Introduction
Experimental evidence has indicated that inhalational anesthetics have organ-protective effects against the consequences of ischemia–reperfusion injury. Although these protective effects have been most extensively characterized in myocardial tissue, it becomes increasingly obvious that these effects are also present in other tissues.
The organ-protective effects of inhalational anesthetics have been related to not only pharmacologic preconditioning and postconditioning effects but also a protective effect during ischemia by modulation of the inflammatory response. Although a number of underlying pathways have been identified, the exact mechanisms involved in organ protection after ischemia–reperfusion injury are still under investigation. It is beyond the scope of this chapter to discuss this point, and the interested reader is referred to a number of recent review articles on the topic.
Because cardiovascular complications still represent a significant health risk to both the cardiac and the noncardiac surgical populations, any measure that may help reduce these adverse events should be part of the perioperative treatment of patients, especially those patients that are at increased risk of perioperative myocardial ischemia.
Prevention of ischemia is traditionally focused on maintaining the balance between myocardial oxygen supply and demand. It is well-known that all inhalational anesthetics decrease myocardial loading conditions and contractility. Even the newer compounds such as desflurane and sevoflurane demonstrate a similar dose-dependent depression of myocardial function. These depressant effects decrease myocardial oxygen demand and may therefore have a beneficial role on the myocardial oxygen balance during myocardial ischemia. In addition to these indirect protective effects, the direct protective properties of inhalational anesthetics against ischemia–reperfusion injury, already discussed, might represent an additional tool in the treatment and the prevention of ischemic cardiac dysfunction in the perioperative period.
Options/Therapies
On the basis of these theoretical considerations and the experimental evidence, several study groups have hypothesized that the implementation of organ-protective properties of inhalational anesthetics in clinical practice might be associated with less organ damage and dysfunction after ischemia–reperfusion injury, ultimately resulting in a better postoperative outcome with less morbidity and mortality.
The organ that has been best explored with regard to anesthetic protection against ischemia–reperfusion injury is the heart. This is, in part, related to the fact that hemodynamic monitoring is easily accessible and that troponin assays allow for a reliable quantification of myocardial damage. Such straightforward measurements of organ function and organ damage are less available for other organ systems. The majority of clinical studies have been performed in the cardiac surgical setting. This is because cardiac surgery, unlike noncardiac surgery, is associated with a predictable and somewhat standardized period of myocardial ischemia, allowing for comparable experimental conditions.
The first clinical studies mainly focused on protective effects of an anesthetic preconditioning protocol (i.e., the protective anesthetic trigger is applied before myocardial ischemia occurs). Later on, applications during myocardial ischemia and postconditioning protocols (i.e., the protective anesthetic trigger is applied after myocardial ischemia has occurred [during early reperfusion]) were explored.
Evidence
Coronary Surgery
In contrast with the large amount of data obtained in the experimental setting, only a limited number of studies have addressed the potential cardioprotective properties of volatile anesthetics in the clinical practice. This is mainly because the experimental protocol necessitates myocardial ischemia to be instituted in a standardized and reproducible way. This situation is normally not present in clinical practice, where all efforts are directed toward the prevention of myocardial ischemia. The clinical situation that most closely resembles the sequence of standardized myocardial ischemia and reperfusion is the setting of coronary artery surgery. This type of surgery therefore allows us to transpose the experimental setting of preconditioning and postconditioning protocols into a clinical protocol sequence.
Clinical studies mainly involved either preconditioning protocols (i.e., administration of the inhalational agent before the institution of myocardial ischemia [aortic cross-clamping]) or a protocol in which the inhalational agent was administered throughout the entire operative period. It is of interest to note that the experimental anesthetic preconditioning protocols consistently showed a beneficial effect on the extent of myocardial damage and dysfunction after ischemia but that this cardioprotective effect was not as obvious in the clinical situation. A number of studies did indeed report a beneficial effect on markers of myocardial damage or hemodynamic function, but this was not confirmed in other studies.
Only recently, it was observed that the preconditioning protocol used might be crucial in generating an anesthetic protective effect. Both Bein et al and Frässdorf et al observed a cardioprotective effect only with an intermittent administration of sevoflurane and not with a continuous administration.
In the meantime, a number of research groups have evaluated the cardioprotective effects of an inhalational anesthetic regimen when administered throughout the entire surgical procedure. In contrast to the clinical preconditioning protocols, these studies observed a consistent cardioprotective effect with less evidence of myocardial damage and better preservation of myocardial function after ischemia. Only one study failed to observe such protective effects; however, in this particular study, depth of anesthesia was deeper and concomitant opioid concentrations were higher in the control group compared with the sevoflurane group, which obscures potential different effects. In addition, inhalational anesthetic agents were also shown to be cardioprotective when administered during the period of myocardial ischemia and during the reperfusion period. Taken together, it seems that a clinically significant cardioprotective effect of inhalational agents is most obvious in protocols in which the agent is given throughout the entire procedure: before (preconditioning), during, and after myocardial ischemia (postconditioning).
In all these studies, cardioprotective effects of inhalational anesthetic agents were apparent from the preservation of variables of myocardial function and the decreased release of markers of myocardial damage or dysfunction. However, at this moment it is unclear whether these effects also result in a decreased incidence of outcome variables such as perioperative morbidity and mortality rates. Although some studies have observed trends such as a shorter intensive care unit and hospital length of stay, a lower incidence of postoperative atrial fibrillation, an improved 1-year cardiovascular outcome after coronary surgery, and a decreased 1-year mortality with a volatile anesthetic regimen, all these studies were severely underpowered to address any outcome issue. A Danish retrospective study on data from 10,535 cardiac surgical procedures retrieved from a national Danish registry from 1999 to 2005 compared cardiac outcome between patients anesthetized with propofol and with sevoflurane. No difference in postoperative 30-day mortality rate was observed in patients with preoperative unstable angina and/or a recent myocardial infarction. However, in the group of patients without these characteristics, the mortality rate was lower in the group anesthetized with the inhalational agent (2.28 versus 3.14; p = 0.015). However, a number of confounding factors such as the retrospective design, the lack of randomization, the different use of anesthetic agents, and cardioplegic protection make interpretation of these results hazardous.
A few meta-analyses have also been performed on this subject ( Table 19-1 ). The meta-analysis by Yu and Beattie included 32 trials on the subject with a total of 2841 patients. The meta-analysis by Symons and Myles included 27 trials with a total of 2979 patients. In both these meta-analyses, no differences were observed in perioperative mortality and myocardial infarction rates between patients anesthetized with a volatile or an intravenous anesthetic regimen. However, it should be noted that these two reports also included studies in which halothane, enflurane, and isoflurane were used as inhalational anesthetics. On the contrary, the most recent meta-analysis including only studies with the newer inhalational anesthetics desflurane and sevoflurane (22 trials with a total of 1922 patients) observed a lower incidence of postoperative mortality (odds ratio, 0.35; 95% confidence interval, 0.14 to 0.90) and postoperative myocardial infarction (odds ratio, 0.53; 95% confidence interval, 0.32 to 0.86) with the use of an inhalational anesthetic regimen.
| Incidence of Outcome | |||||
|---|---|---|---|---|---|
| Study (Year) | No. of Trials | No. of Patients | Inhalational Agents Included | inhalational mortality PMI | intravenous mortality PMI |
| Yu and Beattie (2006) | 32 trials | 2841 patients | Halothane Enflurane Isoflurane/sevoflurane Esflurane | 18/1156 54/1402 | 30/1222 62/1459 |
| Symons and Myles (2006) | 27 trials | 2979 patients | Halothane Enflurane Isoflurane Sevoflurane Desflurane | No difference (data not reported) 51/1569 | No difference (data not reported) 28/840 |
| Landoni et al (2007) | 22 trials | 1922 patients | Sevoflurane Desflurane | 4/977 24/979 | 14/872 45/874 |
Noncoronary Cardiac Surgery
The majority of data on the perioperative cardioprotective properties of inhalational anesthetic agents has been obtained in the setting of coronary artery surgery. It is unclear whether such an effect is also present in other types of surgery. One study reported similar cardioprotective effects of an inhalational anesthetic regimen in patients undergoing aortic valve surgery. In patients undergoing mitral valve surgery, the situation seems to be more complex. Data from a recent study indicated that application of a desflurane preconditioning protocol in patients undergoing isolated mitral valve surgery did not decrease postoperative troponin release. However, in patients undergoing a combined mitral valve and coronary artery surgery procedure, the application of desflurane preconditioning was associated with less myocardial damage. A more recent study from the same group, however, found no difference in postoperative troponin release in patients with coronary disease undergoing mitral surgery with either a sevoflurane or a propofol-based anesthesia. These observations seem to indicate that the occurrence and the extent of inhalational-induced cardioprotection may depend on specific clinical conditions.
Noncardiac Surgery
Cardioprotection
Although it can be expected from a pathophysiologic point of view that the cardioprotective properties of inhalational anesthetic agents will also have beneficial effects in patients at risk of perioperative myocardial ischemia undergoing noncardiac surgery, the unequivocal evidence for such a clinical effect may be difficult to obtain. Indeed, it seems that the extent of cardioprotection depends on specific clinical variables such as the occurrence of perioperative myocardial ischemia. Because both the occurrence of perioperative myocardial ischemia and its extent and duration may vary greatly in patients undergoing noncardiac surgery, the potential beneficial effects of an inhalational anesthetic regimen may be blunted. Consequently, the available data on potential cardioprotective effects in noncardiac surgery are limited and mainly negative. One study in 60 high-risk vascular surgery patients examining the effects of a goal-directed fluid therapy observed a lower incidence of postoperative cardiac complications in patients anesthetized with sevoflurane than in those anesthetized with propofol (0 versus 4; p = 0.005).
Of note, although coronary angioplasty is associated with a more predictable and reproducible cardiac ischemic event, application of a sevoflurane preconditioning protocol seemed not to be associated with a measurable cardioprotective effect.
Organ Protection
Another question is whether the protective effects against the consequences of ischemia observed at the level of the myocardium also extend to other organ systems. Data from a recent study in healthy volunteers indicated that the peri-ischemic administration of sevoflurane improved the postocclusive hyperemic reaction, suggesting a protective effect against the consequences of ischemia at the level of the endothelium. Another study in coronary artery surgery patients observed lower postoperative levels of serum glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, and lactate dehydrogenase in patients anesthetized with an inhalational anesthetic regimen. However, it could not be concluded from this study whether the beneficial effect on biochemical markers of hepatic dysfunction was related to a direct protective effect on hepatic function or whether this effect was merely the consequence of better perioperative organ perfusion due to the preservation of cardiac function. However, more direct evidence has suggested that inhalational agents appear to be protective against consequences of ischemia–reperfusion injury during liver surgery and one-lung ventilation.
Areas of Uncertainty
Although several studies have indicated that inhalational anesthetic agents may have a beneficial action in decreasing the harmful effects of myocardial ischemia, controversies remain with regard to these reported properties. These controversies mainly focus on two topics: (1) the reliability of the phenomenon of anesthetic preconditioning in the clinical setting and (2) the concern about the clinical relevance of the reported organ-protective properties, certainly with respect to outcome issues. For instance, although some studies suggest lower mortality rates in coronary surgery patients treated with a volatile anesthetic regimen compared with those treated with an intravenous anesthetic regimen, others fail to find such relationships. It is to be expected that any potential effect on short- and long-term outcomes is probably related to perioperative organ protection. If, for any reason, such protection is not observed, no effects on outcome are to be expected. The result is that, although sufficient clinical evidence points toward an organ-protective effect of inhalational agents, a number of clinicians still doubt the clinical relevance of the phenomenon.
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