挥发性麻醉剂 z-bo 2020-12-17 320

　　Background: Volatile anesthetic gases are used to induce and maintain general anesthesia, and have the advantages of rapid induction and rapid recovery. It has acceptable effects on the peripheral organs of most patients. In 1275, Spanish physician Raymond Lullus made a volatile liquid, which he called "sweet sulfuric acid-ether, which was later used as an anesthetic. A few years later, an American physician Crawford W. Long discovered that when When his colleague was injured, they would not feel pain if ether had an effect on it. In 1842, Long performed his first operation, using ether as an anesthetic, and his patient underwent neck tumor resection and no pain was reported. Long He published his report in 1849. On October 16, 1846, William TG Morton successfully publicly demonstrated ether anesthetics for the first time in the operating arena of the Massachusetts General Hospital. In the process of stroke and delaying the development of brain injury, VA was in Many medical conditions have advantages, such as for stroke patients, by reducing the number of cerebral ischemia injuries, providing a wide range of medical advantages for stroke patients. Or as a kidney protectant to prevent ischemia and reperfusion injury, reduce plasma creatinine and reduce renal necrosis Other volatile anesthetic gases such as isoflurane, desflurane, and sevoflurane have been proven to protect the heart by reducing and preventing myocardial ischemia during and after surgery. However, myocardial suppression and vasodilation are associated with VA The use of serotonin can lead to symptoms of intraoperative hypotension during surgery, which may disrupt the balance between myocardial oxygen supply and demand and cause myocardial ischemia. Therefore, many clinicians choose to limit or avoid coronary artery bypass surgery (CABG) patients Use VA. For example, the Italian Heart Surgery Center reported that 40% of heart patients use VA, while coronary artery bypass surgery (CABG) uses VA only 25%. Similarly, an analysis investigating the impact of VA found: nearly half Of patients were given total intravenous anesthesia during cardiac surgery.

　　Furthermore, during the use of VA, it was found that if the patient has severe cardiac ischemia and cardiovascular instability before cardiac surgery, the use of VA will have more serious consequences. In addition, the rapid induction effect of inhaled anesthetics can prolong the QT interval and cause the risk of ventricular fibrillation during acute myocardial ischemia, which requires patients to pay more attention.

　　This review will focus on the myocardial protection of isoflurane, desflurane and sevoflurane as inhaled anesthetics obtained from recent laboratory and clinical data. Also discuss the possible heart-related risks of inhaled anesthetics.

　　Literature search strategy: The literature reviewed this time focuses on volatile anesthetics isoflurane, desflurane, and sevoflurane. The following search criteria are used for each volatile anesthetic: volatile anesthetics and cardiovascular protection, or cardiac ischemia, or cardiac injury or cardiotoxicity, or cardiac ischemic preconditioning, or cytotoxicity, or myocardial ischemia, Hypoxia or cardiomyocytes, heart hemorrhage, or heart tolerance, or cardiac post-processing, or cardiac preconditioning, or cardiomyocyte apoptosis, or arrhythmia. Articles that are not in English are excluded. The existing literature discusses key areas related to cardioprotection research and clinical medicine.

　　Ischemic preconditioning: Ischemic injury is a pathological process. When the blood supply to a specific area of the tissue is interrupted, the oxygen demand exceeds the oxygen supply. In the case of ischemia, the heart muscle continues to perform its glycogen storage function. However, if hypoxia occurs for more than 15? minutes, myocardial tissue necrosis will occur, which will cause irreversible damage. Pretreatment is a process that causes a certain degree of damage to an organ or tissue, but this damage will protect the tissue during the process of greater damage. By inducing a short period of ischemia, "cardiomyocytes reduce the number of contractions within a few seconds, and stop contracting within a few minutes." By saving energy by cardiomyocytes, it helps to protect myocardial tissue and reduce the amount of tissue necrosis. Cardiac ischemic preconditioning can lead to fatal consequences, because the damage to the heart has a direct impact on the rest of the body, leading to the interruption of blood supply to all organ systems, which can lead to brain damage, kidney failure, pulmonary edema, etc. 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 and colleagues demonstrated that the area of myocardial infarction in canine ischemic preconditioning was reduced from 29% in the control group to 7% in the ischemic preconditioning group receiving coronary artery occlusion. The dog underwent a brief coronary artery occlusion (4-5?min) before a 40-minute arterial occlusion consisting of an ischemic event. Murry et al. observed a 22% reduction in infarct size. Prompt the protective mechanism of ischemic preconditioning.

　　In addition, he also studied the ischemic preconditioning phenomenon related to several intracellular signaling pathways. The main target of all these pathways seems to be adenosine triphosphate (ATP)-sensitive potassium channel (KATP)?+?. KATP channels are located in mitochondria, cell membranes and nuclear membranes of cardiomyocytes, and are found in the brain, as well as in pancreatic beta cells, bones, smooth muscles, and nerves. The open mitochondrial KATP channel leads to the generation of reactive oxygen species (ROS), which activates downstream protein kinases, leading to myocardial protection. It has been confirmed: The initial increase of ROS activates cytokine channels such as protein kinase C (PKC) channels and tyrosine kinase (TK) channels. This will lead to the opening of mitochondrial KATP channels leading to a decrease in ROS. Therefore, the initial increase of reactive oxygen species caused by ischemic stimulation will lead to the opening of the channel and thus reduce ROS. In addition, the activation and expression of KATP channels shorten the action potential time and save energy, which is the protective effect of heart tissue.

　　Reperfusion injury: Ischemic injury can lead to reperfusion injury, when blood flow is stored to the ischemic area. The process of reperfusion leads to severe calcium accumulation-due to cell membrane damage-leading to the opening of mitochondrial permeability transition pores (mPTP). This causes the mitochondrial membrane to collapse, uncouple oxidative phosphorylation, and cause ATP depletion and cell death. Due to lack of oxygen, ischemia causes the conversion of xanthine dehydrogenase to xanthine oxidase in the metabolism of cardiomyocytes. Xanthine oxidase produces an accumulation of hypoxanthine. During reperfusion, hypoxanthine xanthine oxidase is metabolized, resulting in overproduction of ROS. This phenomenon may cause the damaged tissue to produce superoxide free radicals, which will further damage the tissue and cause irreversible contractile dysfunction.

　　Volatile anesthetic pretreatment: The use of anesthetics activates some of the same channels, leading to the protective mechanism of ischemic preconditioning. Zaugg et al. confirmed that exposure to volatile anesthetics (isoflurane or sevoflurane) is more beneficial to reduce myocardial ischemic damage in a dose-dependent manner (similar to ischemic preconditioning) than myocardial ischemia. Through the use of KATP blocker 5-HD (mitochondrial KATP blocker HMR-1098) and (cell membrane KATP blocker) and KATP channel activator, diazoxide, they were able to prove that isoflurane and sevoflurane are the main mitochondria KATP channels but does not affect the myocardial cell membrane KATP channels. Zaugg and colleagues explained that sevoflurane and isoflurane cause mitochondrial KATP channel activation similar to that seen in ischemic preconditioning. The same research team found that compared with the placebo pretreatment, the use of sevoflurane coronary artery bypass graft surgery significantly improved the results, reducing the incidence of advanced cardiac ischemia and congestive heart failure. However, it is not clear that the effect of volatile anesthetic preconditioning is added to the effect of occlusive cerebral ischemic preconditioning. Warltier et al. study showed that when VA is performed before coronary artery occlusion, 15 minutes after coronary artery occlusion, VA shows better myocardial recovery function. In this experiment, dogs were anesthetized with halothane or isoflurane, and their myocardial function returned to baseline values after 5 hours of reperfusion. The myocardial function of dogs without anesthesia preconditioning decreased by 50%. Further studies have shown similar ischemic myocardial protection and 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, while sevoflurane has no similar important effects. And halothane and isoflurane pretreatment induced the same myocardial protection. However, sevoflurane pretreatment also provides protection to the myocardium in other models.

　　Additional mechanisms appear to be involved in myocardial protection due to ischemic preconditioning. These mechanisms include Akt, ERK, and ROS signaling pathways. The channels that will be involved have been determined: MPTP, myocardial membrane KATP channel, and mitochondrial KATP channel.

　　Mechanical pathways: Several key signal transduction mechanisms have been identified as mediators. Including KATP channel activation preconditioning protective mediators and cytokine regulators, MPTP modulation pathway (Akt/PI3K). In ischemic preconditioning, KATP is established as a myocardial protective medium and has been studied in volatile anesthetic preconditioning. It has been proven that the opening of mitochondrial KATP channels leads to the generation of ROS. In a study using rat bone trabeculae, de Ruijter et al. showed that the myocardial protection of sevoflurane is through the activation of PKC, which leads to the opening of mitochondrial KATP channels. Trabecular bone ischemia in rats is reperfused for 60 minutes, and then, the restoration of the main power is used as a measure of cardiac function after myocardial infarction (MI). Sevoflurane improved the main power recovery to 67%, while in the control group, it was only 28%. However, when the KATP channel inhibitor (5-HD) is used together with sevoflurane, the main power recovery is only 31%, and when the active oxygen scavenger and sevoflurane are used together, the main power recovery is only 33%. This data indicates that both KATP channels and ROS are involved in the myocardial protective mechanism of sevoflurane. According to the report of Marinovic et al., the KATP channel of the myocardial cell membrane is a preconditioning effector, while the mitochondrial KATP channel is the sensor and effector. This is based on the management of mitochondria and cell membrane KATP channel inhibitors in the isoflurane pretreatment group of rat cardiomyocytes. 5-HD administration in the sevoflurane pretreatment group has reduced myocardial protection, but it is not observed in the HMR-1098 group To the same phenomenon. However, if HMR-1098 is applied during the experiment, instead of pretreatment, it has no protective effect.

　　Piriou et al. pointed out that KATP channels are also associated with MPTP. This study shows that ischemic preconditioning and VA preconditioning delay the opening of MPTP channels. Delaying the opening of the MPTP channel is to protect the mitochondrial matrix swelling caused by the opening of the mPTP channel, which causes the mitochondrial membrane to collapse, uncouple the electron transport chain, release cytochrome C and other apoptotic factors such as Bax, Caspase-9 and ATP. The administration of 5-HD abolished the improved tolerance of calcium-induced MPTP channel opening. This indicates a possible connection between MPTP and KATP channels.

　　Another pathway that has been clinically determined to have a cardioprotective effect is the Akt / PI3K signaling pathway, which is a key intracellular signaling pathway for apoptosis. Raphael et al. studied the role of Akt/PI3K signaling pathway in the cardioprotective function of VA. DNA fragment detection by TUNEL method showed that isoflurane pretreatment significantly reduced the percentage 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 in the ischemia-reperfusion and isoflurane preconditioning groups. The use of LY294002 (PI3K inhibitor) and wortmannin resulted in the inhibition of Akt phosphorylation. In addition, the use of wortmannin and LY294002 abolished the myocardial protective effect of anesthetic pretreatment, indicating that phosphorylated Akt has myocardial protective effect. The extracellular signal kinase (ERK) pathway has been associated with myocardial protection caused by VA preconditioning. Toma et al. studies have shown that pretreatment with desflurane can induce phosphorylation of ERK (the active form of ERK); in rat myocardial ischemia and reperfusion experiments. In the desflurane pretreatment group, the MEK/ERK1/2 inhibitor PD98059 was used together with desflurane to eliminate its myocardial protective function. This indicates that MEK/ERK1/2 is better than injury as a modulator of VA myocardial protection. Western blot analysis showed that: 10 minutes after myocardial infarction, the use of desflurane increased the phosphorylation of early ERK. It has been confirmed that ERK1/2 is a downstream effector of PKC-mediated effects. And found that: ERK's phosphoric acid is not dependent on PKC. Western blotting found that the administration of Calphostin C (PKC inhibitor) to rats did not affect the phosphorylation of ERK1/2. These results indicate that the activator of ERK1/2 and a single dose of desflurane are used as myocardial protection, but the use of additional doses can reduce this myocardial protection. Highlight VA pretreatment and have myocardial protection. Finally, the literature shows that the activation of ERK1/2 depends on PKC.

　　In addition, the pretreatment of VA found that Ca2 + flow has been related to myocardial protective function and nuclear factor B (NF-κBκκ) participation. Calcium ion concentration measured by fluorescence method showed that pretreatment group with sevoflurane can improve coronary blood flow and reduce calcium ion load. Furthermore, western blotting found that the sevoflurane pretreatment group can reduce the destruction of sarcoplasmic reticulum Ca2 +??? circulating protein. The result of the decrease of Ca2+ during systole is the myocardial protection caused by reperfusion injury, and the irreversible damage is Ca2+ excess. The accumulation of Ca2 + after ischemia and reperfusion will lead to the activation of NF-κB, leading to the release of inflammatory mediators. Further studies have shown that the protection of calcineurin in the myocardial ischemia-reperfusion model of myocardial ischemia-reperfusion model, Konia et al. study showed that the sevoflurane pretreatment group NF-κB inhibitor, parthenolide ((IF-κB inhibitor) is used to prevent the activation of NF-κB. It is concluded that NF-κB inhibitor has greater myocardial protection after ischemia than sevoflurane; the sevoflurane group exhibited 19% of the infarct area; the parthenolide group exhibited 18% of the infarct area, the sevoflurane + parthenolide group exhibited 10% of the infarct area, and the control group 59% of the myocardial infarction area. Anesthesia preconditioning NF -κB participation requires further research and anesthesia preconditioning function.

　　Clinical research: Randomly demonstrated in the laboratory that anesthesia preconditioning has myocardial protection, but whether these myocardial protection functions can also be used in clinical practice is the key to this question. Cardiac surgery is a model suitable for studying VA pretreatment. However, the use of other anesthetics can also provide protection during cardiac surgery. It is not clear whether VA has clinical cardioprotective effects. Evaluations of clinical trials have shown that VA preconditioning for cardiac surgery patients, especially coronary artery bypass graft (CABG) patients, some of which support the beneficial effects of VA, such as reducing myocardial infarction, cardiac troponin release, hospitalization days and patient death. For example, in a study involving CABG patients, Guarracino et al.

　　And Meco et al. found that: compared with general intravenous anesthesia, the desflurane group had less postoperative myocardial injury biomarkers. In contrast, the experiment of De Hert et al. compared with general intravenous anesthesia and found no difference in biochemical indicators of myocardial injury in patients receiving desflurane or sevoflurane pretreatment. However, patients given VA pretreatment have reduced hospital stay and lower mortality within 1 year. In a retrospective study of more than 10,000 cardiac surgery patients, patients undergoing cardiac surgery using VA preconditioning had good prognosis. However, in patients with severe myocardial ischemia or cardiovascular instability before surgery, the use of VA has a poorer effect than general intravenous anesthesia.

　　Bignami et al provided additional evidence that VA preconditioning patients is beneficial in their cardiac surgery. He found that patients undergoing cardiac surgery have better postoperative results after using VA. This analysis shows that the use of VA is beneficial to patient pretreatment to a certain extent. Amr et al. found that both ischemic preconditioning and isoflurane preconditioning in CABG patients have better myocardial protection than cold blood cardioplegia for general intravenous anesthesia. Further studies have shown that: VA preconditioning is beneficial to CABG patients, remote ischemic preconditioning and the use of VA preconditioning have a protective function on the myocardium, while the use of propofol does not. An international consensus meeting provided expert support: the use of VA pretreatment in cardiac surgery patients has a stabilizing effect on their hemodynamics. As a means to reduce myocardial damage and death. The conclusion of this consensus is that further expansion of the use of VA preconditioning for patients undergoing cardiac surgery is necessary.

　　Several studies have used human heart tissue to examine the benefits of VA pretreatment, and to identify similar mechanical pathways including animal studies that caused it. Some key signal transduction mechanisms have shown that antagonistic ion channels using drugs are involved in the preconditioning process of anesthesia. Jiang et al. used human ventricular myocytes not suitable for transplantation to study the activity of mitochondrial KATP channels in human tissues. By providing 5-HD to cells, it shows that both human and animal cardiomyocyte mitochondrial KATP channels are involved in the process of ischemic injury. In the treatment group, the use of 5-HD can attenuate KATP ion channel activity. In other groups, isoflurane increased the activity of mitochondrial KATP channels and increased the peak current of the control group, indicating the function of KATP channels after clinical VA pretreatment. Further clinical studies have shown that ROS participates in the myocardial protection of anesthesia preconditioning. Therefore, they studied the role of exogenous hydrogen peroxide in their equipment. First, ATP inhibits KATP channels in mitochondria. Furthermore, the administration of hydrogen peroxide led to the activation of KATP channels (despite holding ATP). In vitro experiments showed that ROS affects the KATP channels in human mitochondria.

　　In an in vitro study, adult patients underwent cardiac surgery using right atrial appendages. Mio et al. discussed the mechanical effects of VA pretreatment. They suggested that the KATP channel is involved in the cardioprotective function of inhaled anesthetics preconditioning, and the results indicate that isoflurane reduces stress-induced cell death and maintains mitochondrial function. Isoflurane maintains mitochondrial oxygen consumption, it is stimulated by pyruvate and accelerated by adenosine diphosphate. Oxygen-consuming storage of mitochondria indicates the protective effect of isoflurane on myocardial ischemia. In addition, they pointed out that the myocardial protection of isoflurane is through the myocardial membrane KATP mechanism. The use of HMR-1098 reduced the cardioprotective function of isoflurane, from 21% cell death percentage (without HMR-1098) and 41% cell death percentage (with HMR-1098) suggesting that KATP channels are involved in cardioprotection.

　　Hanouz et al. used human right atrial trabeculae cultured in vitro to study the effect of preconditioning active oxygen with sevoflurane and desflurane on myocardial protection. In the study to observe the recovery of contractility, the control group, sevoflurane pretreatment group and desflurane pretreatment group. The contraction resilience was significantly improved in the sevoflurane group (from 53% to 85%) and the desflurane group (from 53% to 86%). Use MPG (ROS scavenger) to prevent contraction resilience: in the desflurane? +? MPG group, the myocardial contractility changed from 53% to 48%; in the sevoflurane? +? MPG group, the contractility changed from 53% to 56% (Same as the control group). Because the use of MPG deprived the recovery of myocardial contractility in the desflurane and sevoflurane groups, they believed that ROS played a role in the myocardial protection mechanism induced by VA pretreatment. Through in vitro experimental studies, the signal transduction mechanism of myocardial protection in human tissues was evaluated. However, further in vivo studies are necessary to clearly establish that VA pretreatment as a treatment option has a protective effect on the myocardium of patients with myocardial ischemia.

　　Side effects of gas anesthetics on the heart Given conventional anesthetic concentrations, all VAs have clinically relevant myocardial inhibitory effects. The use of VA can help protect eyesight, but it should be considered for patients with obvious cardiac insufficiency.

　　In addition, myocardial inhibitory effect can cause blood vessel dilation when using clinically relevant VA concentrations, leading to hemodynamic instability in patients with ischemic heart disease. In addition, some studies have shown that the use of VA can lead to prolongation of the QT interval. This is because the extension of the QT interval increases the risk of arrhythmia. The QT interval is the central ventricular depolarization and repolarization part of the electrical activity cycle in the ECG that represents the heart. Extending the QT interval increases the risk of patients with torsade de pointes ventricular tachycardia, which may cause ventricular fibrillation, as reported in the use of VA anesthetics. Nevertheless, patients using VA are known as safe and known QT prolonged syndrome. In addition, although studies have shown that VA use can prolong the QT interval, the incidence of ventricular arrhythmias is lower in 10535 coronary artery bypass graft patients given sevoflurane compared with propofol anesthesia. No other patients undergoing coronary artery bypass grafting have reported an increase in ventricular arrhythmia after VA pretreatment. In addition, animal studies have shown that pre- or post-treatment of VA provides an anti-arrhythmic effect. However, patient conditions may induce arrhythmia or hemodynamic instability, such as severe myocardial ischemia before surgery. When using VA pretreatment to give cardioprotection, more caution is needed.

　　No cardioprotective function: Angrilo et al. recently found that VA preconditioning has no cardioprotective function in non-cardiac surgery. This study showed that patients with non-cardiac surgery did not experience any reduction in troponin release.