A Practical Approach to Cardiac Anesthesia (Practical Approach Series) 5th Ed.

23 Intraoperative Myocardial Protection

John W.C. Entwistle, III, Percy Boateng, and Andrew S. Wechsler


 1. Mechanisms of myocardial ischemic injury are multifactorial and include some of the following: Depletion of high-energy phosphates, intracellular acidosis, alterations in intracellular calcium homeostasis, complement activation, generation of oxygen-free radicals upon reperfusion, and myocardial edema.

 2. Myocardial stunning represents viable myocardium that has systolic and/or diastolic dysfunction in the presence of normal myocardial perfusion.

 3. Hibernating myocardium is viable myocardium that is chronically underperfused and subsequently has downregulated its contractile elements.

 4. The ultimate measure of improved myocardial protection is improved survival or lessening of low-output syndrome (LOS). While LOS has declined in frequency over the decades, its prognosis has worsened with a high mortality associated with LOS.

 5. The purpose of cardioplegia in addition to preservation of cardiac function is to provide cardiac quiescence and a bloodless operative field.

 6. Diastolic arrest with potassium-rich solution and hypothermia are the mainstays of cardioplegic protection.

 7. Although benefits to blood cardioplegia may include improved systolic functional recovery, decreased ischemic injury, and decreased myocardial anaerobic metabolism, it appears that there is no difference in operative mortality or long-term ventricular function when compared to crystalloid cardioplegia. However, most operative centers in the United States use blood cardioplegia.

 8. Cardioplegia can be delivered anterograde through the aorta or coronary ostia or retrograde through the coronary sinus. There are advantages and disadvantages to each and both are often combined in the same procedure.

I. Introduction

Cardiac surgery is performed to preserve or restore cardiac function in a diseased heart. However, the performance of the procedure is, by necessity, accompanied by myocardial injury. This injury occurs when there is a significant imbalance between myocardial oxygen delivery and energy requirements. In the vast majority of cases, perioperative myocardial injury is minimal and is well tolerated. However, severe perioperative myocardial dysfunction is often lethal. Unlike the situation of a myocardial infarction, ischemia during cardiac surgery is usually planned, global in nature, and starts with the application of the aortic cross-clamp or some other intentional maneuver. The ischemic period may be continuous or intermittent, depending on the conduct of the operation.

Adequate myocardial protection can minimize the detrimental effects of the operation on the heart and can allow the heart to tolerate the prolonged periods of planned ischemia that are often necessary to conduct the operation. A proper strategy of myocardial protection encompasses events before, during, and after the initiation of planned myocardial ischemia, including treatment of the patient both preoperatively and postoperatively. As such, all medical personnel involved in the perioperative care of the cardiac patient should be cognizant of the implications of their actions toward myocardial preservation. A strategy of myocardial protection may be made infinitely complex, but most patients will be adequately served through the use of a limited number of techniques and agents designed to minimize the difference between oxygen delivery and utilization during ischemia. Beating heart surgery requires different strategies for myocardial protection, but they remain based on the balance between the supply and demand of oxygen. In addition, the use of minimally invasive techniques, such as port access, has increased the role of the anesthesiologist in the perioperative aspects of myocardial protection.

II. History of myocardial protection

   A. Before the introduction of the cardiopulmonary bypass machine, the earliest cardiac procedures were performed without myocardial protection. Topical cooling and systemic hypothermia were used to facilitate the conduct of the operation with relatively little regard to the metabolic needs of the heart.

   B. In 1955, Melrose advocated the use of hyperkalemic cardioplegia to provide cardiac quiescence during the operation. This approach was later abandoned because of the permanent myocardial injury (“stone heart”) produced by the high potassium concentrations used.

   C. In 1956, Lillehei introduced the technique of administration of cardioplegia through the right atrium or coronary sinus (“retrograde cardioplegia”) for use in operations on the aortic valve.

   D. Procedures used to provide myocardial standstill, such as intermittent aortic cross-clamping, were primarily performed to facilitate the conduct of the operation, with less regard to the ischemic consequences to the myocardium. Interest and research in chemical cardioplegia persisted but was not used clinically.

   E. Topical myocardial cooling with iced saline or slush was used as an early form of myocardial protection once it was possible to support the circulation with cardiopulmonary bypass.

   F. A correlation was made between poor myocardial protection and the development of myocardial necrosis in patients who succumbed to postoperative cardiogenic shock. Clinical confirmation was obtained when a high rate of perioperative myocardial infarction was demonstrated in patients undergoing either coronary artery bypass grafting (CABG) or valvular procedures.

   G. In 1973, Gay and Ebert reintroduced hyperkalemic cardiac arrest but with potassium concentrations less than 20 mmol, thus preventing the occurrence of stone heart syndrome seen with the earlier use of potassium cardioplegia. This marked the beginning of the use of a technique that provided a combination of effective myocardial protection and cardiac quiescence.

   H. In the late 1970s, Follette et al. [1] and Buckberg popularized the use of blood cardioplegia, citing the advantages gained by using the intrinsic characteristics of potassium-enriched blood, such as its natural buffers and oxygen delivery capabilities.

III. Cardiac physiology

   A. The myocardium has a high rate of energy consumption under normal circumstances. This requires a constant supply of oxygen to the myocardium. Myocardial ischemia occurs when the supply of oxygen is exceeded by the demand, and infarction occurs when this occurs for a prolonged period of time.

   B. Oxygen delivery to the myocardium is dependent upon the concentration of hemoglobin in the blood, the arterial oxygen saturation, and the flow of oxygenated blood to the myocardium. Under normal conditions, the blood flow to the myocardium is controlled by autoregulation, in which blood flow is matched to myocardial requirements. Autoregulation is not active when the blood pressure is above or below the autoregulatory range (roughly 60 to 180 mm Hg).

   C. The subendocardium receives its nutritive flow primarily during diastole and is vulnerable to variations in blood flow.

      1. Flow is dependent upon the transmural gradient, which is the difference between the aortic diastolic pressure and the intraventricular end-diastolic pressure.

      2. Oxygen delivery may be insufficient because of either a decrease in perfusion pressure (systemic hypotension or coronary artery disease) or an increase in ventricular end-diastolic pressure (aortic stenosis, ventricular fibrillation, or ventricular distension).

      3. The right ventricle may be less susceptible to injury since its subendocardium receives nutritive flow throughout the cardiac cycle as a consequence of RV systolic pressures well below systemic levels, with the exception of instances of severe pulmonary hypertension.

   D. The heart depends upon a continuous supply of oxygen to maintain full function.

      1. Adenosine triphosphate (ATP) is generated at a rate of 36 moles per mole of glucose in the presence of oxygen.

      2. Under anaerobic conditions, ATP production falls to 2 moles of ATP per mole of glucose. Lactate and hydrogen accumulate in the tissues, which further inhibit glycolysis and other cellular functions.

   E. Myocardial oxygen consumption is dependent upon the work performed by the heart (Fig. 23.1) [2,3].

Figure 23.1 LV myocardial oxygen uptake of the beating empty, fibrillating, and arrested perfused hearts at varying myocardial temperatures. The greatest decrease in myocardial oxygen uptake at a given temperature occurs with mechanical arrest. The addition of hypothermia decreases the oxygen consumption to a lesser degree. (From Buckberg GD, Brazier JR, Nelson RL, et al. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart. J Thorac Cardiovasc Surg. 1977;73:87–94, with permission.)

      1. Normal working ventricular myocardium consumes 8 mL of O2 per 100 g of myocardium per minute.

      2. This decreases to 5.6 mL of O2 per 100 g of myocardium in the empty beating heart and to 1.1 mL of O2 per 100 g of myocardium per minute in the potassium-arrested heart.

      3. Myocardial cooling provides an additional decrease to 0.3 mL of O2 per 100 g of myocardium.


IV. Mechanisms of myocardial ischemic injury.

The mechanisms by which ischemia and reperfusion injure the heart are complex, and the contributions of the individual components to this process are hotly debated. It is possible that the process of reperfusion may be equally as harmful to the myocardium as the ischemic insult itself. Thus, in the field of myocardial protection, it is important to have an understanding of the components thought to contribute to the damage. Strategies to ameliorate these factors may lessen the injury, whereas ignoring important aspects of ischemia–reperfusion injury may make all other protective interventions ineffective.

   A. Depletion of high-energy phosphates occurs during ischemia. Breakdown products may be washed away with reperfusion, prohibiting the rapid conversion back to ATP once perfusion is restored.

   B. Intracellular acidosis develops during anaerobic metabolism, and the accumulation of hydrogen ions interferes with the function of many intracellular enzymes.

   C. Calcium is important in numerous cellular functions. The intracellular fluxes in calcium concentration are responsible, in part, for contraction and relaxation of the myocardium. Alterations in intracellular calcium homeostasis have been documented after ischemia and reperfusion. Changes in the rate of calcium uptake or release within the cell can have profound functional consequence and injured ischemic myocardium rapidly becomes calcium overloaded.

   D. Direct myocellular injury from ischemia may cause myocardial dysfunction.

   E. In addition to the alterations in calcium homeostasis that have been documented, intracellular calcium overload can occur at the time of reperfusion as calcium is released from the sarcoplasmic reticulum or enters the cell through calcium channels, such as the sodium–calcium exchanger or the L-type calcium channel. Alterations in intracellular calcium levels may activate enzymes, trigger second messenger cascades, or alter excitation–contraction coupling. Calcium concentrations may be so high that contracture develops. In the presence of ischemia, ATP necessary for extrusion of sodium is absent and cells become sodium loaded which leads to intracellular calcium loading through the sodium–calcium exchanger.

   F. Generation of oxygen-derived free radicals occurs upon reperfusion. These are highly unstable compounds that are capable of damaging proteins, nucleic acids, phospholipids, and other cellular components. Natural free-radical scavengers prevent damage under normal circumstances, but these endogenous systems are depleted during a significant period of ischemia and are quickly overwhelmed.

   G. Complement activation may occur as part of the generalized inflammatory process that occurs with injury.

   H. Adverse endothelial cell–leukocyte interactions occur after ischemia and reperfusion. Under normal conditions, the endothelium and neutrophils are the producers of, and responsive to, numerous signaling compounds. There is a delicate balance between vasoconstriction and vasodilation, as well as between the promotion and prevention of thrombosis. Adenosine, nitric oxide, endothelin, and thromboxane are a few of the potent substances whose production and effects are altered after ischemia and reperfusion. This may produce a state of altered endothelial cell–leukocyte interaction, leading to areas of myocardial malperfusion and damage from increased endothelial adherence [4].

   I. Myocellular edema may result from ischemia–reperfusion injury. Edema may occur in response to numerous injurious events and can alter the function of all of the cells within the myocardium. Edema has been implicated in contractile dysfunction, decreased ventricular compliance, and capillary plugging that inhibits reperfusion of the coronary microcirculation.

   J. Damage to non-myocyte components of the heart may cause systolic and diastolic dysfunction. This includes injury to the endothelium of the coronary circulation, as well as to fibroblasts and other structural components of the heart.

V. Consequences of ischemia–reperfusion injury.

The severity of myocardial injury after a period of ischemia and reperfusion depends on numerous factors, including the length of ischemia (Fig. 23.2) [5], the temperature of the myocardium, the conditions of the myocardium before, during, and after the ischemia, and the method in which the myocardium is reperfused. The resulting myocardial injury can be described according to the established criteria.

Figure 23.2 Relationship among myocardial temperature, duration of ischemia, and recovery of aortic blood flow. Two sets of experiments are shown. In the duration of ischemia studies (top horizontal axis, blue line), the heart was made ischemic for varying times at 30°C and then reperfused. The percentage myocardial recovery is shown on the vertical axis, and it declines steadily with time. In the temperature studies (lower horizontal axis, red line), hearts were subjected to 60 min of ischemia at varying myocardial temperatures and then reperfused. As the temperature of the myocardium is decreased below 28°C, myocardial recovery increases. (From Hearse DJ, Stewart DA, Braimbridge MV. Cellular protection during myocardial ischemia. The development and characterization of a procedure for the induction of reversible ischemic arrest. Circulation. 1976;54:193–202, with permission from Lippincott Williams & Wilkins.)


   A. Brief periods of ischemia may produce no readily identifiable functional deficit.


   B. Myocardial stunning represents ischemia–reperfusion injury in its mildest form. Although stunning may be severe, it represents viable myocardium that has systolic and/or diastolic dysfunction in the presence of normal myocardial perfusion. The etiology of the functional changes seen in stunning is multifactorial and likely includes altered calcium handling, cellular edema, and other factors. By definition, there is no necrosis in stunned myocardium. Given sufficient time, stunned myocardium will manifest complete functional recovery in the absence of additional injury. Stunned myocardium is distinct from hibernating myocardium, which is viable myocardium that is chronically underperfused and subsequently has downregulated its contractile elements. Upon revascularization, hibernating myocardium begins to return to its normal phenotype and subsequently returns to normal function.

   C. Myocardial necrosis occurs when myocytes are irreversibly injured. Necrosis may not be readily identifiable by functional or histologic means early after injury and thus may not be distinguishable from stunned myocardium at this early time point. However, these cells eventually die despite reperfusion and are replaced by a noncontractile scar.


VI. Measuring success.

Myocardial protection in cardiac surgery has advanced a long way since the first cardiac operations were performed, and morbidity and mortality rates have dropped significantly. The ultimate measure of improved myocardial protection is improved survival or a lessening in the occurrence of “low-output syndrome” (LOS). While the occurrence of LOS has declined in frequency over the decades, its prognosis has worsened with a higher mortality rate associated with LOS [6]. Since mortality and LOS are rather uncommon in elective cardiac cases today and the incremental benefit of a new protection strategy is likely to be small, randomized trials to demonstrate a benefit in terms of survival or LOS will have to be large. Due to this impracticality, many current trials use surrogate endpoints such as lowered levels of cardiac enzymes or shorter ICU stays. However, the clinical significance of these endpoints is less well defined. Importantly, many agents touted to improve myocardial protection have shown remarkable results in animal studies only to fail to achieve significance in humans. Thus, it is important to determine if a protective strategy has a clinically meaningful endpoint in humans, and to ensure that not too much weight is given to results from animal studies, regardless of the degree of benefit seen.


VII. Purpose of cardioplegia.

Historically, most cardiac operations performed over the past few decades have been done under conditions of cardiac arrest. Despite the availability of beating heart surgery techniques, cardiac arrest is still predominantly used during valve repair/replacement, cardiac transplantation, procedures on the aortic root, and most cases of cardiac revascularization. Cardioplegia serves separate, but often interrelated, purposes.

   A. Cardiac quiescence facilitates most cardiac procedures as they are more easily performed on the flaccid, noncontracting heart than on the beating heart. Additionally, this lessens the possibility of air embolism occurring during open procedures performed on the left-sided chambers of the heart. Although cardiac standstill was originally produced via cooling of the heart, potassium-based cardioplegia can provide rapid and reversible arrest.

   B. Interruption of myocardial blood flow facilitates the operation by providing a bloodless field, enhancing visibility. During most cardiac procedures, a cross-clamp is applied across the ascending aorta, which eliminates continuous coronary blood flow. Through the use of cardioplegia, the energy requirements of the myocardium can be significantly reduced, thus increasing the safety and allowable duration of this interruption of blood flow.

   C. Through the reduction in myocardial energy consumption produced by electromechanical arrest, there is preservation of myocardial function, despite significant periods of myocardial ischemia.

   D. Current methods of cardioplegic myocardial arrest allow for the rapid resumption of contractile activity at the end of the procedure. The period of contractile arrest can be lengthened by the administration of additional doses of cardioplegia, and it can be shortened by the restoration of myocardial blood flow with washout of the cardioplegia. This control allows the surgeon to minimize the time of cardiopulmonary bypass awaiting the return of cardiac function while providing maximal myocardial protection during the performance of the procedure.

VIII. Interventions before the onset of ischemia (aortic cross-clamping).

Optimal myocardial protection requires a complete, well-conceived strategy that takes into consideration the unique characteristics of the individual patient. While it may be possible to treat every patient the same, a tailored approach is more likely to minimize cardiac damage and thus mortality. Aortic insufficiency, ventricular hypertrophy, and severe obstructive coronary disease are a few of the factors that may alter the intraoperative management in order to obtain maximal cardiac protection. As a part of planning ahead, there are several interventions before the onset of global cardiac ischemia (aortic cross-clamping) that influence the effectiveness of myocardial protection. Almost all aspects of myocardial protection involve maintaining balance between myocardial oxygen supply and demand.

   A. Minimization of ongoing ischemia may require the use of nitrates, anticoagulants, antiplatelet agents, or insertion of an intra-aortic balloon pump in the preoperative period. Since there may be asymptomatic cardiac ischemia at baseline, hypertension, tachycardia, and patient anxiety should be controlled. Supplemental oxygen should be used liberally.

   B. Perioperative b-blockade has been shown to decrease cardiac-related mortality in most patients undergoing surgical revascularization, although there may be a slight increase in mortality in those patients with an ejection fraction less than 30% who are treated with preoperative β-blockers. Unless contraindicated, preoperative β-blockers should be given in patients undergoing CABG surgery in the absence of severe depression of left ventricular (LV) function.

   C. Rapid revascularization. Any sign of ischemia should warrant aggressive diagnosis and management. If ischemia cannot be readily controlled and infarction is imminent, then emergent operation to alleviate ischemia is required unless otherwise contraindicated. This requires the active involvement of all members of the surgical team so that the operation can proceed without delay. In this setting, rapid reversal of ischemia may require the use of saphenous vein grafts as opposed to arterial conduits if the harvesting of the internal mammary artery would unduly delay resolution of the ischemia. Similarly, the choice between on-pump and beating heart revascularization may depend upon the urgency of the operation and stability of the patient.

   D. Nutritional repletion may be possible in the setting of elective cardiac surgery. The depleted heart has little reserve and may not tolerate ischemia well. Depressed glycogen levels have been correlated with poor postoperative outcomes, and repletion with the preoperative administration of GIK solution (glucose, insulin, potassium) [7] has been demonstrated to reduce complications and improve early postoperative cardiac function.

   E. Avoidance of ischemia. Although some regional myocardial ischemia is required during any bypass operation, the intraoperative global cardiac ischemia that accompanies aortic cross-clamping may be avoided through one of several mechanisms.

      1. CABG may be performed using beating heart techniques. This strategy allows continuous perfusion of the coronary vasculature, with the exception of the territory being bypassed while the anastomosis is being performed. With the use of an intraluminal flow-through device (shunt), some blood flow can be maintained to the distal vessel during the creation of the anastomosis, except for brief periods of time. However, perfusion pressure must be maintained within the physiologic range to avoid cardiac and peripheral ischemia. Insertion of an intra-aortic balloon pump may be useful in this setting if hemodynamic instability results from cardiac manipulation.

      2. Bypass grafting may be performed with minimal cardiac ischemia through the use of cardiopulmonary bypass without aortic cross-clamping. In the setting of the empty beating heart, perfusion to both the body and coronary arteries is supported by the bypass machine, eliminating the hemodynamic instability and subsequent hypoperfusion that may be associated with cardiac manipulation in some off-pump patients. Although this technique does not avoid the systemic effects of extracorporeal perfusion, it eliminates the effects of systemic hypothermia and avoids the myocardial effects of cardioplegia. By eliminating the work performed by the heart, myocardial energy requirements may drop by 20% to 30% of those in the working heart.

      3. Intracardiac procedures may be performed without significant cardiac ischemia with the patient on bypass, without aortic cross-clamping. Although visibility may be limited, procedures such as tricuspid or mitral valve repair or replacement, or atrial or ventricular septal defect repair may be performed with continuous coronary perfusion. On procedures of the left heart, the heart is often briefly fibrillated while the chambers are opened. The LV must remain decompressed to avoid the ejection of air through the aortic valve and subsequent air embolization.

   F. Fibrillatory arrest creates a nearly motionless heart to allow the performance of many cardiac procedures. It may be produced through either electrical stimulation or myocardial cooling.

     1. Normothermic fibrillatory arrest is produced by placing an alternating current generator in contact with the ventricular myocardium. As long as contact is maintained, the ventricle will remain in fibrillation, allowing procedures to be performed upon the heart with little ventricular motion. In this state, the left side of the heart can be opened to allow procedures such as closure of an atrial septal defect, without the fear of ejecting air into the arterial circulation.

        a. Since the myocardium remains warm and the heart is essentially in a continuous state of contraction, energy consumption remains high.

        b. The fibrillating myocardium has increased wall tension since it is in a state of continuous systole.

        c. Since perfusion to the endocardium occurs primarily during diastole, endocardial perfusion is compromised, thus allowing possible subendocardial infarction.

        d. Thus, it is impossible to produce a balance between oxygen supply and demand. Since myocardial ischemia is the inevitable result, this technique is not recommended.

     2. Hypothermic fibrillatory arrest [8] occurs as the myocardial temperature falls when the body is cooled. Energy consumption of the myocardium is less than during warm ventricular fibrillation, but not as low as during complete arrest. Procedures such as CABG or mitral valve replacement may be performed without interruption of myocardial perfusion in the cold fibrillating heart. Fibrillation should be avoided in the setting of ventricular hypertrophy (Fig. 23.3) [9] or significant aortic insufficiency (see “Prevention of ventricular distention”).

Figure 23.3 LV myocardial flow distribution in the normal and hypertrophied heart. In LV hypertrophy, endocardial blood flow is compromised during fibrillation, as the ratio of endocardial to epicardial flow decreases. This does not occur in the normal ventricle. (From Hottenrott CE, Towers B, Kurkji HJ, et al. The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1973;66:742–753, with permission.)

     3. Intermittent aortic cross-clamping may be combined with hypothermic myocardial ventricular fibrillation (or brief periods of ischemic arrest) during performance of the distal anastomoses of a bypass operation to improve visibility while minimizing the time of myocardial ischemia. The aorta is unclamped between each distal anastomosis to reperfuse the myocardium intermittently.

   G. Prevention of ventricular distention is important because increases in wall tension dramatically increase oxygen consumption while at the same time decreasing oxygen delivery to the subendocardium. Ventricular distention is more likely to occur in the setting of aortic valve insufficiency. This can be due to either native aortic valve disease or distortion of the valve during manipulation of the heart. This is particularly dangerous in the setting of ventricular hypertrophy or fibrillation where subendocardial perfusion is already jeopardized. Since the LV is out of sight during many portions of a cardiac procedure, distention can go unrecognized. Intermittent palpation of the LV or monitoring of the pulmonary artery pressure for increases may alert the surgeon to a potential problem.

      1. After the patient is on bypass and the heart is no longer ejecting blood into the aorta, a vent is inserted into the LV. This is usually performed through the right superior pulmonary vein.

      2. The vent is actively drained into the cardiotomy reservoir of the cardiopulmonary bypass machine at a rate of 100 to 300 mL/min to keep the LV decompressed.

   H. Myocardial preconditioning refers to the concept that myocardium that has undergone a brief limited period of ischemia may be better able to tolerate a subsequent, longer period of ischemia [10].

      1. Experimentally, hearts exposed to a brief ischemic stimulus sustain a smaller area of necrosis following a second longer period of ischemia. Numerous stimuli may induce the preconditioning response, including ischemia, hyperthermia, or the use of drugs (bradykinin, nitric oxide, phenylephrine, endotoxin, and adenosine). Some experimental data have also implicated the role of inhalational anesthetic agents (sevoflurane, desflurane, and isoflurane) in myocardial protection through a preconditioning process, with potential improvements in mortality as well as troponin release [11]. Remote preconditioning is the process where brief ischemia to a remote area of the body (arm or leg through the use of a blood pressure cuff) may lead to cardiac protection [12].

      2. Clinically, the effect of preconditioning is controversial. Adenosine has been demonstrated in one randomized trial to provide improved cardiac function in patients undergoing elective revascularization. However, it is more likely to be relevant in the absence of myocardial protection, making it potentially more applicable in the setting of beating heart surgery or when myocardial protection is suboptimal, as with severe ventricular hypertrophy or occlusive coronary artery disease.

   I. The use of warm, oxygenated cardioplegic solution to induce myocardial arrest (warm induction) minimizes energy consumption by arresting the ventricle while it provides oxygen and substrates to the myocardium. Distribution of the cardioplegia to the subendocardium is maximized because the heart is arrested in diastole. This preischemic administration of cardioplegia has been shown to be beneficial in myocardial protection [13].


   J. Diastolic arrest is the most common method of myocardial protection when aortic cross-clamping is used. Potassium-rich solutions are used to produce and maintain arrest until reperfusion. The electrical potential across the cellular membrane is determined by the concentrations of the ions on either side of the membrane at any given time. The resting potential across the cellular membrane is about 90 mV. During activation, the membrane depolarizes (becomes less negative), which allows the influx of sodium through voltage- and time-dependent sodium channels. Intracellular calcium concentrations rise, producing contraction. Relaxation occurs when calcium is sequestered into its intracellular sites. When cardioplegia is administered, with a potassium concentration of 8 to 10 mEq/L, depolarization occurs. Sodium influx occurs, and the channels close in a time-dependent manner. However, because the concentration of potassium remains elevated in the extracellular space, the membrane remains depolarized, and the sodium channels remain closed and inactivated. Thus, the cell is unexcitable in a state of diastolic arrest. As the cardioplegia washes out of the extracellular space, the cell will repolarize and become excitable again. This is one reason why cardioplegia may require multiple doses over the course of the procedure.

IX. Interventions during ischemia.

The period of myocardial ischemia is when the myocardium is most vulnerable to injury. Numerous interventions are possible in order to minimize the injury, but not all are required in every circumstance. The overall strategy of myocardial protection must be individualized to the situation at hand.

   A. Determination of the desired myocardial temperature is central to planning the protective strategy [1416]. Although procedures can be performed on either the warm or hypothermic heart, the other components of the protective strategy must be chosen with the myocardial temperature in mind.

     1. Hypothermia is useful because the myocardial oxygen consumption decreases by 50% for every 10°C decrease in myocardial temperature (Q10 effect). Thus, the greatest absolute decrease in myocardial energy consumption occurs as the myocardial temperature decreases to 25°C, with relatively lesser gains with a progression to profound hypothermia. The major advantage of hypothermia is that it allows the interruption of myocardial blood flow for short periods of time, enabling the conduct of the operation to occur with minimal myocardial ischemic damage [2]. However, hypothermia itself is associated with injury to the myocardium, including alterations in cellular fluidity and transmembrane gradients, with the production of myocardial edema and a resultant decrease in ventricular performance. Intracellular pumps normally critical for ionic homeostasis are inhibited during hypothermia, thus favoring sodium and calcium loading of cells, which can have detrimental effects upon the myocardium. When desired, myocardial cooling can be produced through several mechanisms:

        a. Myocardial cooling is most frequently produced through the administration of cold cardioplegia. Cardioplegia is usually given at a temperature of 4 to 10°C and will produce myocardial cooling to 15 to 16°C. Cardioplegia may be administered through either the antegrade route via the native coronary arteries or the retrograde route through a special cannula placed in the coronary sinus.

        b. Profound systemic hypothermia as a method of routine myocardial protection is impractical, because it takes a long time to cool and rewarm the patient. However, myocardial cooling in the absence of systemic hypothermia can allow the unintentional rewarming of the myocardium through contact of the heart with the body and the return of warm blood to the heart through the cavae and noncoronary collaterals.

        c. Topical cooling of the myocardium can be achieved through the use of chilled saline or slush, or through the use of a cooling jacket. Ice may produce uneven myocardial cooling. Slush may produce injury to the phrenic nerve through prolonged contact and increase atelectasis and pleural effusions. In addition, topical methods of cooling do not provide cooling to the deep myocardium and thus are better suited for cooling the less muscular and relatively thin RV than the LV. In the setting of LV hypertrophy, topical methods are clearly inadequate. Although data to support the use of topical cooling are sparse, it is still occasionally used as an adjunct to cooling with cardioplegia, especially with retrograde cardioplegia to improve cooling of the RV.

      2. Warm cardioplegia may be used before the initiation of ischemia as warm induction (discussed previously). However, the entire operation may be conducted with warm cardioplegia. Since the myocardium is maintained at a warm temperature, metabolic activity continues, albeit at a lesser degree because mechanical activity of the heart is abolished. This constant oxygen requirement prohibits the use of significant periods of ischemia during the conduct of the operation [17,18].

        a. Warm cardioplegia must be supplied continuously to avoid ischemic injury.

        b. Its use is associated with less postoperative myocardial infarction and a lower incidence of low-output state.

        c. It requires the use of blood cardioplegia because crystalloid-based cardioplegia cannot carry enough oxygen to meet the demands of warm myocardium.

        d. Warm cardioplegia may not provide adequate protection in the presence of severe coronary artery disease, where uneven distribution may lead to poor protection.

     3. Tepid cardioplegia, administered at 29°C, may provide some of the benefits of warm cardioplegia while minimizing the effects of hypothermia upon the myocardium.

   B. The ideal composition of cardioplegia is hotly debated. Cardioplegia comes in two basic varieties, namely, crystalloid and blood. Blood cardioplegia is the most commonly used solution in adult cardiac surgery today, although the “recipe” varies significantly between surgeons. Cardioplegia can be made infinitely complex in nature by the use of additives and variations in administration. Most of these additives are chosen to combat the presumed causes of ischemia–reperfusion outlined in Section IV. The available evidence is controversial concerning the superiority of one cardioplegic regimen over the other, and any differences that exist are likely to be small [19,20]. Although benefits to blood cardioplegia may include improved systolic functional recovery, decreased ischemic injury, and decreased myocardial anaerobic metabolism, it appears that there is no difference in operative mortality or long-term ventricular function when compared to crystalloid cardioplegia.


     1. Crystalloid cardioplegia is uncommonly used in adult patients in the United States. A notable exception is in the preservation of the donor heart during cardiac transplantation.

        a. Crystalloid solutions do not contain hemoglobin and thus deliver dissolved oxygen only. This small amount of oxygen is adequate to sustain the myocardium at cold temperatures, but is insufficient in warm myocardium. Therefore, crystalloid cardioplegia can be used only with a strategy of myocardial hypothermia.

        b. All components may be rigorously controlled. However, each additive increases the complexity of the cardioplegia. In addition, most additives serve to replace substances already present in blood cardioplegia.

     2. Blood cardioplegia is produced by mixing blood to crystalloid in a defined ratio (often 4 to 1), with a final hematocrit usually of 16 to 20 vol%.

        a. Blood contains hemoglobin and thus has a high oxygen-carrying capacity. However, at low temperatures, the oxygen–hemoglobin dissociation curve is shifted to the left, diminishing the amount of oxygen available to the myocardium. Due to the hemoglobin and the resultant increase in oxygen-carrying capacity compared to crystalloid solutions, blood cardioplegia may be administered either warm or cold. The frequency of administration varies with the temperature.

        b. Blood contains buffers, free-radical scavengers, colloids, and numerous other substances that may have important benefits in myocardial protection. Because of these components, fewer additives may be required with blood cardioplegia.

        c. Blood has increased viscosity compared to crystalloid, and this is compounded with the addition of hypothermia. However, blood cardioplegia produces good myocardial protection, suggesting that the concerns over viscosity and capillary sludging are overstated.

        d. The ideal hematocrit for blood cardioplegia is unknown, but it may depend on the temperature of the myocardium and the frequency of administration. Microplegia refers to the use of blood that is minimally diluted with crystalloid containing only the elements necessary for achieving cardiac arrest. Theoretically, the avoidance of hemodilution lessens myocardial edema and thus improves postoperative LV function. Clinical studies using microplegia have been small, and have shown a possible advantage over standard 4:1 diluted blood cardioplegia [21].

   C. Route of cardioplegia delivery. Cardioplegia may be administered in either an antegrade or a retrograde direction.

     1. Antegrade cardioplegia is delivered to the myocardium through the coronary arteries.

        a. Usually, it is delivered through a cannula placed into the aortic root, after the aortic cross-clamp is applied. Flow is often started at a rate of 150 mL/(min · m2) and adjusted to maintain an optimal aortic root pressure. Rapid infusion leads to uneven distribution and poor protection. A typical initial dose is 10 to 15 mL/kg, up to 1,000 mL. A low perfusion pressure results in uneven distribution of cardioplegia, and high perfusion pressure may cause damage to the endothelium. Perfusion pressure is typically between 70 and 100 mm Hg.

        b. Antegrade cardioplegia through the aortic root cannot be used in the presence of significant aortic valve insufficiency. First, it is difficult to obtain adequate aortic root pressure when the aortic valve is incompetent. Second, cardioplegia enters the LV, causing increased intraventricular pressure and wall tension and impeding delivery of the cardioplegia to the subendocardium. Finally, a significant portion of the cardioplegia fails to perfuse the coronary arteries, further leading to inadequate protection. In this setting, antegrade cardioplegia may be administered directly down the left and right coronary arteries by using special cannulae that are placed into the coronary ostia after the aortic root is opened.

        c. In the presence of severe occlusive coronary artery disease, especially in the absence of collateral vessels, uneven distribution of cardioplegia may occur through the antegrade route. Topical cooling with iced saline or slush may improve cooling in this setting. Supplemental cardioplegia administered retrograde may also augment the myocardial protection in this setting (see “Retrograde delivery”).

        d. During CABG, additional doses of cardioplegia can be given down each graft as it is completed. Not only does this allow the surgeon to check the flow of the graft, but it allows cardioplegia to be given distal to a flow-limiting lesion where the initial dose of cardioplegia may not have been adequate.

     2. Retrograde delivery of cardioplegia may be used as either an adjunct to antegrade delivery or as the primary route of myocardial protection [22]. Cardioplegia is administered to the myocardium through the coronary veins by way of the coronary sinus.

        a. A special cannula is directed into the coronary sinus through a small hole in the right atrium. Cardioplegia is delivered at a pressure of less than 40 mm Hg. Higher pressures may cause damage.

        b. Improper placement of the catheter can cause injury to the coronary sinus.

        c. Since the coronary veins draining the RV enter the coronary sinus near the right atrium, or enter the right atrium directly, retrograde cardioplegia may not adequately protect the RV because the tip of the cardioplegia catheter is positioned further into the coronary sinus.

        d. Retrograde delivery has been associated with a larger leak of cardiac enzymes in the postoperative period, but there have not been associated clinical consequences of this leak.

        e. The primary advantage of retrograde cardioplegia is in the performance of valvular procedures. In aortic valve replacement, multiple doses of cardioplegia can be administered without stopping the procedure and cannulating the coronary ostia individually. In mitral procedures, retraction on the heart limits the effective distribution of antegrade cardioplegia, so repeat doses require release of the retractors. However, in retrograde cardioplegia, multiple doses can be given without changing the retractors, thus simplifying the procedure.

        f. During all arterial grafting with in situ (internal mammary and gastroepiploic) arteries, additional doses of cardioplegia can be administered through the retrograde route to achieve protection in areas supplied by diseased coronaries because cardioplegia cannot be given down the completed grafts.

        g. During acute coronary artery occlusion, where collateral vessels have not developed, retrograde cardioplegia may provide some protection to the ischemic myocardium before the bypass can be completed.


     3. Antegrade and retrograde cardioplegia are often used together, in a variety of different combinations. Studies have demonstrated that the combined use provides better myocardial protection than with either method alone (Fig. 23.4) [23], particularly in the presence of left main coronary artery disease.

Figure 23.4 Global recovery of left ventricular stroke work index (LVSWI) 30 min after discontinuation of extracorporeal circulation. As left atrial pressure (LAP) increases, LVSWI increases in control hearts. Hearts protected with antegrade perfusion only (ACP, •) recover less function compared to hearts protected with retrograde perfusion (RCP, ~). Hearts with combined antegrade and retrograde perfusion (A/RCP,) exhibit recovery of LVSWI similar to control values (▲) in this model. (From Partington MT, Acar C, Buckberg GD, et al. Studies of retrograde cardioplegia. II. Advantages of antegrade/retrograde cardioplegia to optimize distribution in jeopardized myocardium. J Thorac Cardiovasc Surg. 1989;97:613–622, with permission.)

        a. Antegrade cardioplegia can be used to arrest the myocardium, with additional doses given retrograde with venting of the aortic root. This maximizes the distribution of cardioplegia.

        b. Antegrade and retrograde cardioplegia can be administered throughout the procedure in either an alternating or a simultaneous manner [24]. With the alternating technique, retrograde cardioplegia is administered frequently and interrupted for antegrade cardioplegia down each completed graft or through the aortic root. With the simultaneous method, retrograde cardioplegia is continued while antegrade cardioplegia is given down each graft, minimizing the time spent administering cardioplegia. Venovenous collaterals prevent venous hypertension in the coronary sinus. Clinical outcomes are similar between the two methods.

      4. The frequency of cardioplegia administration is determined by several factors, most importantly the temperature of the myocardium.

        a. Warm myocardium requires a constant supply of oxygen and thus constant administration of cardioplegia. The cardioplegia may be interrupted for brief periods to allow improved visualization. Significant hemodilution is possible when cardioplegia with a high crystalloid content is used continuously because of the high volume of cardioplegia required. In addition, large doses of potassium are required to maintain electromechanical quiescence in the warm perfused myocardium.

        b. With cold myocardium, visualization can be maximized with intermittent administration of cardioplegia. Each administration is essentially a period of reperfusion, so the initial pressure of cardioplegia should be controlled as it is during reperfusion.

        c. Single-dose cardioplegia can be used with cold myocardium if the duration of the operation will be limited and if there is no significant coronary artery disease to limit the distribution of cardioplegia.

        d. Multidose regimens are preferable in most circumstances. The initial dose produces cardiac arrest. Subsequent doses, through the aortic root, down a completed graft, or retrograde, serve to wash out metabolic byproducts and replenish substrates. These advantages may not hold in the immature myocardium. In addition, multidose regimens will help to maintain myocardial hypothermia, especially when the operation is being performed with mild or no systemic hypothermia. Some surgeons monitor the myocardial temperature with a probe and re-dose the cardioplegia with a rise in temperature, but more commonly cardioplegia is re-dosed at time intervals or with the return of electrical or mechanical myocardial activity.

   D. The list of potential additives to cardioplegia is tremendous, and a comprehensive listing and discussion would be overwhelming. Table 23.1 gives a partial list of common additives. The vast majority of additives available serve to combat one or more of the putative causes of ischemia–reperfusion injury. In addition, most additives have functions similar to substances already found in the blood. The cardioplegic solution must balance the goals of simplicity, cost, and effectiveness.

Table 23.1 Common additives to cardioplegia

      1. The electrolyte composition of cardioplegia is important for producing and maintaining rapid myocardial arrest and limiting myocardial edema.

        a. “Intracellular” cardioplegia has an electrolyte composition that mimics that of the intracellular space. It produces myocardial arrest by eliminating the sodium gradient across the cellular membrane and thereby eliminating phase 0 of the action potential.

           (1) Intracellular solutions are crystalloid. Bretschneider solution is a popular example.

           (2) The osmolar gap produced by the low sodium concentration allows the use of several additives without producing a hyperosmolar solution.

           (3) In North America, these solutions are primarily used today for organ preservation in cardiac transplantation. However, intracellular solutions are more popular for use routinely in Europe than in the North America.

        b. “Extracellular” solutions have an electrolyte concentration similar to serum with a higher level of potassium. Diastolic arrest is produced by depolarization of the cellular membrane by high potassium concentrations.

           (1) Potassium concentrations of 8 to 30 mM are used to produce arrest. Cardioplegia administration must continue until there is electrical silence, because persistent electrical activity utilizes ATP stores. Especially when hypothermia is used, subsequent doses of cardioplegia can use lower concentrations of potassium as long as electrical arrest persists.

           (2) Other methods of producing cardiac arrest include the use of magnesium or local anesthetics. However, due to the simplicity of potassium-induced arrest, these methods are not commonly used.

        c. Calcium is critical to cardiac function. However, high calcium concentrations are detrimental to the myocardium. Limiting the calcium in the cardioplegia helps to maintain arrest.

           (1) Calcium-free cardioplegia produces arrest due to lack of calcium influx across the plasma membrane. However, this may lead to the “calcium paradox” in which calcium is depleted from the cell. Upon reperfusion, calcium re-enters the cell and can cause severe damage. Therefore, solutions devoid of calcium are not used.

           (2) Instead of limiting calcium concentration, the effects of calcium can be limited with nifedipine or diltiazem, which are calcium-channel blockers. These drugs may improve myocardial metabolism, but the negative inotropic properties limit their clinical use.

        d. The addition of magnesium to cardioplegia may counter the effects of calcium by competing with calcium for entry via calcium channels, eliminating the need to reduce calcium levels in blood cardioplegia [25]. The benefits of magnesium addition depend on the relative concentrations of the two ions, and there is no benefit to the addition of magnesium to calcium-free cardioplegia.

      2. The pH of the myocardium is critical to the function of the heart. During ischemia, there is a fall in intracellular pH as lactate accumulates within the cell. Buffers in the cardioplegia are important to limit the change in pH associated with the period of ischemia.

        a. Blood contains many naturally occurring buffers, including the histidine and imidazole groups on proteins.

        b. Buffers commonly added to cardioplegia include tromethamine (THAM), Tris, and histidine. These can buffer large amounts of hydrogen ion and have a pKa in the vicinity of 7.4, which makes them good choices. The addition of buffers is probably more important when using crystalloid cardioplegia than with blood.

        c. The method used to monitor pH during hypothermia is important because of the normal rise in pH associated with a fall in temperature.

           (1) With the a-stat protocol, the pH of the blood sample is corrected to 37°C to provide a pH value that is independent of patient temperature.

           (2) Under the pH-stat protocol, the pH value is measured at the temperature of the patient and is corrected to 7.4 by the addition of CO2 into the perfusion circuit. Although this protocol may lead to improved cerebral protection, it results in impaired ventricular function compared to the other method.

      3. The osmolality of cardioplegia is important in limiting the myocardial edema, which may be detrimental to ventricular recovery. Since blood is iso-osmolar, additives serve to make it hyperosmolar with respect to unmodified blood, unless the blood is diluted with hypotonic crystalloid. With crystalloid cardioplegia, on the other hand, the final solution may range from hypotonic to hypertonic, depending on the type and amount of additives used. Mannitol, glucose, and albumin are commonly used to increase the osmolality of the cardioplegia. Mannitol has been shown to lessen myocellular edema and improve postoperative ventricular function when used to produce a mildly hypertonic solution.

     4. Glutamate and aspartate are intermediates in the Krebs cycle and serve to restore high-energy phosphate levels. The addition of these amino acids has been demonstrated to be beneficial in preserving myocardial function, both experimentally and clinically, although the benefit may be limited to substrate-depleted myocardium [26].

      5. The addition of insulin to warm blood cardioplegia has been shown to provide superior protection in patients undergoing revascularization for unstable angina or with ventricular hypertrophy, although such a benefit was not demonstrated in the general population. This effect may be separate from the improved results seen in cardiac surgery patients who have serum glucose tightly controlled.

   E. Intermittent aortic cross-clamping is used by some surgeons during revascularization procedures with good results [27]. In this technique, a cross-clamp is applied and the heart fibrillates or arrests during the performance of a distal anastomosis. The clamp is removed to restore perfusion, and is reapplied for each distal anastomosis. To be successful, each ischemic interval needs to be short to minimize irreversible damage. Potential problems associated with this technique include the necessity to perform each anastomosis quickly to minimize the length of each ischemic interval, and the risk of embolism of aortic debris with each application and removal of the cross-clamp.

X. Interventions during reperfusion

The period of reperfusion is critical to preserving myocardial function. Several potential mechanisms of ischemia–reperfusion injury are active in the reperfusion period, and any chance of minimizing these sources of injury requires action at, or slightly before, the time of reperfusion. If the conditions of reperfusion are not optimized, then potentially viable myocardium may be irreversibly injured. There are many components of the reperfusion period that are important in determining the amount of myocardium that is salvaged.

   A. Substrate washout and terminal warm blood cardioplegia. The final dose of cardioplegia can be used to improve cardiac function after reperfusion through one of two mechanisms:

     1. Substrate washout: In cold myocardium, continued arrest can often be maintained even with removal of potassium from the cardioplegia, allowing washout of metabolic byproducts without continued exposure of the myocardium to a high potassium solution. Since the heart is cold, there is no efficient replenishment of substrates within the myocardium. As the heart rewarms, function returns slowly. If the heart fibrillates, prompt electrical cardioversion minimizes the period of increased wall tension.

     2. Terminal warm blood cardioplegia: Warm hyperkalemic blood cardioplegia administered at the end of the procedure is termed a “hot shot” or terminal warm blood cardioplegia [28,29]. This allows the maintenance of electromechanical arrest with replenishment of metabolic substrates. It has been shown to preserve intracellular ATP and amino acid levels and to produce improved metabolic recovery.

   B. Controlled reperfusion. The pressure of reperfusion is important in limiting the damage to the myocardium [30]. The endothelium is injured during ischemia, and its vasoregulatory properties are limited. This damage can be worsened through unregulated reperfusion.

     1. After cross-clamp removal, the perfusion pressure should be limited to 40 mm Hg for the first 1 to 2 min of reperfusion by decreasing pump flows. The pressure during this period should not be increased abruptly with phenylephrine, or other agents, until after 1 or 2 min.

      2. Pump flows are increased to maintain a mean pressure of 70 mm Hg subsequently. Pressors may be required to achieve this. Hypertension should be avoided.

   C. Postconditioning. Brief periods of reperfusion interrupted by brief periods of reocclusion reduce many of the consequences of ischemic injury such as infarct size through a process termed postconditioning, although there is no convincing evidence that this is useful in clinical cardiac operations.

   D. Avoiding ventricular distention. The contractile state of the ventricle is critical to recovery, particularly in the early postischemic period. Ventricular distention is detrimental to the myocardium, especially during this period.

      1. The ventricle should remain empty during the early period of reperfusion, while contractile function is recovering. This can occur by maintaining full bypass with right heart decompression or rapidly introducing a vent into the left ventricle if this is not sufficient.

      2. In the presence of aortic insufficiency, not severe enough to require valve replacement, venting of the LV through a vent placed via the superior pulmonary vein can maintain decompression.

      3. Ventricular fibrillation is likewise harmful in the warm myocardium, especially as the ventricle begins to fill with blood. Rapid electrical cardioversion is required to prevent the rapid depletion of substrates. Prophylactic lidocaine is given near the completion of bypass to lessen the frequency of arrhythmia.

   E. Deairing of the heart is important to prevent the embolization of air, either down the coronary arteries or into the cerebral or peripheral vessels. The right coronary artery is particularly vulnerable due to its anterior location on the aortic root. Air down this coronary can lead to malperfusion in its distribution and subsequent RV dysfunction in the early postoperative period. Techniques for removal can include the following:

      1. Placement of a vent through the right superior pulmonary vein into the LV, particularly in the case of mitral valve procedures

      2. Venting of the aortic root with a small cannula placed to suction controlled by the perfusionist

      3. Aspiration of the LV by piercing the apex of the heart with an intravenous catheter

      4. Restoring some blood flow through the heart. The perfusionist fills the right atrium with blood by temporarily impeding venous return, then the anesthesiologist fills the lungs with air. This produces increased blood flow through the pulmonary vasculature and into the left side of the heart to displace air that can then be removed with a vent.

          Adequacy of air removal from the left cardiac chambers can be assessed with the use of intraoperative transesophageal echocardiography. It is important that air removal from the left chambers precede the onset of LV ejection, to minimize the incidence of air embolization.

      5. The deleterious consequences of air embolism may be mitigated by flooding the operative field with carbon dioxide during open heart portions of the procedure, thereby displacing nitrogen-rich gas with highly soluble CO2 which dissolves rapidly in the event of an embolic occurrence.

   F. Oxygen-derived free radicals are normally produced in living cells, but the rate of production increases significantly at the moment of reperfusion. At the same time, the natural defense mechanisms are weakened.

      1. To be effective, scavengers must be present and active at the initial moment of reperfusion.

      2. Since each dose of cardioplegia in a multidose protocol is a period of reperfusion, scavengers may be important in the cardioplegia.

      3. Free-radical injury involves a cascade of radicals. Different scavengers are active at different points along the cascade. The physical properties of scavengers dictate their distribution within the myocardium, potentially limiting access to areas of free-radical production. Therefore, the optimal use of free-radical scavengers likely involves the use of several agents with activity at different points along the cascade.

      4. Blood cardioplegia contains many natural free-radical scavengers. Addition of extra scavengers may not be critical [31].

   G. Calcium management. Intracellular hypercalcemia at the time of reperfusion can have detrimental effects. Although calcium is necessary at the time of reperfusion, the calcium concentration in the initial reperfusate may be effectively decreased with citrate or calcium-channel blockers (diltiazem).

XI. Special circumstances

   A. Beating heart surgery. The popularity of beating heart surgery appears to have plateaued, with approximately 20% of surgical revascularization procedures performed in the United States using these techniques. However, the rate of beating heart revascularization varies among surgeons between 0% and nearly 100%. The anesthetic management in beating heart surgery is discussed elsewhere in this text. There are a few caveats of myocardial protection that deserve mention.

      1. Coronary perfusion pressure must remain adequate, especially because there are already flow-limiting lesions in the vessels. Similarly, hypertension increases the afterload and ventricular wall tension, decreasing subendocardial perfusion. Options to maintain perfusion pressure include volume loading, altering the position of the table to increase venous return, the judicious use of pressors, the use of an intra-aortic balloon pump, and appropriate positioning of the heart to provide a balance between visualization of the target vessels and cardiac function.

      2. The order in which bypasses are performed is often critical. If required, the internal mammary artery to the left anterior descending artery is often a good choice for the first bypass, because an open graft can provide perfusion and stability to the myocardium during manipulation of the heart for subsequent bypasses.

      3. Proximal anastomoses may be performed early, such that flow may be delivered down each graft after the distal is completed.

      4. The use of flow-through shunts may permit adequate perfusion of the distal vessel while the anastomosis is completed. However, a shunt does not guarantee adequate myocardial perfusion, and injury or instability may still occur.

      5. Bypasses to totally occluded vessels are often well tolerated by the heart because occlusion during the anastomosis does not usually cause additional significant ischemia. This is especially true when collateral vessels are well established.

      6. Off-pump surgery probably represents a hypercoagulable state compared to its on-pump counterpart. The coagulopathy from extracorporeal circulation and the establishment of hypothermia are avoided. Many surgeons do not fully reverse the heparinization with protamine, instead aiming for an activated clotting time (ACT) of approximately 180 s at the conclusion of the procedure. In addition, many surgeons use antiplatelet agents, such as clopidogrel (Plavix), to inhibit graft thrombosis in the early postoperative period, although data regarding this are lacking.

   B. Redo operations often present unique challenges to myocardial preservation.

      1. Patent bypass grafts are a potential source of atheroemboli and subsequent myocardial infarction. The rate of postoperative infarction is higher in redo operations than for primary grafting procedures. Avoidance of graft manipulation can minimize the embolization of loose debris.

      2. Dense adhesions from the prior operation may limit the safe dissection required to perform the standard maneuvers required for myocardial protection. Therefore, the risk of obtaining exposure to permit topical cooling of the RV, placement of an LV vent, or temporary occlusion of a patent internal mammary graft may outweigh the potential benefits of these maneuvers. Therefore, the surgeon must be well versed in alternative exposures or methods of myocardial protection.

        a. For a patent internal mammary artery that cannot be safely occluded, hypothermic fibrillatory arrest may represent the best alternative.

        b. A right thoracotomy approach to the mitral valve provides excellent exposure, especially in a reoperation. Dissection of the aorta through the right chest is possible for placement of a cross-clamp, but many procedures can be done with femoral cannulation and a beating or fibrillating heart on bypass.

   C. Port-access surgery. Popularized by Heartport, Inc. (now a Johnson and Johnson subsidiary), port-access surgery allows common cardiac procedures to be performed through smaller incisions. The operative procedure should be similar to that for standard cardiac surgery, but the limited exposure requires alternative methods of cardioplegia administration, ventricular venting, and aortic occlusion. The technology provides the surgeon with the ability to use the limited exposure, but the entire operative team must embrace the technology for it to be successful. Transesophageal echocardiography is important for the preparation and conduct of the operation. Myocardial protection requires vigilance of the surgeon, anesthesiologist, and perfusionist. Since very little of the heart is exposed, the monitors play an increased role in the assessment of the electromechanical state of the heart and provide vital information with regard to the pressures within the unseen cardiac chambers.

   D. Acutely ischemic myocardium requires that energy demands on the myocardium be diminished as soon as possible and that delivery of oxygen to the ischemic territory is prompt.

      1. The patient should be prepared for surgery promptly. Delays should be minimized to those necessary for patient safety. The patient should be well oxygenated, and perfusion pressure is critical. A preoperative intra-aortic balloon pump may be useful.

      2. Once on bypass, normothermic induction of cardioplegia can provide substrate to the stressed myocardium that is still perfused.

      3. Retrograde cardioplegia is often used in this situation to provide cardioplegia to the territory that is served by the occluded vessel.

      4. The acutely ischemic area should be revascularized first, with cardioplegia administered down the graft to the occluded vessel. There may be advantages to warm reperfusion to this segment of myocardium, and perfusion can be continued at a controlled pressure while other grafts are placed.

      5. Special attention is directed to the period of time at which cardiopulmonary bypass is terminated, as the ischemic myocardium is likely to exhibit contractile dysfunction. It may be necessary to place the patient back on bypass temporarily to adjust inotropes or volume status and to give the myocardium additional time to recover contractile function before permanent separation from bypass is possible. Improper weaning may result in myocardial infarction in regions that are potentially recoverable.

   E. Pediatric heart. The pediatric heart is unique in its physiology and thus requires special attention. Some of the differences are due to the disease states seen in the pediatric population, whereas others are inherent differences in the immature myocardium. Many of these are due to differences in myocardial gene expression seen in the fetal and neonatal heart, and result in differences in myocardial metabolism and energy consumption compared to the adult heart. For a complete discussion of the management of the pediatric myocardium, see the review by Allen et al. [32].

      1. The normal immature myocardium is more resistant to ischemic injury than adult myocardium. However, cyanosis, pressure overload, or volume overload, which are all common in hearts with congenital defects, make these hearts more susceptible to ischemic injury.

      2. In contrast to the cardiac surgery in the adult heart, crystalloid cardioplegia is frequently used in pediatric cardiac surgery. Although most studies have not demonstrated a difference in outcome, blood cardioplegia may be beneficial in the neonatal heart that has been subjected to hypoxic stress.

      3. The immature myocardium is more susceptible to damage from high calcium concentrations due to its diminished capacity for calcium sequestration. Calcium levels may be reduced with citrate. In addition, magnesium supplementation of the cardioplegia provides increased protection from transient increases in intracellular calcium concentration.

      4. The hypoxic immature heart is sensitive to the delivery pressure of cardioplegia. This must be controlled to both provide adequate distribution yet prevent myocardial edema and damage from high-pressure delivery.

XII. Conclusion

This chapter has covered many of the facets of contemporary myocardial preservation during heart operations. However, effective myocardial preservation should not be thought of as a “technique” but rather a strategy that utilizes an array of techniques best suited for an individual patient. Moreover, the operating team must be ready at any moment to pursue alternate strategies and tactics when previously unanticipated intraoperative events occur. It is important to remember that myocardial protection begins before the patient enters the operating room, and does not end until after the operation is over.


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32. Allen BS, Barth MJ, Ilbawi MN. Pediatric myocardial protection: An overview. Semin Thorac Cardiovasc Surg. 2001;13:56–72.

24 Protection of the Brain during Cardiac Surgery

John M. Murkin


 1. The incidence of overt stroke is 2% to 6% for closed-chamber cardiac procedures. For open-chamber procedures, the incidence of stroke is increased to 4.2% to 13%.

 2. Risk factors for early stroke have been found to be advanced age, duration of cardiopulmonary bypass (CPB), high postoperative creatinine, and extensive aortic atherosclerosis, while delayed stroke was associated with female gender, postoperative atrial fibrillation, cerebrovascular disease and requirement for inotropic support.

 3. Within the first postoperative week, up to 83% of all patients undergoing bypass surgery using CPB demonstrate a degree of cognitive dysfunction. Efforts to mitigate against early postoperative cognitive dysfunction are warranted since early postoperative cognitive issues are in part reflective of subclinical brain injury.

 4. Watershed lesions are commonly due to profound hypotensive episodes but may also be the result of cerebral embolism. Embolization and hypotension acting together may magnify CNS injury.

 5. The etiology of CNS damage associated with embolization is from multiple sources that are patient related, procedure related, and equipment related.

 6. Leukocytosis is associated with a higher risk for ischemic stroke. The results strongly implicate inflammation and white cell activation as etiologic factors in both the extent and severity of perioperative cerebral events.

 7. α-Stat blood gas management, which maintains a normal transmembrane pH gradient and maintains cerebral autoregulation of blood flow, should be used in adult patients undergoing bypass. This modality may help prevent cerebral embolization. See Table 24.7 for additional evidence-based practice guidelines.

 8. A wide variety of autoregulation thresholds occurs even with α-stat blood gas management and is likely a consequence of increased age and cerebrovascular disease. There is an emerging consensus during normothermic and tepid bypass to maintain MAP greater than 70 mm Hg. See Table 24.8 for other management strategies to decrease CNS brain injury.

I. Central nervous system (CNS) dysfunction associated with cardiac surgery

   A. Overview. Despite the continuing improvements in surgical and cardiopulmonary bypass (CPB) techniques during cardiac surgery, stroke remains a devastating postoperative complication for patients and their families. In a recent study in which 1,800 patients with three-vessel or left mainstem coronary artery disease were randomized to percutaneous intervention (PCI) or conventional coronary artery bypass (CAB) surgery, there was no difference in mortality at 1 yr but a significantly lower incidence of primary composite endpoint of major adverse cardiac or cerebrovascular event in CAB (12.4%) versus PCI (17.8%) patients [1]. However, while the overall outcome should argue strongly in favor of CAB surgery, the stroke rate was significantly higher in CAB (2.2%) than PCI (0.6%) patients. Given the relatively equivalent risk factors between PCI and CAB patients in this study, the mechanism of perioperative stroke must be better understood if we are to further reduce the risk of CNS morbidity related to cardiac surgery. This chapter will review the current incidence and risk factors for brain damage in cardiac surgery and will outline strategies aimed at protection of the brain during cardiac surgical procedures.


   B. Stroke incidence. In most series reported to date, the incidence of clinically apparent neurologic injury or overt stroke is 2% to 6% for closed-chamber cardiac procedures (e.g., CAB surgery). Up to 25% to 65% of strokes after CAB surgeries are bilateral or multiple, suggestive of an embolic etiology [2]. For open-chamber procedures (e.g., valve surgery), the reported incidence varies from 4.2% to 13%, which could be related to increased risk of embolization, increased hemodynamic instability, or prolonged CPB time. However, more subtle neurologic changes, such as development of primitive reflexes (e.g., snouting, palmomental reflex), visual field defects, and subtle motor-sensory abnormalities, can be demonstrated in the early postoperative period in up to 61% of all patients undergoing CPB. By 2 mos postoperatively, the prevalence of such new subtle neurologic dysfunction decreases to about 20% and persists for at least 1 yr [3].


   C. Early versus delayed stroke. In considering the incidence of perioperative stroke, it is apparent that distinguishing stroke as early (i.e., neurologic deficit apparent on emergence from anesthesia) or delayed (i.e., neurologic deficit developing after awakening from anesthesia) is important to better discriminate etiology and assess potential risk-reduction strategies, as it is apparent that only approximately 50% of perioperative strokes present during the first 24 hrs postsurgery [3], and tend to be more severe with a higher permanent deficit and a higher impact on mortality [35]. The higher mortality could be related to sicker patients, or that stroke is just one manifestation of other concomitant embolic/hypoperfusion-mediated complications. Stroke can also have a long-term effect on mortality (Fig. 24.1). In a prospective study on CAB patients, the adjusted survival rates at 1, 5, and 10 yrs were 94.1%, 83.3%, and 61.9% among patients free from stroke versus 83%, 58.7%, and 26.9% for those suffering perioperative stroke [6]. Risk factors for early stroke have been found to be advanced age, duration of CPB, high preoperative creatinine, and extensive aortic atherosclerosis, while delayed stroke was associated with female gender, postoperative atrial fibrillation, cerebrovascular disease, and requirements for inotropic support [5]. Delayed but not early stroke was associated with long-term mortality.

Figure 24.1 Effect of stroke on 10-yr survival after CAB graft. The crude annual incidence of death was 18.1/100 person-years among patients with strokes and 3.7/100 person-years among patients without strokes (p <0.001). (From Dacey L J, Likosky DS, Leavitt BJ, et al. Perioperative stroke and long-term survival after coronary bypass graft surgery. Ann Thorac Surg. 2005;79:532–536, with permission.)

   D. Cognitive dysfunction. It has been demonstrated that within the first postoperative week, up to 83% of all patients undergoing CAB surgery using CPB demonstrate a degree of cognitive dysfunction. Of these patients, 38% have symptoms of intellectual impairment and 10% are considered to be overtly disabled. Concentration, retention, and processing of new information and visuospatial organization are the most frequently affected domains. At 5-yr follow-up, more than 35% of CAB patients exhibit some degree of neuropsychologic dysfunction [7]. Variable definitions, different measurement techniques, and different intervals of postoperative cognitive testing confound this issue, however, giving rise to reported incidences of perioperative cognitive decline that vary from 4% to 90%. Additional confounders include the variability in performance to repeated neuropsychometric testing even in healthy subjects, and an innate decline in cognitive function associated with both aging and the various comorbidities found in cardiac surgical patients. The challenge lies in discerning whether a specific event, for example, cardiac surgery, is causal or coincidental to deterioration in cognitive function. On the basis of more recent studies, the consensus is that longer-term cognitive dysfunction has a similar incidence whether patients undergo cardiac surgery with or without use of CPB, or instead undergo PCI or are managed medically, with the implication that aging and progression of underlying atherosclerosis and related comorbidities are of most significance [8].

   E. Comparison groups. The incidence of new postoperative CNS dysfunction in CAB patients has been compared with that of patients undergoing major abdominal vascular or thoracic surgical procedures. Most of these patients usually have concomitant disease including hypertension, diabetes mellitus, diffuse atherosclerosis, and chronic lung disease. After adjusting for identified risk factors, patients undergoing any surgical procedure have been found more likely to suffer a cerebrovascular accident (CVA) than nonoperated controls with an odds ratio of 3.9. Even after excluding high-risk surgery (cardiac, vascular, and neurologic), the odds ratio is 2.9, which suggests the perioperative period itself predisposes patients to stroke. This observation is of particular relevance in considering the role of inflammatory processes and the salutary effect of statins as discussed below.

   Studies on patients undergoing CAB surgery have demonstrated minimal difference in long-term cognitive function between patients undergoing on-pump versus off-pump procedures [9]. However, in general, it does appear that compared with other noncardiac surgical groups, the incidence of early postoperative cognitive dysfunction is higher in CAB patients, and since new ischemic lesions on magnetic resonance imaging (MRI) studies in valve surgery patients have been correlated with early postoperative cognitive dysfunction [10], as has intraoperative cerebral oxygen desaturation and early postoperative cognitive dysfunction in CAB patients, it does appear as though efforts to mitigate against early postoperative cognitive dysfunction are warranted since early postoperative cognitive dysfunction is in part reflective of subclinical brain injury.


   F. Risk factors. Table 24.1 shows risk factors for both stroke and cognitive dysfunction. Risk factors have been pooled into various risk prediction models, which, while useful to compare patient groups, are still not predictive of a particular individual’s outcome, although the presence of key risk factors may help in deciding the best procedure for a particular high-risk patient (i.e., surgery vs. angioplasty or valvuloplasty). Specific risk factors (i.e., aortic atherosclerosis, recent stroke) should prompt further preoperative investigations (e.g., carotid scanning, modification of intraoperative management) and may even suggest a change in surgical approach (i.e., off-pump CAB [OPCAB] with no instrumentation of the aorta) to minimize the potential for neurologic complications.

Table 24.1 Risk factors for neurologic complications in cardiac surgery

II. Cerebral physiology

   A. Cerebral autoregulation. In normal subjects, cerebral blood flow (CBF) remains constant at 50 mL/(100 g·min) over a wide range of mean arterial pressure (MAP) from 50 to 150 mm Hg. This autoregulatory plateau reflects the tight matching between cerebral metabolic rate for O2 (CMRO2) and CBF, mediated in part by endothelium-derived relaxing factor (EDRF-nitric oxide [NO]). With decreased metabolic activity resulting from certain anesthetics or hypothermia, lowered CMRO2 produces a resultant reduction in CBF and establishment of a lower autoregulatory plateau. It is apparent and should be considered that rather than a single cerebral autoregulatory curve, there are instead a series of autoregulatory curves. Each autoregulatory curve represents a differing set of metabolic conditions of the brain (e.g., normal metabolic activity) at 37°C versus lowered metabolic activity at 28°C. The autoregulatory plateau is a manifestation of intact cerebral flow and metabolism coupling, and it varies with metabolic rate.

   With intact autoregulation, adequate substrate (blood flow) can be delivered at a lower perfusion pressure during conditions of lowered metabolic rate (e.g., anesthesia, hypothermia) in the absence of cerebral vasodilators (Fig. 24.2). Cerebral autoregulation is lacking in patients with diabetes mellitus and appears to be lost during deep hypothermia (e.g., less than 20°C) and for several hours after deep hypothermic circulatory arrest (DHCA). This results in pressure-passive CBF; in these instances, hypotension may entail increased risk for cerebral hypoperfusion. Similarly, in patients with chronic hypertension, cerebral autoregulation has been reset and higher perfusion pressures might be needed during CPB. In these circumstances, an uncoupling of CBF and cerebral metabolism could be related to neurocognitive decline [11].

   It is notable that most of the initial studies on CBF and CMRo2 specifically excluded patients with overt cerebrovascular disease while more recent studies which included elderly patients and those with previous CVA have indicated a striking variability in the autoregulatory threshold [12]. Using transcranial Doppler (TCD) or cerebral near-infrared spectroscopy (cNIRS), lower limits of cerebral autoregulation ranging from 45 to 80 mm Hg have been demonstrated, and in a study of 127 adult patients during CPB, a correlation has been made between loss of cerebral autoregulation during rewarming and postoperative neurologic events [13,14].

Figure 24.2 Cerebral autoregulatory curves during normothermia and hypothermia. The upper curve demonstrates a higher CBF autoregulatory plateau that is appropriate for the higher CMRO2 in the awake state, versus a lower CBF plateau during hypothermia. With maximal cerebral vasodilation, lower CPP results in lower CBF that is appropriate at a lower CMRO2 (hypothermia), but not at higher CMRO2. (From Murkin JM. The pathophysiology of cardiopulmonary bypass. Can J Anesth. 1989;36:S41–S44, with permission.)

   B. pH management. There is an inverse relationship between solubility of respiratory gases and blood temperature. With cooling of blood, CO2 partial pressure (PaCO2) decreases and arterial pH (pHa) increases, producing an apparent respiratory alkalosis in vivo. To compensate for this condition during hypothermic CPB, total CO2 must be increased by addition of exogenous CO2 to the oxygenator, known as pH-stat pH management.

      1. a-Stat maintains pHa 7.4 and PaCO2 40 mm Hg at 37°C without addition of exogenous CO2. Intracellular pH is primarily determined by the neutral pH (pHN) of water. Since pHN becomes progressively more alkaline with decreasing temperature, intracellular pH becomes correspondingly more alkaline during hypothermia. Since this intracellular alkalosis occurs in parallel with the hypothermia-induced increased solubility of CO2 and increased blood pH, the normal transmembrane pH gradient of approximately 0.6 units remains unchanged, thus preserving optimal function of various intracellular enzyme systems. This preservation of normal transmembrane pH gradient is the crux of a- stat pH theory, and, in fact, we function in vivo according to α-stat principles. Since different tissues have differing temperatures (e.g., exercising muscle at 41°C vs. skin at 25°C), they also will have correspondingly different pHa values (e.g., 7.34 vs. 7.6, respectively), although the net pHa at 37°C will be 7.4. a-Stat management acknowledges the temperature dependence of normal pHa and strives to maintain a constant transmembrane pH gradient by maintaining PaCO2 at 40 mm Hg and pHa at 7.4 as measured in vitro at 37°C. For this strategy during CPB, total CO2 is kept constant by not adding exogenous CO2 and thus not compensating for increased solubility of CO2. Blood samples measured at 37°C will show pHa7.4 and PaCO2 40 mm Hg, but those same samples measured at 28°C would have pHa 7.56 and PaCO2 26 mm Hg (Fig. 24.3).

Figure 24.3 Contrasting arterial blood gas values as seen in vitro at 37°C or in vivo at 28°C when using α-stat or pH-stat management. Using pH-stat, laboratory values in vitro would be pHa 7.26 and PaCO2 56 mm Hg, whereas temperature-corrected values in vivo would be pHa 7.4 and PaCO2 40 mm Hg. If α-stat were used, laboratory values in vitro would be pHa 7.4 and PaCO2 40 mm Hg, whereas temperature-corrected values in vivo would be pHa 7.56 and PaCO2 26 mm Hg.

      2. pH-stat management involves addition of exogenous CO2 to maintain PaCO2 40 mm Hg and pHa 7.4 when corrected for the patient’s body temperature in vivo. Until the mid-1980s, pH-stat management was generally the most common mode of pH management during moderate hypothermic CPB. Since it is a potent cerebral vasodilator, such increases in total PaCO2 associated with pH-stat have been shown to produce cerebral vasodilation, impairing cerebral flow and metabolism coupling and producing loss of cerebral autoregulation (Fig. 24.4). There is evidence that pH-stat management can increase the incidence of postoperative cognitive dysfunction when CPB duration exceeds 90 min [15]. This likely reflects both increased delivery of microemboli into the brain resulting from CO2-induced vasodilation, and impairment of regional cerebral autoregulation. It is notable that in recent studies even with use of a-stat, a wide variability of autoregulatory threshold has been found likely as a consequence of the increased age and presence of overt cerebrovascular disease in current surgical populations [12,14].

Figure 24.4 Linear regression analysis of CBF and CMRO2, or CPP, for patients managed using α-stat (non–temperature-corrected) or pH-stat (temperature-corrected) management during moderate hypothermia (28°C). With pH-stat (A), there is no correlation between CBF and CMRO2, demonstrating loss of cerebral flow and metabolism coupling, whereas with α-stat (C) there is a highly significant (p <0.005) correlation. CBF significantly (p <0.002) correlates with CPP using pH-stat (B), reflecting pressure-passive CBF and loss of autoregulation, whereas with α-stat (D), CBF is independent of CPP. (From Murkin JM, Farrar JK, Tweed WA, et al. Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass: The influence of PaCO2Anesth Analg. 1987;66:825–832, with permission.)

III. Etiology of CNS damage

   A. Embolization. In the context of CPB, focal ischemia is most often a consequence of isolated cerebral arteriolar obstruction by a particulate or gaseous embolus. Emboli vary in size, nature (particulate vs. gaseous), and origin (patient vs. equipment). Embolus factors influencing potential for damage include size, solubility, viscosity, and buoyancy relative to blood. Vessel diameter, anatomical location, and inflammatory responsivity influence tissue vulnerability. Open-chamber procedures generally entail greater risk of embolization than closed-chamber procedures. Calcific or atheromatous macroembolic debris from the ascending aorta or aortic arch appears to be a prime factor in the production of clinical stroke syndromes. It was formerly thought that microembolic elements, either gaseous or particulate, produced cognitive dysfunction. Studies from beating-heart surgery in which CPB is avoided, despite a much lower incidence of embolic events, appear to have a relatively similar incidence of long-term cognitive dysfunction when compared to CAB using conventional CPB. Microgaseous emboli, the numbers of which are greatly reduced by avoidance of CPB, paradoxically appear to be relatively less injurious than otherwise predicted. The use of heparin anticoagulation in cardiac surgical patients has been demonstrated to ameliorate some of the overt effects of cerebral gas emboli [16].

   Areas of brain localized at the boundary limits of major cerebral arteries (e.g., anterior and middle, or middle and posterior cerebral arteries, or superior and posterioinferior cerebellar arteries) are known as arterial boundary zones or watershed zones (Fig. 24.5), and these can manifest as isolated lesions as a consequence of transient global ischemia (see following sections). Although they are commonly due to profoundly hypotensive episodes, watershed lesions are not pathognomonic of a hypotensive episode and may be the result of cerebral emboli. Embolization and hypoperfusion acting together can play a synergistic role and either cause or magnify CNS injury in cardiac surgical patients.


Figure 24.5 Hatched areas showing the most frequent locations of boundary area, or watershed zone infarcts in the brain, situated between the territories of major cerebral or cerebellar arteries. (From Torvik A. The pathogenesis of watershed infarcts in the brain. Stroke.1984;2:221–223, with permission.)

      1. Detection of emboli

        a. Brain histology. Isolated areas of perivascular and focal subarachnoid hemorrhage, neuronal swelling, and axonal degeneration are seen with higher frequency in the brains of patients dying after cardiac surgery than after non-CPB major vascular surgery. After surgery using unfiltered CPB circuits, fibrin and platelet emboli and calcific and atheromatous debris were seen frequently in small arterioles and capillary beds. Small cerebral capillary and arterial dilatations (SCADS) have been demonstrated histologically, occurring in nonsurvivors after proximal aortic instrumentation after either CPB or coronary angiography. These SCADS are increasingly believed to be due in part to lipid microemboli from usage of unprocessed cardiotomy suction blood.

        b. Intraoperative emboli detection. Intraoperative fluorescein retinal angiography has demonstrated that extensive retinal microvascular embolization occurs during CPB. The incidence and extent of retinal obstruction are much greater with bubble than with membrane oxygenators, despite use of 40 μm arterial line filters. Use of TCD insonation enables assessment of blood flow perfusion characteristics through the middle cerebral artery (MCA). TCD insonation permits measurement of blood flow velocity and detection and quantification of emboli, though discrimination of gaseous from particulate emboli remains unreliable. Proximal aortic instrumentation and initiation of CPB have been identified as particularly embologenic events. After open-chamber surgery, cerebral emboli are detected as the heart fills and begins to eject, underscoring the importance of meticulous deairing techniques (see the following sections).


      2. Sources of emboli

        a. Patient-related sources

           (1) Aortic atheroma. Atheromatous debris can be embolized during aortic clamping or cannulation. Intraoperative aortic ultrasonography using either transesophageal echocardiography (TEE; high sensitivity, low specificity) or epiaortic scanning (EAS) (high sensitivity, high specificity) enables visualization of aortic wall and can be used to guide cannulation sites. Ultrasonography has demonstrated that plaque may fracture or shear off and embolize during CPB as a consequence of trauma from aortic clamping and cannulation or from blood “jetting” from the aortic cannula or may result in intimal flap formation with potential for delayed postoperative embolization [17]. Using EAS, Ura et al. compared images before and after CPB in 472 patients undergoing cardiac surgery, and noted new lesions in the ascending aortic intima in 16 patients (3.4%) following decannulation [17]. In 10 patients, 3 of whom suffered postoperative CVA, the new lesions were severe with mobile lesions or disruption of the intima, of which 6 were related to aortic clamping and the other 4 to aortic cannulation. Only the maximal thickness of the atheroma near the aorta manipulation site was a predictor of new lesions. If the atheroma was 3 to 4 mm, the incidence of new lesions was 11.8% and was as high as 33.3% if the atheroma was >4 mm. As such, embolization of plaque or thrombus from such intimal fractures may explain one mechanism of delayed stroke cited above. Proximal aortic atherosclerosis is thus a significant risk factor for neurologic injury.

           (2) Intraventricular thrombi. During closed-chamber procedures in patients with recent mural thrombi, manipulation of the heart can dislodge thrombi that embolize once the heart begins to fill and eject.

           (3) Valvular calcifications. Valve surgery, particularly valve replacement surgery, is associated with increased risk of CVA resulting from embolization of intracavitary valve debris.

           (4) Postoperative atrial fibrillation. Early-onset atrial fibrillation is associated with a variety of adverse outcomes and has been strongly linked to increased perioperative stroke risk, and is particularly associated with increased risk of delayed-onset postoperative stroke [5]. Even transient new-onset atrial fibrillation is associated with increased risk of 30-day and 1-yr cardiovascular events composed of stroke, cardiac death, and myocardial infarction (MI). In cardiac surgical patients a decreased incidence of atrial fibrillation has been associated with perioperative statin therapy as discussed below. Increased efforts should thus be aimed in part at reducing even transient new-onset postoperative atrial fibrillation.

        b. Procedure-related sources

           (1) While open-chamber procedures (e.g., septal repair, ventricular aneurysmectomy, valve surgery) expose the arterial circulation to air or particulate debris, closed-chamber procedures also can be associated with ventricular air. Use of a ventricular vent, particularly if active suction is applied and the heart is empty, produces localized subatmospheric pressure at the vent tip within the left ventricle (LV) and cause air to be entrained retrograde from the vent insertion site (usually through the superior pulmonary vein) into the LV. Use of TEE can assist in visualization and guide the removal of residual intracavitary air (see following discussion). Inadvertent opening of the left atrium (LA) or LV while the heart is beating also caused rapid air entrainment and increased potential for cerebral emboli.

           (2) Aortic cannulation and clamping are associated with cerebral embolization, particularly in the presence of extensive aortic atherosclerosis.

           (3) Duration of CPB is an independent risk for postoperative brain dysfunction. After 90 min of CPB, the incidence of cognitive dysfunction is increased compared to CPB of shorter duration. It is important to note that duration of CPB may be increased by factors (e.g., extensive atherosclerotic disease), which may independently contribute to neurologic injury [3,4].

        c. Equipment-related sources

           (1) Incorporation of a 25 μm filter into the aortic inflow line effectively reduces cerebral embolic load and has been shown to decrease the incidence of postoperative cognitive dysfunction.

           (2) Membrane oxygenators give rise to markedly fewer gaseous microemboli than bubble oxygenators, but this does not entirely eliminate the risk of air emboli. Similarly, air entrained into the venous side of a membrane oxygenator, or gaseous emboli resulting from drug administration via injection directly into CPB circuitry can transit the membrane and appear in the arterial inflow line, despite use of arterial line filters.

           (3) Use of 20 to 40 μm filters in the cardiotomy return line prevents particulate debris from the operative site from entering the CPB circuit. Use of cardiotomy blood washing techniques (cell saver) is associated with reduced amounts of cerebral lipid microemboli but has also been shown to result in greater transfusion requirements and has not been shown to consistently improve CNS outcomes.

           (4) Use of nitrous oxide (N2O) before commencement of CPB has been associated with increased evidence of ischemic damage, likely because residual N2O increases the size of any microgaseous emboli in the cerebral circulation. This is especially true for several hours after CPB when high fractional inspired oxygen (FIO2) should be used to minimize the size of residual gaseous microemboli.

   B. Hypoperfusion

      1. Watershed areas. Collateral perfusion of the brain can occur via extracerebral anastomoses (primarily through the circle of Willis) or by way of intracerebral anastomoses between major cerebral arteries, known as arterial boundary zones (watershed zones; Fig. 24.5). Rapid severe hypoperfusion can produce ischemic lesions within these boundary zones found at the territorial limits of the major cerebral arteries. The most frequently affected area is the parieto-occipital sulci located at the limits of the anterior, middle, and posterior cerebral arteries. Despite a global ischemic stress, these watershed lesions may be focal and asymmetrical. Placement of electroencephalogram (EEG) electrodes using a parasagittal montage (see following) may allow increased sensitivity for border zone ischemia detection.

      2. Cerebral perfusion pressure (CPP). During moderate hypothermia (28 to 30°C) using α-stat pH management, autoregulation is preserved in patients without overt cerebrovascular disease over the CPP range from 20 to 100 mm Hg. However, studies in elderly cardiac surgical patients and those with cerebrovascular disease indicate a wide variability of lower limit of autoregulation between 45 and 80 mm Hg [12]. Additionally, there are several conditions in which autoregulation may be lost (Table 24.2). With profound hypothermia (15 to 20°C), there appears to be loss of autoregulation as a result of hypothermia-induced vasoparesis, while diabetic patients have been shown to have impaired cerebral autoregulation even at moderate hypothermia.

Table 24.2 Factors associated with loss of cerebral autoregulation

          During CPB, there may be dissociation between MAP and CPP as a result of unrecognized cerebral venous hypertension. Particularly with use of a single two-stage venous cannula, cerebral venous drainage may be impaired specially during performance of posterior distal anastomoses (Fig. 24.6). Consequently, jugular venous pressure should be measured proximally within the superior vena cava (SVC; e.g., via introducer port of pulmonary artery or central venous catheter). CPP can also be compromised during performance of off-pump coronary surgery especially while performing multiple-graft procedures. During these operations the patient is often placed head-down and the heart is lifted to expose the distal targets, two factors which can increase central venous pressure and thus decrease CPP. Concurrent systemic arterial hypotension and low cardiac output often occur concomitantly with resultant cerebral hypoperfusion.

Figure 24.6 A: Systolic, mean, and diastolic arterial blood pressures, with commencement of CPB indicated at 3:15 p.m., after which MAP is shown. B: Pulmonary artery systolic, mean, and diastolic pressures with proximal jugular venous pressure (JVP) recorded at 3:15 p.m., with commencement of CPB. A single two-stage venous cannula was used for CPB. With rotation of the heart, venous return to the oxygenator decreased and JVP approached MAP values. (Modified from Murkin JM. Intraoperative management. In: Estaphanous FG, Barash PG, Reves JG, eds. Cardiac Anesthesia: Principles and Clinical Practice. Philadelphia, PA: J.B. Lippincott Company; 1994:326, with permission.)

      3. Circulatory arrest. During circulatory arrest for surgical procedures, profound hypothermia (16 to 18°C) is used to minimize CMRO2 and increase tolerance for ischemia (see following). During circulatory arrest under normothermic conditions, O2 levels are depleted within a few seconds of onset of ischemia, EEG activity is lost (isoelectric EEG) within 30 s, high-energy phosphates are exhausted within 1 min, and ischemic neuronal damage is found after periods of anoxia as brief as 5 min.

          For certain cardiac electrophysiologic procedures (e.g., diagnosis and treatment of certain refractory arrhythmias), transient ventricular fibrillation (VF) is often induced at normothermia and without circulatory support. Duration of VF must be limited to less than 1 min, and prompt hemodynamic resuscitation with at least 4 min of reperfusion should be maintained between episodes of VF [18]. Monitoring and management of these patients should follow the principles outlined herein.

      4. Intracerebral and extracerebral atherosclerosis. Patient-related factors including intracerebral and extracerebral atherosclerosis also modify the impact of perioperative hypotension. Neurologic injury after cardiac surgery is higher in patients with previous stroke, hypertension, advanced age, diabetes, and carotid bruit [25], which are all factors related to more extensive cerebrovascular disease. In one series of 206 perioperative CABG patients, over 50% exhibited concomitant cerebrovascular disease [19]. Such patients are more prone to cerebral ischemia secondary to perioperative hemodynamic instability.

IV. Pathophysiology of neuronal ischemia

Ischemia is defined as diminution of blood flow below a critical level that propagates tissue damage. Whether from embolization or hypoperfusion, neuronal ischemia is the final common pathway leading to cerebral damage. The extent of ischemic changes will depend on the duration of the ischemic insult, the affected vascular territory, the presence of collateral circulation, and factors that either ameliorate (e.g., hypothermia) or increase (e.g., hyperglycemia) the impact of ischemia on neuronal tissue [20].

   A. Lactic acidosis. Glucose is essentially the sole substrate for energy production by the brain, being metabolized to produce 36 moles of adenosine triphosphate (ATP) per mole glucose. Oxygen is essential for oxidative phosphorylation, and in the presence of ischemia, anaerobic glucose metabolism yields only 2 moles of ATP and results in lactate production with accumulation of hydrogen ion (H+). Anaerobic glycolysis is the primary cause of acidosis during ischemia, and the severity of lactic acidosis is directly related to preischemia glucose concentrations. Hyperglycemia is associated with worsening of neurologic injury after cerebral ischemia, and should be avoided in the perioperative interval.

   B. Apoptosis, necrosis, and inflammation. Two distinct phases of cellular death have been described after cerebral ischemia: apoptosis and necrosis. These are related to the intensity and duration of ischemic insult. Apoptosis is programmed cerebral cell death. Its main features include cell shrinkage with preservation of cell membrane and mitochondrial integrity and lack of inflammation and injury to surrounding tissue. There is some evidence that CPB may exacerbate apoptotic processes accelerating neuronal loss manifest as delayed postoperative CNS injury. Necrosis is a nonprogrammed event leading to cellular swelling, disruption of cell membrane and mitochondrial damage with inflammatory reaction, vascular damage, and edema formation [20]. The core of the ischemic tissue will show predominantly necrosis, and apoptosis will be found mostly in the periphery of the ischemic area. The sensitivity of neurons to ischemic insult varies by region with hippocampal areas exhibiting marked vulnerability.

   C. Ion gradients and role of calcium. Neuronal function and structural integrity are dependent on ionic gradients, such that up to 75% of ATP produced by resting neurons is utilized by sodium–potassium ATPase and for extrusion of calcium by calcium-dependent ATPase. With ischemia, decreased ATP production and evolving lactic acidosis impair transmembrane ionic pumps and consequently diminish cellular electrochemical gradients leading to cell depolarization. Extraneuronal leakage of K+ depolarizes adjacent neurons, thereby decreasing synaptic transmission and, along with calcium, promoting vasospasm in adjacent vasculature.

   D. Calcium. With ischemia, ATP depletion causes loss of ionic gradients, resulting in cell membrane depolarization and influx of calcium ion (Ca2+) through voltage-sensitive channels. Intracellular accumulation of Ca2+ is likely the final common pathway leading to neuronal death through enhanced protein and lipid catabolism. Elevated intracellular calcium will activate both phospholipases, which leads to membrane cell breakdown and arachidonic acid and free radical formation, and endonucleases, which induces fragmentation of genomic DNA, mitochondrial dysfunction, and energy failure. The intensity of intracellular calcium overload is the key element leading to irreversible cellular damage. Influx of Ca2+ can be minimized by calcium antagonists. Nimodipine has shown clinical benefit in decreasing vasospasm after subarachnoid hemorrhage, but has been associated with increased bleeding and mortality in cardiac surgical patients.

   E. Free fatty acids. Some of the earliest cell membrane changes with ischemia involve production of free fatty acids (FFAs) from membrane phospholipids. Intracellular Ca2+ activates calcium-dependent phospholipases C and A2, transforming membrane phospholipids into FFAs, which themselves are neurotoxic. FFAs are powerful uncouplers of oxidative phosphorylation and can undergo further oxidation from arachidonic acid, with resultant free radical formation. During cerebral ischemia, FFA production is decreased by administration of calcium antagonists and 21-aminosteroids (lazaroids), potent inhibitors of lipid peroxidation. Despite laboratory promise, clinical trials have so far been disappointing.

   F. Excitotoxicity. Glutamate is the most abundant excitatory amino acid (EAA) in the brain. It serves metabolic, neurotransmitter, and neurotropic functions and is normally compartmentalized in the neuron. Under normal conditions the brain has the ability to quickly uptake extracellular glutamate. Glutamate stimulates two kinds of receptors: Ionophore-linked receptors and metabotropic receptors; the last ones act only as modifiers of the excitotoxic injury. The main excitotoxic role lies in the ionophore-linked receptors, and these include NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-methylisoxazole-propionic acid), and kainate, responsible for mediating transmembrane Ca2+ and Na+K+ passage. Ischemia produces enhanced presynaptic EAA release and decreased reuptake, which causes activation of postsynaptic NMDA and AMPA receptors and produces massive efflux of K+ and influx of Na+ and Ca+ and resultant osmolysis and calcium-related damage. EAAs also are increasingly implicated in free radical formation. Administration of ketamine, an NMDA receptor antagonist, has shown variable efficacy to decrease neuronal ischemic injury (see later).

   G. Nitric oxide. NO is a free-radical gas synthesized from L-arginine by NO synthase (NOS). NO functions as a neurotransmitter and has a role in regulating CBF and inflammation. In brain ischemia, the elevation of intracellular calcium markedly increases the activity of NOS. Increased NO combined with superoxide anion leads to formation of other reactive oxygen species, hydroxyl free radicals, and nitrogen dioxide producing proteolysis and cell damage. NO also mediates activation of ADP-polymerase leading to ATP and nicotinamide consumption and cell death [20]. Experimentally, lazaroids ameliorate neuronal ischemic damage when administered for ischemic stress, but results of clinical trials have not been positive.

   H. Leukocytosis. In a subanalysis of a trial randomizing 18,558 patients with symptomatic vascular disease to aspirin or clopidogrel, it was observed that in the week prior to a second vascular event, the quartile with highest leukocyte counts had higher risks for ischemic stroke, myocardial infarction, and vascular death after adjustment for other risk factors [21]. In the week before a recurrent event, but not at earlier time points, the leukocyte count was significantly increased over baseline levels, suggesting that leukocyte counts and mainly neutrophil counts are independently associated with ischemic events in these high-risk populations. Consistent with this, in a prospective study of 7,483 patients who underwent CAB or valvular surgery or both, leukocyte count was compared with the occurrence of postoperative stroke [22]. There were a total of 125 postoperative strokes and it was demonstrated that leukocyte count was significantly higher preoperatively and directly postoperatively in patients with stroke and that the magnitude of elevation of leukocyte count was correlated with magnitude and extent of stroke. These results strongly implicate inflammation and white cell activation as etiologic in both the extent and severity of perioperative cerebrovascular events.


V. Intraoperative cerebral monitoring

As shown in Table 24.3, there are various confounds for EEG monitoring, which along with the complex etiology of perioperative neurologic morbidity, suggest multimodal neuromonitoring as the best approach for systematic detection and avoidance of perioperative cerebral complications.

Table 24.3 Electroencephalogram confounds

   A. Brain temperature. Accurate monitoring of brain temperature is essential because temperature profoundly influences CMR and thus tolerance for ischemia. Mild hypothermia (less than 35°C) is disproportionately effective in decreasing ischemia-related injury due to inhibition of EAA release (see previous sections). During CPB, thermal gradients exist between various tissues; thus, brain temperature must be measured independent of other sites. Because of the small risk of trauma associated with placement of a tympanic thermistor, nasopharyngeal temperature (NPT) is the preferred site for clinical monitoring of brain temperature. Thermistor insertion should be through the nares to the level of the midpoint of the zygoma, a depth of 7 to 10 cm in an adult. Insertion of the thermistor before heparinization, using lubrication and exerting gentle pressure parallel to the floor of the nose, will prevent epistaxis and trauma to mucosa and turbinates. Esophageal temperature is a poor substitute for NPT because it variously reflects aortic inflow temperature, temperature of surrounding tissue, and the influence of residual ice or cooled fluid within the pericardial sac. For DHCA and high-risk patients, a thermistor/oximetric catheter can be placed retrograde into the jugular bulb, thus providing the most sensitive clinical measure of global brain temperature and oxygenation.

   B. EEG. EEG represents the amplified, summated, spontaneous electrical activity of the superficial cerebral cortex. Each electrode reflects microcurrent (10 to 200 μV) generated by electrical gradients across layers of neurons aligned at right angles to the monitored cortical surface in a 2 to 3 cm radius. Electrode placement should be based on the standard 10- to 20-electrode system and modified according to the number of channels being monitored (Fig. 24.7). EEG activity is commonly divided into four bands according to frequency: δ less than 4 Hz; θ 4 to 8 Hz; α 9 to 12 Hz; and β greater than 13 Hz. In general, slower frequencies indicate a deeper level of anesthesia. Several factors can confound interpretation of intraoperative EEG (Table 24.3) which, along with its technical complexity, have limited its clinical use to monitoring cooling during DHCA. Recordings are potentially made in the presence of various anesthetic agents, during profound changes in body temperature, and in the electrically hostile environment found in an operating room. Although subtle EEG changes may be difficult to interpret, development of asymmetric EEG activity should be considered to represent hemispheric compromise (Table 24.4).

Table 24.4 Causes of electroencephalographic asymmetry

Figure 24.7 Standard bipolar parasagittal montage based on the international 10–20 system. FP1 and FP2 refers to frontal pole; F3F4F7, and F8 refer to frontal; C3 and C4 refer to central; P3 and P4 refer to parietal; O1 and O2 refer to occipital; and T3T4T5, and T6 refer to temporal positions. (From Murkin JM, Moldenhauer CC, Hug CC Jr, et al. Absence of seizures during induction of anesthesia with high-dose fentanyl. Anesth Analg. 1984;63:489–494.)

      1. Processed EEG. After initial electronic filtering, analog EEG voltages are rapidly digitized (150/s) and analyzed over “epochs” (generally 2 to 4 s in duration) using analyses based on either frequency-domain or time-domain processing.

        a. Compressed spectral array (CSA) and density-modulated display of power spectrum analysis (DSA). For frequency-domain processing, many EEG applications use power spectral analysis. In this application, each EEG epoch is converted into a series of sine-wave components using Fourier transformation that treats the digitized EEG as a sum of sine waves of variable frequency and power. The amplitude (power) of each of the sine-wave components is indicated as a function of its frequency, and in the CSA each EEG epoch is shown over time in a three-dimensional representation (frequency vs. power vs. time) with the most current epoch in the foreground. The vertical displacement, representing both power and time, hinders recognition of low-amplitude activity followed by high-amplitude activity in the same frequency band. DSA is a representation in which each epoch is displayed using gray-scale intensity or dot size proportional to the power of the individual frequency band plotted. Consequently, it can be difficult to recognize small changes in frequency using this display.

        b. Spectral edge frequency (aperiodic analysis). Aperiodic analysis is time-domain–based processing and does not use Fourier transformation. Instead it is based on assessing voltage versus time of the raw EEG. For each component EEG wave in an epoch, the frequency is determined as the reciprocal of the time interval measured between zero axis voltage crossings, the zero-crossing frequency (ZXF), while the amplitude is the square root of the sum of squares of the voltages of the wavelets. Fast- and slow-wave components are analyzed separately, then combined for display. This model of analysis is also used to calculate the burst-suppression ratio, which can be an indicator of anesthetic depth and cerebral metabolism depression. Epileptiform activity and artifact have been reported to be most readily identified by time-domain processing. EEG frequency carrying the median power (median frequency power) correlates with plasma levels of several narcotics. The spectral edge frequency (frequency below which 95% of summated EEG power is contained) correlates with clinical assessment of anesthetic depth achieved with barbiturates or volatile anesthetics.

      2. Bispectral (BIS) index. Most frequency-domain processing (CSA, DSA) treats those component waveforms resulting from Fourier transformation as independent. Bispectral (BIS) analysis measures potential interactions between the waves to determine the presence of interactive components (harmonics) indicative of phase coupling (biocoherence), information that is not present in power spectral analysis. It has been recognized that EEG slowing and synchrony often occur in relation to increasing depth of anesthesia. The BIS measurement is the first device specifically for the measurement of the hypnotic effects of drugs approved by the US Food and Drug Administration (FDA).

      3. Evoked potentials. Metabolic and hemodynamic homeostasis determines the state of cerebral functional integrity. The latter can be inferred from EEG changes in response to repeated stimulation of intact afferent pathways. Separated from raw EEG and averaged, these evoked potentials (EPs) are described in terms of latency (time between the stimulus and respective EEG change) and amplitude (cortical microcurrent 1 to 5 μV). Reduction in CBF below 18 mL/(100 g · min) causes progressive decrease of the latter, which disappears at CBF below 15 mL/(100 g · min). In clinical practice, only the response of sensory neurons of gray matter can be tested in this way. More commonly, EPs serve to monitor the function of sensory tracts. Certain anesthetic agents complicate the recognition of specific effects of changing metabolic environment on EPs (e.g., isoflurane increases latency and decreases amplitude of somatosensory EPs) and have opposite effects on different EPs (visual somatosensory). As temperature changes also affect the latency and amplitude of EPs, the net result is potential intraoperative variability in EP during cardiac surgery potentially limiting its clinical applicability.

   C. TCD. Insonation of blood moving within a vessel produces a characteristic shift in signal frequency (Doppler shift) that is proportional to the flow velocity. Use of low-frequency sound waves (2 to 4 MHz) from depth-gated, direction-sensitive probes allows transmission through thin areas of skull (e.g., temporal window located above zygomatic arch between ear and orbit). This transmission enables continuous assessment of blood flow velocity within major intracerebral arteries (e.g., proximal MCA). Cerebral perfusion characteristics also can be assessed using TCD insonation for demonstration of laminar versus pulsatile flow or for detection of emboli. Because dissimilar acoustic echoes reflect inhomogeneities in the insonated substrate, microaggregate or microgaseous emboli can be detected within the bloodstream. Because TCD essentially functions as a microphone, artifactual noise transients can register as emboli. However, certain criteria have been employed to distinguish embolic signals from noise artifact (Table 24.5). Much greater acoustic resonance of gas emboli relative to formed elements creates limits of TCD detection for formed elements greater than 100 μm. In addition, the amplitude of signal is proportional to the size of the embolus, whereas for bubble emboli, limits of resolution are 50 μm and the amplitude of the reflected signal is unrelated to size of the bubble.

   Because of the ability to focus a pulsed U/S beam, however, by using a dual gating technique in which the vessel is insonated at two discrete sites, emboli can be discriminated from artifacts. This reflects the fact that emboli propagate with blood motion and artifact does not and thus emboli but not artifact will be detected sequentially at different depths along the insonated cerebral artery.

   One of the major goals in intraoperative TCD monitoring is discriminating solid versus gaseous cerebral emboli. Solid and gaseous microemboli may be differentiated with a new generation of multifrequency transducers, using both 2- and 2.5-MHz crystals, based on the principle that solid microemboli reflect more ultrasound at the higher than at the lower frequency, whereas the opposite is the case for gaseous microemboli. How robust this will prove in clinical practice remains to be seen and the results to date remain unconvincing.

Table 24.5 Transcranial Doppler characteristics of emboli versus noise

   D. Jugular oximetry. The characteristic attenuation of 650 to 1,100 nm infrared light by a few specific light-absorbing chromophores (primarily oxyhemoglobin, deoxyhemoglobin, and oxidized cytochrome c oxydase) imparts wavelength (color) shift on the incident light. This spectral shift is proportionate to the degree of oxygenation enabling quantification of tissue oxygenation using optical spectroscopic devices. Placement of a fiberoptic oximetric catheter into the jugular bulb provides continuous monitoring of the hemoglobin saturation of effluent cerebral venous blood and reflects global cerebral O2 supply and demand balance. Jugular oximetry may provide an appropriate endpoint for termination of cooling before DHCA (see below). After jugular saturation has increased maximally and stabilized, CMRO2 is at its lowest. Such monitoring has identified an association between rewarming after hypothermic CPB and significant cerebral venous blood desaturation. This indicates mismatching between cerebral O2 supply and metabolic rate, and increasing either hemoglobin concentration or depth of anesthesia (greater metabolic suppression) may be appropriate.

   E. NIRS. Similar principles of light absorbance are used during noninvasive cerebral optical spectroscopy using scalp-attached probes. Most of the currently available commercial devices employ two-channel monitoring using adhesive pads with one or more transmitting and two or more separately spaced receiving optodes. Differential spacing of the receiving optodes enables correction for extracerebral tissues to be made, allowing an assessment of regional oxygen saturation (rSO2) of cerebral cortex (Fig. 24.8). Current studies estimate that there is between 5% and 15% influence of extracerebral tissue on cerebral oximetry values as measured. Advantages and limitations of NIRS cerebral oximetry monitoring are shown in Table 24.6. This device enables indices of cerebral oxygenation to be determined in a continuous manner in a variety of clinical circumstances. There is no requirement for pulsatile blood flow enabling continuous monitoring during CPB, and there are no temperature-related artifacts. A potential limitation is the fact that the cerebral sample volumes are on the order of 1 mL of frontal cortical tissue, thus rendering them highly localized in nature. It is also apparent that since NIRS measures total tissue oxygenation, various factors including patient age, hemoglobin concentration at the measurement site, and sensor location can affect rSO2 values. A prospective study demonstrated that avoidance of low intraoperative cerebral oximetry values decreases major organ morbidity and death in patients undergoing CABG surgery [23], and a strong correlation has also been made between low preoperative baseline cerebral oximetry values and short- and long-term morbidity and mortality in cardiac surgical patients [13]. While there is increasing clinical consensus that cerebral oximetry is beneficial in patients undergoing hypothermic circulatory arrest with direct cerebral perfusion [24], other studies report skeptical results about cerebral oximetry technology [24,25] to counterbalance the argument against routine use in cardiac surgical patients. Large-scale multicenter clinical outcomes studies will be required in order to make a solid recommendation for the widespread use of cerebral oximetry in cardiac surgical patients or other specific subgroups of patients.

Table 24.6 Advantages and limitations of NIRS cerebral oximetry

Figure 24.8 Schematic representation of tissue layers through which light must propagate to reach the brain. Light propagating from source to receiver 1 has a mean tissue path length such that it predominantly samples superficial tissue (scalp and skull), whereas light propagating to receiver 2 has a deeper mean path length into brain. The signal from receiver 1 is used to correct the signal from receiver 2 for superficial tissue contamination. (From McCormick PW, Stewart M, Goetting MG, et al. Noninvasive optical spectroscopy for monitoring cerebral oxygen delivery and hemodynamics. Crit Care Med. 1991;19:89–97, with permission.)

   F. CPP. It represents the difference between driving pressure, or MAP, and downstream pressure, or intracranial pressure. During CPB, direct measure of intracranial pressure is not available; thus, CVP is often used as a surrogate. In the presence of impaired drainage from the SVC, which may occur during dislocation of the heart (particularly with use of a single two-stage cannula), cerebral venous hypertension may occur. Because atrial drainage is unimpaired, CVP measured from the atrium will be low; hence, this condition may be unrecognized. If sustained, cerebral venous hypertension can lead to cerebral edema and substantially decreased CPP, despite apparently adequate MAP (see Fig. 24.6). NIRS cerebral oximetry has been demonstrated to rapidly detect such events when cerebral desaturation occurs. During CPB, cerebral venous pressure should be monitored by a catheter placed proximally (usually pulmonary artery catheter introducer sheath) in the SVC and by visual inspection of the face.


VI. Prevention of CNS injury.

     As discussed in detail below, Table 24.7 shows a series of evidence-based recommendations designed to limit the risk of perioperative cerebral injury in cardiac surgical patients [26]. Table 24.8 outlines specific interventions designed to limit or avoid particular risk factors.

Table 24.7 Evidence-based guidelines for best practice bypass

Table 24.8 Perioperative strategies minimize CNS brain injury

   A. Embolic load

      1. Aortic instrumentation

        a. Although still the standard of care, palpation of the aorta has not proven sensitive to detect aortic atherosclerosis. Direct EAS scan of ascending aorta is the most sensitive technique for assessment of atherosclerotic burden. Alternatively, initial TEE screening of descending aorta, followed by EAS if TEE detects descending aortic atherosclerosis, represents an acceptable screening strategy. With extensive aortic atherosclerosis, distal aortic arch or axillary artery cannulation should be considered.

        b. Minimize the number of aortic clampings. Use of all arterial grafts (e.g., mammary, gastroepiploic) or sutureless proximal anastomotic devices eliminates the need for aortic side clamping for proximal anastomoses. In cases of severe atherosclerosis, “no touch” techniques (OPCAB with zero manipulation of the ascending aorta) have been shown to significantly decrease stroke rate [27].

   B. Off-pump versus conventional CAB

In one of the most recent meta-analyses of risk of stroke in OPCAB versus conventional on-pump CAB (CCAB) surgery, analysis of 59 most recent randomized clinical trials involving 8,961 patients, of whom 4,461 patients underwent OPCAB and 4,500 were randomized to CCAB, determined a significant difference in composite stroke incidence of 1.4% in OPCAB versus 2.1% in CCAB groups [28]. Not inconsistent with this result, no studies have reported a higher stroke risk with OPCAB but have shown either no effect or a trend for decreased stroke rate associated with OPCAB. Accordingly, selective use of OPCAB for patients at increased risk of stroke related to aortic atherosclerosis would appear to be an important strategy to minimize early stroke risk.


      1. Perfusion equipment and techniques

        a. Precirculation of CPB circuit for a minimum of 30 min with a 5 μm filter before usage removes plasticizers and other manufacturing microdebris.

        b. Incorporation of a micropore (20 to 40 μm) filter into the cardiotomy return line keeps tissue and other particulate debris from the surgical field out of the CPB circuit.

        c. Retransfusion of cardiotomy suction blood after processing using cell saver. Of note, while this may decrease embolic load it has not been consistently shown to improve early postoperative cognitive outcomes but has been associated with increased transfusion requirements.

        d. Use of a 40 μm filter on the arterial inflow line decreases delivery of emboli into the arterial circulation.

        e. To minimize gas bubble formation due to decreased solubility with rewarming, the temperature gradient between the arterial inflow blood and the patient must be less than 10°C, particularly with use of a bubble oxygenator.

        f. During rewarming, arterial blood inflow temperature must not exceed 37°C.

        g. Be aware of the possibility of air entrainment from cardiac vents in the surgical field, and ensure meticulous deairing of CPB venous cannulae and syringes for injection into the CPB circuitry to decrease arterial gas embolization.

      2. Open-chamber deairing techniques

        a. Before ventricular ejection, needle aspiration of the LV and LA, combined with manual agitation of the heart, to dislodge air entrapped in trabeculae. This process should be combined with concomitant manual ventilation of the lungs to mobilize residual air within the pulmonary veins.

        b. Use of TEE to detect residual intracavitary air and to direct needle aspirations.

        c. Tilting the patient’s head down. This procedure achieves a dependent position of the great vessels of the head and is thought to minimize cerebral embolization although evidence for its efficacy is lacking.

        d. Transient bilateral carotid compression during defibrillation and initial filling and commencement of heart ejection. This maneuver should be reserved for instances where the risk of intracavitary air remains high and there is no suspicion of carotid atherosclerosis.

   C. Cerebral perfusion. In normal individuals during moderate hypothermia, relative hypotension is well tolerated because cerebral autoregulation is preserved down to CPP 20 mm Hg with α-stat blood gas management. However, in elderly patients or those with cerebrovascular disease, higher pressure should be maintained as the lower autoregulatory threshold has been shown to vary markedly in such patients [12,14]. As assessed by NPT, the brain rewarms rapidly; therefore, hypotension (MAP less than 50 mm Hg) should be avoided after commencement of rewarming in all patients. Inadvertent compromise of CPP should also be avoided by monitoring proximal SVC pressure to detect cerebral venous hypertension. Diabetics and patients with previous CVA have impaired cerebral autoregulation and CBF is directly dependent on MAP. Such patients, as well as those with chronic hypertension, may benefit from close CNS monitoring (see previous discussion) and maintenance of higher perfusion pressures.

   D. Euglycemia. There is considerable evidence from experimental models and from patients with CVA that hyperglycemia increases the magnitude and extent of neurologic injury during ischemia. Hyperglycemia should be avoided as a basic approach. Glucose-free infusions and a glucose-free prime should be used for CPB circuit, because insulin resistance develops during CPB (partially as a result of increased endogenous catecholamines), producing glucose intolerance and increasing the tendency for refractory hyperglycemia. A structured approach to maintain normal values of blood glucose is considered favorable to patients’ outcomes and is a recognized element of best practice CPB guidelines as shown in Table 24.7 [26].

   E. Mild hypothermia. There is increasing evidence showing that EAAs are pivotal in the genesis of ischemic neurologic injury (see preceding discussion). Since EAA synthesis and release are critically temperature dependent and are significantly inhibited below 35°C [20], brain temperature (NPT) should be monitored continuously during rewarming, hyperthermia (NPT greater than 37°C) must be avoided, and brain temperature should be maintained less than 37°C until after separating from CPB and decannulation [26].

   F. Best practice CPB. Recommendations from an evidence-based review for conducting safe, patient-centered CPB as based on a structured MEDLINE search coupled with a critical review of scientific literature and debates stemming from presentations at regional and national conferences, with the level of evidence and findings graded using criteria promulgated by the American Heart Association and American College of Cardiology Task Force on Practice Guidelines, are shown in Table 24.7 [26].

VII. Pharmacologic cerebral protection

Despite a profound and ongoing increase in the understanding of the mechanisms involved in ischemic neuronal injury and the development of new classes of drugs, currently none represent a standard of practice; but these or related compounds may become part of the therapeutic armamentarium in the near future.

   A. Metabolic suppression

      1. Rationale and limitations. Metabolic activity is temperature dependent, and hypothermia produces an exponential decrease in CMR. Unlike pharmacologic metabolic suppressants, hypothermia decreases metabolic activity related both to functional activity (e.g., EEG activity) and basal activity (e.g., ion pumps). Hypothermia prolongs the tolerance for global ischemia (Fig. 24.9) and is undertaken particularly for circulatory arrest (see following discussion). During cardiac surgery, however, greatest risk for cerebral emboli occurs during normothermia with cannulation and decannulation; hence, pharmacologic metabolic suppressants have been investigated. While there was previously some interest in high-dose thiopental, no consistent clinical benefit was demonstrated likely since any potential benefit resulting from such therapy was derived from the suppression of CMR associated with suppression of synaptic activity which would likely result only in prolongation of ischemia tolerance of a very few minutes.

Figure 24.9 Nomogram of probability of “safe” total circulatory arrest according to duration of total arrest time as NPTs of 37°C, 28°C, and 18°C, defined as the duration of total arrest after which no structural or functional damage has occurred. (From Kirklin JK, Kirklin JW, Pacifico AD. Deep hypothermia and total circulatory arrest. In: Arciniegas E, ed. Pediatric Cardiac Surgery. Chicago, IL: Year Book; 1985:79–85, with permission.)

      2. Agents. As shown in Figure 24.10, various anesthetics have the ability to produce EEG burst suppression and result in profound decreases in CMR to approximately 50% of awake CMRO2, averaging 25 mL/(100 g · min).

Figure 24.10 EEG tracings from three patients during normothermic CPB. The top tracing demonstrates characteristic low-voltage activity occurring during high-dose fentanyl anesthesia. The middle tracing shows the burst-suppression pattern resulting from thiopental administration. The lower patterndemonstrates burst suppression occurring during isoflurane administration. (From Woodcock TE, Murkin JM, Gentile PS, et al. Pharmacologic EEG suppression during cardiopulmonary bypass: Cerebral hemodynamic and metabolic effects of thiopental or isoflurane during hypothermia and normothermia. Anesthesiology. 1987;67:218–224, with permission.)

        a. Thiopental. A dosage of 5 to 8 mg/kg results in 5 min of EEG suppression at normothermia. Proportional decreases in both CBF and CMRO2 are produced. An infusion at 0.5 to 1 mg/(kg · min) is required for prolonged EEG suppression, results in prolonged recovery and extubation times, and may increase the need for inotropic support because of myocardial depression.

        b. Propofol. Transient EEG burst suppression is obtained at dosages of 2 to 3 mg/kg and results in proportional decreases in CBF and CMRO2. Infusion at 0.1 to 0.3 mg/(kg · min) produces sustained EEG suppression and is rapidly metabolized; therefore, it does not prolong recovery and extubation times. Hypotension from systemic vasodilation may require administration of phenylephrine or other such vasoconstrictor.

        c. Sevoflurane and Deflurane. At inspired concentrations of 1.5 to 2 MAC, burst suppression is produced. Unlike the intravenous agents, EEG suppression with inhalational agents is not accomplished by any decrease in CBF, although CMRO2 is significantly reduced. Rapid elimination is characteristic of volatile anesthetics. Of particular interest is the evidence of ischemic preconditioning and neuroprotection associated with administration of volatile anesthetics which have been variously demonstrated to decrease glutamate release, modulate calcium flux, and inhibit generation of free radicals as well as modulate apoptosis [29]. Large-scale clinical studies are currently lacking but it does appear as though usage of volatile anesthetics does not increase and may have a salutary effect on postoperative CNS dysfunction.

   B. Calcium-channel blockers. Massive calcium influx is likely the final common pathway of ischemic neuronal injury (see preceding comments). In clinical trials, calcium-channel antagonists (nimodipine) have demonstrated efficacy in decreasing vasospasm after subarachnoid hemorrhage; however, nimodipine also has been associated with increased bleeding and higher mortality in cardiac surgical patients.

   C. Glutamate antagonists. Since excitotoxicity is recognized as central to ischemic neuronal injury (see previous discussion), EAA receptor antagonists are being actively investigated. NMDA and AMPA receptor antagonists have been found to be neuroprotective following cardiac arrest but clinical studies in cardiac surgical patients remain inconclusive [30].

   D. Lidocaine. Given its ability to decrease ischemia-mediated neuronal membrane depolarization and attendant excitotoxic cascades, two small clinical trials of lidocaine versus placebo have demonstrated lowered incidences of cognitive dysfunction in cardiac surgical patients. However, preliminary results from a larger clinical trial have been unable to confirm these results.

   E. Statins: An increasingly promising line of investigation is the role of perioperative statin therapy, either alone or in combination with other medications. Evidence is accruing that when administered prior to CAB surgery, statins reduce the risk of perioperative mortality, stroke, and atrial fibrillation, and when combined with β-blocker administration there is suggestive evidence that statins may result in a significantly decreased risk of perioperative stroke in CAB patients [21]. Whether these results will be borne out in large-scale prospective studies is currently unclear but current evidence suggests that benefits seem to outweigh the risks associated with their use, both in the preoperative and postoperative period.


   A. Clinical indications. DHCA sometimes is used for major surgical procedures because it provides a motionless, cannula-free, bloodless field. By allowing unobstructed surgical access, DHCA facilitates repair of complex congenital anomalies in neonates and infants. In adults, DHCA allows temporary interruption of cerebral perfusion, primarily for aortic arch reconstruction or for resection of giant cerebral aneurysms.

   B. Technique

      1. Core and external cooling. In most North American centers, active external cooling (e.g., ice baths) has been eliminated but packing the head in ice is still recommended to inhibit secondary rewarming prior to onset of reperfusion. Core cooling using CPB allows efficient and controlled onset of hypothermia, and cooling persists until core temperature (bladder, rectal) is stable at 15 to 20°C. Cooling must be continued until stable brain temperature (e.g., NPT, jugular thermistry) has been achieved. Some centers use development of isoelectric EEG as the endpoint for cooling, necessitating careful selection and titration of anesthetic agents.

      2. Decannulation. Before circulatory arrest, administration of long-acting muscle relaxants is essential to ensure profound paralysis in order to minimize systemic O2 consumption. With cessation of perfusion, venous cannulas are unclamped, allowing passive exsanguinations into the CPB circuit and decreasing distention of the heart and bleeding into the surgical site. For pediatric surgery, venous cannulas are usually removed to facilitate surgical exposure. Often passive circulation of blood within the CPB circuit is continued ex vivo to avoid stasis and setting of blood with platelet clumping.

   C. Brain protection

      1. Temperature. Hypothermia is the primary component of brain protection during circulatory arrest. The temperature coefficient (Q10), which is the ratio of metabolic rates at temperatures 10°C apart, has been shown to be 2.3 for human brain such that CMR is still 17% of baseline at 15°C [31]. A 20°C (37 to 17°C) decrease in brain temperature enhances cerebral tolerance for ischemia (see Fig. 24.9). Cooling the patient to a temperature of 10 to 15°C seems to offer the best protection to the brain. Minimizing rewarming of the brain is essential; therefore, external heat sources (e.g., overhead lights, ambient room temperature) should be minimized. Application of external ice packs to the head has been shown experimentally to delay brain rewarming and increase ischemic tolerance. Thiopental and/or steroids are administered before circulatory arrest in some centers, although any beneficial effect is unproven.

      2. Anterograde and retrograde perfusion. Because of cerebral autoregulation with preferential shunting of blood to the brain, even low perfusion rates (e.g., 10 to 25 mL · kg · min) during deep hypothermia have been shown to significantly improve cerebral ischemic tolerance in comparison to total circulatory arrest. A prospective randomized study has shown that continuous low-flow perfusion (0.71/min · m2) at 18°C for pediatric patients younger than 3 months undergoing arterial switch operations results in significantly lower incidences of clinical seizures and brain creatinine kinase isoenzyme versus HCA and is now the standard of care.

          For aortic arch procedures in which arterial inflow is restricted, selective cerebral perfusion (SCP) via brachiocephalic or carotid perfusion is employed in many centers. Since these techniques assume adequacy of circle of Willis, there is increasing clinical interest in bihemispheric NIRS cerebral oximetry to assess adequacy of unilateral SCP. NIRS cerebral oximetry has been reported to detect catheter kinking or inadequacy of flow in a number of cases. Retrograde cerebral perfusion does not provide sufficient substrate supply to maintain brain metabolic demand but may prevent rewarming and decrease cerebral embolization. In a recent case report, RCP with pressure-augmented perfusion guided by cNIRS was felt to provide enhanced cerebral perfusion and was not associated with neurologic deficit despite prolonged duration of perfusion [32]. There is general clinical consensus that cerebral oximetry monitoring is beneficial when SCP or RCP is employed.

      3. pH management. Although in a large randomized clinical trial, use of α-stat versus pH-stat acid–base management strategy during reparative infant cardiac operations with deep hypothermic CPB was not consistently related to either improved or impaired early neurodevelopmental outcomes, experimental and clinical studies have demonstrated more homogeneous brain cooling with pH-stat. Conversely, pH-stat impairs cerebral autoregulation and potentially increases cerebral embolization; therefore, a considered approach is to employ pH-stat during cooling and α-stat during rewarming.

   D. Summary (Table 24.9)

Table 24.9 Summary of deep hypothermic circulatory arrest (DHCA)

IX. Cardiac surgery in patients with cerebrovascular disease

   A. Incidence. Coronary atherosclerosis increases the likelihood of coexisting carotid arteriopathy. Presence or absence of carotid bruits is a poor predictor of carotid stenosis or the risks of perioperative stroke. In a survey of patients undergoing CABG, 5.5% showed significant unilateral carotid stenosis, 2.2% had bilateral stenoses, and 1.5% of patients had unilateral or bilateral carotid occlusion. Another study of over 200 CABG patients demonstrated a 54% incidence of significant cerebrovascular (carotid or intracranial) atherosclerosis preoperatively [19]. In general, however, noninvasive (ultrasonography) and invasive (contrast arteriography) investigations are usually reserved for patients who have had overt symptoms of cerebrovascular insufficiency (e.g., transient ischemic attacks or stroke) during the previous 3 to 6 months [33]. In part, this reflects the clinical recognition that carotid endarterectomy (CEA) does not appreciably reduce risk of perioperative CVA in cardiac surgical patients (see later) [33].

   B. Morbidity. Neurologic injury associated with cardiovascular surgery is a consequence of both cerebral emboli and hypoperfusion. Carotid disease is an important etiologic factor in the pathophysiology of post-CAB stroke but is probably only responsible for, at most, about 50% of all strokes [1,33]. Carotid stenosis is associated with a greater incidence of aortic atherosclerosis and concomitant cerebrovascular disease. The presence of combined carotid and cardiac disease suggests more advanced and severe atherosclerosis and a higher risk of embolization and/or hypoperfusion during cardiac surgery and emphasizes the role of adequate intraoperative management (e.g., neuromonitoring and avoidance of hypoperfusion) in susceptible patients.

   C. Combined carotid and cardiac procedures

      1. Rationale. Indications for CEA and CAB should be considered independently. There is no compelling evidence that, in the absence of significant symptomatology, CEA decreases perioperative stroke risk [1,33]. The role of carotid stenting is promising and remains to be defined. Approximately 9% to 11% of patients undergoing either staged or synchronous procedures will die or suffer a nonfatal stroke/MI in the perioperative period. Prospective community-based studies have reported the worst outcomes [1,33].

      2. Morbidity. In asymptomatic patients CEA does not decrease perioperative stroke risk. The reported combined risk of death, CVA, and MI for synchronous procedures (CEA + CAB) is 11.5%, and for staged procedures (CEA then CAB) it is 10.2%, suggesting that institutional experience is of primary importance. Because of the paucity of natural history data, there is no systematic evidence that staged or synchronous operations confer any benefit over isolated CAB surgery [1,33].

          As such, while there is a strong correlation between risk of perioperative stroke and presence of carotid stenosis, it is not clear that CEA in any way mitigates this risk. In a meta-analysis of 11 studies in which 760 CAB patients underwent either staged or synchronous CAB plus CEA, it was noted that 87% of the patients were neurologically asymptomatic and 82% had unilateral carotid disease [34]. Overall, the 30-day risk of death or stroke was 9.1% and while it was observed that staged CAB then CEA was considered less invasive, the authors concluded that “it remains questionable whether the observed 9% risks of CEA can be justified in any asymptomatic patient with unilateral carotid disease” [34].

X. Summary

There is an evidence-based rationale in support of a number of procedural and technical modifications that have been shown to decrease perioperative CNS complications. Avoidance of instrumentation of ascending aortic atheroma by enhanced screening techniques (e.g., preoperative MRI, intraoperative EAS) and selective use of OPCAB and no-touch techniques for patients with significant aortic atherosclerosis, more judicious use of cerebral monitoring and NIRS for assessing adequacy of cerebral perfusion during CPB, avoidance of cerebral hyperthermia during rewarming on CPB and postoperatively, attenuation of perioperative and CPB-related inflammatory responses, enhanced usage of techniques to decrease postoperative atrial fibrillation, as well as administration of aspirin and statins throughout the perioperative period have all been shown as efficacious in decreasing perioperative CNS complications. The challenge is to better understand which patients are at increased risk and to encourage more widespread assessment and adoption of these various strategies.


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