Journal of Cardiothoracic and Vascular Anesthesia
Volume 23, Issue 5 , Pages 589-593, October 2009

Cardioprotection by Volatile Anesthetics: Established Scientific Principle or Lingering Clinical Uncertainty?

Anesthesia Service, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI

Article Outline

 

IN 1976, Bland and Lowenstein1 reported that the volatile anesthetic halothane attenuated ST-segment changes caused by brief coronary artery occlusion in dogs. These seminal experiments showed, for the first time, that volatile anesthetics may be capable of exerting important anti-ischemic effects. Since this landmark article was published, the ability of modern volatile agents and the anesthetic noble gas xenon to attenuate reversible and irreversible myocardial ischemic injury have been validated repeatedly in several animal species using a variety of experimental preparations. The alterations in receptor activity, intracellular signaling, and mitochondrial physiology presumed to be responsible for anesthetic-induced cardioprotection have been studied comprehensively, yet many fundamental questions remain to be answered about the mechanisms, potential limitations, and clinical relevance of this phenomenon.2, 3, 4, 5, 6, 7 The current issue of the Journal of Cardiothoracic and Vascular Anesthesia contains 3 additional laboratory investigations8, 9, 10 that continue to further the understanding of cardioprotection by inhaled anesthetics and also includes an interesting longitudinal survey of cardiac surgery programs in Italy that draws provocative conclusions about the potential clinical benefits of the use of volatile agents in patients undergoing coronary artery bypass graft (CABG) surgery.11

Smul et al8 tested the hypothesis that desflurane-induced cardioprotection is dependent on the timing of administration in rabbits subjected to prolonged (30 minutes) coronary artery occlusion and reperfusion (3 hours). The administration of 1.0 minimum alveolar concentration (MAC) of desflurane before the ischemic event (preconditioning) or immediately upon reperfusion (postconditioning) reduced myocardial infarct size (quantified using triphenyltetrazolium chloride staining), but the combination of pre- and postconditioning did not preserve additional myocardium. These findings are similar to those obtained with sevoflurane in Langendorff-perfused rat hearts,12 but most likely occurred because a limited amount of myocardium is available for salvage when 1.0 MAC anesthetic concentrations are used for pre- and postconditioning.13 As expected, the administration of desflurane solely during coronary artery occlusion did not affect the extent of myocardium infarction, most likely because the volatile agent was unable to access and thereby activate signaling pathways within the ischemic zone.8 Desflurane postconditioning also was dependent on nitric oxide (NO) metabolism because pretreatment with the nonselective NO synthase inhibitor abolished reductions in myocardial necrosis produced by the volatile agent during early reperfusion. These latter data also confirmed previous findings implicating a role for NO in desflurane preconditioning14 and isoflurane pre- and postconditioning.15, 16, 17

Another investigation using the identical rabbit model showed that a brief (10 minutes), repetitive (3 cycles) administration of 0.5 MAC of desflurane, but not a 30- or 90-minute continuous administration at this concentration, produced reductions in myocardial infarct size that were equivalent to those observed with continuous administration of 1.0 or 1.5 MAC of the volatile agent.9 The study concluded that brief, repetitive exposure reduced the threshold of desflurane preconditioning in vivo. Such a response previously has been observed during ischemic preconditioning produced by a series of brief coronary artery occlusions interspersed by reperfusion before a prolonged ischemic episode, but has yet to be shown using a volatile anesthetic. Interestingly, brief, repetitive administration of higher concentrations of desflurane did not provide additional protective effects compared with continuous administration, findings that were most likely again observed because there is a finite amount of myocardium that can be preserved by anesthetic preconditioning associated with a 30-minute coronary artery occlusion.13 The causes of this threshold reduction were, unfortunately, not examined. However, it is certainly plausible to hypothesize that brief, intermittent exposure to desflurane may have produced repetitive bursts of small quantities of reactive oxygen species known to mediate anesthetic preconditioning,18 thereby providing a more potent stimulus of cardioprotective signaling compared with a single, more prolonged exposure to the volatile agent. The findings also extended previous results19, 20 showing a role of β-adrenergic receptors in desflurane pre- and postconditioning because pretreatment with selective β1- and β2-adrenoceptor antagonists abolished reductions in myocardial necrosis produced by the administration of desflurane for the initial 30 minutes of reperfusion after prolonged coronary artery occlusion. The current investigation also implicated the β2-adrenoceptor in desflurane preconditioning because a selective antagonist inhibited decreases in infarct size produced by the volatile agent. Thus, the β2-adrenoceptor and its downstream signaling elements appear to play a central role in anesthetic-induced cardioprotection.

Baumert10 examined the effects of isoflurane on xenon preconditioning in acutely instrumented pigs subjected to a 1-hour left anterior descending coronary artery occlusion and reperfusion. The ability of the xenon to protect myocardium against ischemic injury has been the subject of intense interest at least in part because xenon is otherwise essentially devoid of cardiovascular effects.7, 21, 22 The mechanisms responsible for pre- and postconditioning by xenon have been shown to be very similar to those implicated in cardioprotection by volatile anesthetics. Brief (10 minutes), repetitive administration of xenon (3 cycles of 70% xenon-30% oxygen interspersed with 70% nitrogen-30% oxygen) did not affect myocardial infarct size, whereas the administration of 70% xenon before and during ischemia and reperfusion modestly reduced the extent of myocardial injury, myeloperoxidase activity, and plasma tumor necrosis factor-α and interleukin-6 concentrations in porcine models of left and right ventricular infarction.23, 24 In the current investigation, the combination of isoflurane and xenon (0.55 MAC of each inhaled agent) administered continuously throughout ischemia and reperfusion did not produce additive cardioprotective effects compared with either agent alone.10 The relative lack of efficacy of xenon shown in the previous studies23, 24 and its failure to produce an additive effect with isoflurane in the current investigation10 may be related to the more prolonged coronary artery occlusion (60-90 minutes) used in pigs compared with rats or rabbits (25-30 minutes) or, alternatively, may indicate species specificity. Furthermore, ischemic postconditioning did not occur25 or only modestly reduced26 infarct size in a similar porcine model. Notably, the crucial reperfusion injury salvage kinase cascade was not activated during ischemic postconditioning in pigs,26 which is in contrast to the results in other species.27 Considering these data, the current results suggest that the relatively minor cardioprotective action of xenon and its lack of an additive effect with isoflurane observed in pigs may have occurred because the reperfusion injury salvage kinase pathway appears to play a substantially less important role in pre- and postconditioning than in small mammals.

These 3 studies,8, 9, 10 as well as another related article28 that also appears in this issue, share 2 common features with the vast majority of other laboratory studies in which the cardioprotective actions of volatile anesthetics have been examined: the intentional production of reversible or irreversible myocardial ischemia and the subsequent evaluation of the consequences of this severe, premeditated damage (eg, functional recovery, infarct size, and apoptosis). Conversely, vigilant avoidance and prompt treatment of myocardial ischemia are essential objectives of every clinical anesthesiologist caring for patients at risk of such injury undergoing cardiac or noncardiac surgery. As a result, studies examining the potential for volatile anesthetics to protect myocardium against ischemic injury in humans rely primarily on alterations in clinical and, hence, often more subtle endpoints of unintended injury (eg, biochemical assays, use of vasoactive drugs, and duration of intensive care unit or hospital stay). Evaluation of the cardioprotective effects of volatile agents in patients at risk for myocardial ischemia is further complicated by simultaneous alterations in systemic and coronary hemodynamics; variations in the extent of coronary collateral perfusion; the use of other anesthetics, analgesics, or vasoactive drugs; other pre-existing disease states; the influence of surgery on cardiovascular homeostasis; and differing volatile anesthetic administration protocols, variables that may either be measured precisely or, alternatively, may be eliminated completely or mitigated to some degree in animal models. It is clear based on preliminary evidence accumulated to date that cardioprotection by volatile anesthetics most likely occurs in human myocardium in vitro,29, 30, 31 although age certainly appears to attenuate these beneficial effects to some degree.32 However, whether these laboratory observations with isolated human myocardium may be extrapolated directly to patients at risk for myocardial ischemia and infarction remains open to question.

Ten years ago, 2 independent groups first suggested that volatile anesthetics had the potential to produce cardioprotective actions in cardiac surgical patients. Penta de Peppo et al33 reported that the administration of enflurane (0.5%-2.0%) before cardioplegic arrest enhanced postischemic contractile functional recovery in patients undergoing CABG surgery. Shortly thereafter, Belhomme et al34 showed that brief (5 minutes) exposure to 2.5 MAC of isoflurane during cardiopulmonary bypass (before aortic cross-clamping) reduced postoperative release of troponin I and the myocardial form of creatine kinase in patients undergoing CABG surgery. These initial observations were subsequently confirmed and extended by the results of several additional small-scale clinical investigations. For example, volatile anesthetics, but not propofol, preserved myocardial function in patients undergoing CABG surgery with or without pre-existing left ventricular dysfunction or those undergoing aortic valve surgery concomitant with a reduction in troponin I release.35, 36, 37 The beneficial effects of volatile anesthetics were most apparent when the drug was administered throughout CABG surgery compared with before cardiopulmonary bypass or after the construction of the coronary anastomoses alone.38 Inhalation of 4% sevoflurane for the first 10 minutes of cardiopulmonary bypass reduced the postoperative release of brain natriuretic peptide concomitant with the activation and translocation of key isoforms of protein kinase C in atrial myocardium obtained from CABG surgery patients.39 Brief (10 minutes) administration of 4% sevoflurane also reduced platelet-endothelial cell adhesion molecule-1 (an important determinant of leukocyte migration through vascular endothelium during ischemic injury) and increased catalase (an enzymatic scavenger of large quantities of deleterious reactive oxygen species encountered during early reperfusion) expression in atrial biopsies concomitant with reductions in biochemical indices of myocardial injury and function (eg, cardiac troponin T and N-terminal pro–brain natriuretic peptide) in patients undergoing CABG surgery and cardiopulmonary bypass.40 Desflurane reduced troponin I release, inotropic drug use, and the number of patients requiring prolonged hospitalization compared with a propofol-opioid–based anesthetic technique in patients undergoing off-pump CABG surgery.41 Sevoflurane-induced alterations in genetic regulatory control of myocardial energy metabolism also were shown to predict postoperative cardiac function in off-pump CABG surgery patients.42 Finally, 2 meta-analyses incorporating the aforementioned and other clinical studies suggested that the use of a volatile anesthetic may be associated with the preservation of myocardial integrity, enhanced cardiac performance, and decreased inotrope requirements after cardiopulmonary bypass.43, 44 Nevertheless, these salutary effects did not appear to translate into reduced mortality or improved long-term outcome; conclusions that, in general, concurred with the results of several large clinical trials examining the relative safety of volatile anesthetics in cardiac surgical patients published 2 decades ago45, 46, 47, 48 in the wake of the isoflurane and “coronary steal” controversy.49, 50

It is within this context that Bignami et al11 conducted a longitudinal survey of 64 cardiac surgery centers to investigate the correlation between the use of volatile anesthetics and 30-day mortality in 34,310 patients undergoing CABG surgery. The authors' risk-adjusted analysis suggested that the use of a volatile anesthetic was weakly but significantly associated with a reduction in 30-day mortality (r2 = 0.07, p = 0.035). The data further suggested that a longer duration of intraoperative administration of a volatile agent appeared to be associated with a lower rate of mortality. Interpretation of the current results is clearly limited by the study's uncontrolled, retrospective design and the statistical techniques used to estimate, rather than directly measure, 30-day mortality; but the data nevertheless suggest that there may be a positive relationship between the use of a volatile anesthetic and perioperative outcome in patients undergoing myocardial revascularization. As controversial as such a conclusion may be based on the findings of the aforementioned studies, there are some recent data supporting the hypothesis that mortality may be reduced by the use of volatile anesthetics in this patient population. For example, a small, prospective, randomized trial of 72 patients undergoing CABG surgery showed that the brief administration of 4% sevoflurane during cardiopulmonary bypass reduced the incidence of late cardiac events (eg, congestive heart failure and coronary arterial reocclusion) during the first year after surgery compared with placebo.40 More recently, a retrospective study of 10,535 patients conducted in Denmark suggested that sevoflurane anesthesia was associated with a lower mortality in patients without recent myocardial infarction or unstable angina (ie, those who had already sustained an “ischemic preconditioning-like” episode) compared with a propofol-based anesthetic technique.51 In addition, a meta-analysis of 22 randomized clinical studies examining the potential protective effects of desflurane and sevoflurane in 1,922 cardiac surgical patient suggested that the use of one of these volatile agents was associated with a reduction in perioperative myocardial infarction and mortality compared with a total intravenous anesthetic technique.52 Thus, the current11 and previous studies40, 51, 52 provide very intriguing, albeit primarily indirect, evidence suggesting that volatile anesthetics may improve outcome by reducing the incidence and consequences of perioperative myocardial ischemia and infarction, but this contention has not been confirmed in a well-designed, large-scale, randomized, controlled clinical trial. It also may be very tempting to invoke the subcellular mechanisms responsible for anesthetic pre- and postconditioning when contemplating the potential beneficial actions of volatile agents in patients undergoing cardiac surgery, but such a direct cause and effect relationship has not been established definitively by studies conducted to date. Thus, the current data are incomplete, and additional research will be required in the laboratory and the operating room to convincingly determine whether volatile anesthetics do indeed exert clinically relevant anti-ischemic effects.

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References 

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PII: S1053-0770(09)00265-1

doi:10.1053/j.jvca.2009.07.001

Journal of Cardiothoracic and Vascular Anesthesia
Volume 23, Issue 5 , Pages 589-593, October 2009

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