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Euroanaesthesia 2006 Annual Meeting of the European Society of Anaesthesiology

Madrid, Spain / June 3-6, 2006

Strategies Against Ischemic Injury

According to Dr. Stefan De Hert, Assistant Director and Professor, Department of Anesthesiology, University of Antwerp, Edegem, Belgium, “Cell death and myocardial dysfunction are the consequences of myocardial ischemia during surgery when reperfusion is not achieved within the first few minutes. But reperfusion, too, is inevitably associated with injury or stunning that leads to transient functional problems. From the moment we get myocardial ischemia, whether we are able to reperfuse or not, we will always have a transient interval of myocardial dysfunction and it is this myocardial dysfunction we will want to prevent or diminish.”

Dr. De Hert enumerated three windows of intervention in the heart at risk: before ischemia occurs by modulating myocardial oxygen balance, often with b-blockers, a2 agonists or calcium channel blockers, or by anesthetic preconditioning; during ischemia through the administration of a direct anti-ischemic agent such as a volatile anesthetic; and after ischemia via anesthetic post-conditioning administered during early reperfusion.

“An interesting phenomenon is that volatile anesthetic agents could be used in all these different time frames to help protect the myocardium,” Dr. De Hert told the audience. “The volatile anesthetic agents we administer all have vasodilating effects, hence they play a positive, beneficial role in myocardial oxygen balance. When you give the preconditioning volatile anesthetic agent before ischemia occurs, it has a continuing effect after ischemia develops.”

Dr. De Hert described “ischemic preconditioning” as a rapid adaptive response to brief ischemic insults which is capable of slowing the rate of cell death and myocardial dysfunction during subsequent ischemia, and appears to be a natural intrinsic defense mechanism present in practically all organs in all species. Short periods of transient myocardial ischemia seem to protect the heart from extensive damage during subsequent longer periods of ischemia. For example, in normal conditions, sustained ischemia results in myocardial infarction which may be very extensive, but with an ischemic preconditioning protocol, the result would have been a significantly smaller infarct size than in a control population.

First, activation of a receptor triggers intracellular signalling pathways that lead to activation and translocation of protein kinase C. This, in turn, can activate KATP channels at the level of the mitochondria and sarcolemma, resulting in decreased energy utilization which is the factor responsible for protection in ischemic preconditioning.

Apparently, there is a short ischemic period preceding the longer one which is capable of diminishing the extent of myocardial injury associated with a prolonged period of myocardial ischemia, Dr. De Hert explained. That is ischemic preconditioning.

Anesthetic Preconditioning

Many studies have now illustrated that the new volatile anesthetic agents such as sevoflurane and desflurane are able to duplicate ischemic preconditioning, but without the need for occlusion. Given before the onset of ischemia, they can reduce the extent of myocardial injury associated with myocardial ischemia.

Dr. De Hert further added that a KATP channel blocker, given simultaneously with the volatile anesthetic agent before coronary occlusion, cancels out the protection provided by anesthesia, which indicates that the KATP channel plays a pivotal role in volatile anesthetic cardioprotection. The mechanisms involved in ischemic and anesthetic preconditioning, therefore, strongly resemble each other, meaning that ischemic and anesthetic preconditioning could possibly enhance each other, resulting in an improved cardioprotective effect.

Dr. Wolfgang Schlack, Düsseldorf University Hospital, Germany, recently demonstrated that combining ischemic and anesthetic preconditioning, both of which achieve statistically significant reductions of infarct size in animal models, can reduce myocardial infarction size to a greater extent than either procedure alone.

Anesthetic Post-Conditioning

Dr. Schlack also called attention to the possibility of protecting the myocardium from extreme damage with anesthetic post-conditioning, even after ischemia occurs, by administering the volatile anesthetic agent early during reperfusion. In one of the first studies to show that anesthetic post-conditioning protects against reperfusion injury, he used left ventricular diastolic pressure to assess myocardial function and creatine kinase release to establish cellular injury in isolated rat heart preparations subjected to anoxia and reoxygenation.

Upon reoxygenation—when one would expect a slow, minor recovery of myocardial function, at best, in control conditions—halothane administered at the initiation of reperfusion significantly improved recovery of left ventricular function and diminished reperfusion injury, Dr. Schlack reported.

Although the mechanisms of such improvements are not altogether clear, reoxygenation is known to trigger hypercontracture of cardiomyocytes which cause cytoskeletal alterations and massive spontaneous intracellular calcium oscillations followed by troponin release and cell death.

However, the administration of the volatile anesthetic agent early in reperfusion resulted in significantly fewer oscillatory calcium shifts and less hypercontracture during reoxygenation. “When you administer a volatile anesthetic agent early during reperfusion, you can prevent or at least diminish the extent of myocardial damage associated with myocardial ischemia,” Dr. Schlack noted, adding that “another group has shown that when you combine preconditioning and post-conditioning, there is an even more impressive additive effect. So using your volatile anesthetic agent before ischemia and immediately after ischemia results in better protection.”

Administration Strategies

Noting that halogenated agents in clinical trials have usually been administered for short time periods, Dr. Vincent Piriou, Centre hospitalier universitaire Lyon-Sud, Pierre-Bénite, France, who believes volatile anesthetics do have clinical cardioprotective properties, doubts that even 15 minutes is sufficient to induce preconditioning. Earlier studies have shown that extended administration of sevoflurane before, during and after cardiopulmonary bypass decreased post-operative troponin levels and improved cardiac output.

His group randomized 72 elective CABG surgery patients to anesthesia with propofol and sufentanyl, while a preconditioning group received 1 MAC sevoflurane for 15 minutes. He reported that patients with low post-operative cardiac index (<2.0 l/min-1m-2) were fewer in the preconditioning arm, 10.7% vs. 35.3% of controls. Twenty-five per cent of preconditioning patients required inotropic support during the post-operative period compared with 36.1% in the control group. There were no differences in troponin or tissue enzyme measurements between the groups.

Dr. Piriou interpreted the results to mean that 15 minutes of sevoflurane preadministration is insufficient to induce a preconditioning signal in a clinical setting. “A longer preadministration protocol is probably necessary,” he concluded.

Volatile Anesthesia Throughout Surgery

Dr. De Hert and colleagues sought to determine whether the choice of anesthetic regimen affects myocardial function. They compared total intravenous anesthesia with propofol/remifentanil to volatile-agent anesthesia with sevoflurane/remifentanil throughout the entire surgical procedure, during preconditioning, ischemia and reperfusion in cardiac surgery, with and without cardiopulmonary bypass.

“As usual, there were the expected post-operative transient increases in troponin release and myocardial injury among subjects receiving total intravenous anesthesia,” he reported. “But the interesting phenomenon is that those transient increases were significantly lower when volatile-agent anesthesia was administered during the entire procedure, suggesting that a volatile anesthetic regimen throughout is probably or possibly able to decrease the extent of myocardial injury associated with the ischemic events of cardiac surgery.”

Moreover, the usual transient decrease in myocardial function, i.e. lower stroke volume which accompanies coronary surgery was not improved with intravenous anesthesia over 12 hours, whereas myocardial function was preserved in patients given the volatile anesthetic in that time period. So this volatile anesthetic regimen is not only capable of reducing the extent of myocardial injury, but also of preserving myocardial function even after a period of myocardial ischemia, he added. “This is true for both off-pump and on-pump coronary surgery and, in our hands, for aortic valve replacement surgery.”

According to Dr. De Hert, “If you take these data comparing intravenous and inhalational anesthesia regimens together, they all show both functional and biochemical improvement. If you give the volatile anesthesia throughout the procedure, you will get better functional recovery and less myocardial damage. This suggests that the timing or modalities of administration can be very crucial in the extent of myocardial protection.”

Another problem in demonstrating protection is that in the setting of cardiac surgery, complications of anesthesia are very low-incidence risk events, which makes it very difficult to show that a given action can result in clinical improvement, Dr. De Hert explained. For example, statistical power to prove that cardiac-related perioperative mortality can be reduced from 1.2 to 0.6 would require more than 4000 patients, and more than 1000 would be needed to show perioperative cardiac infarctions can be reduced from 4% to 2%.

Reducing Time in the Intensive Care Unit

Assuming that patients stay longer in hospital and intensive care units (ICUs) when they are experiencing complications, the Antwerp investigators assessed those parameters as surrogate markers for outcome in 320 elective coronary surgery patients. They observed that the extent of hospital and/or ICU stay was significantly shorter when a volatile anesthetic regimen with sevoflurane or desflurane was used compared to total propofol- and midazolam-based intravenous anesthesia. Choosing a cutoff value that would distinguish between uncomplicated and complicated recovery, they chose 48 hours because patients with complications typically remain longer in the ICU.

Dr. De Hert indicated that the number of patients needing an ICU stay longer than 48 hours was significantly lower (P<0.01) with volatile anesthetics (propofol 31/80; midazolam 34/80; sevoflurane 10/80; desflurane 15/80). Three independent variables were identified as the reasons for longer ICU stays: atrial fibrillation; post-operative troponin I concentrations >4 ng/mL; and the need for prolonged inotropic support beyond 12 hours.

There was no significant difference in the incidence of atrial fibrillation and pulmonary edema between the treatment groups, he reported. However, transient post-operative troponin I increased significantly less with sevoflurane and desflurane anesthesia. The number of patients experiencing important myocardial damage (troponin I >4 ng/mL) was also significantly reduced in the volatile anesthesia groups. The need for inotropic support was also significantly lower (P<0.05) with the halogenated agents.

“This leads to the suggestion that the use of volatile anesthetic agents probably results in better recovery of myocardial function, leading to improved early organ perfusion and fewer complications at the level of the different organs,” Dr. De Hert observed. “We found that liver and kidney function damage was significantly lessened with volatile anesthetic agents. These data indicate that both ICU and hospital length of stay were significantly shorter with sevoflurane and desflurane.”

He concluded that volatile anesthetic agents offer cardioprotection independently of myocardial oxygenation. He stressed that it is important for clinicians to know that these cardioprotective effects are present in clinical protocols, and that they are direct effects mediated by pharmacologic preconditioning and post-conditioning.

Researchers still need to determine if a similar degree of protection is afforded by different volatile anesthetic agents, as well as their optimal dose and timing. It would appear that anesthesia administered throughout the entire surgical procedure is likely best, but how frequently it should be given as a preconditioning stimulus has not been established. What impact these cardioprotective effects are likely to have on cardiac morbidity and mortality has yet to be determined. Data presented here have been derived from cardiac surgery patients, but many people who undergo surgery for other conditions have untreated cardiac disease, and they may likely benefit most from cardioprotective strategies with volatile anesthetic agents.