To the Editor:—  We read with interest the article recently published by Kevin et al. , 1“Anesthetic preconditioning: Effects on latency to ischemic injury in isolated hearts.” The recent observation that anesthetic preconditioning (APC) by volatile anesthetics may possess therapeutic benefit on postischemic myocardial injury is of intense interest. The study of Kevin et al.  1shows that, in ischemic-reperfused isolated guinea pig hearts, the therapeutic time frame for APC against postischemic contractile dysfunction and infarction is approximately 25–40 min. The protection is maximal when ischemic duration is between 30 and 35 min. 1The authors suggested that APC may be useful therapy if the typical duration of ischemia during coronary artery bypass falls within this range. By contrast, APC is unlikely to be of benefit in patients who undergo more prolonged ischemia. This study provides a strong message reminding us of the potential clinical limitations to APC.

Mechanistically, studies by the same group have shown that brief exposure of the heart to volatile anesthetics before ischemia may lead to decreased formation of reactive oxygen species (ROS) during ischemia and subsequent reperfusion. 2,3This would seem to be a promising approach. It is well known that increased ROS formation during ischemia and reperfusion may contribute significantly to myocardial ischemia–reperfusion injury. It should be noted, however, that volatile anesthetic–mediated APC primarily requires the generation of ROS in advance (i.e. , before ischemia) as a trigger of myocardial preconditioning. 2,3Theoretically, the additional generation of ROS in a population with preexisting high degrees of oxidative stress, e.g. , chronic heart failure and diabetes, may stimulate increased mitochondrial permeability transition, releasing large amounts of ROS (involving radical-induced radical release). 4This would overwhelm endogenous antioxidant defenses, resulting in extensive lipid peroxidation and cellular destruction. 4It is reasonable to postulate that APC is unlikely to be of benefit or even to be detrimental in high-risk patients whose endogenous antioxidant capacity is reduced. Hence, the clinical utility of APC may be further limited, and alternative approaches to APC are required.

We have focused our efforts on the development of a therapeutic regimen using propofol as antioxidant supplementation during global myocardial ischemia–reperfusion injury. We found that propofol, when applied before ischemia, during ischemia, and during the early phase of reperfusion at clinically achievable high doses, can enhance myocardial tissue antioxidant capacity after prolonged (40 min) global ischemia and subsequent reperfusion in the isolated rat heart. 5,6The enhancement in tissue antioxidant capacity is associated with better postischemic functional recovery. Propofol increased the latency to the onset of ischemic contracture and decreased the magnitude of contracture development during ischemia in a dose-dependent manner. 5When the ischemia duration is shorter than 25 min, propofol applied in concentrations of 5 or 12 μg/ml attenuates the magnitude of ischemic contracture to a similar degree. 5However, propofol at 5 μg/ml essentially has no effect in attenuating the magnitude of ischemic contracture, as compared with untreated control, when the ischemic duration reaches 35 min. Significant reduction in the magnitude of ischemic contracture is seen with propofol at 12 μg/ml when the ischemic duration is prolonged to 40 min. Postischemic contracture, represented as the increase in left ventricular end-diastolic pressure (LVEDP), reflects diastolic functional impairment. Propofol at 12 μg/ml completely prevents the increase in LVEDP during 90 min of reperfusion after 40 min of global ischemia in isolated rat hearts. 5In contrast, a significant increase in LVEDP during reperfusion (12 ± 6 mmHg at reperfusion 60 min vs.  0 ± 0 at baseline) was observed after 40 min of global ischemia in the APC group studied by Kevin et al.  1LVEDP also significantly increased during reperfusion in the APC group when the ischemic interval was between 30 and 35 min, the time frame thought to demonstrate maximal therapeutic potential. 1We suspect that anesthetic treatment with high-dose propofol could be superior to APC with volatile anesthetics in protecting myocardial ischemic injury, in particular when the duration of aortic cross clamp may be prolonged, when patients with abnormally high levels of oxidant stress present for cardiac surgery, or both. Because the postischemic contracture and subsequent myocardial injury are generally attributable to cytosolic free Ca2+overload, the property of propofol in inhibiting myocyte Ca2+influx may also contribute to its cardiac protection.

In conclusion, despite laboratory evidence supporting cardiac protection by APC, the traditional administration of volatile anesthetics throughout the course of cardiac surgery has not been associated with a decrease in morbidity or mortality. 7Large prospective clinical trials comparing volatile anesthetic preconditioning and intravenous “anesthetic treatment” or trials comparing a combination of the two are merited.

University of British Columbia, Vancouver, British Columbia, Canada.

Kevin LG, Katz P, Camara AKS, Novalija E, Riess ML, Stowe DF: Anesthetic preconditioning: Effects on latency to ischemic injury in isolated hearts. Anesthesiology 2003; 99:385–91
Kevin LG, Novalija E, Riess ML, Camara AK, Rhodes SS, Stowe DF: Sevoflurane exposure generates superoxide but leads to decreased superoxide during ischemia and reperfusion in isolated hearts. Anesth Analg 2003; 96:949–55
Novalija E, Kevin LG, Camara AK, Bosnjak ZJ, Kampine JP, Stowe DF: Reactive oxygen species precede the epsilon isoform of protein kinase C in the anesthetic preconditioning signaling cascade. Anesthesiology 2003; 99:421–8
Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ: Reactive oxygen species (ROS)-induced ROS release: A new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 2000; 192:1001–14
Xia Z, Godin DV, Chang TK, Ansley DM: Dose-dependent protection of cardiac function by propofol during ischemia and early reperfusion in rats: Effects on 15-F2t-isoprostane formation. Can J Physiol Pharmacol 2003; 81:14–21
Xia Z, Godin DV, Ansley DM: Propofol enhances ischemic tolerance of middle-aged rat hearts: Effects on 15-F(2t)-isoprostane formation and tissue anti-oxidant capacity. Cardiovasc Res 2003; 59:113–21
Slogoff S, Keats AS: Randomized trial of primary anesthetic agents on outcome of coronary artery bypass operations. Anesthesiology 1989; 70:179–88