Anesthetic protection against hepatic injury

In this review article, hepatocyte injury by volatile anesthetics, effects of anesthetics on hepatic perfusion, protection offered by either ischemic preconditioning or anesthetic preconditioning against hepatic ischemia-reperfusion injury and effects of anesthetics on sepsis-induced hepatic injury are discussed. Halothane poses significant risk of immunologically-mediated hepatocyte injury and disturbances of hepatic blood supply. Other modern volatile anesthetics such as isoflurane, sevoflurane and desflurane seem to have only minor risks. Several animal studies demonstrate that volatile anesthetics offer more protection against ischemia-reperfusion injury than intravenous anesthetics. On the contrary, intravenous anesthetics may be more protective against sepsis-induced hepatic injury than volatile anesthetics.     

Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures

BACKGROUND: Volatile anesthetics are known to ameliorate experimental ischemic brain injury. A possible mechanism is inhibition of excitotoxic cascades induced by excessive glutamatergic stimulation. This study examined interactions between volatile anesthetics and excitotoxic stress. METHODS: Primary cortical neuronal-glial cultures were exposed to N-methyl-D-aspartate (NMDA) or glutamate and isoflurane (0.1-3.3 mM), sevoflurane (0.1-2.9 mM), halothane (0.1-2.9 mM), or 10 microM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801). Lactate dehydrogenase release was measured 24 h later. In other cultures, effects of volatile anesthetics on Ca++ uptake and mitochondrial membrane potential were determined in the presence or absence of NMDA (0-200 microM). RESULTS: Volatile anesthetics reduced excitotoxin induced lactate dehydrogenase release by up to 52% in a dose-dependent manner. At higher concentrations, this protection was reversed. When corrected for olive oil solubility, the three anesthetics offered equivalent protection. MK-801 provided near-complete protection. Ca++ uptake was proportionally reduced with increasing concentrations of anesthetic but did not account for reversal of protection at higher anesthetic concentrations. Given equivalent NMDA-induced Ca++ loads, cells treated with volatile anesthetic had greater lactate dehydrogenase release than those left untreated. At protective concentrations, volatile anesthetics partially inhibited NMDA-induced mitochondrial membrane depolarization. At higher concentrations, volatile anesthetics alone were sufficient to induce mitochondrial depolarization. CONCLUSIONS: Volatile anesthetics offer similar protection against excitotoxicity, but this protection is substantially less than that provided by selective NMDA receptor antagonism. Peak effects of NMDA receptor antagonism were observed at volatile anesthetic concentrations substantially greater than those used clinically.     

Anesthetics and brain protection

PURPOSE OF REVIEW: There is a considerable risk of cerebral ischemia during anesthesia and surgery. Anesthetic agents have been shown to have a profound effect on the pathophysiology of cerebral ischemia. The present review provides a brief historical review and details new information about the anesthetic effects on the ischemic brain. RECENT FINDINGS: Although anesthetics have been shown to reduce ischemic cerebral injury, the durability of this neuroprotection has been questioned. Recent data indicate that, under the right circumstances, anesthetic neuroprotection can be sustained for at least 2-4 weeks; the durability of this protection is dependent upon the experimental model, control of physiologic parameters and the assurance of the adequacy of reperfusion. In addition, volatile anesthetics have been shown to accelerate postischemic neurogenesis; this suggests that anesthetics may enhance the endogenous reparative processes in the injured brain. SUMMARY: The available data indicate that anesthetics can provide long-term durable protection against ischemic injury that is mild to moderate in severity. Experimental data do not provide support for the premise that anesthetics reduce injury when the ischemic injury is severe.     

糖尿病与吸入性麻醉药心肌保护作用研究新进展

目前研究表明,对于心肌缺血/再灌注(isehemic/reperfusion,I/R)损伤,适当的刺激可以激活机体的内源性保护机制,即缺血预处理(ischemic preconditioning,IPC)和缺血后处理(ischemic postconditioning,I-post),最终达到心肌保护效果.同时现有的研究发现,吸人性麻醉药同样可以诱导产生内源性的心肌保护作用,其作用机制及临床应用前景成为目前广泛关注的焦点,现就以七氟醚为代表的吸入性麻醉药的心肌保护作用及糖尿病与吸人性麻醉药心肌保护作用的关系作一简要综述.     

Myocardial protection by anesthetic agents against ischemia-reperfusion injury: An update for anesthesiologists

PURPOSE: The aim of this review of the literature was to evaluate the effectiveness of anesthetics in protecting the heart against myocardial ischemia-reperfusion injury. SOURCE: Articles were obtained from the Medline database (1980-, search terms included heart, myocardium, coronary, ischemia, reperfusion injury, infarction, stunning, halothane, enflurane, desflurane, isoflurane, sevoflurane, opioid, morphine, fentanyl, alfentanil sufentanil, pentazocine, buprenorphine, barbiturate, thiopental, ketamine, propofol, preconditioning, neutrophil adhesion, free radical, antioxidant and calcium). PRINCIPAL FINDINGS: Protection by volatile anesthetics, morphine and propofol is relatively well investigated. It is generally agreed that these agents reduce the myocardial damage caused by ischemia and reperfusion. Other anesthetics which are often used in clinical practice, such as fentanyl, ketamine, barbiturates and benzodiazepines have been much less studied, and their potential as cardioprotectors is currently unknown. There are some proposed mechanisms for protection by anesthetic agents: ischemic preconditioning-like effect, interference in the neutrophil/platelet-endothelium interaction, blockade of Ca2+ overload to the cytosolic space and antioxidant-like effect. Different anesthetics appear to have different mechanisms by which protection is exerted. Clinical applicability of anesthetic agent-induced protection has yet to be explored. CONCLUSION: There is increasing evidence of anesthetic agent-induced protection. At present, isoflurane, sevoflurane and morphine appear to be most promising as preconditioning-inducing agents. After the onset of ischemia, propofol could be selected to reduce ischemia-reperfusion injury. Future clinical application depends on the full elucidation of the underlying mechanisms and on clinical outcome trials.     

Effects of Volatile Anesthetics on N-methyl-d-aspartate Excitotoxicity in Primary Rat Neuronal-Glial Cultures

Background: Volatile anesthetics are known to ameliorate experimental ischemic brain injury. A possible mechanism is inhibition of excitotoxic cascades induced by excessive glutamatergic stimulation. This study examined interactions between volatile anesthetics and excitotoxic stress.

Methods: Primary cortical neuronal-glial cultures were exposed to N-methyl-d-aspartate (NMDA) or glutamate and isoflurane (0.1-3.3 mm), sevoflurane (0.1-2.9 mm), halothane (0.1-2.9 mm), or 10 [mu]m (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801). Lactate dehydrogenase release was measured 24 h later. In other cultures, effects of volatile anesthetics on Ca++ uptake and mitochondrial membrane potential were determined in the presence or absence of NMDA (0-200 [mu]m).

Results: Volatile anesthetics reduced excitotoxin induced lactate dehydrogenase release by up to 52% in a dose-dependent manner. At higher concentrations, this protection was reversed. When corrected for olive oil solubility, the three anesthetics offered equivalent protection. MK-801 provided near-complete protection. Ca++ uptake was proportionally reduced with increasing concentrations of anesthetic but did not account for reversal of protection at higher anesthetic concentrations. Given equivalent NMDA-induced Ca++ loads, cells treated with volatile anesthetic had greater lactate dehydrogenase release than those left untreated. At protective concentrations, volatile anesthetics partially inhibited NMDA-induced mitochondrial membrane depolarization. At higher concentrations, volatile anesthetics alone were sufficient to induce mitochondrial depolarization.     

Local anesthetic-induced protection against lipopolysaccharide-induced injury in endothelial cells: the role of mitochondrial adenosine triphosphate-sensitive potassium channels

Lidocaine attenuates cell injury induced by ischemic-reperfusion and inflammation, although the protective mechanisms are not understood. We hypothesized that lidocaine and other amide local anesthetics protect against endothelial cell injury through activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channels. We determined the effects of amide local anesthetics (lidocaine, ropivacaine, and bupivacaine), ester local anesthetics (tetracaine and procaine), one amide analog (YWI), and two non-amide local anesthetic analogs (JDA and ICM) on viability of human microvascular endothelial cells after exposure to lipopolysaccharide (LPS) in the absence or presence of the mitoK(ATP) channel antagonist 5-hydroxydecaonate. Flavoprotein fluorescence was used to investigate the effects of local anesthetics on diazoxide-induced activation of mitoK(ATP) channels. Lidocaine, ropivacaine, bupivicaine, YWI, JDA, and ICM attenuated by 60% to 70% the decrease in cell viability caused by LPS. Amide local anesthetics and YWI protection was inhibited by 5-hydroxydecaonate, whereas the protection induced by JDA and ICM was not. Tetracaine and procaine did not protect against LPS-induced injury. The amide local anesthetics and the amide analog (YWI) enhanced diazoxide-induced flavoprotein fluorescence by 5% to 20%, whereas ester local anesthetics decreased diazoxide-induced flavoprotein fluorescence by 5% to 60% and the non-amide local anesthetic analogs had no effect. In conclusion, amide local anesthetics and the amide analog (YWI) attenuate LPS-induced cell injury, in part, through activation of mitoK(ATP) channels. In contrast, tetracaine and procaine had no protective effects and inhibited activation of mitoK(ATP) channels. The non-amide local anesthetic analogs induced protection but through mechanisms independent of mitoK(ATP) channels.     

Organ protective effects of volatile anesthetics and perioperative outcomes

Anesthetic agents, especially, volatile anesthetics are considered to exert organ toxicity such as nephrotoxicity and hepatotoxicity; however, recent aggressive researches explored the beneficial effects of volatile anesthetics as an organ protectant. Ischemic preconditioning is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the myocardium and brain against prolonged ischemic insult. General anesthesia showed the protection against both ischemic myocardial and brain reperfusion injuries. This phenomenon is called anesthetic preconditioning. Regarding the organ protection, anesthetic preconditioning is one of the useful ways to diverse the organ protective effects not only to heart but also brain. Nowadays, ischemic postconditioning, consisting of repeated brief cycles of ischemia-reperfusion performed immediately after reperfusion following a prolonged ischemic insult, dramatically reduces infarct size in experimental models and such clinical studies are reported. Both preconditioning and postconditioning share the same signal transduction pathway and inhibit the mitochondrial permeability transition (MPT) that leads to either apoptosis or necrosis of myocardium and neuronal cell. Both phenomena look very promising, but we still lack the real evidence for human reserach in terms of the clinical outcome and further analysis is necessary. Neurotoxicities of anesthetic agents are very crucial problems for the patient and they are considered to be due to the activation of IP3 receptor in ER after exposure to volatile anesthetics. Massive release of Ca2+ from ER induces Ca2+ overload leading to mitochondria permeability transition (MPT) and induces apoptosis in the brain or aggravates the neurodegenerative disease. Susceptible mechanisms and beneficial treatment for the toxicity of general anesthesia is considered as a critical subject to discuss and challenge to solve for our future.     

Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in vivo

BACKGROUND: Volatile anesthetics protect against cardiac ischemia-reperfusion injury via adenosine triphosphate-dependent potassium channel activation. The authors questioned whether volatile anesthetics can also protect against renal ischemia-reperfusion injury and, if so, whether cellular adenosine triphosphate-dependent potassium channels, antiinflammatory effects of volatile anesthetics, or both are involved. METHODS: Rats were anesthetized with equipotent doses of volatile anesthetics (desflurane, halothane, isoflurane, or sevoflurane) or injectable anesthetics (pentobarbital or ketamine) and subjected to 45 min of renal ischemia and 3 h of reperfusion during anesthesia. RESULTS: Rats treated with volatile anesthetics had lower plasma creatinine and reduced renal necrosis 24-72 h after injury compared with rats anesthetized with pentobarbital or ketamine. Twenty-four hours after injury, sevoflurane-, isoflurane-, or halothane-treated rats had creatinine (+/- SD) of 2.3 +/- 0.7 mg/dl (n = 12), 1.8 +/- 0.5 mg/dl (n = 6), and 2.4 +/- 1.2 mg/dl (n = 6), respectively, compared with rats treated with pentobarbital (5.8 +/- 1.2 mg/dl, n = 9) or ketamine (4.6 +/- 1.2 mg/dl, n = 8). Among the volatile anesthetics, desflurane demonstrated the least reduction in plasma creatinine after 24 h (4.1 +/- 0.8 mg/dl, n = 12). Renal cortices from volatile anesthetic-treated rats demonstrated reduced expression of intercellular adhesion molecule 1 protein and messenger RNA as well as messenger RNAs encoding proinflammatory cytokines and chemokines. Volatile anesthetic treatment reduced renal cortex myeloperoxidase activity and reduced nuclear translocation of proinflammatory nuclear factor kappaB. Adenosine triphosphate-dependent potassium channels are not involved in sevoflurane-mediated renal protection because glibenclamide did not block renal protection (creatinine: 2.4 +/- 0.4 mg/dl, n = 3). CONCLUSION: Some volatile anesthetics confer profound protection against renal ischemia-reperfusion injury compared with pentobarbital or ketamine anesthesia by attenuating inflammation. These findings may have significant clinical implications for anesthesiologists regarding the choice of volatile anesthetic agents in patients subjected to perioperative renal ischemia.     

吸入麻醉药对冠脉搭桥术心肌保护作用的Meta分析

目的 评价吸入麻醉药对冠状动脉搭桥术(CABG)心肌缺血-再灌注损伤的保护作用.方法 检索Medline和中国期刊全文数据库,收集各研究中的心脏指数、使用正性肌力药的例数和术后24 h内心肌肌钙蛋白I(cTnI)的最高数值.计数资料采用优势比(OR)和95%可信区间(CI)表示.计量资料用加权平均差(WMD)和95%可信区间表示,统计分析用Revman 4.2.10软件完成.结果 符合标准的文献共23篇,1398例患者.分析显示,吸入麻醉约都能使CABG患者术后的心脏指数增加[WMD=0.41;95%CI(0.17,0.64)],使cTnI明显降低[WMD=-1.61;95%CI(-2.25,-0.96)],需用正性肌力药的患者数减少[OR=0.45;95%CI(0.35,0.58)].结论 七氟醚等吸入麻醉药用于CABG具有明显的心肌保护作用.     

Polyhalogenated methyl ethyl ethers: solubilities and anesthetic properties.

The several potent inhaled anesthetics released for clinical use in the past four decades have been halogenated ethers, and, with one exception, methyl ethyl ethers. In the present report, we detail some structural and physical properties associated with anesthetic potency in 27 polyhalogenated methyl ethyl ethers. We obtained new data for 22 compounds. We used response/nonresponse of rats to electrical stimulation of the tail as the anesthetic end point (i.e., we measured the minimum alveolar anesthetic concentration [MAC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers, which gave products of MAC x oil/gas partition coefficient ranging from 1.27 to 18.8 atm, compared with a product of 1.82+/-0.56 atm for conventional inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide anesthesia, 2 of 22 ethers (CCIF2OCCIFCF3 and CCIF2OCF2CClF2) had no anesthetic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administered alone. As with other inhaled anesthetics, anesthetic potency seemed to correlate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled anesthetics act. IMPLICATIONS: The several potent, inhaled, polyhalogenated methyl ethyl ether anesthetics released for clinical use in the past four decades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have implications for the future development of anesthetics and the mechanisms by which they act.     

A specific alteration in the electroretinogram of Drosophila melanogaster is induced by halothane and other volatile general anesthetics

In higher organisms, physiological investigations have provided a valuable complement to assays of anesthetic effects on whole-animal behavior. However, although complex motor programs of Drosophila melanogaster have been used to identify genes that influence anesthesia, electrophysiological studies of anesthetic effects in this invertebrate have been limited. Here we show that the electroretinogram (ERG), the extracellular recording of light-evoked mass potentials from the surface of the eye, reveals a distinct effect of halothane, enflurane, isoflurane, and desflurane. Behaviorally relevant concentrations of these volatile anesthetics severely reduced the transient component of the ERG at lights-off. Other prominent ERG components, such as the photoreceptor potential and the lights-on transient, were not consistently affected by these drugs. Surprisingly, for most anesthetics, a diminished off-transient was obtained only with short light pulses. An identical effect was observed in the absence of anesthetic by depressing the function of Shaker potassium channels. The possibility that halothane acts in the visual circuit by closing potassium channels was examined with a simple genetic test; the results were consistent with the hypothesis but fell short of providing definitive support. Nevertheless, our studies establish the ERG as a useful tool both for examining the influence of volatile anesthetics on a simple circuit and for identifying genes that contribute to anesthetic sensitivity. IMPLICATIONS: Electroretinography (ERG) provides a useful monitor of anesthetic effects on the fruit fly. The effects of volatile anesthetics on the ERG are recapitulated by inactivation of potassium channels.     

Brain protection by anesthetics

Many investigators have attempted to protect the brain against ischemia by reducing the cerebral metabolic rate using anesthetic agents. However, the magnitude of suppression of the cerebral metabolic rate does not correlate with neuroprotective effects of anesthetics, suggesting that other factors besides reduction in the cerebral metabolic rate contribute to the protection. Facilitation of protein synthesis, GABAergic activity, and anti-oxidant action are likely factors responsible for beneficial effects of barbiturates and propofol. Although the brain is protected during anesthesia, anesthetics cannot provide effects sufficiently enough to recover damage caused by severe ischemia. Further, no desired outcome has been reported by treatments after ischemic events.     

Special article: general anesthetic gases and the global environment

General anesthetics are administered to approximately 50 million patients each year in the United States. Anesthetic vapors and gases are also widely used in dentists' offices, veterinary clinics, and laboratories for animal research. All the volatile anesthetics that are currently used are halogenated compounds destructive to the ozone layer. These halogenated anesthetics could have potential significant impact on global warming. The widely used anesthetic gas nitrous oxide is a known greenhouse gas as well as an important ozone-depleting gas. These anesthetic gases and vapors are primarily eliminated through exhalation without being metabolized in the body, and most anesthesia systems transfer these gases as waste directly and unchanged into the atmosphere. Little consideration has been given to the ecotoxicological properties of gaseous general anesthetics. Our estimation using the most recent consumption data indicates that the anesthetic use of nitrous oxide contributes 3.0% of the total emissions in the United States. Studies suggest that the influence of halogenated anesthetics on global warming will be of increasing relative importance given the decreasing level of chlorofluorocarbons globally. Despite these nonnegligible pollutant effects of the anesthetics, no data on the production or emission of these gases and vapors are publicly available. The primary goal of this article is to critically review the current data on the potential effects of general anesthetics on the global environment and to describe possible alternatives and new technologies that may prevent these gases from being discharged into the atmosphere.     

全身麻醉药在脊髓内的作用机制

脊髓是全身麻醉药抑制伤害性刺激体动反应和抗伤害效应的重要作用部位,含有不同配体门控离子受体等多个可能介导麻醉效应的靶点.不同药物在脊髓内经各自特异靶点通过多种分子机制发挥作用.现就全身麻醉药制动和镇痛效应在脊髓内的作用位点和分子机制作一综述.     

Interactions between general and regional anesthesia

Neuraxial blockade is commonly used to abolish sensations elicited by noxious stimuli during surgical procedures. Proven advantages of combined anesthesia include early recovery from general anesthesia and postoperative analgesia, together with likely decreases in blood loss, cardiac dysrhythmias, or ischemic events and postoperative deep vein thrombosis. The side effects of the technique are related to the dose or site of local anesthetic administration and to light general anesthesia, which can result in awareness during surgery. Varying degrees of synergistic interactions have been reported among the drugs used to achieve the anesthetic state. Spinal anaesthesia appears to have sedative effects, and local anesthetics used for neuraxial blockade have been found to reduce the induction and maintenance dosage of midazolam, thiopental, propofol and inhaled anesthetics. The growing interest in combining local and general anesthesia has led to studies investigating possible interactions between general anesthesia and local anesthetics administered via spinal or epidural routes. Neuraxial blockade reduces sedative and anesthetic requirements by decreasing ascending sensory input into the brain. This has important clinical implications, as anesthetists should expect to reduce anesthetic and sedative drug doses during neuraxial blockade, unless the blockade involves lower dermatomes alone. Clinical practice of anesthesia is a polypharmacy, wherein the anesthetic state is the net result of the action of different drugs and their interaction in the presence of a surgical stimulus.     

Reactive oxygen species as mediators of cardiac injury and protection: the relevance to anesthesia practice

Reactive oxygen species (ROS) are central to cardiac ischemic and reperfusion injury. They contribute to myocardial stunning, infarction and apoptosis, and possibly to the genesis of arrhythmias. Multiple laboratory studies and clinical trials have evaluated the use of scavengers of ROS to protect the heart from the effects of ischemia and reperfusion. Generally, studies in animal models have shown such effects. Clinical trials have also shown protective effects of scavengers, but whether this protection confers meaningful clinical benefits is uncertain. Several IV anesthetic drugs act as ROS scavengers. In contrast, volatile anesthetics have recently been demonstrated to generate ROS in the heart, most likely because of inhibitory effects on cardiac mitochondria. ROS are involved in the signaling cascade for cardioprotection induced by brief exposure to a volatile anesthetic (termed "anesthetic preconditioning"). ROS, therefore, although injurious in large quantities, can have a paradoxical protective effect within the heart. In this review we provide background information on ROS formation and elimination relevant to anesthetic and adjuvant drugs with particular reference to the heart. The sources of ROS, the means by which they induce cardiac injury or activate protective signaling pathways, the results of clinical studies evaluating ROS scavengers, and the effects of anesthetic drugs on ROS are each discussed.     

Let's study pharmacokinetics related to anesthesiology by using computer graphics: inhalation anesthetics

The pharmacokinetics of inhalation anesthetics has been out of public interest for 20 years. Partition coefficient or solubility of anesthetic, an important determinant of uptake and distribution of inhaled anesthetics, may be the only remains of the pharmacokinetics of inhaled anesthetics. There still, however, are a few evidences which can not be explained by partition coefficient of anesthetic. The authors applied three compartment model to the rise of the blood concentration of anesthetics, i.e., nitrous oxide, enflurane, halothane, and diethyl ether. We revealed that the change in the blood anesthetic concentration may be related to the size of compartments and their time constants. The size of compartments and their time constants may be determined by interaction of partition coefficient of anesthetic and blood distribution to the tissues which may be different with different anesthetic, and may also be different when the blood concentration of anesthetic is different.     

Anesthesia and epilepsy

The patient with epilepsy is an anesthetic challenge. New drugs and surgical procedures are being used to treat epilepsy. Certain anesthetics have been reported to cause perioperative seizures. This discussion will focus on advances in the treatment of epilepsy, as well as the pro- and anti-convulsant effects of the newer anesthetic agents.     

局麻药骨骼肌毒性作用的研究与临床意义

最新研究证实,局麻药(locae anesthetic,LA)可导致骨骼肌损伤,甚至引起肌肉坏死,临床上使用的LA均存在骨骼肌毒性,因此将其对骨骼肌的损害视为局麻药的潜在并发症,但在临床上相关病例却很少见.现将近来国外对LA骨骼肌毒性的研究进展综述如下.