The concept of anaesthetic-induced cardioprotection: clinical relevance

Experimental evidence has clearly demonstrated that volatile anaesthetic agents have direct protective properties against reversible and irreversible ischaemic myocardial damage. These properties have been related to a direct preconditioning effect but also to an effect on the extent of reperfusion injury. The implementation of these properties during clinical anaesthesia can provide an additional tool in the treatment and/or prevention of ischaemic cardiac dysfunction in the perioperative period. In clinical practice, these effects should be associated with improved cardiac function, ultimately resulting in a better outcome in patients with coronary artery disease. This potential application of anaesthetic agents has only recently been explored, and its applicability in clinical practice is the subject of ongoing research. This review summarizes the current knowledge on this subject.     

The concept of anaesthetic-induced cardioprotection: mechanisms of action

The mechanisms by which ischaemia reperfusion injury can be influenced have been the subject of extensive research in the last decades. Early restoration of arterial blood flow and surgical measures to improve the ischaemic tolerance of the tissue are the main therapeutic options currently in clinical use. In experimental settings ischaemic preconditioning has been described as protecting the heart, but the practical relevance of interventions by ischaemic preconditioning is strongly limited to these experimental situations. However, ischaemia reperfusion of the heart routinely occurs in a variety of clinical situations, such as during transplantations, coronary artery bypass grafting or vascular surgery. Moreover, ischaemia reperfusion injury occurs without any surgical intervention as a transient myocardial ischaemia during a stressful anaesthetic induction. Besides ischaemic preconditioning, another form of preconditioning was discovered over 10 years ago: the anaesthetic-induced preconditioning. There is increasing evidence that anaesthetic agents can interact with the underlying pathomechanisms of ischaemia reperfusion injury and protect the myocardium by a preconditioning mechanism. Hence, the anaesthetist himself can substantially influence the critical situation of ischaemia reperfusion during the operation by choosing the right anaesthetic. A better understanding of the underlying mechanisms of anaesthetic-induced cardioprotection not only reflects an important increase in scientific knowledge but may also offer the new perspective of using different anaesthetics for targeted intraoperative myocardial protection. There are three time windows when a substance may interact with the ischaemia reperfusion injury process: (1) during ischaemia, (2) after ischaemia (i.e. during reperfusion), and (3) before ischaemia (preconditioning).     

Preconditioning and protection against ischaemia-reperfusion in non-cardiac organs: a place for volatile anaesthetics?

There is an increasing body of evidence that volatile anaesthetics protect myocardium against ischaemic insult by a mechanism termed 'anaesthetic preconditioning'. Anaesthetic preconditioning and ischaemic preconditioning share several common mechanisms of action. Since ischaemic preconditioning has been demonstrated in organs other than the heart, anaesthetic preconditioning might also apply in these organs and have significant clinical applications in surgical procedures carrying a high risk of ischaemia-reperfusion injury. After a brief review on myocardial preconditioning, experimental and clinical data on preconditioning in non-cardiac tissues will be presented. Potential benefits of anaesthetic preconditioning during non-cardiac surgery will be addressed.     

Anaesthetic-induced myocardial preconditioning: fundamental basis and clinical implications

OBJECTIVE: Volatile halogenated anaesthetics offer a myocardial protection when they are administrated before a myocardial ischaemia. Cellular mechanisms involved in anaesthetic preconditioning are now better understood. The objectives of this review are to understand the anaesthetic-induced preconditioning underlying mechanisms and to know the clinical implications. DATA SOURCES: References were obtained from PubMed data bank (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) using the following keywords: volatile anaesthetic, isoflurane, halothane, sevoflurane, desflurane, preconditioning, protection, myocardium. DATA SYNTHESIS: Ischaemic preconditioning (PC) is a myocardial endogenous protection against ischaemia. It has been described as one or several short ischaemia before a sustained ischemia. These short ischaemia trigger a protective signal against this longer ischaemia. An ischemic organ is able to precondition a remote organ. It is possible to replace the short ischaemia by a preadministration of halogenated volatile anaesthetic with the same protective effect, this is called anaesthetic PC (APC). APC and ischaemic PC share similar underlying biochemical mechanisms including protein kinase C, tyrosine kinase activation and mitochondrial and sarcolemnal K(ATP) channels opening. All halogenated anaesthetics can produce an anaesthetic PC effect. Myocardial protection during reperfusion, after the long ischaemia, has been shown by successive short ischaemia or volatile anaesthetic administration, this is called postconditioning. Ischaemic PC has been described in humans in 1993. Clinical studies in human cardiac surgery have shown the possibility of anaesthetic PC with volatile anaesthetics. These studies have shown a decrease of postoperative troponin in patient receiving halogenated anaesthetics.     

Remote ischemic preconditioning in major vascular surgery

Remote ischemic preconditioning is a physiologic mechanism in mammalian species whereby brief exposure to nonlethal ischemia in one tissue confers protection against a prolonged ischemic insult in a distant tissue. First described almost 15 years ago, it has been slow to translate into clinical practice. Several clinical trials have recently reported that remote ischemic preconditioning reduces myocardial injury after major cardiovascular surgery. In addition, a randomized trial in patients undergoing open abdominal aortic aneurysm repair reported a significant reduction in perioperative myocardial infarctions. Remote ischemic preconditioning is easily performed and likely to prove highly cost-effective. large-scale trials of the technique are warranted in patients undergoing major vascular surgery.     

The Interactions between β-Blockers and Anaesthetics. Experimental Observations

The possibility of interactions between β-adrenoceptor antagonists and anaesthetic drugs is particularly relevant to the anaesthetic management of patients suffering from arterial hypertension and ischaemic heart disease. Maintenance of adrenergic beta-receptor blockade in patients with ischaemic heart disease and arterial hypertension is now widely accepted in order to avoid the cardiac risks of its sudden withdrawal and also to minimize the effects of sympathetic overactivity on the cardiovascular system. However, maintenance of adrenergic beta-receptor blockade may impose some constraints on the choice of the anaesthetic agent. While no adverse interaction has been found between beta blockade and anaesthesia with halothane, halothane supplementing nitrous oxide, or isoflurane, substantial reductions of cardiac performance have been observed in the case of the association of beta blockade and anaesthesia using methoxyflurane or trichloroethyiene. An adverse interaction has also been observed between propranolol and enflurane anaesthesia but not between oxprenolol and enflurane anaesthesia. Recent studies of the effects of anaesthesia in the presence of critically narrowed coronary arteries have shown that both halothane and enflurane may cause regional myocardial dysfunction. This dysfunction is minimized by oxprenolol and it appears that adrenergic beta-receptor blockade, besides improving cardiovascular stability, protects the myocardium supplied by narrowed coronary arteries.     

Isoflurane and coronary heart disease

Early studies indicated that isoflurane caused coronary steal and should therefore be avoided in patients with coronary heart disease. Subsequently, more detailed trials have disputed this and have shown that as long as coronary perfusion pressure is maintained, isoflurane does not cause coronary steal or myocardial ischaemia. There is now growing evidence, initially in animal work but more recently in human studies, that isoflurane has myocardial protective properties, limiting infarct size and improving functional recovery from myocardial ischaemia. The mechanism for this protection mimics ischaemic preconditioning and involves the opening of adenosine triphosphate-dependent potassium channels. The few studies comparing the myocardial protection offered by individual anaesthetic agents indicate that isoflurane represents the anaesthetic agent of choice for patients with coronary heart disease.     

Volatile anesthetics and cardiac function

All volatile anesthetics have been shown to induce a dose-dependent decrease in myocardial contractility and cardiac loading conditions. These depressant effects decrease myocardial oxygen demand and may, therefore, have a beneficial role on the myocardial oxygen balance during myocardial ischemia. Recently, experimental evidence has clearly demonstrated that in addition to these indirect protective effects, volatile anesthetic agents also have direct protective properties against reversible and irreversible ischemic myocardial damage. These properties have not only been related to a direct preconditioning effect but also to an effect on the extent of reperfusion injury. The implementation of these properties during clinical anesthesia can provide an additional tool in the treatment or prevention, or both, of ischemic cardiac dysfunction in the perioperative period. In the clinical practice, these effects should be associated with improved cardiac function, finally resulting in a better outcome in patients with coronary artery disease. The potential application of these protective properties of volatile anesthetic agents in clinical practice is the subject of ongoing research. This review summarizes the current knowledge on this subject.     

促红细胞生成素对缺血/再灌注心肌保护作用的研究进展

背景 促红细胞生成素(erythropoietin,EPO)是一种造血刺激因子,过去20多年中用于临床多种原因所致的贫血.随着对EPO及其受体在心血管方面作用的认识,增加了EPO在生理和病理生理方面作用的理解. 目的 将心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)减轻到最低限度. 内容 研究EPO在心脏中的表达及其在心肌保护中所涉及的传导机制,EPO在动物心血管疾病实验模型中起到心肌保护作用及目前EPO心肌保护作用的临床相关研究. 趋向 近年来,EPO心肌保护作用临床研究的报道逐渐增多,为临床心肌保护提供了新的方向,但需要更深入研究EPO的心肌保护作用.     

Remote ischaemic preconditioning does not protect the heart in patients undergoing coronary artery bypass grafting

Remote ischaemic preconditioning (RIPC) gained attention as a possibility to reduce myocardial injury after a subsequent sustained episode of myocardial ischaemia. This prospective randomized study was carried out to assess whether RIPC reduces myocardial injury in coronary artery bypass grafting patients. Eighty patients were assigned to remote preconditioning or control treatment. Ischaemic preconditioning was induced by three 5-min cycles of upper limb ischaemia and reperfusion after anaesthesia induction. Haemodynamic and markers of myocardial damage were analysed preoperatively and over 48 h postoperatively. The cardiac index was higher immediately after remote preconditioning in the main group. There were no differences in other haemodynamic, troponin I and creatine kinase-MB concentrations at any time point between groups. Thus, short-term remote preconditioning improves haemodynamics and does not reduce myocardial injury after coronary artery bypass surgery. Further study of high-risk patients may be needed to fully evaluate the clinical effect of RIPC.     

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.     

Perioperative hyperoxia and post‐operative cardiac complications in adults undergoing non‐cardiac surgery: Systematic review protocol

Background

Oxygen therapy is used liberally for all patients undergoing anaesthesia. Recent studies have raised concerns that it may not be without complications when arterial oxygen concentrations reach supranormal concentrations (hyperoxia). Studies of oxygen therapy have raised concerns that the risk of myocardial injury and infarction is elevated in patients with hyperoxia due to vasoconstriction and formation of reactive oxygen species. Due to lack of symptoms or silent ischaemia, post‐operative myocardial injury may be missed clinically. In some studies, perioperative hyperoxia has been linked to increased long‐term mortality, but cardiac complications are sparsely evaluated. The aim of this review is to summarize current evidence to assess the risk and benefits of perioperative hyperoxia on post‐operative cardiac complications.

Methods

This systematic review will include meta‐analyses and Trial Sequential Analyses. We will include randomized clinical trials with patients undergoing non‐cardiac surgery if the allocation separates patients into a target of either higher (above 0.60) or lower (below 0.40) inspired oxygen fraction. To minimize the risk of systematic error, we will assess the risk of bias of the included trials using the Cochrane Risk of Bias Tool. The overall quality of evidence for each outcome will be assessed with the Grading of Recommendation, Assessment, Development and Evaluation (GRADE).

Discussion

This systematic review will provide data on a severe, albeit rare, potential risk of oxygen therapy. We will do a trial sequential analysis to assess the robustness of results as well as help estimate the required patient size for future clinical trials.

     

Ischaemic preconditioning: mechanisms and potential clinical applications

Purpose

Brief ischaemic episodes, followed by periods of reperfusion, increase the resistance to further ischaemic damage. This response is called “ischaemic preconditioning.” By reviewing the molecular basis and fundamental principals of ischaemic preconditioning, this paper will enable the anaesthetic and critical care practitioner to understand this developing therapeutic modality.

Source

Articles were obtained from a Medline review (1960–1997; search terms: ischaemia, reperfusion injury, preconditioning, ischaemic preconditioning, cardiac protection). Other sources include review articles, textbooks, hand-searches (Index Medicus), and personal files.

Principle finding

Ischaemic preconditioning is a powerful protective mechanism against ischaemic injury that has been shown to occur in a variety of organ systems, including the heart, brain, spinal cord, retina, liver; lung and skeletal muscle. Ischaemic preconditioning has both immediate and delayed protective effects, the importance of which varies between species and organ systems. While the exact mechanisms of both protective components are yet to be clearly defined, ischaemic preconditioning is a multifactorial process requiring the interaction of numerous signals, second messengers and effector mechanisms. Stimuli other than ischaemia, such as hypoxic perfusion, tachycardia and pharmacological agents, including isoflurane, have preconditioning-like effects. Currently ischaemic preconditioning is used during minimally invasive cardiac surgery without cardiopulmonary bypass to protect the myocardium against ischaemic injury during the anastomosis.

Conclusion

Ischaemic preconditioning is a powerful protective mechanism against ischaemic injury in many organ systems. Future clinical applications will depend on the clarification of the underlying biochemical mechanisms, the development of pharmacological methods to induce preconditioning, and controlled trials in humans showing improved outcomes.     

Ischemic preconditioning, myocardial stunning and anesthesia

Brief periods of ischemia have been shown to protect the heart against a subsequent prolonged ischemic insult, a phenomenon known as ischemic preconditioning. The protective effects of preconditioning markedly reduce myocardial ischemic injury in vivo. Volatile anesthetics have been shown to protect myocardium against infarction by a mechanism similar to that of ischemic preconditioning. Contractile dysfunction occurs after a brief period of myocardial ischemia, despite restoration of coronary blood flow in the absence of tissue necrosis. This process is known as myocardial stunning and has important clinical ramifications. Evidence indicates that adenosine triphosphate-regulated potassium channel function plays a central role in ischemic preconditioning, stunned myocardium, and in anesthetic-induced protection against ischemic injury.     

Remote ischaemic pre‐conditioning for the prevention of acute kidney injury

Acute kidney injury (AKI) is a common complication associated with high morbidity and mortality in hospitalized patients. One potential mechanism underlying renal injury is ischaemia/reperfusion injury (IRI), which attributed the organ damage to the inflammatory and oxidative stress responses induced by a period of renal ischaemia and subsequent reperfusion. Therapeutic strategies that aim at minimizing the effect of IRI on the kidneys may prevent AKI and improve clinical outcomes significantly. In this review, we examine the technique of remote ischaemic preconditioning (rIPC), which has been shown by several trials to confer organ protection by applying transient, brief episodes of ischaemia at a distant site before a larger ischaemic insult. We provide an overview of the current clinical evidence regarding the renoprotective effect of rIPC in the key clinical settings of cardiac or vascular surgery, contrast‐induced AKI, pre‐existing chronic kidney disease (CKD) and renal transplantation, and discuss key areas for future research.     

The rationale for perioperative brain protection

Perioperative brain protection refers to prophylactic measures instituted during the perioperative period to prevent or reduce ischaemic damage and to improve neurological outcome. In that context, strategies for protecting the brain rely on the control of physiological variables, anaesthesia, administration of non-anaesthetic pharmacological agents and preconditioning. Avoiding hyperthermia, hyperglycaemia and arterial hypotension are passive neuroprotective measures acknowledged in human beings. The protective effect of anaesthesia, compared to the awake state, is demonstrated in animals but remains to be validated in clinical practice. Laboratory studies investigating pharmacological neuroprotection have shown interesting results but most clinical trials have been disappointing except for a few drugs in specific settings. Preconditioning which results in the induction of some resistance to ischaemia appears as a promising strategy. Up to now, the translation of beneficial experimental results into clinical success is considered an entirely permissible hope but remains an unachieved objective.     

The effect of anaesthetics on the myocardium--new insights into myocardial protection

A variety of laboratory and clinical studies clearly indicate that exposure to anaesthetic agents can lead to a pronounced protection of the myocardium against ischaemia-reperfusion injury. Several changes in the protein structure of the myocardium that may mediate this cardioprotection have been identified. Ischaemia-reperfusion of the heart occurs in a variety of clinical situations including transplantations, coronary artery bypass grafting or vascular surgery. Ischaemia may also occur during a stressful anaesthetic induction. Early restoration of arterial blood flow and measures to improve the ischaemic tolerance of the tissue are the main therapeutic options (i.e. cardioplegia and betablockers). There exists increasing evidence that anaesthetic agents interact with the mechanisms of ischaemia-reperfusion injury and protect the myocardium by a 'preconditioning' and a 'postconditioning' mechanism. Hence, the anaesthesiologist may substantially influence the critical situation of ischaemia-reperfusion during surgery by choosing the appropriate anaesthetic agent. This review summarizes the current understanding of the mechanisms of anaesthetic-induced myocardial protection. In this context, three time windows of anaesthetic-induced cardioprotection are discussed: administration (1) during ischaemia, (2) after ischaemia-during reperfusion (postconditioning) and (3) before ischaemia (preconditioning). Possible clinical implications of these interventions will be reviewed.     

Why Did it Take so Long to Start a Non-Heart-Beating Donor Program in Belgium ?

Ischemia-reperfusion injury of the liver causes severe organ dysfunction after both extended liver resections and liver transplantation. In experimental models, ischemic preconditioning has repeatedly been shown to protect the liver from injury after warm and cold ischemia-reperfusion. Herein, we summarize the experimental and clinical evidence considering protection of tissue by ischemic preconditioning and we conclude that it is now time to initiate prospective randomized multicenter trials, in order to confirm the benefit of ischemic preconditioning for the patients undergoing major liver surgery and liver transplantation.     

Ischemic preconditioning: enough evidence to support clinical application in liver surgery and transplantation?

Ischemia-reperfusion injury of the liver causes severe organ dysfunction after both extended liver resections and liver transplantation. In experimental models, ischemic preconditioning has repeatedly been shown to protect the liver from injury after warm and cold ischemia-reperfusion. Herein, we summarize the experimental and clinical evidence considering protection of tissue by ischemic preconditioning and we conclude that it is now time to initiate prospective randomized multicenter trials, in order to confirm the benefit of ischemic preconditioning for the patients undergoing major liver surgery and liver transplantation.