挥发性麻醉剂 z-bo 2020-09-22 610

　　Background: Volatile anesthetic gas is used to induce and maintain general anesthesia, which has the advantages of rapid guidance and rapid recovery. It has an acceptable effect on the peripheral organs of most patients. In 1275, the Spanish doctor Raymond Dorras created a volatile liquid, which he called "sweet ether sulfate." It was later used as an anesthetic. A few years later, the American doctor Crawford W. Long performed his first operations in 1847 and 1847. Although ether played a role, he still used ether as an anesthetic. . The patient underwent neck tumor resection and no pain was reported. On October 16, 1846, William T.G. Morton (William T.G. Morton) was the first to successfully release ether anesthetics at the surgical site of Massachusetts General Hospital. In slowing down the progression of stroke and brain injury, VA has advantages in many medical conditions, such as stroke patients, by reducing the number of cerebral ischemic injuries and providing a wide range of medical benefits for stroke patients. Alternatively, other volatile anesthetic gases (such as isoflurane, desflurane, and sevoflurane) can reduce plasma creatinine and reduce renal necrosis, as a kidney protectant to prevent ischemia and reperfusion injury, and can reduce the duration of surgery and postoperative Myocardial ischemia. It has been proven to protect the heart through prevention. However, myocardial depression and vasodilation are related to VA. The use of serotonin can cause intraoperative hypotension symptoms during surgery and disrupt the balance between myocardial supply and demand and myocardial ischemia. May cause. Therefore, many clinicians use VA, and they choose to use VA to limit or avoid coronary artery bypass surgery (CABG) patients. For example, at the Italian Heart Surgery Center, 40% of heart disease patients use VA, while coronary artery bypass graft (CABG) only uses 25% of VA. Similarly, in an analysis investigating the effects of VA, patients received almost half of complete intravenous anesthesia during cardiac surgery. In addition, in the process of using VA, if the patient shows severe cardiac ischemia and cardiovascular instability before heart surgery, the use of VA will be more effective. The consequences are serious. In addition, the rapid introduction of inhaled anesthetics can prolong the QT interval and cause the risk of ventricular fibrillation during acute myocardial ischemia. Patients need to pay more attention.

　　This review focuses on recent laboratory and clinical data collection. Because inhaled anesthetics have a protective effect on the myocardium, isoflurane, desflurane and sevoflurane have important protective effects. It also discusses the potential risks associated with the heart of inhaled anesthetics.

　　 Literature search strategy: The literature in this review focuses on volatile anesthetics-Soflulan, Desflulan, Sevoflulan. For each volatile anesthetic, use the following search criteria: volatile anesthetics and cardiovascular protection, or cardiac ischemia, or cardiac injury or cardiotoxicity, or blood pretreatment for heart failure, or cytotoxicity, or myocardial deficiency. Blood, hypoxia or cardiomyocytes, heart hemorrhage or cardiac tolerance or cardiac post-processing, cardiac preconditioning or cardiomyocyte apoptosis or arrhythmia. Articles are not included. The existing literature describes key areas of cardioprotection research and clinical medicine.

　　 Ischemic preconditioning: In ischemic injury, when the blood interrupts the fluid supply to a specific area of the tissue, the demand for oxygen may exceed the oxygen supply. In the case of ischemia, the heart muscle continues to perform its glycogen storage function. However, if hypoxia lasts for more than 15 minutes, necrosis of myocardial tissue will occur, causing irreversible damage. Pretreatment is a process that causes certain damage to organs and tissues, but this damage protects the tissues in the process of greater damage. By inducing short-term ischemia, "cardiomyocytes can reduce the number of contractions through the cardiomyocytes in a few seconds, and stop contracting in a few minutes", thereby saving energy and protecting myocardial tissue. Reduce the amount of tissue necrosis. Cardiac ischemia is caused by damage to the heart that directly affects other parts of the body, leading to interruption of blood supply to all organ systems, which may lead to brain damage, kidney failure, pulmonary edema, etc. Pretreatment can lead to fatal consequences. Clinical studies have shown that ischemic preconditioning can reduce the area of myocardial infarction after myocardial ischemia. This concept was first proposed in 1986. Murray et al. showed that in the control group of the ischemic preconditioning group undergoing coronary artery occlusion, the myocardial infarct area of canine ischemic preconditioning decreased from 29% to 7%. The dog experienced a brief coronary artery occlusion (4-5 minutes), followed by a 40-minute artery occlusion caused by an ischemic event. Murry et al. observed a 22% reduction in infarct size. Promote the protective mechanism of ischemic preconditioning. The ischemic preconditioning associated with several intracellular signaling pathways has also been studied. The main target of all these pathways is the potassium channel (KATP) that is sensitive to adenosine triphosphate (ATP)? +? It seems to be. KATP channels exist in the mitochondria, cell membranes and nuclear membranes of cardiomyocytes, not only in the brain, but also in the β cells of the pancreas, bones, smooth muscles and nerves. The open mitochondrial KATP channel leads to the production of reactive oxygen species (ROS), which activate downstream protein kinases to protect the myocardium. Early increases in OS have been shown to activate cytokine channels, such as protein kinase C (PKC) and tyrosine kinase (TK) channels. This leads to the opening of mitochondrial KATP channels, which leads to a decrease in ROS. Therefore, the initial increase in reactive oxygen species caused by ischemic stimuli leads to the opening of the channel, thereby reducing ROS. In addition, the activation and expression of KATP channels can shorten the time of active potential and save energy, which is a protective effect on heart tissue.

　　Reperfusion injury: When the blood flow in the ischemic area remains unblocked, ischemic injury can cause reperfusion injury. The reperfusion process destroys the cell membrane and causes severe calcium accumulation, which leads to the opening of the mitochondrial permeability transition pore (mPTP). It destroys mitochondrial membranes, cleaves oxidative phosphorylation, and may cause ATP consumption and cell death. Due to hypoxia, ischemia results in the conversion of xanthine dehydrogenase in myocardial cell metabolism to xanthine oxidase. Xanthine oxidase produces accumulation of hypoxanthine. During reperfusion, hypoxanthine xanthine oxidase is metabolized, resulting in overproduction of ROS. This phenomenon can cause the damaged tissue to produce superoxide free radicals, which will further damage the tissue and cause irreversible contractile dysfunction.

　　 Volatile anesthetic pretreatment: Anesthetics activate some of the same channels, leading to the protective mechanism of ischemic preconditioning. Zauggetal. It has been shown that exposure to volatile anesthetics (isoflurane or sevoflurane) in a dose-dependent manner (similar to ischemic preconditioning) is more beneficial than myocardial ischemia. done. By using KATP blocker 5-HD (peripheral KATP blocker HMR-1098) and (cell membrane KATP blocker) and KATP channel activator diazoxide, it is proved that isoflurane and sevoflurane are the main mitochondria. This channel does not affect the myocardial membrane KATP channel. Zaugg et al. explained that sevoflurane and isoflurane cause the activation of mitochondrial KATP channels, similar to activation in ischemic preconditioning. The same research team found that compared with placebo pretreatment, the use of sevoflurane coronary artery bypass graft significantly improved results and reduced the incidence of progressive cardiac ischemia and congestive heart failure. However, it is not clear whether the preconditioning effect of volatile anesthetics will increase the effect of obstructive cerebral ischemic preconditioning. Warrtier et al. Studies have shown that when VA is performed before coronary artery occlusion, VA has better myocardial recovery function 15 minutes after coronary artery occlusion. In this experiment, the dogs were anesthetized with herotan or isoflurane, and after 5 hours of reperfusion, myocardial function returned to baseline. The myocardial function of dogs without anesthesia preconditioning was reduced by 50%. Further studies have shown similar ischemic myocardial protection, as well as the use of sevoflurane, desflurane and enflurane-type myocardial dysfunction. Studies on rabbit myocardium have shown that desflurane is the most effective volatile anesthetic for myocardial injury pretreatment, but sevoflurane does not have the same significant effect. The pretreatment of haloalkanes and isoflurane caused the same myocardial protection. However, sevoflurane pretreatment can also provide protection for other types of myocardium.

　　 Other mechanisms seem to be related to ischemic preconditioning. These mechanisms include Akt, ERK and ROS signaling pathways. The channels involved have been determined: MPTP, myocardial KATP channel and mitochondrial KATP channel. Mechanical pathway: Several major signaling mechanisms have been identified as mediators. Including KATP channel activation preconditioning protection mediators and cytokine regulators, MPTP regulation pathway (Akt/PI3K). In ischemic preconditioning, KATP has been established as a myocardial protective medium, and volatile anesthetics are being pretreated. It has been confirmed that the opening of mitochondrial KATP channels leads to the production of ROS. In a study using rat bone tracts, norepinephrine showed that the cardioprotective effect of sevoflurane was mediated by PKC activation, which opened the mitochondrial KATP channel. We reperfused the rat cancellous cerebral ischemia for 60 minutes, and used the restoration of active power as an indicator of cardiac function after myocardial infarction (MI). Sevoflurane increased the median recovery rate to 67%, compared to 28% in the control group. However, when the KATP channel inhibitor (5-HD) is used in combination with sevoflurane, the main power recovery rate is only 31%, and when the active oxygen trap is used in combination with sevoflurane, the main power recovery rate is only 33 %. This data shows that both KATP channels and ROS are involved in the myocardial protective mechanism of sevoflurane. According to a report by Marinovicetal, the KATP channel of the myocardial cell membrane is a preconditioning effector, while the KATP channel of the mitochondria is a sensor and effector. It is based on the management of mitochondria and cell membrane KATP channel inhibitors in the isofulamp repair group of rat cardiomyocytes. 5-HD administration in the sevoflurane repair group can reduce myocardial protection, but it reaches the same phenomenon that was not observed in the HMR-1098 group. However, if HMR-1098 is used instead of pre-treatment during the experiment, it has no protective effect.

　　Point out that KATP channel is also associated with MPTP. This study showed that ischemic preconditioning and VA preconditioning delayed the opening of MPTP channels. Delaying the activation of the MPTP channel can protect the expansion of the mitochondrial matrix caused by the activation of the mPTP channel. This destroys the mitochondrial membrane, cuts the electron transport chain, and releases chitin C and other apoptotic factors (Bax, Caspase-9, ATP, etc.). The use of 5-HD improves the resistance to calcium-induced MPTP channel opening. This shows a possible connection between MPTP and KATP channels. Akt/PI3K signaling pathway is another pathway that has been clinically determined to have cardioprotective effects, namely Akt/PI3K signaling pathway, which is an important intracellular signaling pathway for apoptosis. Raphael et al. The role of Akt/PI3K signaling pathway in VA myocardial protection was studied. Detection of DNA fragments by TUNEL method showed that isoflurane pretreatment significantly reduced the proportion of apoptotic cells. In addition, the expression of Akt and phosphorylated Akt (active Akt) during ischemia and reperfusion showed that the expression of phosphorylated Akt was significantly higher than that of the ischemia-reperfusion and isoflurane revision group. The use of LY294002 (PI3K inhibitor) and wortmannin can inhibit Akt phosphorylation. In addition, the use of wortmannin and LY294002 abolished the myocardial protective effect of pre-anaesthesia treatment, indicating that phosphorylated Akt has myocardial protective effect. The extracellular signal kinase (ERK) pathway is related to myocardial protection caused by VA pretreatment. Toma waited. Studies have shown that pretreatment with desflurane may induce phosphorylation of ERK (the active form of ERK) in rat myocardial ischemia and reperfusion experiments. In the desflurane pretreatment group, MEK/ERK1/2 inhibitor PD98059 combined with desflurane can eliminate myocardial protection. This indicates that MEK/ERK1/2 as a modulator of VA myocardial protection is superior to injury. The analysis of western stains showed that: 10 minutes after myocardial infarction, the use of desflurane will increase the phosphorylation of early ERK. ERK1/2 has been identified as a downstream effector mediated by PKC. Phosphate ERK is PKC independent. Western blotting showed that carhostin C (PKC inhibitor) administered to rats did not affect the phosphorylation of ERK1/2. These results indicate that a single dose of ERK1/2 activator and desflurane can be used for myocardial protection, but increasing the dose may reduce this myocardial protection. .. Highlight VA pretreatment with myocardial protection. Finally, the literature shows that ERK1/2 activation is dependent on PKC. In addition, VA pretreatment showed that Ca2+ flux was related to myocardial protective function and the involvement of nuclear factor B (NF-κBκκ). Calcium ion concentration measured by fluorescence method showed that sevoflurane pretreatment group can improve coronary blood flow and reduce calcium ion load. In addition, Western blotting found that the sevoflurane pretreatment group can reduce the damage to the muscle capsule Ca2 + β circulating protein. The result of Ca 2+ reduction during contraction is myocardial protection caused by reperfusion injury, and irreversible damage is Ca 2+ excess. The accumulation of Ca 2+ after ischemia-reperfusion leads to the activation of NF-κB and the release of inflammatory mediators. Further studies have shown that calmodulin has a protective effect in myocardial ischemia-reperfusion model and Koniaetal myocardial ischemia-reperfusion model. Studies have shown that the NF-κB inhibitor in the sevoflurane pretreatment group, parthenolide (IF-κB inhibitor) can prevent the activation of NF-κB, and NF-κB inhibitors can be used after ischemia. The conclusion is that myocardial protection is better than sevoflurane, the sevoflurane group accounted for 19%, the parthenolide group accounted for 18% of the infarct area, and the sevoflurane + bifenolide group accounted for 10% of the infarct area. , The control group showed 59% of the area of myocardial infarction, participating in the preconditioning function that requires further research and anesthesia

Clinical research: Preconditioning anesthesia has a cardioprotective effect in the laboratory. The key to this question is whether these cardioprotective functions can also be used in clinical practice. This is a good model for studying VA preconditioning, but in cardiac surgery During the operation, other anesthetics can also be used to provide protection. It is not clear whether VA has a clinical cardioprotective effect. Clinical trial evaluations have shown that patients with VA have received pretreatment, especially coronary artery bypass surgery (CABG), Supports the beneficial effects of VA, such as reducing myocardial infarction, cardiac troponin release, length of hospital stay and patient death in CABG patients. In the study, Guarracinoetal and Mecoetal found that compared with general intravenous anesthesia, the deflurane group had fewer biomarkers of myocardial injury after surgery, while the DeHertetal group received general intravenous anesthesia. Comparison: The biochemical indicators of myocardial injury in patients pretreated with fluoroether or sevoflurane are different. However, patients with VA pretreatment have shorter hospital stays and lower mortality within one year. In a retrospective study of more than 10,000 cardiac surgery patients, cardiac surgery patients who received VA preconditioning had a good prognosis, but patients with severe myocardial ischemia or cardiovascular instability before surgery. The use of VA is more effective than general intravenous anesthesia, and the adverse result Bignamietal provides more evidence that patients undergoing VA pretreatment are beneficial for cardiac surgery. It was found that patients who underwent cardiac surgery after using VA had better postoperative results. The analysis showed that using VA has certain benefits in patient pretreatment. It shows. Amletal found that both ischemic preconditioning and isoflurane preconditioning in CABG patients have better myocardial protection than general intravenous anesthesia and cold cardiac arrest. In this study, VA preconditioning is beneficial to patients with CABG. Although the use of remote ischemic preconditioning and VA preconditioning has a protective effect on the myocardium, the use of propofol does not help. The international consensus meeting provides expert support: the use of VA pretreatment in cardiac surgery patients has a stabilizing effect on its hemodynamics. As a means to reduce myocardial damage and mortality. The consensus conclusion is the next extension. Patients undergoing cardiac surgery should use VA pretreatment. The study also uses human heart tissue to explore the benefits of VA pretreatment and identify similar mechanical pathways, including animal experiments that cause this condition. Several important signal transduction mechanisms indicate that drug-based antagonistic ion channels are involved in the pretreatment process of anesthesia. Jiang et al. We will use human ventricular myocytes that are not suitable for transplantation to study the activity of mitochondrial KATP channels in human tissues. By providing 5-HD to cells, we can see that both human and animal myocardial mitochondrial KATP channels are involved in the process of ischemic injury. In the treatment group, the use of 5-HD can attenuate the activity of KATP ion channels. In the other group, isoflurane increased the activity of the mitochondrial KATP channel, increased the peak current in the control group, and proved the function of the KATP channel after clinical VA treatment. Further clinical studies have shown that ROS is involved in myocardial protection during pre-anaesthesia treatment. Therefore, they studied the role of exogenous hydrogen peroxide in the equipment. First, ATP blocks the mitochondrial KATP channel. In addition, in vitro experiments in which KATP channels are activated by the administration of hydrogen peroxide (although ATP is retained) indicate that ROS affects the KATP channels of human mitochondria. In an in vitro study, Mioetal was an adult patient undergoing cardiac surgery using a right atrial appendage to study the mechanical effects of VA pretreatment. They believe that KATP channels are involved in the cardioprotective function of inhaled anesthetics pretreatment, and the results indicate that isoflurane can reduce stress-induced cell death and maintain mitochondrial function. I'm. Isoflurane maintains mitochondrial oxygen consumption, is stimulated by pyruvate, and is accelerated by adenosine diphosphate. The storage of mitochondrial oxygen consumption has shown the protective effect of isoflurane on myocardial ischemia. In addition, he pointed out that the cardioprotective effect of isoflurane is due to the KATP mechanism of the myocardial cell membrane. The use of HMR-1098 can reduce the cardioprotective function of isoflurane. The cell death rate is 21% (without HMR-1098) and 41% (for HMR-1098), and the KATP channel is involved in cardioprotection.

      Someone suggested Hanouzetal. Using the right atrium trabeculae cultured in vitro, the effect of sevoflurane and desflurane pretreatment with active oxygen on myocardial protection was studied. Studies to observe contraction recovery include control, sevoflurane pretreatment and desflurane pretreatment. The recovery of contraction in the sevoflurane group (53% to 85%) and desflurane group (53% to 86%) was significantly improved. Using MPG (ROS scavenger) to prevent contraction of elasticity: deadly running? +? In the MPG group, sevoflurane can change myocardial contractility from 53% to 48%. +? In the MPG group, the shrinkage rate changed from 53% to 56% (the same as the control group). They believe that ROS is involved in the myocardial protection mechanism caused by VA pretreatment, because the use of MPG deprives the recovery of myocardial contraction in the desflurane and sevoflurane groups. Through in vitro experimental studies, the signal transduction mechanism of myocardial protection in human tissues was evaluated. However, other in vivo studies are needed to clearly determine that VA pretreatment as a treatment option has a protective effect on the myocardium of patients with myocardial ischemia. Gas anesthetics can bring traditional anesthetic concentrations to cardiac side effects, and all VAs have clinically relevant myocardial inhibitory effects. The use of VA helps to protect eyesight, but it should be considered for patients with obvious heart failure. In addition, at a clinically appropriate VA concentration, myocardial inhibition may cause vasodilation and make the hemodynamics of patients with ischemic heart disease unstable. In addition, some studies have shown that the use of VA can lead to longer QT intervals. This is because extending the QT interval increases the risk of arrhythmia. The QT interval is the central ventricular depolarization and repolarization part of the cardiac electrical activity cycle in the ECG. As reported with VA anesthetics, extending the QT interval increases the risk of patients with Torsado point ventricular tachycardia, which may cause ventricular fibrillation. However, patients who use VA are called safe and QT prolonged syndrome. In addition, studies have shown that the use of VA can extend the QT interval, but compared with propofol anesthesia, the incidence of ventricular arrhythmia in 10,535 coronary artery bypass graft patients treated with sevoflurane is lower. .. Other patients undergoing coronary artery bypass surgery did not report an increase in ventricular arrhythmia after VA pretreatment. In addition, animal studies have shown that antiarrhythmic effects can be obtained before or after VA treatment. However, depending on the patient's condition, arrhythmia may occur before surgery, such as severe myocardial ischemia and hemodynamic instability. When using VA pretreatment for cardioprotection, extreme care should be taken.