We thank Xia et al. for their gracious comments about our recent work characterizing the role of endothelial nitric oxide synthase in delayed preconditioning against myocardial infarction produced by isoflurane.1The authors mention that isoflurane-induced preconditioning requires the generation of reactive oxygen species. In fact, we have previously demonstrated that isoflurane produces small quantities of reactive oxygen species independent of ischemia and reperfusion as detected using dihydroethidium staining and confocal laser microscopy.2These data provided direct evidence that exposure to isoflurane produces a small burst of reactive oxygen species via opening of mitochondrial adenosine triphosphate–sensitive potassium channels that triggers preconditioning.3
Xia et al. suggest that the duration of coronary artery occlusion may contribute to the relative efficacy of volatile anesthetics during acute or delayed preconditioning. Previous data indicated that isoflurane did not produce delayed preconditioning in dogs exposed to a 60-min left anterior descending coronary artery occlusion,4in contrast to the findings in rabbits when a 30-min coronary occlusion was used.1Although these results may have been related to the duration of coronary occlusion, it is more likely the findings were related to differences in systemic hemodynamics and coronary collateral blood flow between species. Coronary artery occlusions of 30 or 60 min in duration typically produce myocardial infarct sizes of approximately 40 and 33% in rabbits and dogs, respectively. Heart rates in barbiturate-anesthetized rabbits and dogs are approximately 240 and 130 beats/min, respectively. As a result, myocardial oxygen consumption before and during coronary occlusion is substantially higher in rabbits as compared with dogs. In addition to this more pronounced ischemic burden, rabbits have little if any coronary collateral blood flow.5In contrast, the canine model of ischemia and reperfusion used in our previous investigation4is complicated by variable degrees of coronary collateral perfusion, which must be considered when interpreting the results. We believe that it would also be premature to extrapolate our findings in barbiturate-anesthetized, acutely instrumented rabbits1to patients with coronary artery disease undergoing cardiac surgery using cardiopulmonary bypass, as suggested by Xia et al.
In contrast to the arguments of Xia et al. , there is little experimental evidence supporting the hypothesis that propofol produces substantial cardioprotective effects against ischemia–reperfusion injury in vivo . However, a large body of experimental evidence supports the contention that volatile anesthetics exert important protective effects against reversible and irreversible ischemic injury.6To date, several clinical trials have provided preliminary data to corroborate these experimental findings. In particular, De Hert et al. 7demonstrated that sevoflurane but not propofol preserved myocardial function and attenuated increases in troponin I release in patients undergoing coronary artery bypass graft surgery. These data suggested that sevoflurane but not propofol produces myocardial protection in humans at risk for ischemic injury.7Further large-scale, multicenter clinical trials should be performed to define the utility of volatile anesthetics as cardioprotective agents in humans.
*Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin. email@example.com