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Cardioprotection with Volatile Anesthetics: Mechanisms and Clinical Implications

De Hert, Stefan G. MD, PhD*; Turani, Franco MD; Mathur, Sanjiv MD; Stowe, David F. MD, PhD§

doi: 10.1213/01.ANE.0000153483.61170.0C
Cardiovascular Anesthesia: Review Article
Chinese Language Editions

Cardiac surgery and some noncardiac procedures are associated with a significant risk of perioperative cardiac morbid events. Experimental data indicate that clinical concentrations of volatile general anesthetics protect the myocardium from ischemia and reperfusion injury, as shown by decreased infarct size and a more rapid recovery of contractile function on reperfusion. These anesthetics may also mediate protective effects in other organs, such as the brain and kidney. Recently, a number of reports have indicated that these experimentally observed protective effects may also have clinical implications in cardiac surgery. However, the impact of the use of volatile anesthetics on outcome measures, such as postoperative mortality and recovery in cardiac and noncardiac surgery, is yet to be determined.

*Department of Anesthesiology, University Hospital Antwerp, Edegem, Belgium; †Department of Anesthesia and Intensive Care, European Hospital, University of Rome Tor Vergata, Rome, Italy; ‡Department of Anesthesia and Critical Care, Sudbury Regional Hospital, Sudbury, Ontario, Canada; §Departments of Anesthesiology and Physiology, The Medical College of Wisconsin, Department of Biomedical Engineering, Marquette University; Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin

Supported, in part, by Abbott Laboratories.

Accepted for publication November 23, 2004.

Address correspondence and reprint requests to Stefan G. De Hert, MD, PhD, Department of Anesthesiology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium. Address e-mail to stefan.dehert@ua.ac.be.

Perioperative myocardial ischemia is a serious adverse event that can increase morbidity and mortality after cardiac and noncardiac surgery. Between 18% and 74% of patients with coronary artery disease undergoing noncardiac surgery experience perioperative myocardial ischemia (1). Treatment approaches that prevent or lessen myocardial ischemia during and after surgery have been proposed (2). Most of these approaches are directed towards modulation of the myocardial oxygen supply-demand ratio; for example, with β-adrenergic antagonists, α2 agonists, or calcium channel blockers. There are also several potential new targets for reducing perioperative ischemia that focus more on myocardial oxygen demand at the cellular or mitochondrial level, although the clinical benefit of these approaches remains to be demonstrated (2).

The use of particular anesthetics for the induction and maintenance of general anesthesia is one such approach proposed to protect against the adverse effects of ischemia. Experimental data indicate that some anesthetics, such as volatile general anesthetics and morphine, have protective effects against ischemia-reperfusion injury that are independent of their hemodynamic effects.

This review summarizes the recent data on the effects of volatile anesthetics on altering ischemia-reperfusion injury as reported in various experimental and clinical studies.

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Experimental Data

Ischemic Preconditioning

During ischemia, cardiac myocytes reduce their contractile effort within a few seconds and stop contracting within the first few minutes. If ischemia continues for longer than 15 minutes, cellular necrosis will begin and result in decrease of contractile function with continued necrosis of affected cells, even if the blood supply to the myocardium is restored. In addition to necrosis, the process of apoptosis, or cell programmed death, also ensues even after reperfusion if ischemia is severe.

Even in the absence of cellular necrosis or apoptosis, reperfusion of the ischemic myocardium will not result in immediate recovery of myocardial function. Indeed, the heart may remain hypocontractile for several hours (myocardial stunning). The effects of ischemia and reperfusion on cardiac function and the cellular mediators involved in myocardial stunning have been extensively studied and are the subject of a number of excellent reviews (3–10).

In contrast, short periods of transient myocardial ischemia appear to protect the heart from extensive damage during subsequent longer periods of ischemia. This phenomenon was first described by Murry et al. (11). Dogs subjected to 4 5-min episodes of cardiac ischemia before a 40-min occlusion had an average infarct size that was 25% smaller than the infarct size in the control group that had been subjected to the 40-min occlusion alone. This decrease in infarct size could not be attributed to differences in coronary collateral circulation but was instead indicative of a protective action of short episodes of ischemia. This phenomenon was termed “ischemic preconditioning” (11). The same group later reported that a single, brief period of ischemia appears sufficient to induce ischemic preconditioning. Importantly, if the time between preconditioning and prolonged ischemia was longer than 2 h, the effect of preconditioning decreased (12). However, if the period between the preconditioning ischemia and the prolonged coronary artery occlusion was extended to 24 h, the ischemic preconditioning phenomenon was restored, indicating the existence of an additional delayed preconditioning effect, called the “second window” of preconditioning (13).

Further research has identified the involvement of several intracellular signaling pathways in this phenomenon, and the primary target for these signals appears to be the adenosine triphosphate (ATP)-sensitive K+ (KATP) channels (channels that open in response to small alterations in intracellular concentrations of ATP) (4). KATP channels are located on both the sarcolemmal and mitochondrial membranes within cardiac myocytes and are found in smooth muscle, skeletal muscle, brain, and pancreatic β cells (14).

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Anesthetic Preconditioning

The administration of some anesthetics produces a preconditioning-like effect, protecting the myocardium from the effects of myocardial infarction and myocardial dysfunction (15,16). The potential cardiac protective effects of volatile anesthetics were already recognized before the introduction of the concept of anesthetic preconditioning. Warltier et al. (17) described a better recovery of myocardial function after a 15-min coronary artery occlusion when a volatile anesthetic was administered before the occlusion. In dogs anesthetized with isoflurane or halothane, myocardial function returned to baseline levels within 5 h after the start of reperfusion, whereas awake dogs that received the same treatment without anesthesia still had a 50% decrease in myocardial function at the same time point.

Subsequent studies showed that anesthetic preconditioning, (i.e., administration of a volatile anesthetic before the period of myocardial ischemia) resulted in a similar degree of cardioprotection as observed after ischemic preconditioning, both for functional recovery and for protection from ischemic damage to the heart (18) and lungs (19). Beneficial effects on myocardial stunning have been described for all commercially available volatile anesthetics (15,20,21). In addition to attenuating the effects of ischemia on contractility, anesthetic preconditioning also decreased the area of the myocardium that was affected during ischemia. For example, in barbiturate-anesthetized dogs that underwent occlusion of the left anterior descending coronary artery, 1 MAC (minimum alveolar concentration) sevoflurane significantly decreased the infarct size as a proportion of the area at risk by over 40% compared with animals that did not receive the volatile anesthetic (15). This study also demonstrated that if the anesthetic was stopped more than 30 min before the coronary artery was occluded, the preconditioning effect was lost.

The preconditioning effects of volatile anesthetics have been extensively studied in an attempt to elucidate the mechanisms involved, and much of this work has been summarized in a number of recent reviews (10,22,23). The different reported putative mechanisms involved in the preconditioning effects of volatile anesthetics are summarized in Table 1.

Table 1

Table 1

The intracellular pathways involved in ischemic and anesthetic preconditioning have not been completely identified; one possible scenario is displayed in Figure 1 (10). Anesthetic preconditioning appears to be initiated by an increase in reactive oxygen species (ROS). This was suggested by the observation that the introduction of ROS scavengers during exposure to sevoflurane or isoflurane blocks the anesthetic preconditioning response (33,35). Furthermore, fluorescence indicative of previous ROS formation has been observed in cardiac tissue slices after isoflurane exposure (36), and a small increase in ROS formation has been indirectly observed during sevoflurane exposure in the intact heart (32). The increase in ROS is likely mediated by partial inhibition of the electron transport chain with reduced efficiency of electron transport, probably at nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex 1) or ubiquinol:ferricytochrome c oxidoreductase (complex III), thus inhibiting the oxidation of NADH (30,31,46). This results in the release of partially oxidized oxygen free radicals (32).

Figure 1

Figure 1

The sequence of events that occur after ROS release that ultimately result in anesthetic preconditioning is not definitively known, but there is evidence for activation or translocation of protein kinase C (PKC) (47,48), other downstream kinases, such as protein tyrosine kinases (49), and p38 mitogen activated protein kinases (MAPK) (50). The primary action of these intracellular messaging pathways seem to be on the KATP channel (15).

Volatile anesthetics mediate their effects by either priming or indirectly opening the mitochondrial KATP channels (16,23). However, the actual intracellular effects of mitochondrial KATP channel opening are not well understood. One response may be slight depolarization of the mitochondrial membrane potential; another response may be swelling of the mitochondrial matrix. Either of these responses can result in altered mitochondrial bioenergetics (respiration state). Consequences of mitochondrial KATP channel opening are reduced cytosolic and mitochondrial calcium loading and improved myocardial oxygen efficiency during ischemia and reperfusion (39,51,52). Other observed effects include decreased mitochondrial respiration (increased NADH levels) (30,31), modulation of mitochondrial energetic and calcium homeostatic capacity, ATP sparing (53,54), and decreased mitochondrial energy consumption during ischemia (36). Recently, Kevin et al. (32) reported a direct increase in ROS in response to sevoflurane administration that did not appear to be dependent on mitochondrial KATP channels. This observation suggested that the initial increase in ROS observed with volatile anesthetics may in fact precede the mitochondrial KATP channel opening. However, as both KATP channel blockade and ROS scavengers also prevent anesthetic preconditioning (32–34), this effect seems mediated by an intimate feedback interaction between ROS formation and KATP channel opening; i.e., both are necessary components of the mechanism (Fig. 1) (34).

Ischemic and anesthetic preconditioning effects have also been described in the vasculature, where they protect coronary endothelial cells against ischemia and reperfusion (37,55–57). This phenomenon seems also mediated at least partially by adenosine receptors and KATP channels (58–61). This protective effect against ischemia-reperfusion-induced coronary constriction was reported to be greater than its protective effect on contractility (38).

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Reperfusion Injury

In addition to their anesthetic preconditioning effects, volatile anesthetics may also exhibit cardioprotective effects when administered during reperfusion (52,62–64). Volatile anesthetics may also protect the myocardium from cellular damage as a result of proposed antiinflammatory properties that have been described in experimental studies. Several possible pathways have been identified, including attenuation of nuclear factor κB activation and reduced expression of tumor necrosis factor (TNF)-α, interleukin 1, intracellular adhesion molecules, and inducible nitric oxide synthase (43–45).

The relative importance of the preconditioning and reperfusion effects of volatile anesthetics has been investigated, but the results of these studies have been variable. Varadarajan et al. (52) observed that sevoflurane administered either immediately before global myocardial ischemia or on reperfusion immediately after ischemia improved mechanical and metabolic function. However, not only was the administration before ischemia more protective than when administered on initial reperfusion, but there was also no additive protective effect when sevoflurane was administered both before and after ischemia. The authors therefore suggested that the volatile anesthetic initiates its maximal protective effect before ischemia. In contrast, Obal et al. (65) observed in anesthetized rats that the myocardial protection with sevoflurane was further enhanced by its administration during reperfusion (66). Moreover, the cardioprotective effects of the volatile anesthetic were enhanced when administered during reperfusion in comparison with administration as a preconditioning stimulus. Differences in these studies may relate to experimental and species differences.

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Clinical Studies

Ischemic Preconditioning

Several studies indicate that the phenomenon of ischemic preconditioning may also be effective in the clinical environment. For example, the presence of pre-infarction angina was associated with a decreased infarction size, better postoperative ventricular function (66) and a decreased 30-day cardiac event rate (67). Interestingly, this protective effect of prodromal angina seemed to be absent in the presence of diabetes (68).

Another human model of ischemic preconditioning is coronary balloon angioplasty. A number of studies have indicated that repeated balloon angioplasty was associated with fewer symptoms, less ST segment elevation (69), a less frequent in-hospital cardiac event rate, and less frequent 1-yr mortality (70). “Warm-up” angina, which is also correlated with ischemic preconditioning, is a phenomenon where the severity of the symptoms of myocardial ischemia associated with angina during exercise or coronary angioplasty are reduced when they follow a previous period of exercise (71). Coronary artery bypass surgery is yet another area where the application of ischemic preconditioning may have a potential therapeutic role. The application of an ischemic preconditioning protocol during coronary surgery is associated with increased myocardial ATP content (72), decreased troponin T release (73), and reduced incidence of ventricular tachyarrhythmias (74).

Despite these potential protective effects, the routine use of an ischemic preconditioning protocol is hampered by the fact that the induction of an ischemic episode in a coronary patient may greatly exacerbate symptoms and reduce cardiac reserve. Moreover, a distinct difference in the effects of ischemic and anesthetic preconditioning on gene expression has been recently demonstrated, suggesting different cardioprotective mechanisms (75). Continuing research is focused on the use of drugs that may pharmacologically precondition the myocardium, such as adenosine receptor agonists, KATP channel openers, activators of protein kinases including PKC, p38 MAPK, and protein tyrosine kinases, free radical scavengers, and other moieties. However, none of these drugs has entered clinical practice either because of important side effects or because of an absence of measurable clinical benefit (76).

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Anesthetic Preconditioning

From a clinical perspective, a key question is whether the cardioprotective effects of volatile anesthetics observed in the numerous animal studies are applicable clinically. The major obstacle to addressing this question is that myocardial ischemia has to be present in a predictable and reproducible manner. Cardiac surgery, therefore, constitutes a suitable, but suboptimal model for the study of potential cardioprotective effects of anesthetics (Table 2). However, in such studies, it is necessary to differentiate the effects of anesthetic preconditioning from the ischemic preconditioning response observed with cardiopulmonary bypass (CPB).

Table 2

Table 2

In contrast to the straightforward data obtained in the experimental studies, results from clinical studies using preconditioning protocols show highly variable results. The first, limited, study on this issue was published by Belhomme et al. in 1999 (77). Isoflurane at 2.5 MAC was administered for 5 minutes via the oxygenator in the CPB circuit. This was followed by a 10-min washout period before aortic cross-clamping. Isoflurane preconditioning (n = 10) resulted in an increase in cytosolic activity of 5′ nucleotidase, a surrogate marker for activation of PKC. However, postoperative release of creatine kinase MB and troponin I were not different from the control group (n = 10). Similar results were found in a subsequent study that investigated the effect of CPB alone and sevoflurane at 2.5 MAC given during the first 10 minutes of CPB in 20 patients (50). PKC and p38 MAPK were increased with either sevoflurane or CPB alone, suggesting anesthetic preconditioning with sevoflurane may overlap with the preconditioning effects of CPB. However, in the sevoflurane group, tyrosine kinase was also increased, suggesting a greater preconditioning.

In another study of 22 patients, the effects of enflurane, 1.3% (range, 0.5%–2%), administered using a vaporizer connected to the mechanical ventilation fresh gas flow for 5 min immediately before CPB were investigated. In that study group, enflurane enhanced postoperative left ventricular function, but postoperative creatine kinase-MB and troponin I release were not different from the control group (78). In a study of 40 patients, Tomai et al. (79) administered isoflurane, 1.5%, for 15 min, followed by a washout period of 10 min before the start of CPB. No differences were observed between the treatment group and the control group in postoperative cardiac function and peak troponin I values. However, in the subgroup of patients with a left ventricular ejection fraction <50%, troponin I levels 24 h postoperatively were slightly lower in the isoflurane treatment group (n = 9) than in the control group (n = 11).

In another study of 49 patients, Haroun-Bizri et al. (80) administered isoflurane, 0.5%–2%, until the start of CPB and observed a higher postoperative cardiac index in the isoflurane group than in the control group. The largest relevant study (72 patients) was performed by Julier et al. (81). In their study, sevoflurane 4% was administered during the first 10 min of CPB just before aortic cross-clamping. Compared with the control group, a significantly lower reduced postoperative release of brain natriuretic peptide—a sensitive biochemical marker of myocardial contractile dysfunction—was observed. In addition, this study was the first to demonstrate that translocation of PKC δ and ε, isoforms—one of the mechanisms implicated as a pivotal step in anesthetic preconditioning—also occurred in the human myocardium in response to sevoflurane. However, no differences were found between groups for perioperative ST segment changes, arrhythmias, creatine kinase MB, and cardiac troponin T release.

To summarize, it would appear that none of these preconditioning studies, although suggesting some protective action on either a biochemical or a functional variable, unequivocally demonstrate that the use of a volatile anesthetic regimen resulted in a clinical benefit for the patients. This may be partially attributable to the small sample size in many of these studies, resulting in inadequate power to demonstrate differences between treatment groups.

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Anesthetic, Cardioprotective Effects

The absence of clinically straightforward data from anesthetic preconditioning studies has prompted some centers to examine whether the choice of anesthetic regimen during the entire surgical procedure would really have an impact on myocardial outcome. This was particularly of interest because previous studies had indicated that the choice of the anesthetic regimen did not really influence outcome (87,88). The first study, by De Hert et al. (82), compared the effects of sevoflurane and propofol on myocardial function during and after coronary artery surgery. Before CPB, all hemodynamic variables were similar between the two anesthetic treatment groups. However, after CPB, patients who received the volatile anesthetic regimen had preserved cardiac performance, which was evident from a preserved stroke volume, dP/dtmax, and length-dependent regulation of myocardial function. In addition, need for inotropic support in the early postoperative period was significantly less with the volatile anesthetic, and postoperative plasma concentrations of cardiac troponin I were consistently less than after the total IV anesthetic regimen (Fig. 2). These data therefore suggested that volatile anesthetics provided a cardioprotective effect that was not observed with the IV anesthetic regimen (82). This was confirmed in a subsequent study by the same authors (83) in a group of elderly, high-risk patients with documented impaired myocardial function. Sevoflurane and desflurane preserved myocardial function after CPB with less evidence for myocardial damage and better postoperative myocardial function compared with the IV anesthetic regimen.

Figure 2

Figure 2

A retrospective analysis of data, performed in another center before and after the implementation of a volatile anesthetic regimen, was published as a letter to the editor and supported the hypothesis of a cardioprotective effect of a volatile anesthetic regimen. The addition of sevoflurane to an IV anesthesia regimen for cardiac surgery consistently decreased troponin T levels, with less need for inotropic support for weaning from CPB and a reduced incidence of low cardiac output (84).

In another recent study of 20 patients undergoing coronary surgery, El Azab et al. (85) observed that sevoflurane anesthesia was associated with decreased plasma TNF-α concentrations compared with patients who received IV anesthesia with midazolam. These authors suggested that this observation was indicative of protection against ischemia-reperfusion injury.

The cardioprotective effects of a volatile anesthetic regimen were also observed subsequently in off-pump coronary surgery. Conzen et al. (86) found significantly better cardiac function in patients who received sevoflurane for maintenance of anesthesia during surgery compared with patients who received propofol maintenance anesthesia. Additionally, serum troponin I levels were significantly less in the sevoflurane group, although no significant effect on creatine kinase-MB was found between the treatment groups. These clinical results suggest that the cardioprotective effects of volatile anesthetics well described in animal studies do appear to translate to the clinical setting.

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Future Directions

Several questions still remain unanswered about the role of ischemic and anesthetic preconditioning. The first question relates to any possible differences among the available volatile anesthetics in eliciting cardioprotective effects. An investigation of the contractile function of human atrial trabeculae dissected from atrial appendages acquired from patients undergoing coronary surgery demonstrated different preconditioning effects of halothane and isoflurane (89). Isoflurane pretreatment before 30 min of anoxia resulted in a greater recovery of force after restoration of oxygen administration compared with untreated controls. Conversely, halothane pretreatment was not associated with a cardioprotective effect; indeed it even seemed to inhibit the cardioprotection provided by hypoxic preconditioning. In this in vitro study, the preconditioning effect of the volatile anesthetics was not related to their cardiac and systemic vascular actions; therefore, they appeared to be exerting additional actions that cause this phenomenon.

The currently available clinical data on cardioprotective effects of volatile anesthetics are confined to cardiac surgical patients, mostly with an ejection fraction >50%. However, noncardiac surgery is also associated with a risk of perioperative cardiac morbid events. The observation that anesthetic cardioprotection with sevoflurane is also observed during off-pump coronary surgery may suggest that this phenomenon is also present in patients at risk of myocardial events undergoing surgical procedures without CPB (86). The risks associated with noncardiac surgical procedures were evaluated in the American College of Cardiology/American Heart Association practice guidelines on perioperative cardiovascular evaluation for noncardiac surgery (90). The guidelines identified a number of procedures with a more than 5% risk of perioperative cardiac morbidity: major emergency operations, particularly in the elderly; aortic and other major vascular surgery; peripheral vascular surgery; and anticipated prolonged surgical procedures associated with large fluid shifts or blood loss.

The potential beneficial cardioprotective effect of volatile anesthetics may also extend to some nonsurgical revascularization procedures, such as percutaneous transluminal coronary angioplasty and during noncardiac surgery. However, no data are currently available that support the existence of a cardioprotective effect of volatile anesthetics in these various noncardiac surgical populations.

Although the use of a volatile anesthetic regimen appears related to a better and earlier recovery of myocardial function, its implications for outcome remain to be established. The authors of a very recent study (91) observed that the length of stay in the intensive care unit seemed to be related to the choice of anesthetic regimen. The use of a volatile anesthetic regimen during coronary surgery was associated with a decreased incidence of prolonged stay (>48 h) in the intensive care unit compared with use of a total IV anesthetic regimen. The individual variables responsible for a prolonged length of stay were occurrence of atrial fibrillation, increase in postoperative troponin I levels >4 ng/mL, and the need for prolonged inotropic support (>12 h). Although the incidence of atrial fibrillation was similar with all anesthetics studied, the number of patients with an increased troponin I level >4 ng/mL and those receiving prolonged inotropic support were significantly less with the volatile anesthetic regimens compared with the total IV anesthetic regimens (91).

Another important area of clinical research is determination of whether the organ protective effects observed in the myocardium also apply to other tissues. Experimental evidence is emerging that volatile anesthetics may also offer a degree of protection against the effects of ischemia and reperfusion in the brain (92), the liver (93), and the kidney (81).

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Conclusion

Well-designed animal studies have repeatedly demonstrated that exposure of the myocardium to a volatile anesthetic before a period of ischemia significantly protects the myocardium against subsequent ischemia-reperfusion injury. Similar to the protective effects of ischemic preconditioning, the anesthetic preconditioning effect is evidenced by better recovery of contractile function after ischemia and reduced infarct size in animal models.

The cardioprotective effect of volatile anesthetics has been supported by studies in patients during coronary surgery. However, further investigation is needed to determine whether the observed experimental and clinical cardioprotective effects of volatile anesthetics indeed translate into decreased morbidity and mortality in patients undergoing cardiac and noncardiac surgery.

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