围术期脑保护的研究进展

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2012/3/28,#,围术期脑保护的研究进展,解轶,2012,年,3,月,现状,尽管近年麻醉技术及监测手段不断进步，但是术中与术后神经损伤仍是最严重的并发症。,目前尚无足够的临床证据制订的官方指南，其主要原因是脑缺血机制错综复杂。,对脑缺血高风险患者不仅要避免不利因素的影响，而且要积极采取措施来保护神经系统功能稳定。,在一些特殊的外科手术中应用各种手段来提高脑组织对缺血缺氧的耐受力，减少缺血缺氧所导致的神经细胞死亡和神经功能受损，已成为围术期脑保护迫切需要解决的重大课题。,1,生理性的脑保护,1,1,选择性脑降温,1,2,控制血糖,1,3,控制血压和保证氧供,1. 4,血红蛋白浓度,1,1,选择性脑降温,选择性脑降温是指在离头部较近处加强热量散发，使颅内温度低于躯体温度，可以避免全身低温所带来的不利影响，同时又能有效地改善缺血缺氧性脑损伤。,脑保护机制不仅与降低脑代谢率有关，还涉及抑制缺血缺氧诱发的“瀑布式反应”的进展，如抑制谷氨酸释放、减少自由基生成、抑制凋亡、保护血脑屏障等，并且可为其他治疗措施延长治疗时间窗。,The National Acute Brain Injury Study: Hypothermia II was a randomized multicenter trial in which 97 patients with moderate-to-severe TBI received either normothermia or total-body hypothermia to 33C for 48 hours.,The primary outcome measure was the rate of poor outcome (ie, GOS showing severe disability, vegetative state, or death).,This trial was terminated prematurely due to futility. There was no difference in the rate of poor outcome (60% vs. 45% for hypothermia and normothermia, respectively; P=0.67) or death (23% vs. 14%, P=0.52).,Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol. 2011;10:131139.,不过有一点可以肯定,:,围术期高热会使临床结局变得更差,1,2,控制血糖,大量研究证实，围术期控制血糖有助于改善患者神经功能预后。,在一些危重和心脏手术患者中，严格控制围术期的血糖水平可以降低脑缺血发病率和病死率。,围术期持续高血糖可增加缺血性脑损伤的范围，使得临床结局更差。,McGirt,的研究发现，血糖,11,11 mmol /L (,无论患者是否患有糖尿病,),可使颈动脉内膜剥脱术围术期脑卒中发生率增高。但是严格的血糖控制,( 4,44,6,11 mmol /L),可能会增加低血糖的风险。,Sui reported data from 43,933 men who underwent a comprehensive preventative medical between 1971 and 2002,（,were free of myocardial infarction, stroke, cancer, or known diabetes mellitus,）,They were followed until either stroke, death, or the study end date (December 31, 2004) occurred.,BG concentrations were stratified into 3 groups: (1) normal (80 to 109 mg/dL); (2) impaired (110 to 125 mg/dL); and (3) diabetes mellitus (=126 mg/dL).,Nonfatal stroke rate was 10.3, 11.8, and 18.0 per 10,000 person-years in the 3 groups (P=0.002). Fatal stroke, with stroke rates of 2.1, 3.4, and 4.0 per 10,000 person-years (P=0.008).,For fasting plasma glucose concentrations 110 mg/dL, each,10 mg/dL increase,in serum glucose concentration was associated with a,6% greater risk of fatal stroke,events (P=0.05) and,an 8% increase in nonfatal,stroke events (P0.05).,A prospective study of fasting plasma glucose and risk of stroke in asymptomatic men. Mayo Clin Proc. 2011;86:10421049.,Kamouchi utilized data from 3627 patients with primary ischemic stroke with a hemoglobin A,1c,available from hospital admission.,Data were stratified according to admission hemoglobin A,1c,into 4 categories: (1) 8.3%.,Increasing hemoglobin A,1c,was associated with a,reduced,risk of neurologic,improvement,after stroke (P0.001 for trend) and an,increased,risk for,poor functional,outcome.,Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke: the Fukuoka Stroke Registry. Stroke. 2011;42:27882794.,依据目前临床证据,围术期仍应该避免高血糖的发生,1,3,控制血压和保证氧供,首先，脑组织的代谢率较其他组织 器官高。,其次成人脑的重量仅占体质量的,2%,，但其血液灌注量却占全身血流量的,13%,20%,，脑组织对氧的需求量为,42,45 mL /min,，耗氧量占全身耗氧量的,15%,20%.,脑组织对缺氧极为敏感，而其本身的氧储备又微乎其微。,有研究已证实降低平均动脉血压可导致脑缺血患者临床结局的恶化，所以围术期神经并发症高危患者中维持“较高”的平均动脉压是安全、有效、可行的办法。,Cardipulmonary bypass management and neurologic outcome: an evidence-based appraisal of current practices,J,Anesth Analg,，,2006,，,103( 1) : 21-37,维持基础的平均动脉血压和保证足够的氧供是最基本的脑保护措施,1,4,血红蛋白浓度,Optimum serum hemoglobin concentration in patients with ischemic stroke is not well characterized, in part because 2 contradictory theories exist.,A lower serum hemoglobin may lead to reduced blood viscosity and improved microcirculation, but this may occur at the expense of reduced blood oxygen-carrying capacity.,Keller reported that anemia on admission and at day 5 was more common in patients with a poor outcome at 3 months.,Patients with anemia during the first 5 days of hospitalization were 2.61 (P=0.005) times more likely to have a poor outcome at 3 months.,Cerebral oxygen transport failure?: decreasing hemoglobin and hematocrit levels after ischemic stroke predict poor outcome and mortality: Stroke: RelevAnt Impact of hemoGlobin, Hematocrit and Transfusion (STRAIGHT)an observational study. Stroke. 2011;42: 28322837.,Cell-free hemoglobin-based oxygen carriers, such as polynitroxylated pegylated hemoglobin, offer promise in this setting by increasing oxygen-carrying capacity without excessively increasing blood viscosity.,Polynitroxylated pegylated hemoglobin: a novel neuroprotective hemoglobin for acute volumelimited fluid resuscitation after combined traumatic brain injury and hemorrhagic hypotension in mice. Crit Care Med. 2011; 39:494505.,About autologous transfusion,There has been concern recently of possible brain inflammation associated with an intraoperative autologous (ie, “cell saver”) transfusion, as a result of activation of the inflammatory cascade secondary to blood interactions with the extracorporeal circuit.,Lasarzik reported in a rat model, transfusion of autologous blood, even in the presence of cerebral ischemia, does not increase brain concentrations of inflammatory mediators.,Effect of autologous blood transfusion on cerebral cytokine expression. J Neurosurg Anesthesiol. 2011;23:215221.,2,麻醉药的脑保护,2,1,吸入麻醉药,挥发性液体,惰性气体,2,2,静脉麻醉药,巴比妥类药物,丙泊酚与氯胺酮,右旋美托咪啶,利多卡因,挥发性液体,保护机制包括抑制兴奋性神经递质、强化抑制性受体，从而降低对能量的需求以及特有的缺血预适应。,在所有吸入性麻醉药物中，异氟烷的脑保护作用已在多种缺血模型中得到证实，包括局灶性脑缺血模型、半球缺血模型、全脑缺血模型以及体外培养神经细胞或组织的氧糖剥夺模型等。,异氟烷预处理可增加脑组织对缺血的耐受性。一项回顾性研究表明，与氟烷及恩氟烷麻醉比较，异氟烷麻醉时缺血性改变的发生率更低。,相对大量的实验性研究而言，吸入麻醉药脑保 护的临床证据目前并不充分，仍然需要具有充分说服力的神经系统临床结局的前瞻性随机对照研究，并应该采用更为精确的观察终点。,Many mediators and pathways (eg, ubiquitin, mitochondrial potassium channels, nitric oxide synthase, caveolins),，,the mechanisms of anesthetic preconditioning are not fully understood.,Sex steroids, may alter the effectiveness of anesthetic preconditioning.,Recently,reactive oxygen species,have been implicated in mediating sevoflurane preconditioning.,Yang conducted sevoflurane preconditioning experiments in rats.,They discovered that increasing doses of sevoflurane were more effective at inducing preconditioning against cerebral ischemia,The effect of sevoflurane preconditioning was abolished by the administration of dimethylthiourea and N-acetylcysteine .,ROS may also play a key role in remote postconditioning, whereby ischemia is produced in a limb during reperfusion of the brain after an ischemic injury.,Limb remote postconditioning alleviates cerebral reperfusion injury through reactive oxygen species-mediated inhibition of delta protein kinase C in rats. Anesth Analg. 2011;113:1180,1187.,目前就存在脑神经损伤高风险手术时，还是应该考虑吸入麻醉。,惰性气体,惰性气体氙气已逐渐被作为麻醉辅助药用于临床，它通过竞争性拮抗谷氨酸的,N-,甲基,-D-,天冬氨酸亚型受体发挥麻醉作用。,脑缺血损伤在,N-,甲基,-D-,天冬氨酸受体被拮抗后减轻，故氙气也表现出了一定程度的脑保护效应。,巴比妥类药物,巴比妥类药物可使脑电图产生等电位，进而使围术期脑内代谢减慢，从而降低对,ATP,的需求，脑部可以耐受更长时间的缺血状态。,巴比妥类曾被认为是衡量麻醉药脑保护作用的“金标准”。然而，近年来，越来越多的学者开始质疑巴比妥类的脑保护效应，认为其脑保护效应是由麻醉导致的低体温所介导的，而非巴比妥类本身。,自从吸入麻醉药显示出既有巴比妥相似的脑保护作用，又可以缩短苏醒的时间的特性，巴比妥类药物目前在围术期使用也日益减少。,丙泊酚与氯胺酮,丙泊酚与氯胺酮也曾被认为是有脑保护作用的静脉麻醉药，但是现在研究人员认为它们的脑保护作用存在争议。,丙泊酚的脑保护作用机制部分是由于其可减弱缺血缺氧性损伤所导致的,ATP,和钙、钠、钾等离子的改变，及其通过抑制脂质过氧化所表现出来的抗氧化作用,氯胺酮拮抗,N-,甲基,-D-,天冬氨酸受体，交感神经兴奋性降低，使,N-,甲基,-D-,天冬氨酸受体介导的离子内流减少，是神经元坏死减少的原因所在。,丙泊酚与氯胺酮对人体是否具有脑保护作用还缺乏相关的临床证据。然而一些临床研究表明，丙泊酚与氯胺酮不能改善长期的认知能力。甚至还发现丙泊酚麻醉时患者的血清,S100(,神经损伤标志物,),水平还出现短暂升高。,Propofol offers no advantage over isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a preliminary study of S-100beta proteinlevels,J,.Can J Anaesth,，,2004,，,51( 7) : 712-717,利多卡因,利多卡因可通过阻断钠通道，延迟缺血诱导神经元除极的发生从而降低能量消耗，并通过减少细胞的凋亡起到脑保护作用。,一项接受心脏瓣膜手术患者的临床研究显示抗心律失常剂量的利多卡因可以改善患者术后神经精神异常的表现。,另一项临床研究也表明，术中应用利多卡因可减少心脏手术患者早期术后认知功能障碍的发生率。,但是最近一项随机、双盲、对照的临床试验发现，在术中和术后应用利多卡因并不能降低心脏手术后认知功能障碍的发生率。,利多卡因的脑保护作用尚需要大型的前瞻性随机对照临床研究予以确定，且更需进一步研究其最佳治疗剂量和远期的效果。,Randomized, doubleblinded,，,placebo controlled study of neuroprotection with lidocaine in cardiac surgery,J,Stroke,，,2009,，,40( 3) : 880-887,右旋美托咪啶,右旋美托咪啶的脑保护作用还没有得到共识。有学者认为右旋美托咪啶可减少损伤时儿茶酚胺的产生，进而减轻神经组织损伤并改善神经功能预后。,其神经保护机制可能是由于其对促凋亡和抗凋亡蛋白的调节作用以及对兴奋性神经递质谷氨酸释放量的降低作用。,DEX-induced reduction in cerebral blood flow (CBF) is well described, its effect on cerebral metabolic rate is controversial.,Chi randomized rats to receive an infusion of either DEX or a NS during a background isoflurane anesthetic, with or without hemorrhagic hypotension.,In the nonhemorrhagic state during isoflurane anesthesia, DEX caused a,57% in CBF,as measured by the radioactive tracer method without causing a significant decrease in MAP.,Hemorrhage during isoflurane anesthesia caused a,36% in CBF, but hemorrhage in the presence of DEX and isoflurane resulted in an,11% in CBF,also without a significant impact on MAP.,In the cerebral cortex, DEX caused a,57%,in cerebral metabolism,in the nonhemorrhagic state .,Hemorrhage during isoflurane resulted in a,25%, in metabolism, but hemorrhage in the presence of DEX did not significantly affect metabolism (ie,4% ,).,The reduction in CBF and cerebral metabolism induced by DEX in the normotensive group was,matched,(ie, 57% in both groups), in contrast to previous reports that DEX might reduce CBF more than the metabolic rate.,The effects of dexmedetomidine on regional cerebral blood flow and oxygen consumption during severe hemorrhagic hypotension in rats. Anesth Analg. 2011;113:349,355.,3,非麻醉药的脑保护,促红细胞生成素治疗贫血的安全性和有效性早已得到了证实。它还有抑制凋亡和炎症，并诱导血管生长因子及神经营养因子的作用，使得人们推测其有脑保护的功能。,临床研究也表明，大剂量促红细胞生成素可改善急性缺血性脑卒中患者的临床结局。,Mathew,等研究表明，培克珠单抗,(,一种人工合成的抗,C5,补体复合物单克隆抗体,),可减少冠状动脉旁路移植术后患者空间视觉损伤，但并不能减少认知功能障碍的总体发生率。,4,缺血预适应性脑保护,对于高风险患者使用生理或药物等方法预先给予大脑最小限度的短暂性伤害,(,缺血状态,),，来增加其对更严重更持久损伤的耐受力，是一种主动性脑保护概念，也是目前研究较多的脑保护措施之一。,其脑保护的机制可能是激活,ATP,依赖的钾通道和腺苷,A1,受体，从而增强脑组织对缺血的耐受性。,目前有许多方法可以模拟缺血预适应，如低温、高氧、吸入麻醉药及运用钾离子通道开放剂等。,Optimal CPR on Neurologic Outcomes,Many patients resuscitated from cardiac arrest will initially survive but sustain a debilitating or a life-threatening ischemic brain injury.,In recent years, the American Heart Association has focused on enhanced research and education to determine the best methods for providing both optimal cardiac and neurologic outcomes.,Reports of 2 cases by White, published in Mayo Clinic Proceedings in 2011 increased expectations for the upper limits of outcomes.,*Neurologic recovery following prolonged out-of-hospital cardiac arrest with resuscitation guided by continuous capnography. Mayo Clin Proc. 2011;86:544,548.,*Neurologically intact survival following prolonged cardiac arrest monitored with continuous capnography and subsequent treatment with therapeutic hypothermia. Mayo Clin Proc. 2011;86:1124,1125.,In both examples, capnographic measurement of end-expired carbon dioxide was critical in directing patient management.,In both patients, it was assumed that sustained normal carbon dioxide concentrations indicated that blood was being circulated to critical organs and returned to the lungs to expel carbon dioxide.,结束语,神经元细胞损伤或死亡机制的复杂性，以及临床中控制各种生理因素的困难。,大量的实验性研究，得到了令人鼓舞的数据，但是所有药物及措施获得的临床效果却令人失望。,到目前为止，临床仍缺乏有效的脑保护药物和措施。,围术期采用主动性脑保护手段时不能过于主观盲目，而应在更好地,理解,围术期神经元细胞损伤或死亡,机制,的基础上，在,严密,的条件,控制,下，以特定的患者、通过多中心、大样本、前瞻性随机对照的,临床研究证据为指导,，多种切实有效的主动性脑保护方法,联合运用,，以求其更有效、更合理。,