**2.2.5 Transesophageal echocardiography**

One of the earliest signs of acute myocardial ischemia is diastolic dysfunction followed by systolic segmental wall motion abnormalities which occurs within seconds after acute coronary occlusion. Coronary artery disease is associated with segmental wall motion abnormalities more than ECG changes. However, these wall motion abnormalities are not specific for myocardial ischemia; that they may occur during CABG procedure due to loading conditions altering pre- and afterload, transient motion abnormalities caused by myocardial stunning during the ischemic periods of weaning from CPB and also inotropic agents or elevated catecholamine levels. TEE is recommended for high-risk patients for myocardial ischemia with a category II indication (*TEE may be helpful in improving clinical outcomes*) by ASA. This indication is strenghtened when ECG cannot be used for detection of ischemia in situations such as the existence of LBBB, extensive Q waves or ST-T segment changes on baseline ECG. However, it is weakened when there are wall motion abnormalities due to fibrotic, calcified or aneurysmal myocardium at the baseline (London et al,2008).

Category I indications (*TEE is useful in improving clinical outcomes*) for the usage of TEE includes, suspected thoracal aortic aneurysm-dissection or disruption in unstable patients

Elevation of left ventricular end-diastolic pressure (LVEDP) on preoperative

*High-risk patients requiring PAC (Reich et al,2008)*  1. Significant impairment of ventricular function

Other mechanical complications

Recent, large myocardial infarction

Catheterization laboratory PCI 'crash'

Severe chronic obstructive pulmonary disease

loss (CABG-carotid, other vascular procedures)

Renal failure (need for dialysis)

anesthetic management (Reich et al,2008).

**2.2.5 Transesophageal echocardiography** 

Acute or Chronic congestive heart failure

 Need for preoperative intraaortic balon pump (IABP) Acute or chronic severe mitral regurgitation due to ischemia

Ventricular septal defect after myocardial infarction

2. High-risk for intraoperative ischemia or difficult revascularization

Known poor revascularization targets or severe microcirculatory disease

4. Combined procedures that prolonges the duration of surgery or add significant blood

PAC provides detailed information with various parameters such as PCWP, PA diastolic pressure and derived parameters, estimating the left ventricular filling pressures-preload more precisely than CVC (Reich et al,2008;Morgan et al,2002). However, there are some limiting factors altering the accuracy of these measurements such as mitral stenosis, LA myxoma, pulmonary venous obstruction, elevated alveolar pressure, decreased left ventricular compliance and aortic insufficiency; which are to be considered during the

One of the earliest signs of acute myocardial ischemia is diastolic dysfunction followed by systolic segmental wall motion abnormalities which occurs within seconds after acute coronary occlusion. Coronary artery disease is associated with segmental wall motion abnormalities more than ECG changes. However, these wall motion abnormalities are not specific for myocardial ischemia; that they may occur during CABG procedure due to loading conditions altering pre- and afterload, transient motion abnormalities caused by myocardial stunning during the ischemic periods of weaning from CPB and also inotropic agents or elevated catecholamine levels. TEE is recommended for high-risk patients for myocardial ischemia with a category II indication (*TEE may be helpful in improving clinical outcomes*) by ASA. This indication is strenghtened when ECG cannot be used for detection of ischemia in situations such as the existence of LBBB, extensive Q waves or ST-T segment changes on baseline ECG. However, it is weakened when there are wall motion abnormalities due to fibrotic, calcified or aneurysmal myocardium at the baseline (London

Category I indications (*TEE is useful in improving clinical outcomes*) for the usage of TEE includes, suspected thoracal aortic aneurysm-dissection or disruption in unstable patients

EF<40%

catheterization

Severe unstable angina

Reoperation

3. Severe co-morbidities

et al,2008).

in the preoperative period; life-threatening hemodynamic disturbance, valve repair, congenital heart surgery, hypertrophic obstructive cardiomyopathy repair, endocarditis, aortic valve function in aortic dissection repair, evaluation of pericardial window procedures intraoperatively and unexplained hemodynamic disturbances in ICU setting. Category II (*TEE may be helpful in improving clinical outcomes)* indications include hemodynamic disturbances, cardiac aneurysm repair, tumour excision, air emboli, intracardiac embolectomy, aortic dissection repair, pericardial surgery and also increased risk of myocardial ischemia. Category III (*TEE is infrequently useful in improving outcomes)*  indications include evaluation of myocardial perfusion, coronary artery anatomy, graft patency, repair of non-HOCMs, endocarditis in non-cardiac surgery, monitoring emboli in orthopedic surgeries, repair of thoracic aortic injuries, uncomplicated pericarditis, pleuropulmonary disease, monitoring cardioplegia administration and also placement of IABP, ICD or PA catheters (Roscoe,2007).

#### **2.3 Anesthetic induction**

Anesthetic induction of cardiac surgical patients requires titration of drugs in order to avoid any increase in oxygen consumption and decrease in oxygen supply. Titration of induction agents with monitoring of the hemodynamics is more important than the type of the drug chosen (Barnes,2002a). During induction hypertension and tachycardia in patients with normal ventricular function, hypertension and LV hypertrophy should be avoided as well as hypotension and myocardial depression in patients with depressed ventricular function or stenoses. These agents should also provide smooth intubating conditions for those patients. These major concerns of cardiac anesthetic practice can be managed by using small doses of vasopressors for hypotension and by deepening anesthesia or administering β-blockers for the hyperdynamic responses. In terms of intraoperative ischemia, postoperative myocardial infarction or death, there is no single technique superior to others (London et al,2008).

The choice of the anesthetic method depends mainly on left ventricular (LV) function and whether the patient is suitable for early extubation or not. LV function determines the dosages of the anesthetic agents depending on the hemodynamic response of the patient. Early extubation is a desired method in order to reduce the postoperative need for mechanical ventilation resulting in shorter periods of ICU stay, decreasing the cost. There is no single strategy to be recommended for all cardiac surgical patients; hypnotics, opioids and volatile anesthetics are used in different combinations for both the induction and maintenance of anesthesia (London et al,2008).

#### **2.3.1 Thiopental**

Thiopental is the sulphur analogue of the oxybarbiturate pentobarbitone. It is used 3-7 mg/kg intravenously for the induction of anesthesia, rapidly entering the CNS and producing unconsciousness within 30 seconds (Peck,2006; Stoelting&Hillier,2006). The dose that is required for induction depends on patients' age (decreasing with age), weight and cardiac output (Stoelting&Hillier,2006). At sufficient plasma concentrations which is most easily maintained by continuous infusion, thiopental produces an isoelectric EEG, contributing to a maximal reduction of cerebral oxygen requirements. At these concentrations inotropic support may be required to maintain adequate cerebral perfusion (Peck,2006). However, thiopental is seldom used as infusion, because of its long contextsensitive half-time leading to a prolonged recovery period (Stoelting&Hillier,2006).

Thiopental causes a dose-dependent reduction in cardiac output, stroke volume and systemic vascular resistance associated with a compansatory tachycardia. At a dose of 5 mg/kg intravenous thiopental causes a transient 10-20 mmHg decrease in blood pressure with a compansatory 15-20 bpm increase in heart rate. A decrease in myocardial contractility may occur, however it has been shown to be a less reduction when it is compared to volatile anesthetics (Stoelting&Hillier,2006).

Along with the induction of anesthesia with barbiturates mild and transient reduction in systemic blood pressure occurs, which mainly depends on the peripheral vasodilation, depression of the medullary vasomotor center and decreased sympathetic outflow. These minimal alterations in blood pressure and cardiac output with barbiturate induction mainly depend on carotid sinus–mediated baroreceptor reflex responses offsetting the effects of vasodilation. This mechanism explains the vulnerability of the hypovolemic patients to the effects of barbiturate induction (Stoelting&Hillier,2006).

The adverse effects including airway resistance, bronchospasm and postoperative nausea and vomiting, have led to a tendency towards the use of propofol, especially depending on its predictable pharmacokinetics and dynamics (London et al,2008).

#### **2.3.2 Propofol**

Propofol is an isopropylphenol (2,6 diisopropylphenol), replacing the barbiturates for induction, particularly for operations where rapid awakening is desirable, because of the complete awareness after propofol without any residual CNS effects (Peck,2006;Stoelting&Hillier,2006). The major advantage of using propofol as a part of the anesthetic protocol is the early extubation leading to reduced costs by shortening the LOS in ICU (D'Attelis et al,1997; Myeles et al,1997).

In healthy adults the induction dose of propofol is 1.5-2.5 mg/kg intravenous, with a 25-50 % reduction to be used in elderly patients, with 2-6 µg/ml blood level producing unconsciousness depending on combined medications and age, and 1-1.5 µg/ml blood level resulting in awakening (Stoelting&Hillier,2006).

Propofol decreases systemic blood pressure with corresponding changes in cardiac output and systemic vascular resistance. The blood pressure effects may be overt in hypovolemic patients, elderly patients and also patients with coronary artery disease compromising the left ventricle. Adequate hydration is often recommended to offset this effect of propofol. Unlike the effect of thiopental on blood pressure compansated by the increase in heart rate, propofol does not change heart rate. Furthermore, bradycardia and asystoli may also occur most probably because of the reduction in sympathetic outflow more than parasympathetic. It has been shown not to have any effect on sinoatrial or atrioventricular node in normal patients and patients with WPW syndrome allowing the usage of this drug for ablation procedures (Stoelting&Hillier,2006).

#### **2.3.3 Etomidate**

Etomidate is an imidazole derivative and an ester, which is used as an alternative to propofol and thiopental for induction of anesthesia, at a dose of 0.2-0.4 mg/kg intravenously, especially in patients with unstable hemodynamics, because of its least cardiovascular disturbance when compared to other agents (Peck,2006).

After induction, involuntary myoclonic movements can occur, which can be attenuated by using opioids. Awakening after a single dose is more rapid than barbiturates, however duration of action prolongs with intermittently increased dosage or continuous infusion. The main limiting factor of usage is the depression of adrenocortical function (Stoelting&Hillier,2006).

The peripheral vascular resistance may fall slightly but there occurs no change in myocardial oxygen supply, contactility, stroke volume, cardiac output and blood pressure. In a dose-dependent manner, especially at the concentrations more than in clinical practice, etomidate may result in cardiac depression (Peck,2006;Stoelting&Hillier,2006).

#### **2.3.4 Ketamine**

20 Perioperative Considerations in Cardiac Surgery

Thiopental causes a dose-dependent reduction in cardiac output, stroke volume and systemic vascular resistance associated with a compansatory tachycardia. At a dose of 5 mg/kg intravenous thiopental causes a transient 10-20 mmHg decrease in blood pressure with a compansatory 15-20 bpm increase in heart rate. A decrease in myocardial contractility may occur, however it has been shown to be a less reduction when it is

Along with the induction of anesthesia with barbiturates mild and transient reduction in systemic blood pressure occurs, which mainly depends on the peripheral vasodilation, depression of the medullary vasomotor center and decreased sympathetic outflow. These minimal alterations in blood pressure and cardiac output with barbiturate induction mainly depend on carotid sinus–mediated baroreceptor reflex responses offsetting the effects of vasodilation. This mechanism explains the vulnerability of the hypovolemic patients to the

The adverse effects including airway resistance, bronchospasm and postoperative nausea and vomiting, have led to a tendency towards the use of propofol, especially depending on

Propofol is an isopropylphenol (2,6 diisopropylphenol), replacing the barbiturates for induction, particularly for operations where rapid awakening is desirable, because of the complete awareness after propofol without any residual CNS effects (Peck,2006;Stoelting&Hillier,2006). The major advantage of using propofol as a part of the anesthetic protocol is the early extubation leading to reduced costs by shortening the LOS in

In healthy adults the induction dose of propofol is 1.5-2.5 mg/kg intravenous, with a 25-50 % reduction to be used in elderly patients, with 2-6 µg/ml blood level producing unconsciousness depending on combined medications and age, and 1-1.5 µg/ml blood level

Propofol decreases systemic blood pressure with corresponding changes in cardiac output and systemic vascular resistance. The blood pressure effects may be overt in hypovolemic patients, elderly patients and also patients with coronary artery disease compromising the left ventricle. Adequate hydration is often recommended to offset this effect of propofol. Unlike the effect of thiopental on blood pressure compansated by the increase in heart rate, propofol does not change heart rate. Furthermore, bradycardia and asystoli may also occur most probably because of the reduction in sympathetic outflow more than parasympathetic. It has been shown not to have any effect on sinoatrial or atrioventricular node in normal patients and patients with WPW syndrome allowing the usage of this drug for ablation

Etomidate is an imidazole derivative and an ester, which is used as an alternative to propofol and thiopental for induction of anesthesia, at a dose of 0.2-0.4 mg/kg intravenously, especially in patients with unstable hemodynamics, because of its least

After induction, involuntary myoclonic movements can occur, which can be attenuated by using opioids. Awakening after a single dose is more rapid than barbiturates, however duration of action prolongs with intermittently increased dosage or continuous infusion.

cardiovascular disturbance when compared to other agents (Peck,2006).

compared to volatile anesthetics (Stoelting&Hillier,2006).

effects of barbiturate induction (Stoelting&Hillier,2006).

ICU (D'Attelis et al,1997; Myeles et al,1997).

resulting in awakening (Stoelting&Hillier,2006).

procedures (Stoelting&Hillier,2006).

**2.3.3 Etomidate** 

**2.3.2 Propofol** 

its predictable pharmacokinetics and dynamics (London et al,2008).

Ketamine is a phencyclidine derivative, which results in a 'dissociative anesthesia' caused by the dissociation between thalamocortical and limbic systems. The dissociative anesthesia mimics a cataleptic state contributing to open eyes with slow nystagmic gaze; that wakefulness may appear to be present. Amnestic and analgesic properties are profound (Peck,2006;Stoelting&Hillier,2006).

Unlike other induction agents, ketamine produces sympathetic nervous system stimulation with a rise in circulating levels of adrenalin and noradrenalin; increasing the heart rate, cardiac output, blood pressure and myocardial oxygen requirements (Peck,2006). These stimulating effects may be blunted by combination of ketamine with benzodiazepines or opioids or inhaled anesthetic agents (Stoelting&Hillier,2006). It does not seem to precipitate arrhythmias (Peck,2006).

Induction doses of ketamine is 1-2 mg/kg intravenously and 2-4 mg/kg intramuscularly, allowing unconciousness within 30-60 seconds and 2-4 minutes, respectively. Awakening or return of consciousness occurs 10-20 minutes after induction, but full consciousness takes 60-90 minutes. Intermittent doses or continuous infusions lead to prolonged emergence times (Stoelting&Hillier,2006).

#### **2.3.5 Midazolam**

Midazolam can be used for anesthetic induction with a dose of 0.1-0.2 mg/kg intravenously administered over 30-60 seconds. However, thiopental usually produces 50-100% faster induction when it is compared with midazolam, furthermore awakening from general anesthesia including midazolam induction has been shown to be 1-2.5 times longer than that of thiopental (Stoelting&Hillier,2006) (see also the maintenance of anesthesia).

#### **2.3.6 Neuromuscular blocking agents**

All of the available neuromuscular blocking agents (NMBA) have been used for cardiac surgical patients. Pancuronium offsetting the bradycardia effect of high-dose opioids has been the prefered NMBA, however it has also been shown to have potential to produce a tachycardia causing myocardial ischemia during induction. Rocuronium has been compared with pancuronium and reported to provide more adequate conditions especially for fasttrack anesthesia due to its less residual blockade and shorter time to extubation. Neuromuscular transmission monitoring is advised especially if fast-track anesthesia is planned (London et al,2008).

#### **2.4 The maintenance of anesthesia**

#### **2.4.1 Intravenous anesthetic agents**

The anesthesia should be adequate in order to prevent ischemia during incision and sternotomy/sternal spreading; which are the periods of hyperstimulation. Anesthetic dosages and the type of the drugs that are to be used depend on the desire of 'fast-tracking' the patient (Barnes,2002).

High-dose opioid based anesthetic management of the cardiac surgical patients, with more stable hemodynamics providing a long-term mechanical ventilation ensuring the safety of the newly revascularized myocardium, was popular in cardiac anesthetic practice. However the growing interest in fast-track anesthesia and associated intraoperative awareness with high-dose opioid technique limited its usage (London et al,2008;Stoelting&Hillier,2006). As the sickest patients undergoing multi-vessel bypass grafting combined with valve-repair or replacement, repeat operations and other complex procedures such as ventricular septal defect repairs with CABG after acute myocardial infarction require a long duration of surgery, resulting in greater cumulative doses of anesthetic agents leading to a prolonged period of mechanical ventilation; the anesthetic management evolves into a plan including short-acting agents (e.g.sufentanil, propofol, remifentanil), avoiding agents with long half-lives (e.g.midazolam), depending mainly on volatile agents, identifying the adequate candidates and applying a'wait and see' technique for early extubation (London et al,2008).

 Combinations of opioids with benzodiazepines especially low doses of midazolam, because of its ease of use, low cost, hemodynamic stability and postoperative amnesia effects, have been used in order to overcome the adverse effects (Stoelting&Hillier,2006). However, some investigators believe that the combination of midazolam and opioids should be abondoned as general anesthetics; because they believe that this combination only provides general amnesia (Vuylteke et al,1996;Russell et al,1993;Absolam et al,2000). Midazolam has been used in combination with propofol and/or inhaled anesthetics, as well as opioids (Stoelting&Hillier,2006;Barr et al,2000;Lehmann et al,2000;Barvais et al,2000).

Remifentanil is a short-acting, esterase-metabolized without any active metabolites, rapidonset µ-opioid receptor agonist. It provides stable hemodynamics in high-risk cardiac surgical patients. Remifentanil-propofol combination has been proven to be safe with stable hemodynamics, delivering an adequate depth of anesthesia (Lehmann et al,2000).

Sufentanil is a synthetic opioid, that has been used in combination with midazolam, propofol and inhaled anesthetics. Sufentanil combined with propofol has been shown to provide more stable hemodynamics when it is compared with fentanyl-based anesthetic protocols (Howie et al,1991).

Propofol has already been used for maintenance of anesthesia in cardiac surgical patients with reduced left ventricular function or with low cardiac output states in combination with opioids such as fentanyl, remifentanil, sufentanil or alfentanil; providing stable hemodynamics at the recommended doses of 3-8 mg/kg/hour (Philips et al,1993;Sherry et al,1995;Bailey et al,1996). In combination with ketamine propofol provides more stable hemodynamics than its combination with fentanyl (Stoelting&Hillier,2006).

#### **2.4.2 Volatile anesthetic agents**

It was commonly believed that the choice of primary anesthetic agent in cardiac anesthesia does not lead to a different outcome (Tritapepe et al,2007). In 1988, Warltier et al. (1988) reported that both halothane and isoflurane applied before ischemia improved left ventricular systolic function; in 1997 Cason et al. first described the term anesthetic preconditioning, by showing protective effect of isoflurane applied shortly before ischemia. Since than numbers of experimental studies revealed the cardioprotective efficacy of volatile

dosages and the type of the drugs that are to be used depend on the desire of 'fast-tracking'

High-dose opioid based anesthetic management of the cardiac surgical patients, with more stable hemodynamics providing a long-term mechanical ventilation ensuring the safety of the newly revascularized myocardium, was popular in cardiac anesthetic practice. However the growing interest in fast-track anesthesia and associated intraoperative awareness with high-dose opioid technique limited its usage (London et al,2008;Stoelting&Hillier,2006). As the sickest patients undergoing multi-vessel bypass grafting combined with valve-repair or replacement, repeat operations and other complex procedures such as ventricular septal defect repairs with CABG after acute myocardial infarction require a long duration of surgery, resulting in greater cumulative doses of anesthetic agents leading to a prolonged period of mechanical ventilation; the anesthetic management evolves into a plan including short-acting agents (e.g.sufentanil, propofol, remifentanil), avoiding agents with long half-lives (e.g.midazolam), depending mainly on volatile agents, identifying the adequate candidates and applying a'wait and see' technique

 Combinations of opioids with benzodiazepines especially low doses of midazolam, because of its ease of use, low cost, hemodynamic stability and postoperative amnesia effects, have been used in order to overcome the adverse effects (Stoelting&Hillier,2006). However, some investigators believe that the combination of midazolam and opioids should be abondoned as general anesthetics; because they believe that this combination only provides general amnesia (Vuylteke et al,1996;Russell et al,1993;Absolam et al,2000). Midazolam has been used in combination with propofol and/or inhaled anesthetics, as well as opioids

Remifentanil is a short-acting, esterase-metabolized without any active metabolites, rapidonset µ-opioid receptor agonist. It provides stable hemodynamics in high-risk cardiac surgical patients. Remifentanil-propofol combination has been proven to be safe with stable

Sufentanil is a synthetic opioid, that has been used in combination with midazolam, propofol and inhaled anesthetics. Sufentanil combined with propofol has been shown to provide more stable hemodynamics when it is compared with fentanyl-based anesthetic

Propofol has already been used for maintenance of anesthesia in cardiac surgical patients with reduced left ventricular function or with low cardiac output states in combination with opioids such as fentanyl, remifentanil, sufentanil or alfentanil; providing stable hemodynamics at the recommended doses of 3-8 mg/kg/hour (Philips et al,1993;Sherry et al,1995;Bailey et al,1996). In combination with ketamine propofol provides more stable

It was commonly believed that the choice of primary anesthetic agent in cardiac anesthesia does not lead to a different outcome (Tritapepe et al,2007). In 1988, Warltier et al. (1988) reported that both halothane and isoflurane applied before ischemia improved left ventricular systolic function; in 1997 Cason et al. first described the term anesthetic preconditioning, by showing protective effect of isoflurane applied shortly before ischemia. Since than numbers of experimental studies revealed the cardioprotective efficacy of volatile

(Stoelting&Hillier,2006;Barr et al,2000;Lehmann et al,2000;Barvais et al,2000).

hemodynamics than its combination with fentanyl (Stoelting&Hillier,2006).

hemodynamics, delivering an adequate depth of anesthesia (Lehmann et al,2000).

the patient (Barnes,2002).

for early extubation (London et al,2008).

protocols (Howie et al,1991).

**2.4.2 Volatile anesthetic agents** 

anesthetics (Landoni,2009). The first clinical trial that investigates the clinical efficacy of the halogenated anesthetics was in 2002 reporting that sevoflurane preserves global hemodynamic and left ventricular function with a lower postoperative troponin I compared with total intravenous anesthesia (Cason,1997). Desflurane has also been shown to have cardioprotective effect in terms of ICU stay and weaning from mechanical ventilation (De Hert et al,2003). Anesthetic agents were also investigated for the timing of their usage, before or after ischemic episode or continuously during the procedure; sevoflurane has been shown to exert its protective effect more when it is used throughout the whole procedure (DeHert et al,2004).

Despite these beneficial effects, it has also been shown that there is no difference in outcome of the patients with already jeopardized myocardium. The patients without previous unstabil angina or recent myocardial infarction, had lower postoperative mortality after sevoflurane anesthesia (Jakobsen et al,2007). In non-coronary cardiac surgeries, desflurane and sevoflurane have also been shown to reduce troponin I release and result in better outcome in terms of incidence of atrial fibrillation and ICU stay (Landoni et al,2007a;Cromheecke et al,2006). However, volatile anesthetic agents revealed no difference in interventional cardiac procedures (Landoni et al,2009).

The lack of data demonstrating the adverse effects, primarily the coronary steal, of volatile anesthetics, the preconditioning effects of these agents, resulting in a safe and effective fasttracking for patients especially when number of off-pump coronary revascularization is rising; has led to an anesthetic management mainly based on volatile anesthetics (London et al,2008). Volatile anesthetic agents, in comparison to TIVA, provide reductions in the rates of all major end points of cardiac surgery; reduce the risk of myocardial infarction and allcause mortality; increasing in-hospital survival, reducing troponin I release, reducing the need for inotropic support, shortening ICU stay, time to hospital discharge and time on mechanical ventilation. These effects are valid for CABG surgery with or without cardiopulmonary bypass (Landoni et al,2009).

A recent meta-analysis the choice of desflurane and sevoflurane results in better outcome in terms of mortality and cardiac morbidity in cardiac surgical patients (Landoni et al,2007b). Although the results are controversial, the most recent American College of Cardiology/ American Heart Association guidelines recommend the usage of volatile anesthetic agents for non-cardiac surgical patients at risk for MI (Fleisher et al,2007).

#### **2.4.2.1 Preconditioning effects of volatile anesthetic agents**

Myocardial infarction is one of the most serious perioperative complications, that makes myocardium one of the most important vital organ to be protected from ischemia during cardiac and non-cardiac surgeries (Landoni et al,2009; Lango&Mrozinski et al, 2010). Ischemic insult is an integral part especially of cardiac surgery, that reducing the risk of myocardial infarction has led to researchs and revealed anesthetic management as an important factor in protecting myocardium.

A powerful cardioprotective phenomenon was first described in 1986, as an adaptive response to brief sublethal ischemic episodes that are exerted on myocardium, providing protection against subsequent lethal ischemia. This is called ischemic preconditioning, which is not very easy to apply clinically, because of the risk of worsening the vulnerable myocardium (Landoni et al,2009). Oxygen inflow to the heart is discontinued for short terms before the main ischemic episode in ischemic preconditioning, which has been shown to provide higher levels of ATP in myocardium and lower levels of troponin I after surgery. As reperfusion begins, ischemia will result in rapid changes during the reperfusion period; which is called reperfusion injury contributing to impaired function of endothelium and reduced metabolism of cardiocytes. Reperfusion injury may also be attenuated by ischemic preconditioning by restoring blood flow intermittently through the organ. In order to provide optimum protection, timing becomes important as the intervention should be performed within a few minutes or during the first minute of coronary blood flow restoration (Lango&Mrozinski et al,2010). Since the ischemic preconditioning is difficult to apply in clinical practice, pharmacological preconditioning comes to our way.

In general, the mechanisms of the myocardial protection provided by anesthetic agents may include; an effect like ischemic preconditioning, prevention of excessive calcium influx to the cell, an effect like antioxidants and an effect on the relationship between neutrophil/platelet-endothelium. The signalling throughout the cell during anesthetic preconditioning include protein kinase C (PKC), protein tirozin kinase (PTK), mitogenactivated protein kinases (MAPK), protein kinase-B, mitochodria and ion channels (sarcolemmal and mitochodrial ATP-dependent potassium channels) (Figure 1) (Lorsomradee et al,2008).

In pharmacological preconditioning, activators of protein kinases, agonists of adenosine receptors, scavengers of free radicals, opioids, ethyl alcohol, acetylcholine, bradykinin, angiotensin II, noradrenalin, platelet-activating factor were all used, but most of them can not be used for their protective effects because of their side effects or insufficient data of their clinical efficacy (Lango&Mrozinski,2010). In experimental studies, although the exact mechanism is not known, volatile anesthetic agents, known to have cardiac depressant effects that reduces myocardial oxygen demand, were demostrated to have direct cardioprotective effects that are not related to their anesthetic or hemodynamic effects (Landoni et al,2009).

Anesthetic preconditioning depends on the concentration of the drug and also the duration of administration, it does not depend on ischemic preconditioning and does not need preemptive ischemic episodes, furthermore it may have only slight protective effects on the heart that is already exposed to ischemic preconditioning (Landoni et al,2009;Lango&Mrozinski,2010). There are also some factors such as β-blocker usage and perioperative hyperglycemia that may limit the effectiveness of volatile anesthetics. Volatile anesthetic agents can provide their protective effects both before and after ischemia and also during the reperfusion period. In order to achieve maximum cardioprotection in surgeries including ECC, volatile anesthetics should be used before aorta clamping at >1 MAC for longer than 15-30 minutes. Also for the postconditioning effect, to provide adequate concentrations in blood after unclamping, the agents should be initiated several minutes before unclamping via the oxygen-air supply line of ECC and continued for the first 2-5 minutes of reperfusion. The effectiveness of usage during aorta clamping and late reperfusion period has not been clearly demonstrated yet (Lango&Mrozinski,2010). As an analogy to ischemic postconditioning, anestetic postconditioning describes the usage of volatile anesthetic agent after ischemic period contributing to the reperfusion period. This should be done within the first 2 minutes, lenghtening the period does not improve the protective effects (Obal et al, 2003). The protection occurs at two stages; early, lasting for one or 2 hours and late preconditioning, reappearing after 24 hours, lasting up to 72 hours; which means that the protective effect markedly exeeds the drugs elimination time (Landoni et al,2009;Lango&Mrozinski,2010).

reperfusion begins, ischemia will result in rapid changes during the reperfusion period; which is called reperfusion injury contributing to impaired function of endothelium and reduced metabolism of cardiocytes. Reperfusion injury may also be attenuated by ischemic preconditioning by restoring blood flow intermittently through the organ. In order to provide optimum protection, timing becomes important as the intervention should be performed within a few minutes or during the first minute of coronary blood flow restoration (Lango&Mrozinski et al,2010). Since the ischemic preconditioning is difficult to

In general, the mechanisms of the myocardial protection provided by anesthetic agents may include; an effect like ischemic preconditioning, prevention of excessive calcium influx to the cell, an effect like antioxidants and an effect on the relationship between neutrophil/platelet-endothelium. The signalling throughout the cell during anesthetic preconditioning include protein kinase C (PKC), protein tirozin kinase (PTK), mitogenactivated protein kinases (MAPK), protein kinase-B, mitochodria and ion channels (sarcolemmal and mitochodrial ATP-dependent potassium channels) (Figure 1)

In pharmacological preconditioning, activators of protein kinases, agonists of adenosine receptors, scavengers of free radicals, opioids, ethyl alcohol, acetylcholine, bradykinin, angiotensin II, noradrenalin, platelet-activating factor were all used, but most of them can not be used for their protective effects because of their side effects or insufficient data of their clinical efficacy (Lango&Mrozinski,2010). In experimental studies, although the exact mechanism is not known, volatile anesthetic agents, known to have cardiac depressant effects that reduces myocardial oxygen demand, were demostrated to have direct cardioprotective effects that are not related to their anesthetic or hemodynamic effects

Anesthetic preconditioning depends on the concentration of the drug and also the duration of administration, it does not depend on ischemic preconditioning and does not need preemptive ischemic episodes, furthermore it may have only slight protective effects on the heart that is already exposed to ischemic preconditioning (Landoni et al,2009;Lango&Mrozinski,2010). There are also some factors such as β-blocker usage and perioperative hyperglycemia that may limit the effectiveness of volatile anesthetics. Volatile anesthetic agents can provide their protective effects both before and after ischemia and also during the reperfusion period. In order to achieve maximum cardioprotection in surgeries including ECC, volatile anesthetics should be used before aorta clamping at >1 MAC for longer than 15-30 minutes. Also for the postconditioning effect, to provide adequate concentrations in blood after unclamping, the agents should be initiated several minutes before unclamping via the oxygen-air supply line of ECC and continued for the first 2-5 minutes of reperfusion. The effectiveness of usage during aorta clamping and late reperfusion period has not been clearly demonstrated yet (Lango&Mrozinski,2010). As an analogy to ischemic postconditioning, anestetic postconditioning describes the usage of volatile anesthetic agent after ischemic period contributing to the reperfusion period. This should be done within the first 2 minutes, lenghtening the period does not improve the protective effects (Obal et al, 2003). The protection occurs at two stages; early, lasting for one or 2 hours and late preconditioning, reappearing after 24 hours, lasting up to 72 hours; which means that the protective effect markedly exeeds the drugs elimination time (Landoni

apply in clinical practice, pharmacological preconditioning comes to our way.

(Lorsomradee et al,2008).

(Landoni et al,2009).

et al,2009;Lango&Mrozinski,2010).

Fig. 1. The cellular mechanism of the preconditioning with volatile anesthetic agents. Volatile anesthetic agents activate phospholipase-C (PLC) and provide opening of the ATPsensitive potassium channels by stimulating the adrenergic receptors by adenosine A1 and A3 (A1/A3) and activating nitric oxide sythase. (Lorsomradee et al,2008).

B2: bradikinin receptors, Gi protein: Inhibitory guanine nucleotide binding proteins, MAPK: mitogen activated protein kinases, PIP2: phosphotidil inositole bisphosphate, DAG:

diacylglycerol, ITP: inositole 1,4,5 triphosphate, NO: nitric oxide, α1: α1-adrenergic receptor, β: β-adrenergic receptor, δ1: opioid receptors, PKC: protein kinase-C, ROS: reactive oxygen species, SR: sarcoplasmic reticulum (Lorsomradee et al,2008).
