Clinical importance of anaesthetic preconditioning
*Romuald Lango1, Paweł Mroziński2
1Department of Cardiac Anaesthesia, Medical University of Gdańsk
2Unit of Cardiac Anaesthesia, University Clinical Centre in Gdańsk
Myocardial infarction represents one of the most serious perioperative complications. Reducing the risk of perioperative myocardial infarction is one of the most important priorities of anesthetic treatment. Discovery of cardioprotective effects of volatile anesthetics exerted strong impact on everyday anesthetic practice, particularly in cardiac-surgical setting. Anesthetic preconditioning is a complex process which is divided into two separate phenomena initiated by the same event. The first, referred to as early preconditioning, involves activation of protective enzymes within cardiomyocytes and the second, referred to as late preconditioning, is dependent on de novo synthesis of these protective proteins. Although pre-, as well as post-conditioning’s effects on cardiomyocytes are crucial for cardioprotective effects of volatile anesthetics, their influence on coronary endothelium may be even more important for the improvement of the long-term prognosis, demonstrated in coronary surgery patients. Improved outcome after anesthesia with volatile anesthetics in non-cardiac surgical patients at risk of perioperative myocardial infarction has not been univocally demonstrated yet. Some data indicate that volatile anesthetics, especially sevoflurane, reduces inflammatory response to ischaemia-reperfusion and other pro-inflammatory stimuli. The issue of inflammatory modulation exerted by volatile anesthetics and its influence on patients’ clinical condition remains to be addressed in future studies.
Myocardial ischaemia and infarction are serious perioperative complications; in some groups of patients, elevated levels of cardiac necrosis markers in the perioperative period are a significant risk factor for death within a year following surgery . Therefore, the reduction of the risk of perioperative myocardial infarction is one of the priorities of anaesthetic management.
All volatile anaesthetics have cardiodepressive effects. Thanks to them, by decreasing the oxygen requirements of the myocardium, they may also beneficially influence its oxygen balance during ischaemia. Experimental studies have explicitly demonstrated that volatile anaesthetics and xenon exert direct protective effects on the myocardium against ischaemia- and reperfusion-related consequences . The clinical use of these properties, by prevention of perioperative necrosis of the heart and attenuation of its sequels, gives a chance to improve the treatment outcomes not only in patients undergoing cardiac surgery but also those with ischaemic heart disease undergoing some other surgical procedures. Moreover, protective effects of volatile anaesthetics might be relevant for patients without coronary disease, who due to severe haemodynamic abnormalities are at risk of type 2 perioperative myocardial infarction, according to the American Heart Association/European Society of Cardiology classification of 2007.
MECHANISM OF ISCHAEMIC AND ANAESTHETIC CARDIAC PRECONDITIONING
Prolonged cardiac ischaemia leads to activation of apoptosis or necrosis of the cardiocytes. Cellular oxygen deficiency induces elevation in calcium concentration in the cytoplasm resulting in the opening of mitochondrial permeability transition pores (MPTPs) in the inner mitochondrial membrane, which in turn leads to uncoupling of the respiratory chain, release of cytochrome C into the cytoplasm, further decrease in ATP concentration, mitochondrial oedema and resultant cell death .
It has been observed that short-term discontinuation of oxygen inflow to the heart used before the main ischaemic episode attenuates the heart dysfunction or its morphological injury. This phenomenon is called ischaemic preconditioning . Beneficial effects of natural ischaemic preconditioning manifest in smaller extent of the infarct size and lower mortality if infarction has been preceded by unstable angina pectoris . Thanks to ischaemic preconditioning during coronary artery bypass grafting (CABG), higher levels of ATP in the myocardium and lower levels of troponin I after surgery were observed . However, the possible uses of ischaemic preconditioning during cardiac surgical procedures are extremely limited; therefore, simple yet effective methods of its application, which could become the standard of clinical management, are lacking.
Rapidly increasing changes caused by ischaemia observed during reperfusion are referred to as reperfusion injury. Impaired function of the endothelium and reduced metabolism of cardiocytes are essential for the pathophysiology of this phenomenon . Reperfusion injury may be attenuated by ischaemic postconditioning, i.e. the procedure involving alternating stoppage and restoration of blood flow through the organ during reperfusion . However, to provide effective protection, the intervention should be performed before the MPTP opening, i.e. within a few minutes or even during the first minute after coronary flow restoration .
The term of pharmacological cardioprotection denotes the heart protection provided with pharmacological agents, which maintains much longer than the time of their action and elimination. The substances with properties of pharmacological heart preconditioning include activators of protein kinases, agonists of adenosine receptors, scavengers of free radicals, opioids, ethyl alcohol, and natural substances such as acetylcholine, bradykinin, angiotensin II, noradrenaline as well as the platelet-activating factor . However, the majority of substances showing protective properties are not used in practice due to severe side effects or lack of clinically confirmed efficacy of their use . On the other hand, it has been demonstrated that volatile anaesthetics may be easily used clinically for cardioprotection; their action is largely similar to ischaemic preconditioning.
The first studies describing cardioprotection with volatile anaesthetics had been published much earlier than the concept of cardiac preconditioning was conceived. In 1976, Bland and Lowenstein  observed that after short-term clamping of the coronary artery in dogs, halothane decreased the ST segment abnormalities in ECG. However, the protective effects against cardiac ischaemia triggered by isoflurane were not demonstrated until 1997. This initiated a series of studies on the phenomenon of pharmacological preconditioning .
The term “anaesthetic preconditioning” is understood as the activation of cardiac protection mechanisms due to the use of anaesthetics before the onset of cardiac ischaemia, with the protective action of an agent markedly exceeding its elimination time .
Cardioprotective effects of volatile anaesthetics were observed with sevoflurane , desflurane , isoflurane  and halothane . The effects of individual anaesthetics, however, may be different as for the extent and mechanism of cardioprotection, which is evidenced by observations reported by Roscoe and colleagues . They demonstrated that isoflurane protected the heart during ischaemia by activation of the adenosine A1 receptor whereas halothane did not activate this mechanism or could even limit the protective effects of ischaemic preconditioning.
Both transient myocardial ischaemia and the use of volatile anaesthetics trigger the mechanisms of cardioprotection, with its two stages called early and remote preconditioning. Early cardiac protection starting almost immediately after preconditioning and persisting for several hours depends on phosphorylation or translocation of protein kinases . Simultaneously, the second stage of cardiac protection is initiated whose effects are visible after 12-24 h and persist for about 72 h. Its essence is likely to be the activation of genes responsible for synthesis of protective proteins .
Importantly, both preconditioning (before ischaemia) and postconditioning (during early reperfusion) have protective effects on the vascular endothelium .
Caveolae, tiny indentations of the cell membrane rich in sphingolipids, 50-100 nm in diameter, are extremely important for initiation of anaesthetic preconditioning . Anaesthetic preconditioning of the heart starts with the contact of an anaesthetic molecule with the cell membrane, which leads to increased translocation of caveolin-1 and caveolin-3 to caveolae. Simultaneous translocation of glucose transporter-4 (GLUT-4) was also found relevant . It is supposed that caveolae act as the „docking sites” for volatile anaesthetic molecules. Preconditioning may also be initiated by activation of adenosine and opioid receptors.
The next stage of anaesthetic preconditioning is the transmission of a signal inside the cell. The factors involved in the process of preconditioning include inducible synthasis of nitric oxide, cyclooxygenase 2 and 12-lipoxygenase . The production of oxygen radicals increases, which at this stage function as an intracellular modulatory signal. Depending on the type of preconditioning, early or remote, the heat shock proteins 70, 27 and 105 as well as protective proteins such as protein kinase C, tyrosine kinase, kinase p38, phosphatidyloinositol-3/Akt-protein kinase B and mitogen-activated protein kinase, are activated or de novo synthesized [16, 19]. The activation of enzymatic proteins leads to the opening of mitochondrial and sarcolemmal ATP-sensitive potassium channels . A relevant role in the process of cardioprotection is thus played by inhibition of bioenergetic reactions in the mitochondrion already before the onset of ischaemia. Eventually, the phenomena described delay the opening of MPTP s, i.e. reduce their susceptibility to elevated concentrations of calcium ions in the cytoplasm .
Beside the activation or synthesis of protective proteins induced by preconditioning, inhibition of factors stimulating apoptosis is observed . Recently, the importance of “beneficial genetic re-programming“ has been emphasized, which involves the activation of genes responsible for synthesis of substances exerting protective effects on cardiocytes as well as the endothelium . It may be supposed that the release of such substances in the places remote from the heart, e.g. due to short-term ischaemia of the limb, is connected with the phenomenon of remote preconditioning, which is a novel and promising trend of research on cardiac protection.
BENEFICIAL EFFECTS OF ANAESTHETIC PRECONDITIONING IN CARDIAC ANAESTHESIA
The crucial paper published by De Hert  in 2003 confirmed the importance of earlier reports on cardioprotective effects of sevoflurane and desflurane based on experimental studies. Patients anaesthetized with these anaesthetics for CABG surgery showed better contractility of the left ventricle and lower concentration of troponin I after the completion of extracorporeal circulation (ECC) compared to patients anaesthetized with propofol. Another randomized clinical trial demonstrated that sevoflurane pre-conditioning was associated with lower risks of late cardiovascular complications within one year after surgery .
Comparison of anaesthesia with sevoflurane, desflurane and propofol for CABG with ECC, despite the lack of significant differences in the concentration of troponin T, revealed the differences in mortality within one year after surgery - 12.3% in patients anaesthetized with propofol, 6.7% in those administered sevoflurane and 3.3% in the sevoflurane patients . These results suggest that protective effects of anaesthetic preconditioning on the endothelium may be less relevant for improvement of prognosis than its protective action on cardiocytes.
Meco and co-workers  observed lower levels of troponin T and pro-BNP in the group receiving desflurane before aorta clamping during CABG with ECC as well as improved diastolic function of the left ventricle, expressed in increased mobility of the mitral ring in the initial phase of diastole.
Protective effects of sevoflurane expressed in reduced concentration of cardiac necrosis markers and faster restoration of systolic and diastolic functions of the heart after ECC were also observed in patients undergoing aortic valve surgery . This may be particularly important in patients with severe hypertrophy of the heart, in whom optimal cardioprotection against ischaemia might be difficult to obtain.
During off-pump CABG (OPCABG), the application of volatile anaesthetics led to less explicit observations. It was found that during such procedures the diastolic function of the left ventricle was better preserved with sevoflurane compared to propofol . In another study in patients after OPCABG, lower values of troponin T and lower percentages of patients requiring inotropic agents were observed . However, in the unpublished study carried out by the authors of the present paper in the group of 61 patients undergoing OPCABG, no differences in concentrations of CK-MB and troponin T were found between the propofol and desflurane group. We believe that due to short time and usually smaller ischaemic area during this type of surgery, which induces only slight cardiac injury, protective effects of volatile anaesthetics may be difficult to be demonstrated.
Retrospective analysis, involving over 10 000 patients after cardiac surgical procedures, did not show the difference between propofol and sevoflurane anaesthesia in terms of postoperative mortality and incidence of perioperative myocardial infarction . Lower mortality rates in sevoflurane patients were only observed in the group without earlier unstable coronary disease, which supports the hypothesis that anaesthetic preconditioning has only slight protective effects on the heart already affected by ischaemic preconditioning.
Meta-analyses of studies on the use of volatile anaesthetics during CABG with ECC or otherwise demonstrated that patients anaesthetized with volatile anaesthetics had lower concentrations of troponin T, higher cardiac output after surgery, lower demands for inotropic agents, shorter duration of mechanical ventilation and hospital stay. On the other hand, no significant differences in the incidence of perioperative myocardial infarction and mortality were found [29, 30]. Both meta-analyses, however, included also the studies in which neither desflurane nor sevoflurane were used, i.e. agents which might be characterized by stronger cardioprotective effects compared to halothane and enflurane.
The publication based on the results of 22 randomized clinical trials showed that in patients anaesthetized with desflurane or sevoflurane, the incidence of perioperative myocardial infarction was twice lower and mortality rates fourfold lower than in patients anaesthetized with propofol (2.4% vs 5.1% and 0.4% vs 1.6%, respectively) .
The meta-analysis of studies comparing anaesthesia with volatile and intravenous anaesthetics during CABG, involving in total over 34 000 patients, shows that the 30-day mortality was lower in patients receiving volatile anaesthetics . Moreover, it was demonstrated that longer use of volatile anaesthetics was the factor correlating with lower mortality . The studies involving one-year observation of cardiac surgery patients disclosed that the incidence of severe cardiological complications was 8.3% in desflurane or sevoflurane patients and 24.4% in propofol patients .
TIME AND METHODS OF VOLATILE ANAESTHETIC APPLICATION DURING CARDIAC SURGERY TO ACHIEVE MAXIMUM CARDIOPROTECTION
To achieve the desirable cardioprotection, volatile anaesthetics should be used in adequate concentrations and time. However, the most effective method of their use during cardiac surgery has not been known. In the majority of experimental studies, their protective action was observed at concentration > 1 MAC and exposure time between 10-30 min .
The sevoflurane exposure under experimental conditions induced a decrease in infarct size and in concentration of cardiac necrosis markers, an increase in ATP levels in the myocardium and improvement in the left ventricular function; however, to achieve full protective effects over 24-h exposure to this anaesthetic was required . This indicates the importance of remote anaesthetic preconditioning to limit the effects of possible cardiac ischaemia in the postoperative period. Lower concentrations of CK-MB and troponin were observed only in the group in which sevoflurane was used intermittently before ECC as compared to patients undergoing continuous sevoflurane use or those anaesthetized with propofol . Moreover, intermittent exposure to desflurane at the concentration of 1/ 2 MAC, including three 10-minute cycles, induced protective effects corresponding to continuous exposure to this agent at the concentration of 1 or 1.5 MAC . Further increases in concentration, or prolonged exposure to sevoflurane, did not enhance its protective effects. The authors put forward an interesting hypothesis that short-term intermittent exposure to sevoflurane might induce repeated impulses of increased concentrations of ROS, which are important for activation of cardioprotective mechanisms.
Recently, many studies were published in which the effects of ischaemic and anaesthetic preconditioning during reperfusion were analysed. By analogy to ischaemic preconditioning terminology, protective effects of anaesthetics during this period is defined as anaesthetic postconditioning.
The effects of anaesthetic postconditioning were demonstrated with isoflurane, sevoflurane and desflurane. It was observed that combined pre- and postconditioning with sevoflurane provided better cardioprotective effects compared to preconditioning only before ischaemia .
Moreover, the cardioprotective effect of desflurane was observed when the agent was used before and after ischaemia, which confirms the importance of both pre- and postconditioning . In case of anaesthetic postconditioning to protect the heart against reperfusion injury, as in ischaemic postconditioning, such management should be instituted during early reperfusion. It was found that sevoflurane used within the first 2 min of reperfusion caused such a reduction in the infarct size that could not have been improved by lengthening of its application to 5 or 10 min .
A variety of factors limit the beneficial effects of volatile anaesthetics on the heart. It was found that protective effects of desflurane postconditioning were not observed when β-blockers were used . A relevant limitation of anaesthetic preconditioning in the clinical setting is likely to be the presence of perioperative hyperglycaemia. It was demonstrated that hyperglycaemia blocked the beneficial influence of desflurane on the experimental infarct area in rats . Moreover, the experimental studies revealed that effectiveness of protective mechanisms related to anaesthetic preconditioning might be lower in the elderly .
ANAESTHETIC CARDIOPROTECTION DURING NON-CARDIAC SURGERY
For several years, clinical importance of cardioprotective effects of volatile anaesthetics during cardiac surgery as well as non-cardiac procedures in patients at higher risk of perioperative myocardial infarction has been disputed. The study results indicate that the use of volatile anaesthetics in non-cardiac patients may reduce the risk of cardiac complications in patients with coronary disease.
Some clinical trials demonstrated lower levels of troponin in patients anaesthetized with volatile anaesthetics for non-cardiac surgery. The meta-analysis of 79 trials involving 6129 patients undergoing such procedures, however, did not show the advantages of sevoflurane or desflurane anaesthesia over propofol anaesthesia .
The trials performed to date did not allow determining explicitly the recommendations for the use of volatile anaesthetics in patients at higher risk of intraoperative ischaemia and myocardial infarction during procedures other than cardiosurgical . Nevertheless, the conviction about beneficial effects of volatile anaesthetics on the heart resulted in recommendations of the American College of Cardiology/American Heart Association to use volatile anaesthetics during non-cardiac surgeries in patients at higher risk of perioperative myocardial infarction .
EFFECTS OF VOLATILE ANAESTHETICS ON INFLAMMATORY REACTION
Extensive activation of the inflammatory reaction due to strong inotropic-negative action of some mediators may enhance the circulatory failure after cardiac surgery. Many data indicate that volatile anaesthetics have the ability to limit the inflammatory reaction, although this may not always result from their protective effects on the vascular endothelium under ischaemia-reperfusion conditions. The study carried out in rats revealed that under the influence of isoflurane and sevoflurane at concentration of 1 MAC, neutrophils stimulated by the platelet-activating factor produced lower amounts of ROS and had no ability to cause heart dysfunction . Furthermore, isoflurane-induced limitation of harmful effects of cytokines on cultures of rat smooth muscle cells and human endothelial cells was described .
In patients anaesthetized with sevoflurane, reduced secretion of TNF-a ex vivo was described during and after CABG surgery . Moreover, sevoflurane anaesthesia was found to be associated with decreased activation of the inflammatory reaction assessed based on CD-11b/CD18 ratio and IL-6 as well as TNF-a concentrations . During CABG with ECC, sevoflurane induced significant decreases in IL-6 and IL-8 levels . It was also observed that sevoflurane, as opposed to desflurane, attenuated activation of mRNA for adhesion molecules, TNF-a and IL-8 .
The current knowledge on the action of volatile anaesthetics on the inflammatory reaction is fragmentary and does not allow drawing clinically important conclusions. Further studies are needed to explain the mechanisms and assess the clinical relevance of volatile anaesthetic effects on the inflammatory reaction induced by ischaemia and surgical trauma.
Many data, mostly from experimental studies, indicate that protective effects of anaesthetics are not confined to the myocardium. If further studies confirm the protective influence of volatile anaesthetics on the kidneys, brain and liver, observed in experimental works and few clinical trials, the term of cardioprotective effects of volatile anaesthetics can be changed into more universal anaesthetic cytoprotection.
The knowledge of mechanisms of pharmacological cardiac preconditioning induced by volatile anaesthetics is increasingly wide. The findings of original studies and meta-analyses confirm conclusively beneficial effects of volatile anaesthetics on the heart, clinical state and prognosis in patients undergoing cardiac surgery.
To date observations concerning the phenomenon of anaesthetic preconditioning show that to achieve maximum cardioprotection in surgical procedures with ECC volatile anaesthetics should be used before aorta clamping for the period longer than 15-30 minutes and at concentrations > 1 MAC. Many studies demonstrate that volatile anaesthetics may be applied in such a way as to use the postconditioning effect. To achieve the adequate concentration of an anaesthetic in blood during the first minutes after aorta unclamping, its administration via the oxygen and air supply line for ECC should be initiated at least several minutes before unclamping and continued for the first 2-5 min of reperfusion. The available literature data do not explicitly demonstrate that the use of volatile anaesthetics during aorta clamping or late reperfusion might have a relevant impact on cardiac protection.
The findings of experimental studies suggest that clinical meaning of pharmacological preconditioning with volatile anaesthetics may be limited by widespread use of β-blockers in premedication, oral hypoglycaemic drugs and perioperative hyperglycaemia.
Attenuation of the inflammatory reaction to surgical trauma may be one of the factors responsible for improved prognosis observed in patients anaesthetized with volatile anaesthetics for cardiac surgeries. Further studies are required to determine whether volatile anaesthetics, by thier protective effects on organs and attenuation of perioperative inflammatory reaction, might favourably affect prognosis in patients undergoing non-cardiac procedures.
The currently available results regarding the phenomenon of anaesthetic preconditioning do not give grounds for recommending volatile anaesthetics in non-cardiac surgery patients with increased risks of perioperative myocardial infarction. However, numerous reports suggest possible protective effects of volatile anaesthetics on the heart in this group of patients.
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Gdański Uniwersytet Medyczny