Asian Cardiovasc Thorac Ann 2008;16:256-264
© 2008 Asia Publishing EXchange Ltd
Cardioprotection with Volatile Anesthetics in Cardiac Surgery
Suraphong Lorsomradee, MD,
Stefanie Cromheecke, MD,
Sratwadee Lorsomradee, MD,
Stefan G De Hert, MD
Department of Anesthesiology, Academic Medical Center, University of Amsterdam, The Netherlands
For reprint information contact: Stefan G De Hert, MD, Tel: 31 20 566 2533(Secr.), Fax: 31 20 697 9441, Email: S.G.DeHert{at}amc.uva.nl, Department of Anesthesiology, Division of Cardiothoracic and Vascular Anesthesiology, University of Amsterdam, Meibergdreef 9, Postbus 22660 H1Z-115, 1100 DD Amsterdam, The Netherlands.
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ABSTRACT
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Myocardial ischemia during the perioperative period is a major cause of morbidity and mortality after surgery. Experimental data indicate that clinical concentrations of volatile anesthetics protect the myocardium from ischemia and reperfusion injury, as shown by decreased infarct size and more rapid postoperative recovery of contractile function. These anesthetics may also mediate protective effects in other organs, such as the brain and kidney. A number of recent reports have indicated that these experimentally observed protective effects might also be present in the clinical setting. Implementation of such cardioprotection during surgery may provide an additional tool in the treatment and prevention of ischemic cardiac dysfunction in the perioperative period. This review discusses the clinical studies that have focused on the potential cardioprotective effects of volatile anesthetic agents.
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INTRODUCTION
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Myocardial ischemia in the perioperative period is a major cause of morbidity and mortality after surgery.1 Up to 74% of patients with coronary artery disease experience perioperative myocardial ischemia during noncardiac surgery.2 Prevention of ischemia has traditionally focused on maintaining the balance between myocardial oxygen supply and demand, using β-adrenergic antagonists, 
2-agonists and/or calcium-channel blockers. New evidence suggests that volatile anesthetics at clinical concentrations may also be useful in protection against perioperative myocardial ischemia, by a mechanism that is independent of effects on myocardial oxygen balance.3 It has long been known that all volatile anesthetics decrease myocardial loading conditions and contractility. The new volatile anesthetics, such as desflurane and sevoflurane, demonstrate a similar dose-dependent depression of myocardial function.4 These depressant effects decrease myocardial oxygen demand and may therefore have a beneficial effect on myocardial oxygen balance during myocardial ischemia.
In addition to these indirect protective effects, volatile anesthetics also have direct protective properties against reversible and irreversible ischemic myocardial damage. These properties have been related to a direct ischemic preconditioning-like effect, known as pharmacological preconditioning induced by anesthetics (anesthetic preconditioning). Furthermore, volatile anesthetics applied during myocardial ischemia appear to suppress the inflammatory responses that cause myocardial dysfunction.5–12 Volatile anesthetics also appear to reduce the extent of reperfusion injury when administered early in the reperfusion period.13,14 Thus implementation of such cardioprotection during surgery may provide an additional tool in the treatment and prevention of ischemic cardiac dysfunction in the perioperative period.
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MECHANISMS OF ANESTHETIC-INDUCED CARDIOPROTECTION
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The mechanisms of anesthetic-induced cardioprotection have been the subject of recent reviews.15–18 Ischemic injury is defined as the tissue damage caused during ischemia. The severity of ischemic injury depends on the duration of ischemia, but it can be modified by interventions (ischemic preconditioning) before the onset of ischemia (Figure 1
). Ischemic preconditioning represents an adaptive endogenous response to brief sublethal episodes of ischemia, which results in protection against subsequent lethal ischemia. Interestingly, ischemic and anesthetic preconditioning share many common intracellular signaling pathways (Figure 2). These include opening of mitochondrial KATP channels, increasing mitochondrial reactive oxygen species, activation or translocation of protein kinase C, tyrosine kinases and p38 mitogen-activated protein kinase.19–30 These mechanisms decrease cytosolic and mitochondrial calcium loading.31 Volatile anesthetics may also protect coronary endothelial cells by mediating nitric oxide release.32
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Figure 1. Cellular mechanism of ischemic preconditioning; activation of adenosine A1 and A3 (A1/A3), bradykinin2 (B2),  1-opioid (1), 1-adrenergic (1) and -adrenergic (β) receptors stimulate phospholipase C (PLC) through inhibitory guanine nucleotide-binding proteins (Gi protein). PLC produces diacylglycerol (DAG) and inositol 1,4,5-triphosphate (ITP). Both DAG and ITP activate protein kinase C (PKC). PKC enhances opening of ATP-sensitive K+ channels (KATP), channels probably via mitogen-activated protein kinases (MAPK). NO = nitric oxide, NOS = nitric oxide synthase, = PIP2 phosphatidyl inositol biphosphate, ROS = reactive oxygen species, SR = sarcoplasmic reticulum.
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Figure 2. Cellular mechanism of volatile anesthetic preconditioning; volatile anesthetics enhance opening of ATP-sensitive K+ channels (KATP channels) by activation of phospholipase C (PLC) via adenosine A1 and A3 (A1/A3) and adrenergic receptor stimulation, and by nitric oxide synthase (NOS) activation. = B2 bradykinin2 receptors, Gi protein = inhibitory guanine nucleotide-binding proteins, DAG = diacylglycerol, ITP = inositol 1,4,5-triphosphate, MAPK = mitogen-activated protein kinases, NO = nitric oxide, PIP2 = phosphatidyl inositol biphosphate, PKC = protein kinase C, ROS = reactive oxygen species, SR = sarcoplasmic reticulum, 1 = 1-adrenergic receptor, β= β-adrenergic receptor, 1 = 1-opioid receptor.
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Although ischemic myocardium can only be salvaged by reperfusion, reperfusion itself can lead to additional cellular damage that further augments injury. Volatile anesthetics applied during myocardial ischemia appear to suppress neutrophil activation, neutrophil-endothelial interactions and inflammatory responses that cause myocardial dysfunction.5–12 In addition, postischemic administration of volatile anesthetics can also initiate cardioprotection, as evidenced from improved post-ischemic endothelial function, reduced infarct size and less apoptosis.13,14 These protective effects against lethal reperfusion injury were recently named anesthetic post-conditioning.
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CLINICAL STUDIES
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In contrast to the large amount of data obtained in the experimental setting, only a few studies have addressed the potential cardioprotective properties of volatile anesthetics in clinical practice. This is mainly because the experimental protocol necessitates myocardial ischemia to be instituted in a standardized and reproducible way. This situation does not normally occur clinically, where all efforts are directed towards the prevention of myocardial ischemia. The clinical situation that most closely resembles the sequence of standardized myocardial ischemia and reperfusion is coronary artery bypass grafting (CABG). This type of surgery allows transposition of the experimental setting of pre and post-conditioning into a clinical protocol (Tables 1 and 2).
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Table 1. Clinical Studies on Cardioprotective Properties of Volatile Anesthetics before, during and after Myocardial Ischemia
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Table 2. Clinical Protocols on Cardioprotective Effects of Volatile Anesthetics Administered throughout Entire Procedure
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ANESTHETIC PRECONDITIONING PROTOCOLS
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The first clinical anesthetic preconditioning protocol was published in 1999 by Belhomme and colleagues.33 In the study group (n = 10), a 2.5 minimal alveolar concentration (MAC) dose of isoflurane was administered for 5 min in the gas mixture delivered to the oxygenator, followed by a 10-min wash-out period before aortic cross clamping. The control patients underwent a matched time period of isoflurane-free cardiopulmonary bypass (CPB). The study endpoints were serum markers of myocardial damage (creatine kinase-MB and troponin I) and tissue markers of protein kinase C activation (ecto-5'-nucleotidase activity). There was less postoperative creatine kinase-MB (CK-MB) and troponin I release in the study group, however, the difference did not reach statistical significance. In addition, there was a significant increase in ecto-5'-nucleotidase activity in right atrial biopsy samples in the isoflurane preconditioning group, whereas this fraction remained unchanged in the control group. The increase in ecto-5'-nucleotidase activity was taken as an indicator of protein kinase C activation because it is an enzyme that releases adenosine from 5'-cyclic adenosine monophosphate, which is one of the substrates that are phosphorylated by protein kinase C. Because activation of protein kinase C represents a pivotal step in the signal transduction involved in ischemic and anesthetic preconditioning, this phenomenon might indicate a triggering of preconditioning by isoflurane. Nevertheless, this increase in ecto-5'-nucleotidase activity represents only circumstantial evidence for the occurrence of anesthetic preconditioning.
Recent studies have been able to associate volatile anesthetic preconditioning with the activation of protein kinase C in a less equivocal way. Julier and colleagues34 evaluated the effects of sevoflurane preconditioning on biochemical markers of myocardial damage and protein kinase C activation. Seventy-two patients scheduled for CABG were randomly assigned to receive sevoflurane preconditioning (2 MAC) during the first 10 min of CPB or to a time-matched control group that received a sevoflurane-free air-oxygen mixture. This study did not include a wash-out phase because the aorta was cross clamped immediately after preconditioning or the matched 10-min time period. The study endpoints were biochemical markers of myocardial tissue injury (CK-MB and troponin T), myocardial dysfunction (brain natriuretic peptide) and myocardial tissue levels of protein kinase C isoforms and 
. These kinases were obtained from atrial samples that were taken before preconditioning, during cannulation and at the end of preconditioning immediately before cardioplegic arrest. The sevoflurane group demonstrated a significantly lower postoperative release of brain natriuretic peptide than the control group. In addition, this study was the first to demonstrate translocation of protein kinase C and isoforms, which is one of the mechanisms implicated as a pivotal step in anesthetic preconditioning. This phenomenon also occurred in human myocardium in response to sevoflurane. However, no differences were found between the groups in terms of perioperative ST-segment changes, arrhythmias, or CK-MB and cardiac troponin T release. Nevertheless, the sevoflurane group had fewer late adverse cardiac events (cardiac death, nonfatal myocardial infarction, unstable angina, intercurrent coronary angioplasty or CABG, arrhythmias requiring re-hospitalization, and new episodes of congestive heart failure) and better 1-year outcomes.35 However, another study by Pouzet and colleagues36 was unable to demonstrate an association between volatile anesthetic preconditioning and protein kinase C activation. This study evaluated the myocardial tissue levels of protein kinase C, tyrosine kinase, and p38 mitogen-activated protein kinase obtained from 20 right atrial biopsy specimens taken before and 10 min after CPB. Compared with baseline, protein kinase C and p38 mitogen-activated protein kinase activities increased significantly. However, the increase was not significantly different between groups. On the other hand, sevoflurane triggered a significant increase in tyrosine kinase activity that was not observed in the control patients. Although the postoperative troponin I levels tended to be lower in the sevoflurane group, there was no significant difference between groups at any time; but the sample size was very small, and no sample size analysis was included. To prove that a difference in troponin I levels of 1 ng·mL–1 was statistically significant, the authors should have included at least 40 patients in this particular study.
Because protective mechanisms against myocardial dysfunction and damage should result in better myocardial function, it is of interest to know whether application of an anesthetic preconditioning protocol is associated with better myocardial function after ischemia. This issue was addressed by Penta de Peppo and colleagues37 who allocated 22 patients undergoing
CABG to either a preconditioning group or a control group. In the preconditioning group, enflurane was administered 5 min before the start of CPB to reduce systolic blood pressure by 20% to 25%. The control group had a time-matched enflurane-free interval. Myocardial function was assessed by pressure-area relations using a fluid-filled catheter in the ascending aorta as the left ventricular (LV) pressure correlate, and transesophageal echocardiographic automated border detection as the area correlate. Data were obtained during inflow occlusion by ligation of the inferior caval vein before and after CPB. Two patients were excluded because of poor quality of their echocardiographic images, and in another 4 patients, the study could not be terminated because of various perioperative complications. This left 8 patients in each group for final analysis. This study demonstrated a significant decrease in the slope of the end-systolic pressure-area relationship after the end of CPB in the control group, but not in the enflurane group. Based on this finding, the authors suggested that enflurane pretreatment allowed better preservation of LV function after CPB. In contrast, no differences were noted between groups in postoperative release of CK-MB or troponin I. Other possible variables of hemodynamic and myocardial function that could have confirmed the data obtained from the pressure-area relationships were not reported. The same group conducted another study using an isoflurane-preconditioning protocol.38 Forty patients undergoing CABG were randomly assigned to receive 1.5% end-tidal concentration of isoflurane preconditioning for 15 min or an isoflurane-free air-oxygen mixture. A 10-min wash-out period followed, after which CPB was started. Compared with before CPB, the hemodynamic variables of cardiac index, LV stroke work index and ejection fraction remained unchanged after CPB in both groups. Troponin I and CK-MB values transiently increased in the postoperative period, but this increase was similar in both groups. However, in a subgroup of patients with a preoperative ejection fraction < 50%, the release of CK-MB and troponin I 24 hours after the operation was lower in the isoflurane-treated group (n = 9) than in the control group (n = 11). Also, in this subgroup, no differences in hemodynamics were present between the groups.
In another study, Haroun-Bizri and colleagues39 randomly allocated 49 CABG patients to an isoflurane group (n = 28) or a control group (n = 21). In the isoflurane group, baseline anesthesia was supplemented with isoflurane during the pre-CPB period, which was titrated to a concentration of 0.5% to 2% to maintain blood pressure within 20% to 25% of baseline values. Isoflurane was discontinued on initiation of CPB. No volatile anesthetic was administered in the control group. In both groups, hemodynamic variables were comparable before CPB; however, the cardiac index was higher after CPB in the isoflurane-treated group. ST-segment changes in lead V5 were less pronounced in the treated group, but the need for inotropic support and the incidence of arrhythmia after release of the aortic cross clamp were similar between groups. The investigators suggested that the higher cardiac index observed in the treatment group was related to the anesthetic preconditioning properties of isoflurane. However, the study protocol did not allow exclusion of the possibility that a better myocardial oxygen balance profile in the study group before CPB, related to a deeper anesthetic level with isoflurane, was, at least in part, responsible for these observations.
A recent study in 359 consecutive cardiac surgery patients was conducted by Fellahi and colleagues.40 The patients were prospectively divided into 2 groups according to whether or not isoflurane was added to standardized intravenous anesthesia before CPB. Additional isoflurane (1–1.8 MAC over 15–33 min) was given to 138 patients, and the other 221 served as the control group. This study observed no significant difference in postoperative troponin I release, nonfatal cardiac events and hospital outcome between groups.
In a recent in-vitro study on isolated human right atrium obtained from patients undergoing coronary surgery, Yvon and colleagues41 demonstrated that sevoflurane pretreatment preconditioned human myocardium against hypoxia through activation of adenosine triphosphate-sensitive potassium channels and stimulation of adenosine A1 receptors. Taken together, the results of all these clinical preconditioning protocols give widely differing results for the diverse outcome variables. Although this may be partly related to the different administration protocols, it seems that the cardioprotective properties of an anesthetic preconditioning protocol, which appear very straightforward in the experimental setting, have only minor implications in the clinical setting.
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PROTOCOLS DURING ISCHEMIA
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Inflammatory response and LV function were evaluated by Nader and colleagues.42 Coronary artery bypass grafting patients were allocated to a total intravenous anesthetic (TIVA) regimen (n = 10) or a sevoflurane anesthetic regimen (n = 11). The cardioplegia mixture was vaporized with 2% sevoflurane and oxygen in the study group, and with oxygen only in the control group. It was observed that sevoflurane decreased the inflammatory response after CPB, as measured by the release of interleukin 6, neutrophil β-integrins CD 11b and CD 18, and tumor necrosis factor-. Left ventricular regional wall motion abnormalities and LV stroke work index were also improved in the sevoflurane group.
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REPERFUSION (POST-CONDITIONING) PROTOCOLS
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De Hert and colleagues43 observed that administration of sevoflurane (0.5–1 MAC) in CABG patients at early reperfusion until the end of the operation caused no significant difference in postoperative troponin I release. However, a faster recovery of stroke volume after CPB was observed in the sevoflurane post-conditioned group compared to the control group.
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DOES CHOICE OF ANESTHETIC REGIMEN MATTER IN CLINICAL PRACTICE?
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The results of these studies seem to indicate that the clinical implications of pre or post-conditioning protocols are, at best, debatable. Therefore, a number of studies aimed to evaluate whether the choice of a volatile anesthetic regimen throughout the whole perioperative period might improve postoperative cardiac function. This issue was first addressed in a study in patients undergoing CABG with CPB.44 Twenty patients with preserved myocardial function (preoperative LV ejection fraction > 50%) were randomly assigned to receive either an intravenous anesthetic regimen with propofol or sevoflurane-based anesthesia. Except for this difference, anesthetic and medical treatments were similar in both groups. Preserved global hemodynamic and LV function and lower postoperative release of troponin I were observed with the volatile anesthetic regimen compared to TIVA. It was concluded that the use of a volatile anesthetic regimen appeared to be associated with a cardioprotective effect in CABG patients. Another study by the same group confirmed these observations: 45 CABG patients with preoperative impaired myocardial function (LV ejection fraction < 45%, age > 70 years, 3-vessel disease and impaired myocardial reserve capacity) were randomly assigned to TIVA or a regimen using the volatile anesthetics sevoflurane or desflurane.45 In these patients also, a volatile anesthetic regimen was associated with preservation of global hemodynamic and LV function and significantly lower postoperative release of troponin I compared to TIVA. The cardioprotective effects of a volatile anesthetic regimen during CABG were confirmed in other reports that used different anesthetic and surgical protocols, and in patients undergoing off-pump CABG.46–53 These clinical studies clearly indicate that volatile anesthetics protect the myocardium during CABG. However, another study in patients undergoing off-pump CABG observed no significant difference in the incidence of myocardial ischemia.50 In addition, the impact of this phenomenon on postoperative morbidity and clinical recovery remains to be definitively established.
This issue was first addressed by El Azab and colleagues.51 They observed that use of sevoflurane during CABG was associated with less postoperative release of tumor necrosis factor- and also with a shorter length of stay in the intensive care unit compared with patients who had TIVA. In another larger study population, 320 CABG patients were randomly assigned to receive either TIVA or a volatile anesthetic.54 Those who received a volatile anesthetic had significantly shorter intensive care and hospital lengths of stay. Multiple regression analysis revealed that prolonged stay in the intensive care unit in this particular study was related to the following independent predictors of outcome: occurrence of atrial fibrillation, postoperative troponin I > 4 ng·mL–1 and need for > 12 hours postoperative inotropic support. Although the incidence of atrial fibrillation was not significantly different between groups, the numbers of patients with postoperative troponin I > 4 ng·mL–1 and who needed prolonged postoperative inotropic support were significantly lower in the volatile anesthetic group. These findings were associated with better myocardial function in the early postoperative period. The same group conducted another study in patients undergoing aortic valve replacement.55 This demonstrated the use of a volatile anesthetic was associated with preserved cardiac function after CPB and less postoperative release of troponin I compared to TIVA. These data indicate that the clinically protective properties of volatile anesthetics observed in CABG surgery are also present during aortic valve surgery.
There is some evidence that a volatile anesthetic may have beneficial effects on other organ systems. Julier and colleagues34 observed that sevoflurane preconditioning in CABG patients was associated with reduced release of cystatin C, a marker of renal dysfunction. Similarly, Lorsomradee and colleagues56 noted in patients undergoing CABG that use of a volatile anesthetic was associated with significantly lower postoperative levels of markers of hepatic dysfunction compared to TIVA. From these data, it seems that the duration and timing of administration of volatile anesthetics are important in the extent of myocardial protection. A recent study hypothesized that postoperative release of biochemical markers of myocardial damage would be lower and myocardial function immediately postoperatively would be better when the agent was administered throughout the procedure, rather than during a limited period before ischemia or after completion of coronary anastomoses.43 This study analyzed postoperative levels of troponin I and indices of myocardial function in patients undergoing CABG with CPB under 4 different anesthetic protocols: intravenous propofol throughout, sevoflurane before CPB only, sevoflurane after completion of coronary anastomoses only and sevoflurane throughout. The cardioprotective effects were clinically most apparent when the volatile anesthetic was administered throughout the surgical procedure. This was evident from reduced postoperative troponin I release and preserved postoperative cardiac function compared to TIVA. When administered only before CPB or after completion of anastomoses, postoperative recovery of stroke volume occurred earlier, but release of troponin I was not significantly different from the pattern observed with TIVA.
The effects of anesthetic choice on real outcome variables, such as postoperative mortality and morbidity, remain to be established. This is mainly because sample size in the different studies is too low to address these issues. Very recently, 2 meta-analyses of myocardial protection with volatile anesthetics were performed. Yu and colleagues57 conducted a systematic review of studies that assessed the effects of volatile anesthetics on cardiac ischemic complications and morbidity in 2,841 CABG patients. Compared to TIVA, a volatile anesthetic was associated with reduced all-cause mortality. Sevoflurane and desflurane reduced cardiac troponin I at 6, 12, 24, and 48 hours after the operation. The other meta-analysis by Symons and colleagues58 compared volatile and nonvolatile anesthetics in 2,979 CABG patients. There was no significant difference in myocardial ischemia, myocardial infarction, intensive care unit stay or hospital mortality between the groups. Post-CPB, patients who received volatile anesthetics had a 20% higher cardiac index, significantly lower serum troponin I, and less requirement for inotropic support compared to those who received TIVA. Duration of mechanical ventilation was reduced by 2.7 hours, and there was a 1-day decrease in hospital stay. Although most of the volatile anesthetics have cardioprotective properties, some differences may exist in the extent of vascular or other effects.59,60
There is some evidence that the cardioprotective effects of volatile anesthetics can be altered by oral antidiabetic drugs. Sulfonylurea receptor 1 is the regulatory subunit of the pancreatic ATP-sensitive K+ channel (KATP channel) that is essential for triggering insulin secretion via membrane depolarization. Sulfonylureas, the widely used oral antidiabetic drugs that act as KATP channel blockers, prevent isoflurane-induced cardioprotection in diabetic patients undergoing coronary surgery. However, these protective effects can be restored by a preoperative switch from sulfonylurea to insulin.61 Experimental studies have shown that opioids protect the myocardium from ischemic injury, and that opioid cardioprotection is enhanced by the coadministration of volatile anesthetics.62 The -opioid receptor on cardiac myocytes appears to mediate opioid-induced cardioprotection.63,64 The stimulation of -opioid receptors results in KATP channel activation and cardioprotection in animal models and isolated human atrial tissue.65,66 Experimental data also suggest that morphine produces a potent cardioprotective effect via a mechanism linked to the -opioid receptor and KATP channel.67 The preconditioning effects of other opioids used in clinical practice are less certain.
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CONCLUSIONS
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There is a large amount of experimental evidence that volatile anesthetics exert beneficial effects on the consequences of myocardial ischemia-reperfusion injury. Research has been focused on the possible implementation of this property in patient care. Although there is some promising evidence that volatile anesthetics may also be associated with a cardioprotective effect in the clinical setting, and improved outcome in patients at high risk of cardiovascular complications, further well-designed prospective multicenter studies should be carried out to elucidate definitively whether the cardioprotective properties of volatile anesthetic agents really do affect the outcomes of the surgical patient.
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ABSTRACT
INTRODUCTION
