异丙酚输注综合征

输注速率超过5 mg·kg1@h-1的长时间异丙酚输注可能导致异丙酚输注综合征.主要表现为不明原因的心律失常、代谢性酸中毒、高血钾和心肌细胞溶解,最终发展成严重的心力衰竭,甚至导致病人死亡.脑外伤病人和儿童尤其容易出现.发病机制目前还不清楚,也没有确实有效的治疗措施.目前以预防为主.     

丙泊酚对线粒体氧化呼吸链的作用研究进展

丙泊酚是一种临床常用的静脉麻醉药,具有起效快、镇静强、蓄积少的特点。丙泊酚对线粒体氧化呼吸链的功能有双重影响,包括保护作用和损害作用。近年来,丙泊酚所致的线粒体氧化呼吸链障碍在丙泊酚输注综合征的发生发展中起到重要作用,引起人们广泛关注。本文就丙泊酚导致的线粒体氧化呼吸链障碍在丙泊酚输注综合征发病过程中所起的作用进行综述,加强临床医师认识,尽可能避免其发生,从而提高临床麻醉安全。     

不同浓度与不同赋形剂异丙酚对细菌生长影响的比较

异丙酚为脂肪乳制剂,由异丙酚(2,6-双异丙基苯酚)、10%大豆油、1.2%卵磷脂和2.25%甘油组成.研究证明,脂肪乳是细菌良好的培养基,大豆油乳剂可促进细菌生长[1-2].因此,异丙酚一旦被污染,细菌会迅速繁殖生长.重症监护病房使用异丙酚镇静时异丙酚的暴露时间较长,增加了接触和滋生细菌的机会,因此静脉输注异丙酚和围术期感染的关系越来越受到关注.美国疾病控制中心报道了四组怀疑由于输注异丙酚导致的术后感染,病原体包括金黄色葡萄球菌、白色念珠菌和奥斯陆莫拉氏菌[3].Veber等[4]报道了4例手术病人,由于静脉输注异丙酚而导致了严重的脓毒血症.Bennett等[5]通过病因学分析证明了静脉输注异丙酚和手术后感染有关,并且在注射器中正在使用的异丙酚经细菌培养呈阳性,其菌株与感染病人体内分离出的菌株一致.本研究拟探讨不同浓度与不同赋形剂的异丙酚对细菌生长的影响,以分析其与院内感染的关系.     

异丙酚研究的现状

异丙酚应用于临床已有12年,已成为常用的静脉全麻药。本文将最近的研究成就综合归纳为:①异丙酚的靶控输注系统,按异丙酚的药代模式,以该药的血药浓度控制给药量,具有操作简便,易控制的优点;②异丙酚的抗氧化剂作用,无论在活体或在体异丙酚均有保护细胞线粒体抵御过氧化酯侵袭的作用;③异丙酚的抗呕吐 作用;④异丙酚应用于婴幼儿的经验。     

不同剂量右美托咪定对靶控输注异丙酚病人意识消失半数有效血浆靶浓度的影响

目的 评价不同剂量右美托咪定对靶控输注异丙酚病人意识消失半数有效血浆靶浓度(EC5o)的影响.方法 择期全麻病人80例,ASA分级Ⅰ或Ⅱ级,年龄18～64岁,体重指数≤25 kg/m2,采用随机数字表法,将病人随机分为4组(n=20):对照组(C组)和不同剂量右美托咪定组(D1～3组).D1～3组分别静脉输注右美托咪定0.4、0.5和0.6 μg/kg,输注时间10 min,C组输注等容量生理盐水.随后靶控输注异丙酚,采用序贯法进行试验,异丙酚初始血浆靶浓度2.0 μg/ml,相邻浓度比值为1.1.意识消失的标准为睫毛反射消失、两次呼之不应.计算异丙酚使病人意识消失的EC50及其95％可信区间(95％CI).观察心动过缓、低血压和呼吸抑制等不良反应的发生情况.结果 C组和D1～3组异丙酚使病人意识消失的EC50及其95％ CI分别为2.59(2.51 ～ 2.67)、2.09(2.02 ～ 2.16)、1.82(1.70 ～1.95)和1.60 (1.49～ 1.72) μg/ml.C组、D1～3组异丙酚使病人意识消失的EC50依次降低(P＜0.05).与C组比较,D1～3组心动过缓和低血压发生率降低(P＜0.05);与D1组比较,D2,3组心动过缓发生率和D3组低血压发生率升高(P＜0.05);D2组和D3组心动过缓和低血压发生率比较差异无统计学意义(P＞0.05).各组无一例病人发生呼吸抑制.结论 靶控输注异丙酚时复合静脉输注右美托咪定0.4 μg/kg为适宜剂量,既可降低靶控输注异丙酚病人意识消失的EC50,又不发生不良反应.     

异丙酚研究的现状

异丙酚应用于临床已有１２年，已成为常用的静脉全麻药。本文将最近的研究成就综合归纳为：（１）异丙酚的靶控输注系统，按异丙酚的药代模式，以该药的血药浓度控制给药量，具有操作简便，易控制的优点；（２）异丙酚的抗氧化剂作用，无论在活体或在体异丙酚均有保护细胞线粒体抵制过氧化酯侵袭作用。（３）异丙酚的抗呕吐作用；（４）异丙酚应用于婴幼儿的经验。     

靶控输注与静脉输注瑞芬太尼复合异丙酚用于局部麻醉患者镇静镇痛术效应的比较

目的 比较靶控输注与静脉输注瑞芬太尼复合异丙酚用于局部麻醉患者镇静镇痛术的效应.方法 局部麻醉辅助镇静镇痛术下择期整形外科手术的患者60例,年龄18 ～ 55岁,体重指数＜ 30 kg/m2,ASA分级Ⅰ或Ⅱ级,采用随机数字表法,将患者随机分为2组(n=30):静脉输注组(V组)和靶控输注组(T组).T组局部麻醉前靶控输注瑞芬太尼(初始靶浓度1.0 ng/ml)和异丙酚(初始靶浓度1.0 μg/ml),V组瑞芬太尼静脉负荷剂量0.25 μg/kg,维持速率0.05μg-kg-1·min-1,异丙酚负荷剂量0.5 mg/kg,维持速率3mg· kg-1·h-1.术中调整靶浓度或输注速度以维持改良的OAA/S评分2或3分,术中记录低氧血症、呼吸过缓和/或暂停的发生情况,计算异丙酚和瑞芬太尼的总用量.结果 与V组比较,T组术中低氧血症、呼吸过缓和/或暂停的发生率明显降低,异丙酚和瑞芬太尼总用量明显减少(P＜0.05).结论 靶控输注瑞芬太尼复合异丙酚用于局部麻醉患者镇痛镇静术具有良好的安全性目效应优于静脉输注.     

恒速静脉输注异丙酚时脑摄取的研究

目的研究恒速静脉输注异丙酚时脑摄取与输注速率、输注时间的关系.方法14例ASAⅠ～Ⅱ级择期手术患者,随机分为A、B两组,恒速静脉输注异丙酚的速率分别为6、12mg.kg-1@h-1,持续30～35min.于给药后不同时点同步采取桡动脉及颈内静脉球部血样,以高效液相色谱-荧光法检测异丙酚的血药浓度.结果恒速静脉输注异丙酚起始15min,两组桡动脉血药浓度(Ca)随时间逐渐升高,15min后维持恒定不变;A组颈内静脉球部血药浓度(Cijbv)静注异丙酚30min期间随时间升高,但低于相应Ca(P＜0.05),30～35min时维持恒定,并接近于Ca;而B组Cijbv静注异丙酚20min期间随时间升高,但低于相应Ca(P＜0.05),20～30min时维持恒定,并接近于Ca;脑摄取达稳态前各时点累积桡动脉、颈内静脉球部血药浓度-时间曲线下累积面积差(AUCa-v)组间差异显著(P＜0.05).结论恒速静脉输注异丙酚麻醉脑摄取达平衡前,异丙酚摄取量呈速率和时间依赖性.异丙酚脑摄取动态平衡滞后于动脉血药浓度的平衡.人脑对异丙酚基本无代谢或代谢极少.     

新辅助化疗对乳腺癌患者靶控输注异丙酚意识消失时半数有效效应室靶浓度的影响

目的 探讨新辅助化疗对乳腺癌患者靶控输注异丙酚意识消失时半数有效效应室靶浓度(EC50)的影响.方法 择期拟行乳腺癌切除术患者90例,女性,ASAⅠ或Ⅱ级,年龄30～60岁,体重指数<30kg/m2,根据术前是否接受新辅助化疗及其化疗方案分为3组(n=30),未化疗组(Ⅰ组)术前不使用任何化疗药物;紫杉醇化疗组(Ⅱ组)及环磷酰胺+阿霉素+5-氟尿嘧啶联合化疗组(Ⅲ组)均进行4个疗程化疗,并于第4个疗程结束后10～15d时行乳腺癌切除术.麻醉诱导:靶控输注异丙酚,按序贯法确定异丙酚的效应室靶浓度,第1例患者异丙酚效应室靶浓度为2.07μg/ml,各相邻靶浓度之比为1.09.以睫毛反射消失及对言语指令无反应作为判断意识消失的标志.若患者意识消失,则持续靶控输注该浓度异丙酚,并静脉注射芬太尼3μg/kg及罗库溴铵0.6 mg/kg后气管插管;若患者意识未消失,则停止靶控输注,静脉注射异丙酚2mg/kg、芬太尼3μg/kg及罗库溴铵0.6 mg/kg后气管插管.计算靶控输注异丙酚意识消失时的EC50.结果 与Ⅰ组比较,Ⅱ组及Ⅲ组患者靶控输注异丙酚意识消失时的EC50.均降低(P<0.05),Ⅱ组和Ⅲ组间上述指标差异无统计学意义(P>0.05).结论 新辅助化疗可降低乳腺癌患者靶控输注异丙酚意识消失时的EC50.     

异丙酚对脓毒症大鼠肝线粒体呼吸功能的保护作用

目的探讨异丙酚对脓毒症大鼠肝线粒体呼吸功能的保护作用。方法 健康SD大鼠 18只,随机分为3组(n=6):假手术组(C组)、生理盐水组(NS组)、异丙酚组(P组)。NS、P组采用盲 肠结扎穿孔法(CLP)制备脓毒症模型,C组仅做开腹、分离盲肠远端、关腹手术。CLP后12 hP组颈外 静脉输注异丙酚5 mg／kg负荷量,继以10 mg·kg-1·h-1维持,C组、NS组输注生理盐水0.5 ml／h。持续 静脉输注异丙酚4 h时处死大鼠,取肝脏,采用Clark氧电极技术测定线粒体呼吸功能,分光光度法测 定丙二醛(MDA)、超氧化物歧化酶(SOD)、NO2／NO3-(NO)水平,采用定磷法测定ATP酶活性。结果 与C组比较,NS组、P组SOD及ATP的酶活性、呼吸控制率(RCR)、磷／氧比(ADP／O)降低,MDA水平、 态3及态4的呼吸速率升高(P<0．01);与NS组比较,P组SOD及ATP酶的活性、RCR及其ADP／O水 平升高,MDA、NO水平、态3及态4的呼吸速率降低(P<0．01)。结论 异丙酚通过中和自由基,对 脓毒症大鼠肝线粒体呼吸功能产生一定的保护作用。     

Clinically Relevant Concentrations of Propofol Have No Effect on Adenosine Triphosphate-sensitive Potassium Channels in Rat Ventricular Myocytes

Background: Activation of adenosine triphosphate-sensitive potassium (KATP) channels produces cardioprotective effects during ischemia. Because propofol is often used in patients who have coronary artery disease undergoing a wide variety of surgical procedures, it is important to evaluate the direct effects of propofol on KATP channel activities in ventricular myocardium during ischemia.

Methods: The effects of propofol (0.4-60.1 [mu]g/ml) on both sarcolemmal and mitochondrial KATP channel activities were investigated in single, quiescent rat ventricular myocytes. Membrane currents were recorded using cell-attached and inside-out patch clamp configurations. Flavoprotein fluorescence was measured to evaluate mitochondrial oxidation mediated by mitochondrial KATP channels.

Results: In the cell-attached configuration, open probability of KATP channels was reduced by propofol in a concentration-dependent manner (EC50 = 14.2 [mu]g/ml). In the inside-out configurations, propofol inhibited KATP channel activities without changing the single-channel conductance (EC50 = 11.4 [mu]g/ml). Propofol reduced mitochondrial oxidation in a concentration-dependent manner with an EC50 of 14.6 [mu]g/ml.     

Neuroprotective effects of propofol in models of cerebral ischemia: inhibition of mitochondrial swelling as a possible mechanism

BACKGROUND: Propofol (2,6-diisopropylphenol) has been shown to attenuate neuronal injury in a number of experimental conditions, but studies in models of cerebral ischemia have yielded conflicting results. Moreover, the mechanisms involved in its neuroprotective effects are yet unclear. METHODS: The authors evaluated the neuroprotective effects of propofol in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. To investigate its possible mechanism of action, the authors then examined whether propofol could reduce Ca2+-induced rat brain mitochondrial swelling, an index of mitochondrial membrane permeability, as well as the mitochondrial swelling evoked by oxygen-glucose deprivation in CA1 pyramidal cells by transmission electron microscopy. Finally, they evaluated whether propofol could attenuate the infarct size and improve the neurobehavioral outcome in rats subjected to permanent middle cerebral artery occlusion in vivo. RESULTS: When present in the incubation medium during oxygen-glucose deprivation and the subsequent 24 h recovery period, propofol (10-100 microM) attenuated CA1 injury in hippocampal slices in vitro. Ca2+-induced brain mitochondrial swelling was prevented by 30-100 microM propofol, and so were the ultrastructural mitochondrial changes in CA1 pyramidal cells exposed to oxygen-glucose deprivation. Twenty-four hours after permanent middle cerebral artery occlusion, propofol (100 mg/kg, intraperitoneal) reduced the infarct size by approximately 30% when administered immediately after and up to 30 min after the occlusion. Finally, propofol administered within 30 min after middle cerebral artery occlusion was unable to affect the global neurobehavioral score but significantly preserved spontaneous activity in ischemic rats. CONCLUSIONS: These results show that propofol, at clinically relevant concentrations, is neuroprotective in models of cerebral ischemia in vitro and in vivo and that it may act by preventing the increase in neuronal mitochondrial swelling.     

Neuroprotective Effects of Propofol in Models of Cerebral Ischemia: Inhibition of Mitochondrial Swelling as a Possible Mechanism

Background: Propofol (2,6-diisopropylphenol) has been shown to attenuate neuronal injury in a number of experimental conditions, but studies in models of cerebral ischemia have yielded conflicting results. Moreover, the mechanisms involved in its neuroprotective effects are yet unclear.

Methods: The authors evaluated the neuroprotective effects of propofol in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. To investigate its possible mechanism of action, the authors then examined whether propofol could reduce Ca2+-induced rat brain mitochondrial swelling, an index of mitochondrial membrane permeability, as well as the mitochondrial swelling evoked by oxygen-glucose deprivation in CA1 pyramidal cells by transmission electron microscopy. Finally, they evaluated whether propofol could attenuate the infarct size and improve the neurobehavioral outcome in rats subjected to permanent middle cerebral artery occlusion in vivo.

Results: When present in the incubation medium during oxygen-glucose deprivation and the subsequent 24 h recovery period, propofol (10-100 [mu]m) attenuated CA1 injury in hippocampal slices in vitro. Ca2+-induced brain mitochondrial swelling was prevented by 30-100 [mu]m propofol, and so were the ultrastructural mitochondrial changes in CA1 pyramidal cells exposed to oxygen-glucose deprivation. Twenty-four hours after permanent middle cerebral artery occlusion, propofol (100 mg/kg, intraperitoneal) reduced the infarct size by approximately 30% when administered immediately after and up to 30 min after the occlusion. Finally, propofol administered within 30 min after middle cerebral artery occlusion was unable to affect the global neurobehavioral score but significantly preserved spontaneous activity in ischemic rats.     

Clinically relevant concentrations of propofol have no effect on adenosine triphosphate-sensitive potassium channels in rat ventricular myocytes

BACKGROUND: Activation of adenosine triphosphate-sensitive potassium (K(ATP)) channels produces cardioprotective effects during ischemia. Because propofol is often used in patients who have coronary artery disease undergoing a wide variety of surgical procedures, it is important to evaluate the direct effects of propofol on K(ATP) channel activities in ventricular myocardium during ischemia. METHODS: The effects of propofol (0.4-60.1 microg/ml) on both sarcolemmal and mitochondrial K(ATP) channel activities were investigated in single, quiescent rat ventricular myocytes. Membrane currents were recorded using cell-attached and inside-out patch clamp configurations. Flavoprotein fluorescence was measured to evaluate mitochondrial oxidation mediated by mitochondrial K(ATP) channels. RESULTS: In the cell-attached configuration, open probability of K(ATP) channels was reduced by propofol in a concentration-dependent manner (EC(50) = 14.2 microg/ml). In the inside-out configurations, propofol inhibited K(ATP) channel activities without changing the single-channel conductance (EC(50) = 11.4 microg/ml). Propofol reduced mitochondrial oxidation in a concentration-dependent manner with an EC(50) of 14.6 microg/ml. CONCLUSIONS: Propofol had no effect on the sarcolemmal K(ATP) channel activities in patch clamp configurations and the mitochondrial flavoprotein fluorescence induced by diazoxide at clinically relevant concentrations (< 2 microm), whereas it significantly inhibited both K(ATP) channel activities at very high, nonclinical concentrations (> 5.6 microg/ml; 31 microm).     

Propofolinfusionssyndrom

The propofol infusion syndrome is a rare but potentially lethal complication resulting from a prolonged continuous administration of propofol. It was first described in the beginning of the 1990's and in recent years there have been frequent reports of problems in association with the use of propofol sedation. The cardinal signs and symptoms of the propofol infusion syndrome are metabolic acidosis, rhabdomyolysis, renal failure, cardiac arrhythmias and a progressive, often therapy-resistant cardiac failure. The pathophysiology of this syndrome appears to involve a disturbance of mitochondrial metabolism induced by propofol. Our report involves a case of propofol infusion syndrome in a patient having undergone cardiac surgery.     

Role of glycogen synthase kinase 3β in protective effect of propofol against hepatic ischemia–reperfusion injury

Background

It was previously reported that propofol, an intravenously administered hypnotic and anesthetic agent, protects organs from ischemia–reperfusion (I/R) injury. However, the underlying mechanisms are largely unknown. Glycogen synthase kinase 3β (GSK-3β) is known to play an important role in the oxidative stress–induced apoptosis. In this study, we investigated the role of GSK-3β and mitochondrial permeability transition pore (MPTP) in the protective effects of propofol against hepatic I/R injury.

Materials and methods

The left and median hepatic artery and the portal vein branches were blocked by no-damage artery clips to create the model of partial ischemia (70%), and liver lobes were subjected to warm ischemia for 30, 60, 90 min, respectively. Reperfusion of 120 min was then initiated by the removal of clamp. The MPTP opening was assessed by measuring mitochondrial large amplitude swelling and mitochondrial membrane potential.

Results

Pretreatment with propofol in conditions of hepatic I/R inhibits the apoptosis of hepatocytes as evidenced by decreased terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells. Importantly, propofol suppressed the mitochondrial GSK-3β by promoting or preserving its phosphorylation at Ser9, thus restraining the opening of MPTP and preventing the mitochondrial swell and mitochondrial membrane potential collapse.

Conclusions

Propofol protects liver from I/R injury by sustaining the mitochondrial function, which is possibly involved with the modulation of MPTP and GSK-3β.     

The 'propofol infusion syndrome': the facts, their interpretation and implications for patient care

AstraZeneca (the manufacturer of Diprivan) presents its review of the history of the so-called 'propofol infusion syndrome', highlighting the difficulties in analysing the incomplete information available. Theories as to its causality are presented and discussed; these include mitochondrial toxicity, mitochondrial defects, impaired tissue oxygenation and carbohydrate deficiency. A review of published and confidential safety data is presented and discussed; it concludes that the major risk factors for its development appear to be poor oxygen delivery, sepsis, serious cerebral injury and high propofol dosage. In some reports an increasing lipaemia was noted and was likely to be due to a failure of hepatic lipid regulation, possibly related to poor oxygenation and/or possibly a lack of glucose. In some cases an increasing lipaemia was the first indication of impending 'propofol infusion syndrome' onset and it should not be viewed as a benign sign. The lipaemia can lead to sequestration of propofol into the lipid phase, leading to lowered free propofol levels and apparent insensitivity to propofol. In conclusion AstraZeneca advocates good haemodynamic and oxygen delivery management, adequate glucose provision, adherence to recommended propofol dosing regimes together with active management of lipaemias to both prevent and treat 'propofol infusion syndrome'.     

Short-term low-dose propofol anaesthesia associated with severe metabolic acidosis

Propofol-induced metabolic acidosis is well recognised in the paediatric literature, but the existence of such a syndrome in adults remains contentious. In most reported cases, metabolic acidosis complicated prolonged administration of propofol in critically ill patients. We present a case of severe non-fatal reversible metabolic acidosis, without ventilatory depression or hypoxia, related to short-term propofol infusion in an adult during and after coronary artery bypass grafting. We suggest that lactic acidosis occurred in a genetically susceptible patient with an abnormality of mitochondrial function. This report discusses an unusual adverse effect of propofol anaesthesia and sedation and highlights the need for further investigation to define propofol toxicity.     

Anesthetic Effects on Mitochondrial ATP-sensitive K Channel

Background : Volatile anesthetics show an ischemic preconditioning-like cardioprotective effect, whereas intravenous anesthetics have cardioprotective effects for ischemic-reperfusion injury. Although recent evidence suggests that mitochondrial adenosine triphosphate-regulated potassium (mitoKATP) channels are important in cardiac preconditioning, the effect of anesthetics on mitoKATP is unexplored. Therefore, the authors tested the hypothesis that anesthetics act on the mitoKATP channel and mitochondrial flavoprotein oxidation.

Methods : Myocardial cells were isolated from adult guinea pigs. Endogenous mitochondrial flavoprotein fluorescence, an indicator of mitochondrial flavoprotein oxidation, was monitored with fluorescence microscopy while myocytes were exposed individually for 15 min to isoflurane, sevoflurane, propofol, and pentobarbital. The authors further investigated the effect of 5-hydroxydeanoate, a specific mitoKATP channel antagonist, on isoflurane- and sevoflurane-induced flavoprotein oxidation. Additionally, the effects of propofol and pentobarbital on isoflurane-induced flavoprotein oxidation were measured.

Results : Isoflurane and sevoflurane induced dose-dependent increases in flavoprotein oxidation (isoflurane: R2 = 0.71, n = 50; sevoflurane: R2 = 0.86, n = 20). The fluorescence increase produced by both isoflurane and sevoflurane was eliminated by 5-hydroxydeanoate. Although propofol and pentobarbital showed no significant effects on flavoprotein oxidation, they both dose-dependently inhibited isoflurane-induced flavoprotein oxidation.