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).     

The mitochondrial permeability transition pore and its role in anaesthesia-triggered cellular protection during ischaemia-reperfusion injury

This review summarises the most recent data in support of the role of the mitochondrial permeability transition pore (mPTP) in ischaemia-reperfusion injury, how anaesthetic agents interact with this molecular channel, and the relevance this holds for current anaesthetic practice. Ischaemia results in damage to the electron transport chain of enzymes and sets into play the assembly of a non-specific mega-channel (the mPTP) that transgresses the inner mitochondrial membrane. During reperfusion, uncontrolled opening of the mPTP causes widespread depolarisation of the inner mitochondrial membrane, hydrolysis of ATP, mitochondrial rupture and eventual necrotic cell death. Similarly, transient opening of the mPTP during less substantial ischaemia leads to differential swelling of the intermembrane space compared to the mitochondrial matrix, rupture of the outer mitochondrial membrane and release of pro-apoptotic factors into the cytosol. Recent data suggests that cellular protection from volatile anaesthetic agents follows specific downstream interactions with this molecular channel that are initiated early during anaesthesia. Intravenous anaesthetic agents also prevent the opening of the mPTP during reperfusion. Although by dissimilar mechanisms, both volatiles and propofol promote cell survival by preventing uncontrolled opening of the mPTP after ischaemia. It is now considered that anaesthetic-induced closure of the mPTP is the underlying effector mechanism that is responsible for the cytoprotection previously demonstrated in clinical studies investigating anaesthetic-mediated cardiac and neuroprotection. Manipulation of mPTP function offers a novel means of preventing ischaemic cell injury. Anaesthetic agents occupy a unique niche in the pharmacological armamentarium available for use in preventing cell death following ischaemia-reperfusion injury.     

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.     

Effects of systemic and regional taurine on skeletal muscle function following ischaemia-reperfusion injury.

INTRODUCTION: Tissues subjected to prolonged ischaemia are paradoxically further damaged when their perfusion is restored. The mechanisms underlying this ischaemia-reperfusion injury are complex, but oxidative attack is a central feature. Among the therapeutic agents used to attenuate ischaemia-reperfusion injury, endogenous agents such as taurine which form part of the native defence mechanism against oxidative damage are of particular interest. METHODS: Using a model of hindlimb ischaemia-reperfusion injury in the rat, taurine solution was administered either into the operated hindlimb, into the systemic circulation, or both. Contraction strengths of gastrocnemius biopsies from the operated and contralateral (control) hindlimbs of each animal were measured. RESULTS: Fast twitch strength was impaired significantly by ischaemia-reperfusion injury, and taurine injected into the operated limb conferred partial protection. A similar trend was observed for tetany, but protection by taurine was not statistically significant for tetanic contraction strength. CONCLUSION: Preservation of fast twitch strength following ischaemia-reperfusion injury by administration of taurine before ischaemia has clinical potential. However, delivery to the affected tissues during ischaemia presents technical difficulties.     

Peri‐operative anaesthetic myocardial preconditioning and protection – cellular mechanisms and clinical relevance in cardiac anaesthesia

Preconditioning has been shown to reduce myocardial damage caused by ischaemia–reperfusion injury peri‐operatively. Volatile anaesthetic agents have the potential to provide myocardial protection by anaesthetic preconditioning and, in addition, they also mediate renal and cerebral protection. A number of proof‐of‐concept trials have confirmed that the experimental evidence can be translated into clinical practice with regard to postoperative markers of myocardial injury; however, this effect has not been ubiquitous. The clinical trials published to date have also been too small to investigate clinical outcome and mortality. Data from recent meta‐analyses in cardiac anaesthesia are also not conclusive regarding intra‐operative volatile anaesthesia. These inconclusive clinical results have led to great variability currently in the type of anaesthetic agent used during cardiac surgery. This review summarises experimentally proposed mechanisms of anaesthetic preconditioning, and assesses randomised controlled clinical trials in cardiac anaesthesia that have been aimed at translating experimental results into the clinical setting.     

Xenon - noble gas with organprotective properties

Besides it's anaesthetic properties, xenon may induce biological effects that may protect various organs from ischaemia-reperfusion injury. Xenon is an antagonist of the NMDA-receptor and reduces the neuronal injury mediated via these receptors. In contrast to other NMDA-receptor antagonists, xenon has no neurotoxic side effects. Xenon also protects the heart in ischaemia-reperfusion situations. Xenon reduces the post-ischaemic reperfusion injury and offers cardioprotection by inducing pharmacological preconditioning. These organ protective properties of xenon might be useful in special clinical situations.     

Mitochondria in anaesthesia and intensive care

Objective

Mitochondria play a key role in energy metabolism within the cell through the oxidative phosphorylation. They are also involved in many cellular processes like apoptosis, calcium signaling or reactive oxygen species production. The objectives of this review are to understand the interactions between mitochondrial metabolism and anaesthetics or different stress situations observed in ICU 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: mitochondria, anaesthesia, anaesthetics, sepsis, preconditioning, ischaemia, hypoxia.

Data synthesis

Mitochondria act as a pharmacological target for the anaesthetic agents. The effects can be toxic like in the case of the local anaesthetics-induced myotoxicity. On the other hand, beneficial effects are observed in the anaesthetic-induced myocardial preconditioning. Mitochondrial metabolism could be disturbed in many critical situations (sepsis, chronic hypoxia, ischaemia-reperfusion injury). The study of the underlying mechanisms should allow to propose in the future new specific therapeutics.     

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.     

Carotid endarterectomy; local or general anaesthesia?

OBJECTIVES: to review the evidence for theoretical and clinical benefits of local or general anaesthesia for carotid endarterectomy. METHODS: literature review. RESULTS: animal studies suggest cerebral protection by a variety of general anaesthetic agents but clinical evidence is lacking. There is some clinical evidence that normal cerebral protective reflexes are preserved with local anaesthesia. Shunt insertion is the most widely used method of providing cerebral protection with awake testing the most reliable monitoring technique for the identification of ischaemia. There are therefore theoretical arguments for a reduced risk of perioperative stroke when local anaesthesia is used and this is supported by a meta-analysis of non-randomised studies. Intraoperative blood pressure is always higher with local anaesthesia but the incidence of postoperative haemodynamic instability seems to be independent of anaesthetic technique. There is little evidence that myocardial ischaemia is more common with either anaesthetic technique but meta-analysis of non-randomised again suggests fewer cardiac complications with local anaesthesia. Cranial nerve injury and haematoma formation may be less common with local anaesthesia but the evidence is weak. There is no evidence that surgery is more difficult with local anaesthesia or that it is poorly tolerated by the patients. CONCLUSIONS: there are theoretical arguments and clinical evidence that the outcome from carotid endarterectomy may be better when local anaesthesia is used with no significant disadvantages. An appropriately designed randomised trial is required to confirm this.     

The cerebral protective effect of anaesthetics

The concept of cerebral protection refers to any prophylactic measure initiated before an ischaemic insult to improve the tolerance of the central nervous system to that insult. Theoretical strategies for protecting the brain proceed from pathophysiology and rely on both the metabolic and biochemical theories. Decreasing cerebral metabolism and, more importantly, preventing the cascade of biochemical events consecutive to cerebral ischaemia are central to this process. This article will consider the potential neuroprotective effect of anaesthetic agents. The tolerance to ischaemia appears to be better during anaesthesia than during the awake state. According to basic studies and experimental data, most of the anaesthetic agents share interesting properties consistent with the potential mechanisms of cerebral protection. However, experimental success does not automatically result in clinical benefit. Although cerebral protection seems to depend more on specific drugs and techniques, it cannot be concluded that anaesthetic agents play a substantial role as first choice adjuvants. Answering that question and defining the modalities of a neuroprotective anaesthetic is an exciting challenge for the future.     

Remote ischaemic conditioning: cardiac protection from afar

For patients with ischaemic heart disease, remote ischaemic conditioning may offer an innovative, non‐invasive and virtually cost‐free therapy for protecting the myocardium against the detrimental effects of acute ischaemia‐reperfusion injury, preserving cardiac function and improving clinical outcomes. The intriguing phenomenon of remote ischaemic conditioning was first discovered over 20 years ago, when it was shown that the heart could be rendered resistant to acute ischaemia‐reperfusion injury by applying one or more cycles of brief ischaemia and reperfusion to an organ or tissue away from the heart – initially termed ‘cardioprotection at a distance’. Subsequent pre‐clinical and then clinical studies made the important discovery that remote ischaemic conditioning could be elicited non‐invasively, by inducing brief ischaemia and reperfusion to the upper or lower limb using a cuff. The actual mechanism underlying remote ischaemic conditioning cardioprotection remains unclear, although a neuro‐hormonal pathway has been implicated. Since its initial discovery in 1993, the first proof‐of‐concept clinical studies of remote ischaemic conditioning followed in 2006, and now multicentre clinical outcome studies are underway. In this review article, we explore the potential mechanisms underlying this academic curiosity, and assess the success of its application in the clinical setting.     

Cardioprotection by breathing hyperoxic gas—relation to oxygen concentration and exposure time in rats and mice

Objectives: Breathing a hyperoxic gas (≥95% O₂) protects against ischaemia-reperfusion injury in rat and mouse hearts. The present study investigated how oxygen concentration and duration of hyperoxic exposure influenced cardioprotection, and whether hyperoxia might induce delayed cardioprotection (after 24 h). Methods: Animals were kept in normal air or in a hyperoxic environment, and their hearts were isolated and Langendorff-perfused immediately or 24 h thereafter. Global ischaemia was induced for 25 min in rats and 40 min in mice, followed by 60 min of reperfusion. Infarct size was determined by triphenyl tetrazolium chloride staining. Results: In rats exposure to ≥95, 80, and 60%, but not to 40% of oxygen immediately before heart isolation and perfusion improved postischaemic functional recovery. Eighty or more percent of oxygen also reduced infarct size. A preconditioning-like effect could be evoked by 60 or 180 min of hyperoxia, giving both immediate and delayed protection. In the mouse heart protection could be induced by pretreatment for 15 or 30, but not by 60 min with ≥95% oxygen. The protective effect of hyperoxia in mice could be evoked in the immediate model only. Conclusions: Hyperoxia protects the isolated rat and mouse heart against ischaemia-reperfusion injury, but some species-different responses exist. The protection depends on both oxygen concentration in inspired air, and duration of hyperoxic exposure.     

Therapeutic hypothermia

Hypothermia is common during anaesthesia and surgery owing to anaesthetic-induced inhibition of thermoregulatory control. Perioperative hypothermia is associated with numerous complications. However, for certain patient populations, and under specific clinical conditions, hypothermia can provide substantial benefits. Lowering core temperature to 32–34 °C may reduce cell injury by suppressing excitotoxins and oxygen radicals, stabilizing cell membranes, and reducing the number of abnormal electrical depolarizations. Evidence from animal studies indicates that even mild hypothermia provides substantial protection against cerebral ischaemia and myocardial infarction. Mild hypothermia has been shown to improve outcome after cardiac arrest in humans. Randomized trials are in progress to evaluate the potential benefits of mild hypothermia during aneurysm clipping and after stroke or acute myocardial infraction. However, as hypothermia can cause unwanted side-effects, further research is needed to better quantify the risks and benefits of therapeutic hypothermia.     

Effects of anaesthesia on thermoregulation

Hypothermia is a common and serious complication during anaesthesia and surgery. It mainly results from anaesthetic-induced inhibition of thermoregulatory control and exposure to cold operating room environment. Perioperative hypothermia develops in three distinct phases: (1) anaesthetic-induced vasodilation during induction of anaesthesia results in core-to-peripheral redistribution of body heat and decreases core temperature 1–1.5°C during the first hour of general anaesthesia; (2) subsequently core temperature decreases linearly as heat loss to the environment exceeds metabolic heat production; (3) after 3–5 h of anaesthesia, core temperature often stops decreasing. This core temperature plateau results from reactivation of thermoregulatory vasoconstriction which decreases cutaneous heat loss and constrains metabolic heat to the core thermal compartment. Perioperative hypothermia is associated with numerous complications such as myocardial ischaemia, increased risk of wound infection and coagulopathy. On the other hand temperatures only 1–3°C below normal provide substantial protection against cerebral ischaemia and hypoxaemia in numerous animal species. Consequently, most anaesthesiologists believe mild hypothermia is indicated during operations likely to cause cerebral ischaemia such as carotid endarterectomy and neurosurgery or cardiac procedures. Thermal perturbations, therefore, deserve the same risk/benefit analysis as other medical interventions. Fortunately, effective methods of cooling and warming surgical patients are now available.     

内质网应激与缺血后处理的心肌保护

内质网应激(endoplasmic reticulum stress,ERS)是细胞对各种伤害性刺激的适应性反应.在心肌缺血/再灌注(ischemia/reperfusion,I/R)过程中,过度的ERS引起心肌细胞凋亡导致心肌损伤.缺血后处理(ischemic postconditioning,I-postC)是心肌对抗I/R损伤的内源性保护现象,可通过多条信号转导途径发挥心肌保护作用,对ERS的调节是其重要方面.现将从ERS的角度探讨I-postC的心肌保护机制.     

内质网应激与缺血后处理的心肌保护

内质网应激(endoplasmic reticulum stress,ERS)是细胞对各种伤害性刺激的适应性反应.在心肌缺血/再灌注(ischemia/reperfusion,I/R)过程中,过度的ERS引起心肌细胞凋亡导致心肌损伤.缺血后处理(ischemic postconditioning,I-postC)是心肌对抗I/R损伤的内源性保护现象,可通过多条信号转导途径发挥心肌保护作用,对ERS的调节是其重要方面.现将从ERS的角度探讨I-postC的心肌保护机制.     

内质网应激与缺血后处理的心肌保护

内质网应激(endoplasmic reticulum stress,ERS)是细胞对各种伤害性刺激的适应性反应.在心肌缺血/再灌注(ischemia/reperfusion,I/R)过程中,过度的ERS引起心肌细胞凋亡导致心肌损伤.缺血后处理(ischemic postconditioning,I-postC)是心肌对抗I/R损伤的内源性保护现象,可通过多条信号转导途径发挥心肌保护作用,对ERS的调节是其重要方面.现将从ERS的角度探讨I-postC的心肌保护机制.     

Myocardial ischaemia and reperfusion injury: reactive oxygen species and the role of neutrophil

A growing body of evidence suggests that oxygen radicals can mediate myocardial tissue injury during ischaemia and, in particular, during reperfusion. This review focuses on the role of neutrophil as a mediator of myocardial damage. Upon reperfusion, neutrophils accumulate and produce an inflammatory response in the myocardium that is responsible, in part, for the extension of tissue injury associated with reperfusion. It has shown that the inhibition of neutrophil accumulation and adhesion is associated with decreased infarct size. This strongly suggests that myocardial cells at risk region undergo irreversible changes upon reperfusion and accumulation of neutrophils. Several pharmacological agents (ibuprofen, allopurinol, prostacyclin, and prostaglandin E analogues) protect the myocardium from reperfusion injury. In addition, the mechanisms by which these agents act and directions of research that may lead to therapeutically useful approaches are also discussed in this review.     

Hypertrophied hearts: what of sevoflurane cardioprotection?

Background: Recent studies have demonstrated that inhalation anaesthetics, like sevoflurane, confer cardioprotection both experimentally and clinically. However, coexisting cardiac disease might diminish anaesthetic cardioprotection and could partly explain why the clinical results of cardioprotection with anaesthetics remain controversial – in contrast to solid experimental evidence. Concomitant left ventricular hypertrophy is found in some cardiac surgery patients and could change cardioprotection efficacy. Hypertrophy could potentially render the heart less susceptible to sevoflurane cardioprotection and more susceptible to ischaemic injury. We investigated whether hypertrophy blocks sevoflurane cardioprotection, and whether tolerance to ischaemia is altered by left ventricular hypertrophy, in an established experimental animal model of ischaemia–reperfusion.
Methods: Anaesthetized juvenile pigs ( n =7–12/group) were subjected to 45 min distal coronary artery balloon occlusion, followed by 120 min of reperfusion. Controls were given pentobarbital, while sevoflurane cardioprotection was achieved by 3.2% inhalation throughout the experiment. Chronic banding of the ascending aorta resulted in left ventricular hypertrophy development in two further groups and these animals underwent identical ischaemia–reperfusion protocols, with or without sevoflurane cardioprotection. Myocardial infarct sizes were compared post-mortem.
Results: The mean myocardial infarct size (% of area-at-risk) was reduced from mean 55.0 (13.6%) (±SD) in controls to 17.5 (13.2%) by sevoflurane ( P =0.001). Sevoflurane reduced the infarct size in hypertrophied hearts to 14.6 (10.4%) ( P =0.001); however, in hypertrophic controls, infarcts were reduced to 34.2 (10.2%) ( P =0.001).
Conclusion: Sevoflurane abrogated ischaemic injury to similar levels in both normal and left ventricular hypertrophied hearts.     

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.