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

Minguet, G.*; Joris, J.*; Lamy, M.*

European Journal of Anaesthesiology: September 2007 - Volume 24 - Issue 9 - p 733–745
doi: 10.1017/S0265021507000531
Review
Free

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.

*University of Liège, Department of Anaesthesia and Intensive Care Medicine, Belgium

Correspondence to: Grégory Minguet, Department of Anaesthesia and Intensive Care Medicine, CHU de Liège, B35 Domaine Universitaire du Sart Tilman, B-4000 Liège 1, Belgium. E-mail: gminguet@chu.ulg.ac.be; Tel: +32 4 366 71 79; Fax: +32 4 366 76 36

Accepted for publication 9 March 2007

First published online 7 June 2007

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Introduction: myocardial preconditioning

Myocardial ischaemic preconditioning

In 1986, Murry and colleagues [1] described, for the first time, the phenomenon of ischaemic preconditioning in canine myocardium, an intrinsic mechanism of profound protection against ischaemia. Subjecting hearts to four brief ischaemic episodes (ligation of the circumflex coronary artery) interspersed with brief periods of reperfusion before a prolonged ischaemic insult reduced myocardial infarct size by 75%. Ischaemic preconditioning is associated with two forms of protection: an early phase immediately after the preconditioning ischaemia and lasting for approximately 2 h, and a delayed phase 1 day later and lasting for approximately 3 days [2]. Cardiac preconditioning represents a potent and consistently reproducible protection of the heart against irreversible ischaemic damage. The potential of clinical applications for this innate cardioprotective mechanism has therefore generated enormous interest [3].

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The cross-tolerance of preconditioning

A characteristic of ischaemic preconditioning is the cross-tolerance phenomenon. Various non-ischaemic stimuli can confer cellular tolerance to a subsequent major ischaemia by mechanisms similar to those mediating ischaemic preconditioning. Hyperthermia [4], stretching of the myocardial fibres [5], transient pacing [6,7], reactive oxygen species (ROS) [8] or elevated extracellular calcium [9] applied before ischaemia have been shown to precondition the myocardium. This cross-tolerance phenomenon provides the basis for pharmacological preconditioning that activates the signalling cascades of preconditioning at various levels. This can be elicited by volatile anaesthetics and a variety of ligand receptors (endothelin, δ-opiate, α-adrenergic) that increase protein kinase C (PKC) activity and drugs such as K(ATP) channel openers (e.g. nicorandil or cromakalim) [10].

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Myocardial anaesthetic preconditioning

Efficacy of anaesthetic preconditioning, first described in 1997 with isoflurane in animal [11,12], was then confirmed by several studies. Cardiac function is preserved and ischaemic damages are reduced by volatile anaesthetic exposure before the ischaemic insult. The signalling cascade and cytoprotective mechanisms involved were also widely investigated [3].

Despite the straightforward data obtained in experimental studies, results from clinical studies using anaesthetic preconditioning protocols show highly variable results [13]. Nevertheless, a recent meta-analysis of randomized trials comparing volatile with non-volatile anaesthesia in coronary artery bypass graft surgery suggests protection by volatile anaesthetics. Among 27 trials including almost 3000 patients, post-bypass patients randomized to receive volatile anaesthetics had an overall significantly higher cardiac index, lower troponin serum concentrations and lesser requirement for inotropic support compared with those randomized to receive intravenous anaesthetics [14].

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Mechanisms of ischaemic and anaesthetic preconditioning

The mechanisms of preconditioning are not the purpose of this article and have been extensively reviewed elsewhere [2,3].

Most recent studies have identified mitochondria to play a pivotal role in ischaemic and anaesthetic preconditioning. Both transient ischaemia and volatile anaesthetic exposure have been shown to induce several key events in the mitochondrion that involve modulation of electron transport chain, calcium homeostasis, ROS generation, ATP-dependent potassium channels and mitochondrial permeability transition pore.

During ischaemic preconditioning, small amounts of ROS are produced from electron transport chain and constitutes an initial important triggering mechanism in the preconditioning stimulus [2]. Similarly, anaesthetic preconditioning appears to imply ROS generation through inhibition of electron transport chain, probably at the level of complex I and/or III [13]. The sequence of events that occur after ROS release involve activation of several kinases such as protein tyrosine kinases, mitogen-activated protein kinases (MAPK) and PKC, the later playing a crucial role in amplifying the preconditioning stimulus by phosphorylation and activation of mitochondrial K(ATP) channels [3].

The actual intracellular effects of mitochondrial K(ATP) channel opening are not fully understood. However, membrane depolarization caused by K(ATP) channel opening and potassium influx in the mitochondrial matrix could have several fundamental protective effects. First, membrane depolarization may increase by a feedback loop the production of ROS in the respiratory chain [15,16]. In addition, slight depolarization of membrane potential appears protective through decrease of the electrochemical gradient for calcium entry, which inhibits mitochondrial calcium overload during ischaemia and reperfusion [17]. This effect of ischaemic and anaesthetic preconditioning may contribute importantly to delay calcium-induced membrane permeability transition pore opening that occurs during prolonged ischaemia [18]. This is important since opening of these large pores in the mitochondrial membranes causes matrix swelling, membrane potential collapse, uncoupling of the respiratory chain, efflux of Ca2+ and release of small proteins triggering apoptosis such as cytochrome c, events that are thought to contribute to cell death after ischaemia and reperfusion. An additional consequence of small depolarization of the inner mitochondrial membrane may result in modulation of mitochondrial energetics and respiration [19]. Preconditioning is thought to lead to an improved oxygen efficiency and a decreased energy consumption (ATP sparing effect) during ischaemia [13], whereas during the reperfusion period, preconditioned mitochondria manifest a faster normalization of oxidative phosphorylation and ATP synthesis as well as a decrease in the excess of deleterious ROS produced [20].

A question that remained unanswered until recently is whether volatile anaesthetic exposure can elicit a delayed window of protection-like ischaemic preconditioning (i.e. late preconditioning). In late ischaemic preconditioning, chemical signals released by the stress of ischaemia, such as ROS, are transduced by signalling elements including PKC and NF-κB to the nucleus where they initiate the transcription of protective genes such as NO synthase (NOS), cyclooxygenase (COX)-2 and aldose reductase [21]. Similarly, ROS generation by volatile anaesthetics is responsible for inducing delayed cardioprotection probably through the synthesis of cardioprotective genes that protect the heart against subsequent delayed ischaemia [22]. In support of this hypothesis, volatile anaesthetics have been shown to initiate the synthesis of early response genes, including NF-κB [23] and proteins involved in ischaemic preconditioning-induced delayed cardioprotection such as COX-2 [24]. Part of this signalling pathway may converge to the K(ATP) channels, whose activation contributes not only to an early but also delayed preconditioning [25].

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Preconditioning in non-cardiac tissues

Ischaemia-reperfusion has clinical relevance beyond the heart and profound protection by ischaemic preconditioning has been observed in a wide variety of organs. Furthermore, the cross-tolerance phenomenon of preconditioning is such that different non-pharmacological and pharmacological interventions that activate common signalling cascades can be used to reproduce the profound protection seen with ischaemic preconditioning.

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Blood vessels

In the heart, there is an abundant evidence that ischaemic preconditioning protects the structural and functional integrity of endothelial cells and that this is importantly associated with preservation of the vasodilating capacity of the coronary vasculature after ischaemia and reperfusion [26,27]. In addition, ischaemic preconditioning of blood vessels is known to reduce endothelial intercellular adhesion molecule-1 (ICAM-1) production, therefore reducing the risk of leucocyte entrapment in the vasculature and leucocyte-mediated injury [28]. Moreover, during transient ischaemia, the locally released adenosine acts via specific receptors within the leukocytes to inhibit their activation and their interaction with the vascular endothelium [29]. Additionally, adenosine acts as a potent inhibitor of platelet aggregation, which has been shown to attenuate platelet-mediated thrombosis in damaged coronary arteries [30]. Therefore, ischaemic preconditioning of blood vessels has the potential to afford protection against vascular injury and can prevent endothelial contribution to pro-inflammatory and thrombogenic events associated with ischaemia-reperfusion injury [28]. Importantly, ischaemic preconditioning may even exert longer-term cardiovascular effects over and above the classic early and delayed windows of protection, as brief ischaemic episodes improve endothelial function for up to 1 month in animal models [27,31].

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Lung

Ischaemia-reperfusion of the lung is still a clinical problem, particularly after cardiopulmonary bypass or lung transplantation. The main complication in ischaemia-reperfusion lung injury is dysfunction of the pulmonary vascular endothelium, manifested by pulmonary hypertension, increased vascular permeability, pulmonary oedema and impaired gas exchange [32]. After cardiopulmonary bypass, this may clinically manifest as acute lung injury or acute respiratory distress syndrome, which are associated with prolonged mechanical ventilation, increased morbidity and mortality [33]. After lung transplantation, the most severe form of injury may lead to primary graft failure that frequently leads to death or prolonged mechanical ventilation [34].

Various types of preconditioning have been used in vivo to protect the lung from ischaemia-reperfusion injury. Ischaemic preconditioning, hyperthermic preconditioning and pharmacological preconditioning have been shown to be successful in reducing lung injury in experimental models [34]. In the rabbit, pharmacologic preconditioning with pinacidil, an ATP-sensitive potassium channel opener, provided protection against warm ischaemia-reperfusion injury associated with lung transplantation [35]. In a porcine model of normothermic pulmonary ischaemia, preconditioning by nitric oxide inhalation was protective against ischaemia-reperfusion injury as evidenced by a delayed production of ROS and prevention of pulmonary hypertension and hypoxaemia at reperfusion [36]. However, despite encouraging results from experimental studies, the role of lung peconditioning remains unproven in clinical practice.

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Kidney

Renal failure is a common clinical problem associated with some surgical procedures like kidney transplantation or abdominal aortic aneurysm surgery that induce ischaemia-reperfusion injury of the kidney. Renal ischaemia-reperfusion injury is associated with frequent morbidity and mortality [37,38]. Furthermore, the risk of acute renal failure is significantly increased in patients with impaired preoperative renal function [39]. Therefore, improving the ability of the kidney to tolerate ischaemia-reperfusion injury would have important clinical implications.

Zager and colleagues [40,41] performed the first experiments indicating that proximal tubules isolated 24 hours after an ischaemic episode were protected not only against hypoxia, but also against ROS, or calcium ionophore in vitro. More recently, ischaemic preconditioning of the kidney has been confirmed to protect against subsequent ischaemic exposure in numerous experimental studies [42]. In addition, the cross-tolerance phenomenon of preconditioning has been described in the kidney as demonstrated by the protective effect of sublethal doses of lipopolysaccharide before ischaemic insult [43]. Preconditioning with hyperthermia was also shown to induce ischaemic tolerance in rat models of kidney transplantation with improvement of graft function and animal survival [44]. Moreover, pharmacological preconditioning of the kidney has been rendered possible with administration of adenosine and adenosine receptor agonists [45,46] as well as agents such as cyclosporine or FK 506 used as immunosuppressants in kidney transplant recipients [47]. Nevertheless, despite evidences that preconditioning of the kidney is a useful strategy for renal protection in the experimental setting, it has not yet been shown effective in humans [48].

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Liver

Ischaemia-reperfusion injury may be involved in intraoperative and postoperative hepatic dysfunction such as in liver transplantation, in hepatic surgery requiring repeated cross-clamping of the portal vein and hepatic vascular exclusion, and in haemorrhagic or septic shock [49]. In liver transplantation, ischaemia-reperfusion injury may result in severe graft dysfunction or non-function such that patients have to undergo retransplantation [50]. In hepatectomy, diseased livers with steatosis or fibrosis poorly tolerate ischaemia-reperfusion injury and can develop liver failure even after short periods of ischaemia, with a risk of poor postoperative outcome [51].

Several studies in rodent models have shown significant protection from ischaemic preconditioning of the liver, including increased animal survival after prolonged periods of hepatic ischaemia [52]. Clavien and colleagues provided the first evidence that ischaemic preconditioning may protect against ischaemic injury to the human liver during surgery for hepatectomy, as demonstrated by a significant lower transaminase level at reperfusion in preconditioned group [51,53]. Furthermore, ischaemic preconditioning of the liver was found to provide better intraoperative haemodynamic stability during surgery for hepatectomy [54]. Very recently, ischaemic preconditioning of liver from cadaver donors prior to transplantation was shown to protect allograft and to result in a reduction in the inflammatory markers associated with reperfusion injury [50]. Interestingly, experimental studies suggest that induction of preconditioning may also be elicited by non-ischaemic stimuli such as hyperthermia [55]. Various chemical agents, among which beta-1 adrenoreceptor agonists or doxorubicin, also induce ischaemic tolerance to the liver, reflecting a potential means for pharmacological preconditioning of hepatocytes [56,57].

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Intestine

Ischaemia-reperfusion injury of the intestine is associated with a variety of pathologic conditions and surgical procedures, including abdominal aortic aneurysm surgery, cardiopulmonary bypass, strangulated hernias, neonatal necrotizing enterocolitis and intestinal transplantation. A key consequence of intestinal ischaemia-reperfusion injury is the breakdown of intestinal barrier function, which normally protects the body from the hostile environment within the bowel lumen. Thus, in addition to impaired gut motility and absorption, ischaemia-reperfusion injury is associated with increased intestinal permeability and bacterial translocation into the portal and systemic circulation. This is thought to contribute to the development of a systemic inflammatory response syndrome, multiple organ dysfunction syndrome and death [58,59].

As already described in other organs, ischaemic preconditioning of the intestine has been found to be the most promising strategy against ischaemia-reperfusion injury [58]. In the intestine, ischaemic preconditioning was first described by Hotter and colleagues and subsequent animal studies have confirmed this phenomenon [60]. Although prospective controlled studies in humans involving ischaemic preconditioning of the intestine are lacking, numerous experimental data suggest that intestinal preconditioning may have a potential impact on clinical practice [58]. For instance, ischaemic preconditioning has been reported by several authors to protect against ischaemia-reperfusion injury associated with rat intestinal transplantation [61,62]. In addition, ischaemic preconditioning may importantly limit the systemic consequences of intestinal ischaemia-reperfusion injury. Indeed, in rat models, ischaemic preconditioning of the intestine decreases the translocation of bacteria from the intestine after ischaemia-reperfusion injury [63]. Intestinal ischaemic preconditioning before haemorrhagic shock markedly reduces the systemic inflammatory response and distant organ injury [64]. Furthermore, other forms of preconditioning such as hyperthermia or pharmacologic agents including morphine have successfully been applied to reduce intestinal damage in rat models [65,66].

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Central nervous system

Brain

Ischaemia-reperfusion injury of the brain is involved in many common human diseases such as stroke, traumatic head injury and various surgical procedures among which include carotid endarterectomy, intracranial aneurysm exclusion or aortic repair under deep hypothermic circulatory arrest. Central nervous system ischaemia-reperfusion injury may clinically manifest as significantly worsened sensory, motor, cognitive functioning or death [59]. Although multiple strategies or interventions have been proposed or used to reduce ischaemia-reperfusion-induced cell death, clinically practical methods to reduce ischaemic brain injury and to improve outcome are not yet well established [67].

In the brain, there is a substantial evidence supporting the existence of ischaemic preconditioning in animal models [68]. In a variety of species and models of ischaemia, a prior ischaemic insult in the brain is associated with protection from infarction resulting from a second insult [69]. Clinical studies have suggested that ischaemic preconditioning may also occur in the human brain. Several authors reported that transient ischaemic attack before ischaemic stroke in the same vascular territory is associated with milder initial clinical symptoms and more favourable outcome in stroke, a protective effect attributable to ischaemic preconditioning [70]. A number of additional stimuli have been identified which also can induce ischaemic tolerance, among them short episodes of hypoxia, hyperthermia and lipopolysaccharide exposure [71-73]. Furthermore, pharmacological agents that mimic the potent protective mechanism of ischaemic preconditioning of the brain are now available. For instance diazoxide, an opener of mitochondrial K(ATP) channels, confers neuroprotection in a rat middle cerebral artery occlusion model [74].

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Spinal cord

In the spinal cord, ischaemia-reperfusion injury can result in devastating complications such as neurological deficits and paraplegia. Spinal cord injury after perioperative ischaemia is a well known complication of thoracic and thoracoabdominal aortic surgery for coarctations, dissections or aneurysms [75].

In animal models of spinal cord ischaemia by thoracic aortic occlusion, there is evidence that ischaemic preconditioning reduces neuronal injury and improves neurological outcome [75,76]. Mimicking ischaemic preconditioning with pharmacological agents such as openers of mitochondrial K(ATP) channels (i.e. diazoxide), has been shown to reduce neurological injury after aortic cross-clamping in animal models of spinal cord ischaemia [77]. Hyperthermia [78], hyperbaric oxygen [79] or epidural electrical stimulation [80] are other forms of preconditioning that were also found to protect animal spinal cord to ischaemia-reperfusion injury.

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Anaesthetic preconditioning in non-cardiac tissues

Due to the mechanisms shared by anaesthetic preconditioning and other forms of preconditioning, one may speculate that volatile agents should provide a protective effect, not only on the myocardium, but on a far wider variety of tissues [10]. This is the reason why, over the last years, researcher groups have looked on the extent to which tissues other than myocardium share the beneficial effects of anaesthetic preconditioning and have attempted to define the extent of protection.

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Blood vessels

Experimental findings have pointed to a volatile anaesthetic preconditioning pathway involving an inhibition of inflammatory cells, i.e. neutrophils, and a reduction of their interaction with the vascular endothelium after ischaemia-reperfusion [81]. Hu and colleagues [82] demonstrated that neutrophils pretreated with either isoflurane or sevoflurane lost their ability to cause contractile dysfunction in isolated rat hearts and that this was associated with a reduction of neutrophil adherence to the endothelium. This effect is consistent with observations of a down-regulation of expression of CD11/CD18 (the counterligand to the endothelial adhesion molecule ICAM-1) on the surface of the neutrophils when pretreated with volatile anaesthetics [83]. Neutrophil adenosine receptor system may have a key role in this potent protective mechanism induced by volatile anaesthetics. Exposure of neutrophils to volatile anaesthetics before ischaemia and reperfusion seem to activate adenosine receptors that may lead to reduction of neutrophil adherence within the coronary bed, neutrophil superoxide and myeloperoxydase production and neutrophil-induced myocardial dysfunction [81]. Thus, the concept that emerges from experimental studies is that preconditioning with volatile anaesthetics activates an anti-inflammatory effect on polymorphonuclear neutrophils leading to a reduction of organ dysfunction after ischaemia-reperfusion injury.

In addition to an effect on neutrophils, preconditioning with brief exposure to volatile anaesthetic seems to protect against endothelial and vascular dysfunction that occurs after ischaemia and reperfusion. Novalija and colleagues [84] demonstrated that sevoflurane exposure before ischaemia of isolated hearts mimicked ischaemic preconditioning and resulted in endothelial protection thus improving microcirculatory flow and endothelial nitric oxide production during the reperfusion period. Similar significant microvascular protection by volatile anaesthetics was demonstrated in another recent study in which pretreatment with isoflurane had early and delayed protective effects against cytokine-induced injury in endothelial and vascular smooth muscle cells [85]. Furthermore, volatile anaesthetics have been shown to inhibit platelet adhesion to the vascular wall after ischaemia [86,87] and the ability of platelets to enhance neutrophil-induced vascular endothelial dysfunction in coronary circulation [88]. In these experiments however, volatile anaesthetics were not administered as a preconditioning protocol.

The abovementioned experimental studies seem to have found consistency with the results of a recent prospective randomized clinical study in which preconditioning with sevoflurane was associated with decreased expression of platelet-endothelial cell adhesion molecule-1 (PECAM-1) and improvement in 1-year cardiovascular outcome after coronary artery bypass graft surgery [89].

In summary, the endothelial protection provided by volatile anaesthetics during ischaemia-reperfusion adds to their effects on polymorphonuclear neutrophils and platelets to have profound implications with regard to maintaining vascular integrity during the stressful period of reperfusion. Such protection of anaesthetic preconditioning at the vascular level is one of the mechanisms of its organ protection and because blood vessels are responsible for the supply of nutrients and oxygen to all tissues, anaesthetic preconditioning might beneficially affect a much wider variety of organs than myocardium [90].

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Lung

Volatile anaesthetics exhibit a protective effect on the lung in several experimental circumstances. In a mouse model of multiple organ dysfunction syndrome, isoflurane attenuated lung inflammation and injury, probably due to modulation of the inflammatory response by volatile anaesthetics [91]. A recent study by Reutershan and colleagues [92] tends to confirm these protective anti-inflammatory effects of isoflurane in a mouse model of endotoxin-induced acute lung injury. Halothane afforded an anti-inflammatory protection in a similar model of endotoxin-induced lung injury [93]. Moreover, the protective effect of volatile anaesthetics might even extend to the pulmonary vasculature. This was evidenced by a study indicating reduction in the H2O2-induced endothelial injury in the rat pulmonary artery with low halothane concentrations, although higher concentrations of the volatile anaesthetic may induce toxic effects [94].

In the setting of lung ischaemia-reperfusion injury, a potential for protection with volatile anaesthetics emerged recently. In a study by Liu and colleagues [32], isoflurane administered before ischaemia or during reperfusion protected isolated rabbit lungs as indicated by a significant attenuation in the increase in vascular permeability, pulmonary oedema and pulmonary vascular resistances. Subsequently, this group demonstrated that preconditioning with isoflurane and sevoflurane protected isolated rat lung through inhibition of TNF-α release, an essential component of the cascade of events that leads to ischaemia-reperfusion-induced lung injury. Anaesthetic preconditioning also resulted in a diminished production of nitric oxide metabolites, reduced reperfusion-induced lung oedema and reduced vascular permeability [95]. Although the isolated lung preparation by Liu and colleagues brought encouraging results about preconditioning of the lung with volatile anaesthetic administration, such an isolated lung model does not show many features associated with an actual lung injury. These artificial features make it difficult to extrapolate these findings to the clinical situation. Further studies using in vivo experimental preparations, in addition to clinical studies, are now warranted to define the exact role of preconditioning with volatile anaesthetics against lung ischaemia-reperfusion injury.

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Kidney

Recent experimental studies showed promising results about renal protection with volatile anaesthetics. Indeed, clinically relevant concentrations (1 MAC) of volatile anaesthetics (sevoflurane, desflurane, isoflurane and halothane) given both during and after renal ischaemia protected against ischaemia-reperfusion injury by dramatically reducing tubular necrosis in rats kidney [39]. Attenuation of inflammatory cascades by volatile anaesthetics most likely contributed to the reduction in renal dysfunction after ischaemia-reperfusion. In addition, exposure to isoflurane before renal ischaemia and reperfusion appeared to have a preconditioning effect through modulation of MAPKs and significantly reduced the damage of tubular necrosis in the rat [38]. In contrast to these findings, however, a study by Obal and colleagues [37] did not find sevoflurane preconditioning to protect the rat kidney from ischaemia-reperfusion injury. In clinical practice, a potential for renal protection with volatile anaesthetics was illustrated in a recent study by Julier and colleagues [96]. Their group showed that sevoflurane pretreatment (2 MAC for 10 min) before cardiopulmonary bypass for coronary artery bypass grafting surgery markedly improved the postoperative glomerular filtration rate, as determined by plasma concentrations of cystatin C. However, at present, due to the absence of clinical trials it remains unclear to what extent preconditioning with volatile anaesthetics may prevent manifestation of clinical renal disease such as renal failure or the need for mechanical renal support in high risk situations.

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Liver

The ability to precondition the liver with volatile anaesthetics remains to be investigated. It has been shown that the volatile anaesthetic isoflurane may preserve energy balance (ATP stores) in isolated rat hepatocytes during in vitro anoxic challenge [97,98]. This energy sparing effect of volatile anaesthetics may contribute to a preservation of liver cell function and viability in situations associated with energy supply deficiency. In isolated rat livers, 2 MAC of the volatile anaesthetics halothane, isoflurane and sevoflurane, not only decreased basal O2 consumption, but also protected against hepatic ischaemia-reperfusion injury as evidenced by a reduction in lactate dehydrogenase release during the reperfusion period [49]. In a similar model of isolated rat liver, 1 and 2 MAC isoflurane reduced hypoxia-reoxygenation injury and attenuated deleterious ROS generation during the reperfusion period [99]. Recent experiments demonstrated that isoflurane and sevoflurane induced haeme oxygenase 1 (HO-1) expression in the rat liver [100,101]. The enzyme HO-1, previously identified as the heat shock protein 32 (HSP 32), plays a major protective role in the stress-exposed liver and has been shown to limit reperfusion injury after experimental systemic and regional hepatic ischaemia [102,103]. Therefore, one might speculate that the induction of HO-1 by volatile anaesthetics is part of a preconditioning effect and that pretreatment with these agents may be beneficial in attenuating subsequent ischaemia-reperfusion injury of the liver. Indeed, HO-1 expression has already been shown to be involved in the beneficial effects of preconditioning with transient ischaemia, hypoxia, hyperthermia or pharmacologic agents, in the liver and other organs [57,104-108]. In a human hepatoma cell line in vitro, isoflurane has been shown to up-regulate hypoxia-inducible factor-1 (HIF-1), a transcription factor that acts as a master regulator of gene expression in adaptive response to hypoxic stress. This effect of isoflurane was associated with expression of protective genes in hepatocytes such as HO-1, inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) [109]. Importantly, similar HIF-1-dependent gene activation has previously been associated with infarct size reduction by isoflurane preconditioning in a rat model of myocardial ischemia [110]. Therefore, an increasing body of evidence from experimental studies is accumulating that indicates a potential role for volatile anaesthetic administration to protect the liver against ischaemia-reperfusion injury. Clinical trials are now required to evaluate the impact of anaesthetic preconditioning on liver function and outcome in clinical circumstances associated with ischaemia-reperfusion of the human liver.

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Intestine

The role of volatile anaesthetics on intestinal ischaemia-reperfusion injury has not been investigated. Data available are limited to the effects of volatile anaesthetics on splanchnic circulation. In dogs, it has been suggested that desflurane maintains intestinal blood flow, while halothane and isoflurane decreased it during systemic hypotension associated with general anaesthesia [111]. Using laser doppler flowmetry, O'Riordan and colleagues [112] have shown that during major surgery, desflurane anaesthesia at 1 MAC was associated with a significantly greater gut flow than 1 MAC isoflurane, suggesting that desflurane anaesthesia may be beneficial, particularly in high-risk patients. In addition, experimental studies support a potential role for volatile anaesthetics in reduction of deleterious leucocyte-endothelial interactions in mesenteric microcirculation after lipopolysaccharide or TNF-α challenge [113,114]. One may speculate that similar phenomenon might benefit the intestine during conditions associated with ischaemia-reperfusion-induced inflammation.

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Central nervous system

Brain

There is evidence that volatile anaesthetics applied during cerebral ischaemia confer neuroprotection as demonstrated by a large number of studies in which volatile anaesthetics reduced ischaemic injury in models of global, focal and hemispheric ischaemia [115-117]. This neuroprotective effect observed with volatile anaesthetics has long been thought to be attributable to the profound reduction in cerebral metabolic rate produced by these agents at clinical concentrations [118]. Nowadays, most of the mechanisms proposed for the protective qualities of volatile anaesthetics such as isoflurane have focused on their action on ion channels that contribute to excitotoxic death associated with accumulation of glutamate in the extracellular space during ischaemia. Indeed, isoflurane has been shown in vitro to be an antagonist of glutamate receptors [119,120], a γ-aminobutyric acid (GABA-A) receptor agonist that can serve to diminish glutamate excitotoxicity [121] and an inhibitor of glutamate release during ischaemia [122]. All these properties are presumed to contribute to reduced necrotic cell death during ischaemia [123]. However, in most of the aforementioned investigations on neuroprotection by volatile anaesthetics, the recovery period after initiation of ischaemia has been relatively short (less than several days), whereas recent studies suggest that ischaemic injury is a dynamic process characterized by ongoing neuronal loss for at least 14 days after ischaemia [124,125]. Thus, whether volatile anaesthetic neuroprotection, evident early after ischaemia, is sustained after a much longer recovery period remains a subject of controversy [126]. Indeed, isoflurane reduced neuronal injury within the hippocampus of rats subjected to global cerebral ischaemia when the injury was evaluated 5 days later, but when the injury was evaluated 3 weeks or 3 months after insult, no difference could be detected [127]. These results were consistent with those previously published by Kawaguchi and colleagues [128] who demonstrated that isoflurane-mediated neuroprotection, apparent 2 days after ischaemia, was not sustained 2 weeks later.

Recent investigations have focused on an alternative promising pathway leading to neuroprotection by volatile anaesthetic administration before ischaemia instead of administration during ischaemia, inducing both early and late preconditioning in the brain. In a rat brain slice model, isoflurane preconditioning 15 min before oxygen-glucose deprivation (to simulate ischaemia) is neuroprotective through modulation of glutamate transporter activity [129]. Isoflurane pretreatment (1.5% for 30 min) immediately before cardiac arrest-induced global cerebral ischaemia (for 8 min) ameliorated neurological dysfunction in dogs [130]. Furthermore, sevoflurane conferred not only an early (at 15 min) but also a late (at 24 h) preconditioning protection against hypoxic neuronal injury, via mitochondrial K(ATP) channel activation [131]. Rats pretreated with isoflurane 24 h before permanent middle cerebral artery occlusion had smaller infarct sizes even when evaluated up to 4 days after onset of ischaemia [132]. In a rat model of focal cerebral ischaemia initiated 24 h after isoflurane anaesthesia, Zheng and Zuo [67] demonstrated a sustained 14 days neuroprotective effect of the volatile anaesthetic pretreatment on both neurological function and neuronal viability. It therefore appears that as opposed to the short term neuroprotective effect of volatile anaesthetic administration during ischaemia, volatile anaesthetic pretreatment may confer not only an early but also late preconditioning that leads to sustained neuroprotection long after experimental anaesthesia has terminated. However, the question remains whether preconditioning can also be induced in human brain to elicit neuroprotection in cases in which damages to the central nervous system are anticipated (e.g. neurosurgery, cardiac surgery or delayed vasospasm after subarachnoid haemorrhage) [132].

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Spinal cord

A potential role for anaesthetic preconditioning as a pharmacological strategy to protect the spinal cord against ischaemic insult has been shown recently. In a rabbit model of transient spinal cord ischaemia, preconditioning with isoflurane at 0.5, 1.0 and 1.5 MAC protected against early ischaemic neuronal damage in a dose-response manner via the activation of mitochondrial K(ATP) channels [133]. A recent similar study further demonstrated that repeated inhalation with 1.0 MAC isoflurane induced a delayed phase (up to 48 h after anaesthetic exposure) of ischaemic tolerance to transient spinal cord ischaemia that manifested as improvement of neurological (hind-limb motor function) and histopathologic outcomes [134]. These findings suggest that preconditioning with isoflurane induces early and delayed ischaemic tolerance in the spinal cord as well as in the brain. Conversely, anaesthetic preconditioning with sevoflurane did not reduce neurological injury in a rat model of spinal cord ischaemia whereas ischaemic preconditioning had a strong protective benefit on neurological outcome [135].

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Conclusion

Preconditioning in non-cardiac tissues affords considerable protection against ischaemia-reperfusion injury as previously demonstrated with cardiac preconditioning. The preconditioning stimulus may be non-pharmacological or pharmacological; however, in clinical anaesthesia and surgery, pharmacological preconditioning is a more suitable and practical way to protect organs against ischaemia-reperfusion. Volatile anaesthetics commonly used in clinical practice may have a place to take among the pharmacological strategies of preconditioning. Numerous experimental studies suggest that volatile anaesthetics may protect beyond the heart various tissues and organs subjected to ischaemic insult. Clinical studies are now warranted to define the role of anaesthetic preconditioning in non-cardiac tissue which, if conclusive, would be of significant relevance for reduction of perioperative ischaemic organ damage and its related morbidity and mortality.

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Keywords:

ANAESTHESIA: ANAESTHETICS INHALATION; ISCHAEMIA-REPERFUSION; MITOCHONDRIA; ISCHAEMIC PRECONDITIONING

© 2007 European Society of Anaesthesiology