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Anesthetic Preconditioning: Serendipity and Science

Warltier, David C. M.D., Ph.D.*; Kersten, Judy R. M.D.†; Pagel, Paul S. M.D., Ph.D.‡; Gross, Garrett J. Ph.D.§; Todd, Michael M. M.D., Editor-in-Chief

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THIS issue of the Journal contains a special section devoted to a series of articles 1–7 addressing pharmacological preconditioning of myocardium by volatile anesthetics. These articles represent only a small fraction of the recent publications related to the subject of anesthetic preconditioning (APC). In fact, since 1999, Anesthesiology has published more than 20 investigations on this phenomenon. This year's June and July issues of the American Journal of Physiology-Heart and Circulatory Physiology contained special sections on pharmacological preconditioning, and the 2003 American Society of Anesthesiologists Annual Meeting Journal Symposium will feature the topic of APC.
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Personal Observations
Over the past few years, both serendipity and scientific investigation have revealed that volatile agents may have important cardioprotective properties against myocardial ischemia and reperfusion injury. The findings may ultimately have an impact on the practice of anesthesia for patients with coronary artery disease. Several research laboratories were initially involved in studies of the coronary collateral circulation in animals following reports that coronary steal could produce myocardial ischemia during administration of isoflurane to patients with coronary artery disease. A series of investigations in experimental animals found that this was not the case, and, in fact, the opposite was true—volatile anesthetics have cardioprotective properties. 8 Protection against reversible and irreversible myocardial injury by these agents was not easily explained by simple alterations in myocardial oxygen supply and demand. In contrast, previous clinical investigations had not found evidence to suggest that one anesthetic technique was preferable to another for patients with coronary artery disease. Thus, early laboratory findings went largely unresolved with the appearance of having few if any direct implications for administration of volatile anesthetics to humans.
More recently, medical economics has driven anesthesiologists to assist in reducing healthcare costs by tailoring anesthetics to allow shorter lengths of stay, especially in high-cost centers, such as intensive and postanesthesia care units. Remarkably, instead of scientific investigation guiding decisions as to which anesthetics or techniques to use for improved outcome, shorter-acting drugs that allow patients to be extubated earlier, leave the intensive care unit sooner, and be discharged from the hospital more rapidly are advocated. This resulted in a change from what was largely a high-dose opioid technique to, instead, a primarily volatile anesthetic technique for patients undergoing coronary artery bypass graft surgery. As anesthesia for cardiac surgery changed, more than a few of the authors’ colleagues at this institution and others have suggested that fewer intraoperative ischemic events may be observed in this patient population. Other anesthesiologists have commented that in their practice, the need for pharmacological or mechanical circulatory support was less frequent after revascularization. The reasons for these anecdotal observations are probably multifactorial. Many fundamental changes in the approach to the patient undergoing coronary artery bypass graft surgery have occurred, and only a few are related to the type of anesthetic delivered. Nevertheless, it is possible that economic pressures led to a relatively greater use of volatile anesthetics in patients undergoing cardiac surgery, and this resulted in a reduced frequency of ischemic events because these agents possess cardioprotective properties. Serendipity may have allowed for this as yet untested observation in humans, which was simultaneously being intensively studied in the basic research laboratory.
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Ischemic Preconditioning
Laboratory and clinical investigations have demonstrated that single or multiple brief periods of ischemia are not necessarily deleterious and, instead, can be protective against a subsequent prolonged ischemic insult. The brief periods of ischemia appear to “precondition” myocardium against reversible or irreversible tissue injury, including stunning, infarction, and the development of malignant ventricular arrhythmias. This process, termed ischemic preconditioning (IPC), results in finite periods in which the myocardium is protected following a brief period of ischemia. An early phase or window of IPC persists for 1 to 2 h before “disappearing” and then reoccurring 24 h later. This second or late window of preconditioning may last for as long as 3 days.
Ischemic preconditioning is a fundamental endogenous protective mechanism against tissue injury ubiquitous to all species in which it has been studied. IPC is best characterized in the heart, but it is also present in other tissues. The mechanism(s) whereby IPC reduces the extent of myocardial infarction have been extensively studied over the past few years. A variety of ligands and multiple receptors coupled to G proteins are primarily responsible for activation of an intracellular signal transduction pathway that involves protein kinase C, mitogen-activated protein kinases, protein tyrosine kinases, reactive oxygen species, and nitric oxide synthase. Central to this process is the role of the mitochondrial adenosine triphosphate-sensitive potassium (KATP) channel. Opening of this channel is critical for the beneficial cardioprotective effects of IPC. As the components involved in the intracellular signal transduction pathway of IPC have been better defined, pharmacological agonists and antagonists of various mediators have been tested in an effort to develop new therapeutic agents that might also precondition myocardium. During this time, the beneficial effects of volatile anesthetics against ischemic injury have been revisited, IPC providing a strong stimulus to evaluate mechanisms of APC.
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Anesthetic Preconditioning
The inability to relate the antiischemic effects of volatile anesthetics to improvement of myocardial oxygen supply-demand balance led to the concept that these agents may have direct cardioprotective properties. 9 Volatile anesthetics have been shown to directly precondition 10,11 or indirectly enhance IPC, resulting in cardioprotection against myocardial infarction with the KATP channel playing an important role. 10 Pharmacological preconditioning produced by volatile agents, including isoflurane, desflurane, and sevoflurane, is remarkably similar to IPC and shares many of the same signal transduction elements. Further mechanisms of action are now being explored.
In this issue of the Journal, Zaugg et al.1,2 provide additional evidence that mitochondrial KATP channels are critical to APC by volatile agents and also demonstrate that certain intravenous anesthetics may have deleterious effects on preconditioning produced by KATP channel openers. Cardiac sarcolemmal KATP channels may also be modulated by volatile anesthetics. Kwok et al.3 demonstrate that isoflurane may not directly alter sarcolemmal KATP channels but instead potentiates opening of the channel by other agonists. Other results from this laboratory show that the action of isoflurane on the KATP channel requires endogenous mediators, most likely PKC. 4 Thus, alterations in intracellular kinases, such as PKC, may be involved in APC, 1,5 and the work of de Klaver et al.5 suggests that APC is not limited to cardiomyocytes, but protection against vascular smooth muscle and endothelial cell death by isoflurane and halothane is also possible. Hanouz et al.6 confirm that desflurane is cardioprotective, and this agent may act via multiple mechanisms that ultimately converge on the mitochondrial KATP channel. These investigators further demonstrate that adenosine and α- and β-adrenergic receptors may also be involved in APC signal transduction.
Finally, in this issue of the Journal a small clinical investigation by De Hert et al.7 has suggested that volatile anesthetics are cardioprotective in humans. This study demonstrates that sevoflurane-anesthetized patients had reduced cardiac enzyme release and improved left ventricular function after coronary artery bypass graft surgery as compared to patients anesthetized with propofol. This and several other initial clinical studies 12–14 are extraordinarily provocative. Larger investigations of the impact of volatile anesthetics, including cardiac morbidity (e.g., frequency of myocardial infarction) and mortality using many centers and thousands of patients, are now required to further establish the clinical significance of APC in humans. Experimental results to date demonstrating the existence and mechanisms of APC and preliminary clinical evidence suggesting that APC also occurs in humans warrant such multicenter trials.
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1. Zaugg M, Lucchinetti E, Spahn D, Pasch T, Schaub M: Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitoKATP channels via multiple signaling pathways. A nesthesiology 2002; 97: 4–14

2. Zaugg M, Lucchinetti E, Spahn D, Pasch T, Garcia C, Schaub M: Differential effects of anesthetics on mitochondrial KATP channel activity and cardiomyocyte protection. A nesthesiology 2002; 97: 15–23

3. Kwok W, Martinelli A, Fujimoto K, Suzuki A, Stadnicka A, Bosnjak Z: Differential modulation of the cardiac ATP-sensitive potassium channel by volatile anesthetics. A nesthesiology 2002; 97: 50–6

4. Fujimoto K, Bosnjak Z, Kwok W: Isoflurane-induced facilitation of the cardiac sarcolemmal KATP channel. A nesthesiology 2002; 97: 57–65

5. de Klaver M, Manning L, Palmer L, Rich G: Isoflurane pretreatment inhibits cytokine-induced cell death in cultured rat smooth muscle cells and human endothelial cells. A nesthesiology 2002; 97: 24–32

6. Hanouz J, Yvon A, Massetti M, Lepage O, Babatase G, Khayat A, Bricard H, Gerard J: Mechanisms of desflurane-induced preconditioning in isolated human right atria in vitro. A nesthesiology 2002; 97: 33–41

7. De Hert S, ten Broecke P, Mertens E, Van Sommeren E, De Blier I, Stockman B, Rodrigus I: Sevoflurane but not propofol preserves myocardial function in coronary surgery patients. A nesthesiology 2002; 97: 42–9

8. Warltier DC, Al-Wathiqui MH, Kampine JP, Schmeling WT: Recovery of contractile function of “stunned” myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane. A nesthesiology 1988; 69: 552–65

9. Kersten JR, Schmeling TJ, Hettrick DA, Pagel PS, Gross GJ, Warltier DC: Mechanism of myocardial protection by isoflurane: Role of adenosine triphosphate–regulated potassium (KATP) channels. A nesthesiology 1996; 85: 794–807

10. Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC: Isoflurane mimics ischemic preconditioning via activation of K(ATP) channels: Reduction of myocardial infarct size with an acute memory phase. A nesthesiology 1997; 87: 361–70

11. Cason BA, Gamperl AK, Slocum RE, Hickey RF: Anesthetic-induced preconditioning: Previous administration of isoflurane decreases myocardial infarct size in rabbits. A nesthesiology 1997; 87: 1182–90

12. Belhomme D, Peynet J, Louzy M, Launay JM, Kitakaze M, Menasche P: Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery. Circulation 1999; 100: II-340–4

13. Haroun-Bizri S, Khoury SS, Chehab IR, Kassas CM, Baraka A: Does isoflurane optimize myocardial protection during cardiopulmonary bypass? J Cardiothorac Vasc Anesth 2001; 15: 418–21

14. Penta de Peppo A, Polisca P, Tomai F, De Paulis R, Turani F, Zupancich E, Sommariva L, Pasqualetti P, Chiariello L: Recovery of LV contractility in man is enhanced by preischemic administration of enflurane. Ann Thorac Surg 1999; 68: 112–8

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