With the aging of the popultion and the increasing numbers of elderly people,comorbidities have a significant impact on anaesthesia. The most important comorbidity in our elderly patients is coronary artery disease, which is responsible for one third of all perioperative complications and every second perioperative death. In this context it increasingly recognised by anaesthesiologists that the newer volatile anaesthetic like sevoflurane do not only offer optimum control of the anaesthetic depth together with an excellent haemodynamic stability, but in contrast to the intravenous substances have also pronounced cardioprotective properties that can be used for the benefit of our patients.
Understanding lschaemia-Reperfusion Injury of the Heart:
The severity of myocardial ischaemia not only depends on the duration of ischaemia, but is also modified by the conditions of ischaemia (electrical activity, inotropic state, temperature etc).The last years have profoundly changed our understanding of myocardial injury during an ischaemic event: first, the severity of ischaemia and of myocardial damage can also be modified by interventions before the onset of ischaemia ,i.e.by preconditioning. The current concept is that very short periods of ischaemia (like during angina )trigger the strongest known endogenous cardioprotective mechanism, ischaemic preconditioning. Second, although ischaemic myocardium can only be salvaged by reperfusion, reperfusion itself can lead to additional cellular injury that further augments the ischaemic state of injury .During the initial phase of reperfusion, injury is mainly caused by the consequences of ischaemic calcium overload together with the re-supply of energy that triggers several critical intracellular events, including activation of cellular enzymes and over –activation of contractile apparatus. Later during the time course of reperfusion, injury is furher augmented by leukocytes that become activated and release a variety of mediators including oxygen derived free radicals. Reperfusion injury may cause cell death and infarction (“lethal reperfusion injury”)or may only result in a delayed mechanical dysfunction of the myocardium (“stunning”).
While most previous research has focused on the modification of the ischemic conditions (e.g. by cooling or by using different cardioplegic solutions), the interaction of anaesthetic drugs with the mechanisms of ischaemia-reperfusion injury is a relatively new topic. Anaesthetic substances may interact with nearly all the above mentioned mechanisms and current research strongly suggests that these interactions may become clinically important for the anaesthesiologist.
Anaesthetics and Myocardial lschaemia:It was already described in 1969 that halothane-like all negative inotropic drugs –can reduce the severity of myocardial ischaemia. These findings of an (moderate) anti-ischaemic effect of inhalational anaesthetics were confirmed in a variety papillary of experimental models and ischaemic conditions (isolated hearts, isolated papillary muscle, coronary occlusions with and without reperfusion, global myocardial ischaemia, cardioplegic arrest, hypoperfusion, cold storage of isolated hearts, demand ischaemia in patients etc ).
Anaesthetics and Preconditioning (for review see (1,2)) was originally described as ischaemic preconditioning, i.e., very short periods of ischaemia that precede the main ischaemic period and offer substantial protection against ischemiareperfusion injury. Several non-ischemic stimuli can precondition the heart, including pharmacological challenges by adenosine, opoids, and several halogenated inhalational anaesthetics cardioprotection lasts for some hours afrer the application of the stimulus. After ischaemic preconditioning, a second window of protection appears after 24h lasting for about two days (late ischaemic preconditioning). The cardioprotection by late ischaemic preconditioning can be further augmented by anaesthetic preconditioning: five min of sevoflurane inhalation before a prolonged ischaemia reduced infarct size by 50% in already late preconditioned (short myocardial ischaemia 24h before) rabbit hearts. In addition to animal studies, some work points to the existence of preconditioning in human myocardium: Pre-administration of isoflurane 10 min before aortic cross-clamping and cardioplegic arrest during coronary artery bypass surgery has been shown to reduce myocardial damage in humans. In a recent study, patients receiving a volatile anaesthetic during cardiac surgery, had a better myocardial function and less myocardial damage (measured by troponin).
The protective effect of anaesthetic preconditioning is mediated by opening of the ATP regulated potassium channels of the mitochondrion, which also mediates the protective effect of ischaemic preconditioning. Ketamine can block this channel and prevent the cardioprotective effect of ischaemic preconditioning at clinically relevant concentrations. The effect is stereospecific for the R(-)-isomer and does not occur with S(+)-ketamine. Cardioprotection by late preconditioning is also blocked by a single bolus dose of racemic ketamine, but not by S(+) ketamine. Barbiturates may also block the ATP regulated potassium channels, a blocking effect on preconditioning may only occur at supratherapeutical doses.
Anaesthetics and Lethal Reperfusion Injury (Postconditioning): (for review see 3,4) It was found recently that cardioprotection by halothane was much more pronounced if the substance was given to isolated hearts only during reperfusion compared to the situation when it was giwen before or during ischaemia. In isolated cells, it was possible to identify the underlying protective mechanism which consisted of a suppression of reperfusion induced calcium oscillations that are responsible for immediate cell death at reperfusion. At the molecular level, we found that this mechanism is linked to an interaction of halothane with the sarcoplasmic reticulum ryanodine receptor of reperfused heart cells. In addition, halothane may also reduce secondary reperfusion injury caused by activated leukocytes. Even after cardioprotection by a cardioplegic solution, volatile anaesthetics confer additional protection during reperfusion. It was possible to confirm the protective effect of halothane against lethal reperfusion injury in vivo, where a marked reduction of infarct size was seen if 1 MAC halothane was given for the first 15 min of reperfusion after coronary occlusion. The cardioprotective effects were also shown to be independent of the haemodynamic side effects. Cardioprotection against lethal reperfusion injury was also seen with desflurane, sevoflurane and enflurane in vitro and in vivo preparations, while surprisingly, no cardioprotective effect against lethal reperfusion injury was found for isoflurane, both in vitro and in vivo. After protection against ischaemia by cardioplegic arrest, all inhalational anesthetics were found to have an additional protective effect against reperfusion injury, but there were marked differences in the protective profile of the single substances and protection by some inhalational anaesthetics also depended on the composition of the cardioplegic solution. The protective effects of volatile anaesthetics during reperfusion were recently named “anaesthetic postconditioning”.
Stumming: Some studies found a better functional recovery if isoflurane or halothane were given. However, from these studies it is not entirely clear whether the better functional recovery results from a direct effect on the stunned myocardium or is a secondary effect of a reduction of the severity of myocardial ischaemia because the substances were given already before and during ischaemia.
Clinical perspective: To summarise, there is a large amount of experimental evidence that inhalational anaesthetics exert beneficial effects on different mechanisms of ischaemia-reperfusion injury. Given before ischaemia, they trigger the strongest known endogenous cardioprotective mechanism: preconditioning. Given after ischaemia, they have specific actions against reperfusion injury: postconditioning-even after cardioplegic arrest. Very promising are the rapidly increasing number of studies which confirm the cardioprotective effects of sevoflurane in the clinical setting in patients. Not only markers of myocardial damage like Troponin release after cardiac surgery were reduced (4,5), but also length of ICU and in hospital stay was found to be shorter after sevoflurane anaesthesia for cardiac surgery with cardiopulmonary bypass (6,7) and one recent study could also demonstrate a better one-year outcome (8). Currently, it is unknown if anaesthetic preconditioning alone will give the full protective effect in the clinical setting and in addition, the optimal protocol of anaesthetic administration is for clinical preconditioning is still unknown. Therefore, it appears to be safest to give the volatile anaesthetic throughout the whole procedure (6). While on one side, the volatile anaesthetics have that strong protective action, on the other side, other intravenous anaesthetics like ketamine can block cardioprotection and may be harmful in ischaemia reperfusion situations.
References
1. ZauggM, Lucchinetti E, Uecker M, et al. Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms.Br J Anaesth 2003;91:551-65.
2. Weber, N., Schlack, W. (2005 in press) The concept of anaesthetic-induced cardioprptection – mechanisms of action. In: Schlack, W., Van Aken, H. (Eds.) Best Practice & Research Clinical Anaesthesiology: Renaissance of Inhalational Anaesthesia, Bailliere Tindall (Elsevier)
3. Preckel, B. and Schlack, W. (2002) in Vincent, L . (Editor) Drug effects on ischaemia-reperfusion injury of the heart.Yearbook of Intensive Care and Emergency Medicine 2002, Springer, Berlin, S. 177-185
4. De Hert SG, Cromheecke S, ten Broecke PW, et al. Effects of propofol, desflurane, and sevoflurane on recovery of myocardial function after coronary surgery in elderly high-risk patients. Anesthesiology 2003;99:314-23.
5. De Hert SG, ten Broecke PW, Mertens E, et al. Sevoflurane but not propofol preserves myocardial function in coronary surgery patients. Anesthesiology 2002;97:42-9.
6. De Hert SG, Van der Linden PJ, Cromheecke S, et al. Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 2004;101:299-310.
7. De Hert SG, Van der Linden PJ, Cromheecke S, et al. Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 2004;101:9-20.
8. Garcia C, Julier K, Bestmann L, et al. Preconditioning with sevoflurane decreases PECAM-1 expression and improves one-year cardiovascular outcome in coronary artery bypass graft surgery. Br J Anaesth 2005;94:159-65.
Copy from:http://www.anesthesia.org.cn/2005china/eng/eng14.doc
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