), open dural instantly(T3), end ofoperation (T4),1h after of anesthesia (T5) five times synchronous acquisitionof the internal jugular vein and the radial artery for blood gas analysis and5mlblood samples from the test tube to be centrifugal.
4. Specimens2000r/min,10min, pipette plasma0.4ml,1.2ml anhydrousethanol, after mixing,12000centrifuge30min,the supernatant from pipettes, frozen in-80℃to avoid repeated freezing and thawing.
5. Detection:Serum EAA was measured with HPLC, plasma SOD, MDAcontent was measured using visible light.
Result:
1. There were no significant differences by age, body weight, operationtime, anesthesia time and the dosage of remifentanil infusion amount betweentwo groups of patients (P>0.05).There were no significant differences withMAP and HR in surgical procedures (P>0.05).
2.2.1two groups of patients with Saturation of internal jugular venousbulb blood oxygen （SjvO2）T4and T5were significantly higher thanT1(P<0.05)；there were no significant differences with SjvO2at different timepoint between two groups of patients (P>0.05).2.2two groups of patientswith Content of internal jugular venous bulb blood oxygen (CjvO2) T4and T5were significantly higher than T1(P<0.05)； there were no significantdifferences with CjvO2at different time point between two groups of patients(P>0.05).2.3two groups of patients with Atrerial venous contentdifference(Ca-jvO2) T2、T3、T4and T5were significantly lower than T1(P<0.05)；there were no significant differences with Ca-jvO2at different time pointbetween two groups of patients (P>0.05).2.4two groups of patients withCerebral extraction of oxygen(CERO2) T2、T3、T4and T5were significantlylower than T1(P<0.05)；there were no significant differences with CERO2atdifferent time point between two groups of patients (P>0.05).
3.3.1Two group of patients with Glu concentration in T4、T5have asignificantly increased than T1(P <0.05), of which P group was significantlylower than that in group M in T4and T5(P <0.05).3.2Two group of patientswith Gly concentration in T4、T5have a significantly increased than T1(P<0.05); there were no significant differences with Gly at different time pointbetween two groups of patients (P>0.05).3.3Two patients with GABAconcentration within the group comparison, T5were significantly lower thanT1in P group (P<0.05), T4and T5were significantly lower than T1in M group(P<0.05); T4and T5points between the two groups were significantly different, P group was significantly higher than group M(P<0.05).3.4Twopatients with ETI concentration within the group comparison, T5wassignificantly higher than T1in P group (P<0.05), T4and T5were significantlyhigher than T1in M group (P<0.05);T4and T5points between the two groupswere significantly different, P group was significantly lower than group M(P<0.05).4.4.1Two group of patients with SOD activity T4,T5were significantly lowerthan T1(P <0.05), T4and T5points between the two groups were significantlydifferent, P group was significantly higher than group M(P<0.05). Two groupof patients with MDA content T4,T5were significantly higher than T1(P<0.05), T4and T5points between the two groups were significantly different,P group was significantly lower than group M(P<0.05).
Conclusion:
1. Intracranial tumor resection with propofol total intravenous anesthesia,can play a significant neuroprotective effect by reducing the concentration ofthe intracranial surgery in patients with EAA, increase of GABAconcentration and reduce excitotoxicity index.
2. Propofol intravenous anesthesia can increase the serum SOD activity,reduce the content of MDA, has significant neuroprotective effect.
3. Propofol total intravenous anesthesia with midazolam total intravenousanesthesia in patients compared to improve cerebral oxygen supply anddemand balance advantage is not clear, too few number of cases may beobserved with this study is related to further study.
脑缺血缺氧性损伤机制可能与氧自由基及兴奋性氨基酸（EAA）大量产生、钙超载及细胞凋亡等多种因素共同作用的结果有关。生理条件下脑内EAA与抑制性氨基酸水平保持动态平衡，非生理性灌注可导致脑组织缺氧，诱发EAA的异常释放产生神经毒性作用，从而损伤神经细胞。丙泊酚作为一种在临床麻醉中广泛应用的静脉全麻药，既可通过增强中枢抑制性神经传递，也可通过抑制中枢兴奋性神经传递发挥麻醉作用，其主要作用位点是中枢抑制性的γ-氨基丁酸a受体(GABAa)。丙泊酚既可以降低脑血流量、颅内压和脑代谢率并保持脑血流与脑代谢的良好匹配，亦可抑制EAA的释放，使脑缺血组织谷氨酸（Glu）的浓度降低，从而减轻EAA受体的介导的神经毒性作用。丙泊酚可以直接与氧自由基反应，减轻了脂质过氧化反应的级联反应，而且还能保持自由基清除剂的活性，使超氧化物歧化酶（SOD）含量升高。动物实验表明，丙泊酚对动物脑缺血性损伤有保护作用，但其确切机制仍有待进一步研究。
目前，评价脑缺血缺氧性损伤指标包括监测脑氧供需平衡、检测兴奋性氨基酸浓度、SOD活性和丙二醛（MDA）含量等方法，各代表不同的方面：监测脑氧供需平衡不仅反映脑组织氧的摄取与利用，同时也间接反映脑血流与颅内压变化；检测EAA浓度并计算兴奋性毒性指数（excitatorytoxicity index ETI）可反映脑损伤的程度及预后；检测SOD、MDA反映脑组织中自由基的含量及脂质过氧化程度。鉴于此，脑内EAA、MDA、SOD及颈内静脉球部氧饱和度（SjvO2）检测相结合可以很好的反映脑组织的代谢。目前，临床研究也已有报道丙泊酚对急性颅脑损伤的患者具有脑保护作用，但在颅内手术中通过监测EAA及SOD等指标来衡量丙泊酚的脑保护作用的研究鲜有报道。颅内手术应用丙泊酚麻醉使患者不知不觉得到安全平稳的麻醉同时，又可以降低副作用与减少并发症，有较好的临床应用价值，产生较大的社会效益和经济效益，有广阔的应用前景。
方法：
1一般资料择期行颅内脑膜瘤切除术患者28例，ASAⅠ～Ⅱ级，年龄20～65岁。随机分为丙泊酚组（P组）和咪唑安定组（M组）两组，每组14例。所有患者均为首次择期颅内脑膜瘤切除术患者，术前无明显颅内高压，无冠心病、糖尿病、肾脏疾病以及其它合并症。
2麻醉方法术前常规禁饮、禁食8～12h，入手术室前两组患者均肌注阿托品0.5mg，局麻下桡动脉穿刺置管和右颈内静脉逆行穿刺并置管至颈内静脉球部。全麻诱导：P组顺次静注丙泊酚1.5~2.0mg/kg，芬太尼4μg/kg阿曲库铵0.6mg/kg，给氧去氮3min后气管插管，5min后采用丙泊酚-瑞芬太尼-阿曲库铵静脉复合麻醉；M组顺次静注咪达唑仑0.1~0.2mg/kg，芬太尼4μg/kg和阿曲库铵0.6mg/kg，全麻维持采用咪达唑仑-瑞芬太尼-阿曲库铵静脉复合麻醉。术中根据血压心率等因素综合判断麻醉深度并相应调整全麻复合液的输注量。术中输入液体为乳酸林格氏液溶液和羟乙基淀粉（万汶130/0.4），晶:胶体比例为1:1。Datex-ohmedaAestiva/5PSVPro麻醉机控制呼吸，潮气量8~10ml/kg,呼吸频率10~12次/min。根据血气分析调节潮气量。术中不应用吸入性麻醉药，剔除输血病例，术中不应用含糖的液体，以避免对试验的影响。
3标本采集和测定分别于全麻诱导前（T1）、手术开始（T2）、切开硬脑膜即刻（T3）、术毕（T4）、手术后1h（T5）五个时点同步采集颈内静脉球部和桡动脉血进行血气分析，并取血液标本５ml至真空试管。2000r/min离心10min，移液器取血浆0.4ml，加1.2ml无水乙醇，混匀后，12000r/min离心30min，取上清1ml于-80℃冰箱冻存，避免反复冻融。血清EAA采用高效液相色谱法（HPLC法）测定、血清SOD活性采用改良盐酸羟胺法以及MDA含量采用TBA荧光法测定。所有资料使用SPSS16.0软件做统计分析，所有数据以均数±标准差（x±s）表示，组间数据用单因素方差分析，组内数据用t检验进行统计学处理，P＜0.05为差异有统计学意义（经方差齐性检验，方差不齐时用校正后的P值）。
结果：
1两组患者一般情况的比较
两组患者的年龄、体重、手术时间、麻醉时间、瑞芬太尼的用量和输液量均无明显差异（P>0.05）。手术过程中两组患者MAP和HR均无明显差异(P>0.05)。
2两组患者脑氧供需平衡的比较
2.1两组患者SjvO2T4和T5较T1显著升高(P<0.05)；两组组间各时间点SjvO2无显著差异(P>0.05)。
2.2两组患者颈内静脉血氧含量(CjvO2) T4和T5较T1显著升高(P<0.05)；两组组间各时间点CjvO2无显著差异(P>0.05)。
2.3两组患者动静脉血氧含量差(Ca-jvO2)组内T2、T3、T4和T5较T1显著降低(P<0.05)；两组组间各时间点无显著差异(P>0.05)。
2.4两组组内脑氧摄取率(CERO2) T2、T3、T4和T5较T1显著降低(P<0.05)；两组组间各时间点无显著差异(P>0.05)。
3两组患者血清Glu、Gly、GABA浓度及兴奋性毒性指数（ETI）的比较
3.1两组患者Glu浓度T4和T5较T1显著升高(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著低于M组(P<0.05)。
3.2两组患者Gly浓度T4和T5较T1显著升高(P<0.05)；两组组间各时间点无显著差异(P>0.05)。
3.3两组患者GABA浓度组内进行比较， P组T5较T1显著降低(P<0.05)，M组T4和T5较T1显著降低(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著高于M组(P<0.05)。
3.4两组患者ETI组内进行比较，P组T5较T1显著升高(P<0.05)，M组T4和T5较T1显著升高(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著低于M组(P<0.05)。
4两组患者血清SOD活性和MDA含量的比较
4.1两组组内比较SOD活性有显著差异，T4和T5时点较T1显著降低(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著高于M组(P<0.05)。
4.2两组组内比较MDA含量有显著差异，T4和T5时点较T1显著升高(P<0.05)；两组组间T4和T5时间点有显著差异，P组显著低于M组(P<0.05)。
结论：
1在颅内肿瘤切除术应用丙泊酚全静脉麻醉，通过降低颅内手术患者EAA的浓度、提高GABA的浓度及降低兴奋性毒性指数，可起到显著的脑保护作用。
2丙泊酚静脉麻醉能增加患者血清SOD活性，降低MDA含量，具有显著的脑保护作用。
3丙泊酚全静脉麻醉与咪达唑仑全静脉麻醉相比在改善患者脑氧供需平衡方面优势不明显，可能与本研究所观察的病例数偏少有关，有待进一步研究。
Objective: On brain tissue distraction, compression, electrocoagulationand other factors can cause the surgical field surrounding or its supply areadifferent scope and degree of brain ischemia hypoxia injury in surgicaloperation. Mechanical ventilation and controlled hypotension may also affectthe balance of cerebral oxygen supply and demand. With the development ofintracranial aneurysm, intracranial mass resection, cardiopulmonary bypasssurgery technology swift and violent, cerebral ischemia hypoxia injuries inclinical are more and more prevalent. And intracranial tumor patients oftenlead to intracranial hypertension, cerebral ischemia, hypoxia, edema, necrosisand pathological changes. Intraoperative electrical cutting, coagulation,suction, automatic retractor oppression and pulling operation could inevitablylead to the surrounding normal brain tissue ischemia hypoxia injury. Theneurosurgeries are relatively elaborate and time consuming than the averageoperation, may affect neural cell metabolism and even damage the brain tissue.Therefore, how to reduce and eliminate this injury and to illustrate themechanism of this injury are very important in the clinical application andalso are one of the important and hot spots in recent years.
Hypoxic-ischemic brain injury mechanisms may be related to oxygenfree radicals and excitatory amino acid produced in great quantities and theresult of the role of calcium overload and apoptosis factors. Underphysiological conditions, EAA and inhibitory amino acid level maintainhomeostasis. Non-physiological perfusion can lead to cerebral hypoxia andEAA abnormal release of neurotoxicity, damage the nerve cells.
As a widely used intravenous anesthetics, propofol can enhance centralinhibition of neurotransmitter, but also through inhibition of central excitatoryneurotransmission play a narcotic effect. The main role of propofol is the central inhibitory GABAa receptors. Propofol can reduce cerebral blood flow,intracranial pressure and cerebral metabolic rate and maintain a good match ofthe cerebral blood flow and cerebral metabolism, can also inhibit the releaseof EAA, and reduce the concentration of cerebral ischemia glutamate (Glu),thereby reducing the EAA receptor-mediated neurotoxicity. Propofol canreduce cerebral blood flow, intracranial pressure and cerebral metabolic rateand maintain a good match of the cerebral blood flow and cerebralmetabolism, can also inhibit the release of EAA. So that the cerebralischemia glutamate (Glu) concentration is reduced, thereby reducing theEAA receptor mediated neurotoxicity. Animal experiments show that theprotective effect of propofol on ischemic injury of the animal brain. But itsexact mechanism remains to be studied.
At present, the evaluation of cerebral hypoxic-ischemic injuryindicators include monitoring of cerebral oxygen supply and demand balance,detection of excitatory amino acid concentrations, superoxide dismutase(SOD), malondialdehyde (MDA) and other methods. Each represents adifferent aspect: Monitor the balance of cerebral oxygen and energymetabolism reflects not only the brain tissue oxygen uptake and utilization,but also indirectly reflect changes in cerebral blood flow and intracranialpressure. Detection of excitatory amino acid concentrations calculatedexcitatory toxicity index can reflect the degree of brain injury and prognosis;detection of SOD, MDA in brain tissue reflect the degree of brain tissue thecontent of free radicals and lipid peroxidation. In view of this, the brain EAA,MDA, SOD and SjvO2combined with testing can be a good reflection of brainmetabolism. At present, clinical studies have also reported the effects ofpropofol on acute brain injury patients with cerebral protection effect, but insurgical operation by monitoring the EAA and SOD indexes to measure thecerebral protective effect of propofol are rarely reported. Patients underanesthesia in a benefit, there is some clinical value, has a broad applicationprospect.
Methods:
1. We selected28patients for resection of intracranial meningioma,ASA I~II, age20~55.They were randomly divided into propofol group (groupP) and midazolam group (group M),14cases in each. All patients were firstelective intracranial tumor surgery patients with preoperative non-obviousintracranial pressure, coronary heart disease, diabetes, kidney disease andother complications.
2. Patient before surgery by the provisions of regulation forbidden todrink, fasting for8~12h. They must in both groups inject intramuscularatropine0.5mg, the radial artery catheterization in local anesthesia, the jugularvein puncture and retrograde catheter to the internal jugular venous bulbdepartment. Induction of general anesthesia：group P sequential intravenouspropofol1.5~2.0mg/kg, fentanyl4.0ug/kg atracurium0.8mg/kg induction ofgeneral anesthesia, the oxygen nitrogen removal3min after tracheal intubation,and5minutes after using propofol-remifentanil-atracurium compoundintravenous anesthesia; group M sequential intravenous midazolam0.1~0.2mg/kg fentanyl4.0ug/kg atracurium0.8mg/kg, anesthesia was maintainedwith midazolam-remifentanil-atracurium compound intravenous anesthesia.Intraoperative input liquid as lactated Ringer's solution, hydroxyethyl starchinjection. The ratio of crystal colloidalis1:1. GE Aespire-7100anesthesiamachine control of breathing, tidal volume8~10ml/kg respiratory rate of10to12times per minute, according to blood gas analysis to adjust the tidalvolume. Should not be used inhaled anesthetics, transfusion volume of morethan2unit cases culling; Should not be used of sugar containing liquid, inorder to avoid the impact on the experiment.
3. Respectively before general anesthesia induced by intubationimmmediate(T1), began operation (T2), open dural instantly(T3), end ofoperation (T4),1h after of anesthesia (T5) five times synchronous acquisitionof the internal jugular vein and the radial artery for blood gas analysis and5mlblood samples from the test tube to be centrifugal.
4. Specimens2000r/min,10min, pipette plasma0.4ml,1.2ml anhydrousethanol, after mixing,12000centrifuge30min,the supernatant from pipettes, frozen in-80℃to avoid repeated freezing and thawing.
5. Detection:Serum EAA was measured with HPLC, plasma SOD, MDAcontent was measured using visible light.
Result:
1. There were no significant differences by age, body weight, operationtime, anesthesia time and the dosage of remifentanil infusion amount betweentwo groups of patients (P>0.05).There were no significant differences withMAP and HR in surgical procedures (P>0.05).
2.2.1two groups of patients with Saturation of internal jugular venousbulb blood oxygen （SjvO2）T4and T5were significantly higher thanT1(P<0.05)；there were no significant differences with SjvO2at different timepoint between two groups of patients (P>0.05).2.2two groups of patientswith Content of internal jugular venous bulb blood oxygen (CjvO2) T4and T5were significantly higher than T1(P<0.05)； there were no significantdifferences with CjvO2at different time point between two groups of patients(P>0.05).2.3two groups of patients with Atrerial venous contentdifference(Ca-jvO2) T2、T3、T4and T5were significantly lower than T1(P<0.05)；there were no significant differences with Ca-jvO2at different time pointbetween two groups of patients (P>0.05).2.4two groups of patients withCerebral extraction of oxygen(CERO2) T2、T3、T4and T5were significantlylower than T1(P<0.05)；there were no significant differences with CERO2atdifferent time point between two groups of patients (P>0.05).
3.3.1Two group of patients with Glu concentration in T4、T5have asignificantly increased than T1(P <0.05), of which P group was significantlylower than that in group M in T4and T5(P <0.05).3.2Two group of patientswith Gly concentration in T4、T5have a significantly increased than T1(P<0.05); there were no significant differences with Gly at different time pointbetween two groups of patients (P>0.05).3.3Two patients with GABAconcentration within the group comparison, T5were significantly lower thanT1in P group (P<0.05), T4and T5were significantly lower than T1in M group(P<0.05); T4and T5points between the two groups were significantly different, P group was significantly higher than group M(P<0.05).3.4Twopatients with ETI concentration within the group comparison, T5wassignificantly higher than T1in P group (P<0.05), T4and T5were significantlyhigher than T1in M group (P<0.05);T4and T5points between the two groupswere significantly different, P group was significantly lower than group M(P<0.05).4.4.1Two group of patients with SOD activity T4,T5were significantly lowerthan T1(P <0.05), T4and T5points between the two groups were significantlydifferent, P group was significantly higher than group M(P<0.05). Two groupof patients with MDA content T4,T5were significantly higher than T1(P<0.05), T4and T5points between the two groups were significantly different,P group was significantly lower than group M(P<0.05).
Conclusion:
1. Intracranial tumor resection with propofol total intravenous anesthesia,can play a significant neuroprotective effect by reducing the concentration ofthe intracranial surgery in patients with EAA, increase of GABAconcentration and reduce excitotoxicity index.
2. Propofol intravenous anesthesia can increase the serum SOD activity,reduce the content of MDA, has significant neuroprotective effect.
3. Propofol total intravenous anesthesia with midazolam total intravenousanesthesia in patients compared to improve cerebral oxygen supply anddemand balance advantage is not clear, too few number of cases may beobserved with this study is related to further study.
引文
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15Kobayashi K, Yoshino F.et al． Direct Assessments of the AntioxidantEffects of Propofol Medium Chain Triglyceride/Long Chain Triglycerideon the Brain of Stroke-prone Spontaneously Hypertensive Rats UsingElectron Spin Resonance Spectroscopy Anesthesiology.2008，109(3):426~435
16Naohiro K，Akiyoshi H．Propofol attenuates hydrogen peroxide inducedmechanical and metabolic derangements in the isolated ratheart.Anesthsiology,1996，84(1)：117~127
17Ozturk E, Demirbilek S.et al． Antioxidant properties of propofol anderythropoimletin after closed head injury in rats． ProgNeurosychopharmcol Biol Psychiatry，2005，29(6)：922~927
18Boisset S, Steghens JP. et al．Relative antioxidant capacities of propofoland its main metabolites．Arch Toxicol，2004，78(11)：635~642
19邓小明，曾因明.2009麻醉学新进展.北京：人民卫生出版社，2009,1-36:225
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24陈莲华，薛张纲，蒋豪.异丙酚对局灶性脑敞血再灌注大鼠脑细胞凋亡经时反应进程的影响.中华麻醉学杂志，2005，25：767
25夏建华，石学锟，徐振东等.异丙酚对TNF-n诱导的小鼠曹髓神经元凋亡的影响[J]．中华麻醉学杂志，2006，26：652~655
26赵鑫，金延武，王端玉，等.异丙酚对全身高温大鼠的脑保护作用.中华医学杂志,2009，89(33)16~20
27曹江北，王恒林，李云峰，等.丙泊酚复合咪唑安定对再灌注损伤pc12细胞的保护作用.军医进修学院学报.2005，26（6）410~412
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30Zhu SM, Xiong XX, Zheng YY. et al．Propofol inhibits aquaporin4expression through a protein kinase C-dependent pathway in an astrocytemodel of cerebral ischemia/reoxygenation. Anesth Analg.2009，109(5):1493~1499
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36邓小明，曾因明.2009麻醉学新进展.北京：人民卫生出版社，2009,1(36):225
37曹江北，王恒林，李云峰，等.丙泊酚复合咪唑安定对再灌注损伤pc12细胞的保护作用.军医进修学院学报.2005，26（6）410~412
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2庄心良，曾因明.现代麻醉学（第3版）.北京：人民卫生出版社,2003，21：33
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5庄心良，曾因明.现代麻醉学（第3版）.北京：人民卫生出版社,2003，44：5~7
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7Rehberg B, Duch DS. Suppression of central nervous system sodiumchannels by propofol. Anesthesiology1999，91(2):512~520
8Wilson JX, Gelb AW. Free radicals, antioxidants, and neurologic injury:possible relationship to cerebral protection by anesthetics. J NeurosurgAnesthesiol.2002，14(1):66~79
9Hans P, Bonhomme V, Collette J, et al. Propofol protects cultured rathippoeampal neurons against N-methy-D-aspartate receptor-medatedglutamate toxicity. J Neurosurg. Anesthesiol.1994，6(4):249~253
10赵冬梅，贾树山，刘洪付.异丙酚抑制兴奋性氨基酸神经毒性研究进展.滨州医学院学报.2008,3（3）：211~214
11Wang L, Jing W, Hang YN. Glutamate-induced c-Jun expression inneuronal PC12cells: the effects of ketamine and propofol. J NeurosurgAnesthesiol.2008，20(2):124~130
12张虹，翟所迪，李家仁，等.脑外伤脑脊液中兴奋性氨基酸测定及其意义.中华医学检验杂志.1998,（06）：38~40
13张良成，杨庆，陈雄刚，等.异丙酚对颅脑手术创伤所致脑脊液兴奋性氨基酸和甘氨酸水平的影响.中国临床药理学杂志，2003,2(19)，11~13
14Hans P, Deby C, Deby-Dupont G.et al．Effect of propofo on in vitro lipidperoxidation induced by different free radical gener-sting system acomparison with vitamin E. J Neurosurg Anesthesiol.1996，8(2):154~158
15Kobayashi K, Yoshino F.et al． Direct Assessments of the AntioxidantEffects of Propofol Medium Chain Triglyceride/Long Chain Triglycerideon the Brain of Stroke-prone Spontaneously Hypertensive Rats UsingElectron Spin Resonance Spectroscopy Anesthesiology.2008，109(3):426~435
16Naohiro K，Akiyoshi H．Propofol attenuates hydrogen peroxide inducedmechanical and metabolic derangements in the isolated ratheart.Anesthsiology,1996，84(1)：117~127
17Ozturk E, Demirbilek S.et al． Antioxidant properties of propofol anderythropoimletin after closed head injury in rats． ProgNeurosychopharmcol Biol Psychiatry，2005，29(6)：922~927
18Boisset S, Steghens JP. et al．Relative antioxidant capacities of propofoland its main metabolites．Arch Toxicol，2004，78(11)：635~642
19邓小明，曾因明.2009麻醉学新进展.北京：人民卫生出版社，2009,1-36:225
20Macmanus JP, Buchan AM, Hill IE.et al. Global ischemia can causefragmentation indicative of apoptosis in rat brain. Neurosci Lett.1993，164(1-2):89~92
21Li Y, Chopp M, Jiang N.et al. In situ detection of DNA fragmentationafter focal cerebral ischemia in mice. Brain Res Mol Brain Res.1995，28(1):164~168
22Li Y, Powers C, Jiang N.et al. Intact, injured, necrotic and apoptotic cellsafter focal cerebral ischemia in the rat. J Neurol Sci.1998，156(2):119~132
23Wang H, Bloom O, Zhang M.et al. Vishnubhakat JM. HMG-1as a latemediator of endotoxin lethality in mice. Science.1999，285(5425):248~251
24陈莲华，薛张纲，蒋豪.异丙酚对局灶性脑敞血再灌注大鼠脑细胞凋亡经时反应进程的影响.中华麻醉学杂志，2005，25：767
25夏建华，石学锟，徐振东等.异丙酚对TNF-n诱导的小鼠曹髓神经元凋亡的影响[J]．中华麻醉学杂志，2006，26：652~655
26赵鑫，金延武，王端玉，等.异丙酚对全身高温大鼠的脑保护作用.中华医学杂志,2009，89(33)16~20
27曹江北，王恒林，李云峰，等.丙泊酚复合咪唑安定对再灌注损伤pc12细胞的保护作用.军医进修学院学报.2005，26（6）410~412
28Grasshoff C, Gillessen T. Effects of popofol on N-methyl-D-aspartatereceptor-mediated calcium increase in cultured rat cerebrocorticalneurons．Eur J Anaesthesiol，2005，22(6)：467~470
29蔡英敏王美纳薛荣亮等.麻醉剂量异丙酚对大鼠脑缺血再灌注损伤的保护作用.中华麻醉学杂志，2001，21：160~162
30Zhu SM, Xiong XX, Zheng YY. et al．Propofol inhibits aquaporin4expression through a protein kinase C-dependent pathway in an astrocytemodel of cerebral ischemia/reoxygenation. Anesth Analg.2009，109(5):1493~1499
31Wang HY, Wang GL, Yu YH. et al．The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced post conditioning against focal cerebralischemia-reperfusion injury in rats. Brain Res.2009，1297:177~184
32Rawat S, Dingley J. Closed-circuit xenon delivery using a standardanesthesia workstation. Anesth Analq.2010，110(1):101~109
33Ma D Hossain M, Chow A.Xenon and hypothermia combine to provideneuroprotection from neonatal asphyxia.Ann Neurol,2005,58:182~193
34Zhan RZ,Fujiwara N,Yamakura T. et al. Differential inhibitory effects ofthiopental, thiamylal and phenobarbital on both voltage-gated calciumchannels and NMDA receptors in rat hippocampal slices. Br J Anaesth.
1998，81(6):932~939
35Erd?s G, Tzanova I, Schirmer U. et al. Neuromonitoring andneuroprotection in cardiac anaesthesia. Nationwide survey conducted bythe Cardiac Anaesthesia Working Group of the German Society ofAnaesthesiology and Intensive Care Medicine. Anaesthesist.2009，58(3):247~258