Unresolved acute coronary occlusion will cause myocardial necrosis. Its extent depends on the size of the area at risk, the collateral circulation and the degree and duration of the ischaemic insult. Early restoration of blood flow is, therefore, necessary to prevent myocardial cell death and subsequent postinfarction myocardial dysfunction from occuring. However, also upon reperfusion myocardial dysfunction may occur, which is termed reperfusion injury (Fig. 1). This may manifest as arrhythmias, reversible contractile and endothelial dysfunction. Ultimately, irreversible reperfusion injury may occur, which is defined as injury caused by the restoration of blood flow to an ischaemic area leading to death of cells that were only reversibly injured during the ischaemic episode. Therefore, treatment of myocardial ischaemia should not only be directed towards restoration of blood flow but also should include measures to minimize the extent of reperfusion injury. Protective measures against such events can be subdivided into three phases: measures taken before the period of myocardial ischaemia, measures during the ischaemic period and measures instituted after the ischaemic period. For years, the maintenance of a favourable myocardial oxygen balance has been the cornerstone of perioperative myocardial protective strategies. Although this is still true, there is now both experimental and clinical evidence that strategies modulating different steps involved in the pathophysiology of ischaemia–reperfusion injury may have direct protective actions.
Pathophysiology of ischaemia–reperfusion injury
Lethal reperfusion injury is a complex phenomenon that consists of several steps at subcellular levels. In recent years, the pivotal role of the mitochondria has increasingly become apparent. Mitochondria are indeed essential for cell survival because of their roles as metabolic energy producers and as regulators of programmed cell death. It is beyond the scope of this discussion to treat the different mechanisms of ischaemia–reperfusion injury in detail and the reader is referred to various review papers on the subject [1–13]. Although most of the deleterious effects of reperfusion injury are triggered within the first minutes of reperfusion, it is important to realize that the cellular disturbances occurring at the time of reperfusion are also determined by the ischaemia-induced alterations.
Briefly, during ischaemia, anaerobic glycolysis results in a progressive accumulation of protons and lactic acid, ultimately inhibiting synthesis of adenosine triphosphate (ATP). The cardiomyocyte attempts to correct acidosis via the Na+/H+ exchanger and the cell will consequently load with Na+, which can not be extruded anymore from the cytosol because of failure of Na+/K+ ATPase due to the lack of ATP. Activation of the Na+/Ca2+ exchanger in its reverse mode will help to pump some of the Na+ out of the cell but this will occur at the expense of an accumulation of Ca2+ in the cytosol. Prolonged ischaemia will induce progressive failure of the ionic homeostasis and further decline in the ATP stores, which will eventually cause cytosolic accumulation of Na+ and Ca2+ and ischaemic contracture.
Upon reperfusion, a rapid correction of the acidosis will occur via the Na+/H+ exchanger, the Na+/HCO3− symporter and the washout of lactate. This will, however, also activate the Na+/Ca2+ exchanger, which will aggravate cytosolic Ca2+ accumulation.
At the level of the mitochondria, the abrupt reexposure after the ischaemic event of the mitochondrial respiratory chain to oxygen will generate a massive production of oxygen-derived free radicals and lead to a rapid overload of Ca2+ in the mitochondrial matrix. These two factors constitute the major triggers of the opening of the mitochondrial permeability transition pore (mPTP). In normal physiological conditions, the mPTP is closed and the mitochondrial inner membrane is impermeable to almost all metabolites and ions. During ischaemia, the mPTP is suppressed by the acidosis and the depressed electron transport. During reperfusion, the reoxygenation and the resumption of the electron transport triggers a burst of oxygen free radicals at the same time that intracellular Ca2+ is elevated and adenine nucleotides are depleted. These factors promote mPTP opening. When the mPTP opens, it allows equilibration of molecules less than 1500 Da and the osmotic force of the matrix proteins will result in matrix swelling ultimately leading to rupture of the mitochondrial outer membrane. The fate of the cell will be determined by the extent of mPTP opening. If this is limited, the cell may recover; if this is moderate, the cell may either recover or undergo programmed cell death and if it is severe, the cell may die from necrosis as a consequence of inadequate energy production (Fig. 2).
Myocardial oxygen balance
Myocardial O2 demand depends on heart rate, myocardial contractility and ventricular loading conditions, whereas myocardial O2 supply depends on the adequacy by which the blood is capable of providing sufficient oxygen to the different regions of the ventricles. Whenever myocardial O2 demand exceeds regional O2 supply, myocardial ischaemia may occur. Classical treatment, therefore, aims on the one hand to increase coronary blood flow to the ischaemic areas, while maintaining adequate blood flow to the unaffected areas and on the other hand targets to decrease the determinants of myocardial oxygen consumption.
The application of perioperative β-blocking agents has gained wide interest since the initial observations of Mangano et al.  and Poldermans et al. , suggesting a better postoperative outcome after surgery in patients on β-blocking therapy. Proposed mechanisms for this protective action relate to an action of coronary plaque formation and the prevention of perioperative plaque rupture  (Fig. 3). Subsequently, these positive findings have been challenged by studies that failed to observe such protective actions [17–20]. The recent data of the Perioperative Ischemic Evaluation (POISE) trial even indicated that the beneficial effect of perioperative metoprolol therapy on the primary outcome variable (incidence of 30-day composite events of cardiovascular mortality, nonfatal myocardial infarction and nonfatal cardiac arrest) and myocardial infarction rate was counterbalanced by the occurrence of a higher incidence of stroke and total 30-day mortality compared with the placebo-treated patient group . A recent meta-analysis  of 33 trials including 12 306 patients indicated that β-blockers were not associated with any significant reduction in the risk of all-cause mortality, cardiovascular mortality or heart failure. The observed decrease in nonfatal myocardial infarction and myocardial ischaemia was at the expense of an increase in nonfatal strokes. In addition, β-blocking therapy was associated with a higher incidence of perioperative hypotension and bradycardia requiring therapy. Finally, it appeared that the reported beneficial effects of perioperative β-blocking therapy were driven mainly by studies with a high risk of bias .
Nitrates reduce myocardial oxygen demand by lowering preload and ventricular wall tension while increasing O2 supply by dilating coronary vasculature. Despite these effects, there is no indication that their administration before anaesthesia and surgery is also associated with a decreased risk of perioperative cardiac complications . Also for calcium entry blockers, a straightforward effect on perioperative outcome is lacking despite their well known favourable haemodynamic effects [23,24]. Alpha-2 adrenoreceptor agonists may exert beneficial effects on the cardiovascular system by reducing central sympathetic nervous system activity. Although some data suggest that they may be helpful to attenuate surgery-related increases in sympathetic tone and decrease the risk of perioperative myocardial ischaemia and adverse outcomes, their efficacy to reduce perioperative morbidity and mortality still remains to be definitively established [23,25,26].
Modulation of ischaemia–reperfusion injury
Based on the pathophysiological mechanisms involved in ischaemia–reperfusion injury, potential therapeutic approaches can be proposed that may help to decrease the extent of myocardial reperfusion injury. The outcome of patients with an acute myocardial ischaemic event depends on two essential principles First, infarct size needs to be limited as the prognosis of the patient will depend on the amount of myocardium that is lost . Therefore, prompt reperfusion by thrombolysis, coronary angioplasty or surgery remains the cornerstone of the treatment of acute ischaemic events. Second, therapy should aim to minimize the extent of the myocardial ischaemia–reperfusion injury. The mechanisms behind the ischaemia–reperfusion injury are numerous and may be linked. As described earlier, the three main culprits in this respect seem to be free radical formation, the occurrence of calcium overload and the impairment of the mitochondrial function. Protective strategies will aim to target one or more of these underlying mechanisms. These include strategies to preserve or replenish myocardial high-energy phosphate stores, strategies to modulate intracellular ion gradients, free radical oxygen scavengers and/or antioxidants, inhibitors of the complement systems and the neutrophil activation, modulation of the mPTP and many others [1,4,7].
Pharmacological modulation of cardiac energy metabolism
As the heart consumes large amounts of ATP, a rapid depletion of high-energy phosphates will occur with ischaemia. Restoration or support of cardiac metabolism has been suggested as a possible therapeutic strategy for the treatment of ischaemic heart disease. Such therapeutic approach aims to minimize the metabolic and functional consequences of ischaemia and to redirect flux through the normal metabolic pathways by modulation of the regulatory enzymes and by replenishment of the depleted intermediates. It is beyond the scope of this review to discuss this therapeutic approach in detail and the reader is referred to different reviews on this subject [28–33].
Among the different possible metabolic strategies, the use of a glucose-insulin-potassium administration seems to be associated with the most convincing clinical benefits. It is assumed that the cardioprotective effect of this cocktail acts via the modulation of cardiac and circulating metabolites. This would then provide the heart with an optimal metabolic milieu to resist ischaemia–reperfusion injury. In addition, insulin may also exert direct cardiac cell survival effects in the context of ischaemia–reperfusion injury [34,35]. Initial clinical data supported the effect of the glucose-insulin-potassium cocktail in reducing morbidity and mortality after myocardial infarction [36,37]. However, it has become increasingly obvious that the extent of cardioprotective effects may depend on a number of variables such as the extent of collateral circulation, the presence of heart failure and the dosage scheme used [38–40]. Also in the course of cardiac surgery, the clinical benefits of glucose-insulin solutions seem to be related to patient's characteristics [41,42].
Another compound that has been focus of intensive research is adenosine. It is a direct precursor of adenosine monophosphate and thus essential for the maintenance of the myocardial adenine nucleotide pool. Supplementation of adenosine might, therefore, provide substrate for the necessary resynthesis of the depleted ATP pool with myocardial ischaemia. In addition, adenosine has other protective actions against ischaemia–reperfusion injury. These include activation of the potassium-sensitive ATP channels, inhibition of neutrophil function with a reduced production of reactive oxygen species, less proteases release and less coronary endothelial adherence [43–46]. Several clinical studies have reported beneficial effects with adenosine treatment but the effects were less obvious than those reported by experimental studies [47,48].
Modulation of reactive oxygen species release and of immune system activation
The generation of reactive oxygen species is a key process in the development of reperfusion injury. Interference with their formation and release may attenuate the extent of reperfusion injury. However, the results of studies investigating the protective effects of such agents are conflicting. This controversy might be related to differences in the experimental settings such as the duration of the myocardial ischaemia, the variations in collateral flow, allowing the compound to reach the ischaemic area, the possible influences of concomitant medication and others [4,49].
Attempts to modulate the neutrophil-mediated effects in the development of reperfusion injury included depletion of neutrophils, direct inhibition of neutrophils and inhibition of cell adhesion molecules on neutrophils and endothelial cells. Depletion by administration of specific antibodies against neutrophils or neutrophil clearing filters has been shown – though not unequivocally – to have protective effects on the extent of ischaemia–reperfusion injury. Also, in experimental studies, blocking of adhesion molecules with specific antibodies against intracellular adhesion molecule 1, P-selectin, L-selectin and platelet/endothelial adhesion molecule 1 just before reperfusion was associated with a decrease in extent of reperfusion injury [8,50–55]. The serine protease inhibitor, aprotinin, inhibits neutrophil migration and inhibits endothelial cell activation in response to pro-inflammatory stimuli. Protease inhibitors do indeed appear to reduce infarct size and apoptosis probably by attenuation or inhibition of neutrophil activation and recruitment either direct or by inhibition of cytokine generation . Modulation of the complement cascade by selective inhibition of the different complement proteins involved or by interference with complement receptors also constitutes a potential therapeutic strategy. Several experimental studies have indicated that such approaches were associated with a reduction in infarction size following myocardial ischaemia and reperfusion [2,4], but to date there is no convincing evidence for a clinical application of such strategies.
Modulation of calcium homeostasis
Calcium overload has a major role in the pathogenesis of myocardial ischaemia–reperfusion injury and therefore modulation of the intracellular Ca2+ transients may have a protective effect in the course of ischaemia–reperfusion injury. Calcium antagonists were shown to be cardioprotective when administered prior to the induction of ischaemia. It was, however, not possible from these studies to distinguish between protection against injury induced by ischaemia or by reperfusion [57,58]. It was suggested that the beneficial effects of calcium antagonists were mainly related to the negative inotropic and chronotropic, hence energy-sparing effects of these compounds. However, calcium antagonists may also act as antioxidants and nitric oxide synthase regulators. In addition, more recent studies indicated that calcium antagonists do not only have antiischaemic effects but are also protective against the myocardial injury induced by reperfusion itself [4,59,60].
In-vitro data have shown that the reoxygenated myocardial cell may be protected from hypercontracture by attenuating the oscillatory intracellular movements of Ca2+, thereby reducing the high peak concentrations of cytosolic Ca2+. This can be achieved by specific blockade of the Ca2+ uptake (cyclopiazonic acid) or release (ryanodine) at the level of the sarcoplasmatic reticulum. Interestingly, the volatile anaesthetic halothane also blocks these Ca2+ transients, thereby protecting the myocardial cells against hypercontracture and lethal reperfusion injury [61,62].
Other therapeutic possibilities
Activation of the Na+/H+ exchanger is associated with intracellular calcium accumulation. Inhibition of this exchanger may, therefore, attenuate the consequences of reperfusion injury. Although experimental and early clinical studies were suggestive of a protective effect, the more recently performed larger trials failed to demonstrate a clinical benefit [4,7,63,64].
Nitric oxide is a powerful vasodilator and may, thus, improve blood flow during reperfusion. In addition, nitric oxide inhibits adherence of neutrophils to the vascular endothelium and may act as a scavenger of free oxygen radicals. After ischaemia, bioavailability of nitric oxide seems to be impaired by the enhanced inactivation of nitric oxide by reactive oxygen species and the reduced production of nitric oxide. Administration of nitric oxide or nitric oxide donors may attenuate the extent of ischaemia–reperfusion injury. Also, pretreatment with drugs that enhance nitric oxide release, such as statins, certain calcium antagonists, angiotensin converting enzyme inhibitors, endothelin-1 receptor antagonists or dexamethasone may protect the myocardium against ischaemia–reperfusion injury [4,65,66]. Of special interest in this respect are the corticosteroids and the statins. The potential benefits of the corticosteroids in decreasing the extent of ischaemia–reperfusion injury have been subject of debate for many years. Recent observations indicate that in cardiac surgery patients, treatment with corticosteroids reduces the incidence of postoperative atrial fibrillation [67,68].
More recently, increasing evidence is indicating that statins – in addition to their cholesterol-lowering effects – may exhibit additional pleiotropic effects that help to protect the myocardium against myocardial ischaemia–reperfusion injury [69–71]. A recent meta-analysis of studies in over 30 000 cardiac surgery patients provided evidence that preoperative statin therapy was associated with fewer postoperative adverse events  but a systemic review of controlled studies in both cardiac and noncardiac surgery did conclude that the evidence for statins to reduce perioperative cardiovascular risk seems to be inadequate . Finally, acute preoperative statin therapy withdrawal was shown to be associated with an increased risk for perioperative adverse cardiac events .
Other therapeutic options that have been explored include modulation of the reperfusion injury salvage kinase pathway and the pathways involved in the apoptotic process [4,75]. Targeting the mPTP may also potentially reduce the extent of the ischaemia–reperfusion injury . Very recently, it was shown that pretreatment with cyclosporine A (an inhibitor of mPTP opening) immediately before percutaneous coronary intervention reduced the extent of myocardial damage compared with placebo , suggesting that such approach might also be applicable in the clinical setting .
Intrinsic cardioprotective mechanisms
In 1986, Murry et al. reported that short episodes of ischaemia and reperfusion before a sustained ischaemic event – ischaemic preconditioning – reduced infarct size. Preconditioning represents a potent and consistently reproducible method of protection against ischaemia, which not only reduces infarct size but also alleviates postischaemic cardiac dysfunction and arrhythmias. The protective effects offered by the ischaemic preconditioning are of limited duration and can typically be divided into two phases. The early phase occurs immediately and induces a strong protection but has a limited duration of 1–2 h, whereas the late phase occurs about 24 h after the initial stimulus, induces less protection, but lasts for as long as 3 days. In addition, this protective action is present when the stimulus is applied early before the ischaemic insult (early preconditioning) but may also be active when the preconditioning stimulus has been applied some hours before the actual ischaemic insult (late preconditioning). Finally, recent data indicate that preconditioning stimuli at the level of other organ systems may have a protective effect at the level of the ischaemic myocardium (remote preconditioning). A detailed discussion on the mechanisms involved in the phenomenon of preconditioning is beyond the scope of this article and the reader is referred to a number of reviews on the subject [80–82].
Several studies have indicated that ischaemic preconditioning also occurs in humans and a number of ischaemic preconditioning protocols have been applied in the setting of cardiological interventions and coronary artery bypass surgery with various results [83–95]. However, it should be noted that although the clinical application of an ischaemic preconditioning protocol might help to reduce myocardial ischaemia–reperfusion injury, it also represents an additional risk to further jeopardize an already diseased myocardium.
Ischaemic preconditioning can be either abolished or mimicked by the use of pharmacological agents that block or stimulate certain steps in the intracellular cascade of events. This has led to the concept of pharmacological preconditioning. However, most of the pharmacological compounds used to induce preconditioning were associated with side-effects such as occurrence of hypotension (adenosine), arrhythmias (adenosine, KATP channel openers), or possible carcinogenic effects (protein kinase activators), which seriously limited their clinical introduction.
During the last years, both experimental and clinical evidence has increasingly demonstrated that volatile anaesthetics are able to precondition the myocardium. The mechanisms involved in anaesthetic preconditioning strongly resemble those involved in ischaemic preconditioning and have been subject of different recent reviews [82,96–102]. Not only anaesthetic gases but also noble gases such as xenon and helium have preconditioning effects, involving similar intracellular pathways .
In contrast to the obvious cardioprotective effects observed in the experimental setting, the results of different clinical anaesthetic preconditioning protocols are less straightforward showing highly variable results and fail to demonstrate an unequivocal beneficial effect on the extent of postischaemic myocardial function and damage (reviewed in Ref.  and summarized in Table 1). Two recent studies have provided data indicating that the modalities of the preconditioning protocols may greatly influence the extent of the clinical cardioprotective effects. Fräβdorf et al. observed in coronary surgery patients that a one cycle preconditioning stimulus of 1 MAC sevoflurane for 5 min before ischaemia did not decrease postoperative troponin I values compared with the control group. However, the application of two cycles of 5 min, 1 MAC sevoflurane administration, interspersed by a 5 min washout period significantly decreased postoperative troponin I values. Bein et al. observed also in coronary surgery patients a continuous administration of 1 MAC sevoflurane from induction to start of cardiopulmonary bypass did not result in any additional protection compared with the control group. However, when the administration of sevoflurane before cardiopulmonary bypass was interrupted for 10 min, an improved myocardial performance and decreased postoperative troponin T values were observed. These data suggest that the interrupted administration may be an essential feature for the occurrence of clinically relevant cardioprotective effects.
In 2003, Zhao et al. reported that in an experimental dog model, three 30-s intermittent periods of coronary artery occlusion, applied at the onset of reperfusion after a sustained 60-min occlusion, resulted in a marked limitation of infarction size. This phenomenon was termed ischaemic postconditioning and intensive research is now directed towards unravelling of the underlying mechanisms, of which a substantial part seems to share common pathways with the mechanisms involved in preconditioning [107,108].
Although ischaemic postconditioning has been shown to exhibit a cardioprotective action in the clinical setting of angioplasty procedures [109–111] and cardiac surgery [112,113], the same concern as with the clinical ischaemic preconditioning protocols exists, which is the institution of an ischaemic insult on an already jeopardized myocardium.
When administered immediately before or early during reperfusion, volatile anaesthetic agents are also capable of exerting cardioprotective effects. This phenomenon was first described by Schlack and coworkers [61,62,114–116] and is now also increasingly confirmed by other groups [117,118]. Just as for anaesthetic preconditioning, the mechanisms of anaesthetic postconditioning share common pathways with ischaemic postconditioning and also preconditioning (for review see Ref. ).
Clinical data on anaesthetic postconditioning are scarce. In a study comparing different administration timings of sevoflurane on postoperative cardiac function and myocardial damage in coronary artery surgery patients, De Hert et al. could not demonstrate lower postoperative troponin I values with a postconditioning protocol, but postoperative functional recovery of the myocardium seemed to occur earlier than in the control group.
Clinical cardioprotection: is there a role for anaesthetic agents?
An important obstacle to translate the experimental observations on anaesthetic cardioprotection to the clinical setting is that myocardial ischaemia has to be present in a predictable and reproducible manner. Cardiac surgery constitutes a suitable, but still suboptimal model for the study of potential cardioprotective effects of anaesthetic agents. The first studies that were performed consisted of a protocol in which the anaesthetic agent was administered before the ischaemic episode. As discussed above, highly variable results were obtained with regard to the cardioprotective effects. Part of the variability between studies can be attributed to differences in protocols such as choice of the anaesthetic agent, duration of the administration, inclusion of a washout period and so on. The two recent studies of Bein et al.  and Fraβdorf et al.  underscore the crucial importance of the experimental preconditioning protocol.
The absence of clinically straightforward data from most of the anaesthetic preconditioning studies has initiated the question a few years ago whether the choice of the anaesthetic regimen during the surgical procedure would really influence myocardial outcome. The first study by De Hert et al. compared the effects of sevoflurane and propofol on myocardial function during and after coronary artery surgery. Before cardiopulmonary bypass, all haemodynamic variables were comparable between the two anaesthetic treatment groups. However, after cardiopulmonary bypass, patients who received the volatile anaesthetic regimen had preserved cardiac performance, which was evident from a preserved stroke volume and dP/dtmax, and the preservation of the length-dependent regulation of myocardial function. In addition, need for inotropic support in the early postoperative period was significantly less with the volatile anaesthetic, and postoperative plasma concentrations of cardiac troponin I were consistently lower when compared with patients receiving the total intravenous anaesthetic regimen. These data, therefore, suggested that volatile anaesthetics provided a cardioprotective effect that was not observed with the intravenous anaesthetic regimen. This was confirmed in a subsequent study  by the same authors in a group of elderly, high-risk patients with documented impaired myocardial function. Sevoflurane and desflurane preserved myocardial function after cardiopulmonary bypass with less evidence for myocardial damage and a better postoperative myocardial function compared with the intravenous anaesthetic regimen.
The cardioprotective effects of a volatile anaesthetic regimen during coronary surgery were subsequently confirmed in other reports that used different anaesthetic and surgical protocols [123–128]. All these clinical studies clearly indicated that volatile anaesthetics protect the myocardium during coronary surgery. Only one study in patients undergoing off-pump coronary surgery failed to confirm these positive results . In this study, however, intraoperative remifentanil concentrations were consistently higher and bispectral index values lower in the propofol group compared with the sevoflurane-treated patients, indicating that there were probably differences in anaesthetic depth that may have influenced the results.
Two studies from the same group administered sevoflurane with the cardioplegic solution and observed lower postoperative troponin values and lower levels of a number of markers of inflammation than those in patients who had a total intravenous anaesthesia [130,131]. On the other hand, in a few observational studies on a limited number of cardiac surgery patients, propofol was shown to attenuate free-radical-mediated lipid peroxidation and systemic inflammation [132–134]. Although in one study  this was associated with a lower postoperative troponin release, no differences in outcome were observed.
The available clinical data on cardioprotective effects of volatile anaesthetics to date are largely confined to coronary surgery patients. In aortic valve surgery patients, the use of a volatile anaesthetic regimen was also shown to have a cardioprotective effect  but in mitral valve surgery, on the contrary, such effect was not observed .
Noncardiac surgery is also associated with a risk of perioperative cardiac events. The observation that anaesthetic cardioprotection with volatile anaesthetics is also observed during off-pump coronary surgery may suggest that this phenomenon may also be present in patients at risk of myocardial events undergoing surgical procedures without cardiopulmonary bypass. Among these noncardiac procedures, arterial vascular surgery is considered as a high risk for the development of perioperative cardiac events. Recently, a retrospective analysis has compared the effects of a volatile anaesthetic to a nonvolatile anaesthetic regimen on the incidence of postoperative cardiac events, including the postoperative elevation of troponin I values after vascular surgery in high-risk patients. The data were obtained from a phase II study that compared the Na+/H+ exchanger type I inhibitor, zoniporide, to placebo on the occurrence of cardiac events . Type of anaesthesia was retrieved from the database and patients were subdivided into two groups: inhalational vs. noninhalational anaesthetic regimen. The incidence of postoperative cardiac events and maximum postoperative troponin I levels did not differ between the two groups in the total population and in the patients undergoing peripheral arterial surgery. However, in patients undergoing aortic surgery, the incidence of elevated troponin levels higher than 1.5 and 4 ng ml−1 tended to be lower in the inhalational group (28 vs. 18% and 30 vs. 20%, respectively), but this difference did not reach statistical significance .
The potential beneficial cardioprotective effect of volatile anaesthetics may also extend to some nonsurgical revascularization procedures, such as percutaneous transluminal coronary angioplasty. However, a recent study  failed to demonstrate a protective effect of volatile anaesthetic agents in this setting.
Anaesthetic cardioprotection: is there an effect on outcome?
Although clinical observations indicate that the use of a volatile anaesthetic regimen may protect the myocardium during coronary surgery, the impact of this phenomenon on postoperative morbidity and clinical recovery remains to be established. This is mainly related to the fact that sample size of the different studies is too low to address this issue.
Data from single centre studies suggested that the use of a volatile anaesthetic regimen seemed to be associated with a lower intensive care and hospital length of stay , a lower incidence of postoperative atrial fibrillation  and even a lower incidence of 1-year adverse cardiac events .
A retrospective study  from a Danish national registry on 10 535 cardiac surgery patients operated in three cardiac centres under either a volatile or an intravenous anaesthetic regimen tried to address the outcome question. Although no difference was observed in 30-day total mortality, cardiac-related mortality seemed to be lower with a volatile anaesthetic regimen but this was at the expense of a higher noncardiac-related mortality. Correct interpretation of these data remains difficult because of a number of methodological issues such as the retrospective design including patients over a period of 6 years, the different contribution in number of patients included (6145 in centre A, 1430 in centre B and 4646 in centre C), the centre-specific use of the anaesthetic regimen (total intravenous in centre A, volatile in centres B and C), the cardioprotective strategies (crystalloid cardioplegia in centre A, blood cardioplegia in centre B, and both in centre C) and so on.
The outcome issues were also addressed in three recent meta-analyses [144–146]. One of them focused on studies with only the newer volatile anaesthetics, desflurane and sevoflurane . In this study, 22 trials with a total of 1922 patients, comparing a volatile with an intravenous anaesthetic regimen, were finally included. With the volatile anaesthetic regimen, postoperative troponin release was lower, cardiac index was better with less need for inotropic support, the incidence of perioperative myocardial infarction was lower, and mechanical ventilation time, intensive care length of stay and hospital length of stay were shorter.
Finally, a recent multicentre study  performed in Belgium in eight hospitals on 414 patients undergoing coronary surgery with cardiopulmonary bypass under either a total intravenous anaesthetic regimen or supplementation with desflurane and sevoflurane found no differences in postoperative troponin T values but observed a lower 1-year mortality in the groups in which a volatile anaesthetic agent was used.
Over the years, numerous cardioprotective strategies have been developed to reduce the incidence of perioperative cardiac events. The great majority of these strategies showed promising results in experimental settings but most of them failed to provide convincing significant clinical effects. However, anaesthetic cardioprotection seems to be an exception as the experimentally observed protective effects also seem to translate to a clinically relevant cardioprotection with a beneficial effect on patients' outcome. Although the initial data seem to be promising, further studies will have to confirm these beneficial effects. In addition, clinical studies in noncardiac surgery are needed to determine the impact of potential cardioprotection in this group of patients.
Text of the refresher course on the subject held at the Euroanaesthesia 2009 meeting in Milan (Italy).
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