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Myocardial Management during Cardiac Surgery with Cardiopulmonary Bypass
To whatever extent possible, injury to the myocardium must be avoided during operations utilizing cardiopulmonary bypass (CPB). During these operations, alterations of myocardial blood flow and oxygen demand are often imposed that, unmodified, might injure cellular energetics and morphology. We have chosen to call the following general discussion one of management rather than protection of the myocardium. Most efforts at management will result in protection of function. However, some techniques at times result in injury; at other times perhaps one or another technique may improve myocardial function. Almost all the techniques of myocardial management introduced in the past are in use today by one or more surgical groups, and at this time there is little secure evidence that one method is superior to another, or that the same method is optimal under all circumstances. This chapter is written, nonetheless, with the bias that few if any methods currently available perfectly protect the heart from the damaging effects of an appreciable period of global myocardial ischemia, but that such a method may evolve with additional knowledge. Emphasis is given to methods that are currently satisfactory.
Historical Note
In the early years of cardiac surgery, little mention was made of the possibility that fatal or nonfatal low cardiac output in the early postoperative period was related to damaging effects of the cardiac operation itself. Indeed, in two reviews of complications of open heart operations published in 1965 and 1966, early postoperative low cardiac output was discussed extensively, but no mention was made of myocardial necrosis as a complication of the surgery or as a cause of low cardiac output, nor of temporary depression of myocardial function (stunning) as a result of the operation itself. Then, in 1967, Taber, Morales, and Fine described scattered small areas of myocardial necrosis, estimated to involve about 30% of the left ventricular myocardium, in a group of patients dying early after cardiac operations, and implicated this as the etiology of the patients’ low cardiac output. Najafi and colleagues showed in 1969 that acute diffuse subendocardial myocardial infarction was found frequently in patients who died early after valve replacement; these investigators suggested this was related to methods of intraoperative management of the myocardium. They discussed the possibility that disturbances of the myocardial oxygen supply/demand ratios might be implicated, and that proper perfusion of the subendocardial layer of the myocardium was a particular problem during CPB.
When coronary artery bypass grafting (CABG) began during the early 1970s, cardiologists and cardiac surgeons soon noted that a disturbingly high proportion of surgical patients developed a transmural myocardial infarction perioperatively (immediately before, during, or within 24 hours of operation). Although first widely publicized in connection with CABG, development of transmural myocardial infarction was soon shown to be a complication of cardiac surgery in general. In 1973, in a consecutive series of patients with normal coronary arteries who had undergone various open cardiac operations, Hultgren and colleagues documented a 7% occurrence of acute transmural myocardial infarction. These investigators recognized that “there is clearly an urgent need to further improve the protection of the heart during [cardiac] surgery.” Various autopsy studies have confirmed that acute transmural myocardial infarction, as well as scattered myocardial necrosis and confluent subendocardial necrosis, can occur after cardiac surgery in the presence of normal coronary arteries. The rarely occurring extreme manifestation of ischemic damage, “stone heart,” was recognized at about that time and has been confirmed to be essentially a massive myocardial infarction developing during reperfusion.
Development of knowledge in this area was facilitated by improved methods of identifying myocardial necrosis during life and, to some degree at least, quantifying its extent. Electrocardiographic criteria for diagnosing transmural myocardial infarction and ischemic changes were clarified and applied to postoperative patients. Appearance of cardiac-specific enzymes in plasma was shown to correlate well with other evidence of myocardial necrosis, and their concentrations were shown to correlate directly with amount of muscle that had become necrotic, as judged by other criteria. Isoforms of troponin I and T, sensitive and somewhat specific serum markers of myocardial injury following CPB, were found to be related to duration of ischemic time during cardioplegia, and elevated serum levels were associated with occurrence of delayed post-clamp recovery of ventricular function. Radionuclide imaging identified the presence and extent of perioperative myocardial infarctions.
With these methods, a number of clinical studies have supported the finding of autopsy studies that myocardial necrosis is an important and frequent complication of conventional cardiac surgery. In 1974, the frequency of myocardial necrosis in patients convalescing well was demonstrated in a study of isolated aortic valve replacement. Although hospital mortality was low (2%), 15% of the patients developed electrocardiographic evidence of transmural myocardial infarction, and 70% developed isoenzymatic evidence of myocardial necrosis. In 1974, it was shown that even after the short and simple operation for repair of an uncomplicated atrial septal defect, both adult patients and children developed isoenzymatic evidence of myocardial necrosis. Myocardial necrosis was demonstrated by enzymatic methods in children undergoing surgery for a number of different congenital cardiac defects.
In a 1975 study, early postoperative cardiac output was reported to be inversely proportional to the extent of myocardial necrosis, and thus the amount of myocardial necrosis was a determinant of the early postoperative condition of the patient and of the probability of survival ( Fig. 3-1 ). Subsequently, it became clear that myocardial stunning also occurs after cardiac surgery, as well as after regional myocardial ischemia from coronary artery disease. This also results in a period of low cardiac output of variable duration, albeit without myocardial necrosis in some patients.
It is difficult to identify the individual who first thought about special methods of myocardial management to protect the heart itself from damage during operations. Probably the first special method was retrograde coronary perfusion for surgery on the aortic valve, reported by Lillehei and colleagues in 1956, and subsequently by Gott and colleagues. “Elective cardiac arrest” was advocated by Melrose in 1955, but its use at that time by Cleland in London was for intracardiac exposure, not myocardial management. The first deliberate attempts to protect the myocardium other than by simply perfusing it may have been made by Hufnagel and colleagues in 1961, who introduced profound cardiac cooling using ice slush, and Shumway and Griepp and colleagues, who used ice cold saline for the same purpose. Pharmacologic intervention, designed to provide myocardial protection against the damaging effect of ischemia, began during the 1970s as more knowledge of the pathophysiology of myocardial ischemia evolved. In the late 1970s, Clark and colleagues accumulated evidence of the favorable effect of nifedipine, a calcium channel blocking agent.
The concept of reducing global myocardial ischemic damage by inducing immediate cessation of electromechanical activity— cardioplegia —was discussed generally by cardiac surgeons during the late 1950s, during which time cold Melrose solution was used for this purpose at the Mayo Clinic. Lack of any apparent advantage led to abandoning the method. The concept remained largely unused in the United States for many years thereafter, but in Europe, Hoelscher, Spieckerman and colleagues, Bretschneider and colleagues, and Kirsch continued investigations of induced cardioplegia. Sondergaard reported clinical use of Bretschneider's solution in 1967, and in 1972 Kirsch and Rodewald and colleagues reported use of Kirsch cardioplegic solution in clinical cardiac surgery. Working with the latter group, Bleese and colleagues reported a hospital mortality in 1979 of 12% among 26 patients undergoing complex operations with cold procaine-magnesium cardioplegia and global myocardial ischemic times greater than 150 minutes. About the same time, Hearse and Braimbridge and their colleagues in London were exploring induction of reversible cardiac arrest and its clinical application. Gay and Ebert studied and advocated potassium-induced cardioplegia in 1973, as did Roe and colleagues in 1977. Randomized trials soon confirmed the advantages of cold cardioplegia. Buckberg identified blood as the optimal cardioplegic vehicle in 1979. In the 1990s Wechsler, Damiano, and others began experiments using concepts of membrane hyperpolarization (nearer the resting state) via adenosine triphosphate (ATP)-sensitive K + channels rather than hyperkalemic cell membrane depolarization ; aprikalim and pinacidil are examples of K + channel openers.
In 1960, Danforth, Naegle, and Bing showed the rapidity with which myocardial energy supply is replenished after ischemia when electromechanical quiescence is continued for a few minutes into the reperfusion period. This key observation remained unused until Buckberg and colleagues in 1978 showed experimentally that improved outcome could be obtained through use of an initially hyperkalemic reperfusate. Subsequently, these investigators modified the reperfusate : For acutely energy-deficient hearts, they introduced warm induction of cardioplegia with an enriched, modified, hyperkalemic blood perfusate. Control of perfusion pressure during reperfusion and continuance of controlled reperfusion until full recovery were additional contributions to cardioplegic and reperfusion techniques.
The mode of delivery of the cardioplegic vehicle was the latest contribution to cardioplegic management. Buckberg in North America and Menasche in Europe documented the efficacy and safety of retrograde and combined antegrade-retrograde infusion in valvar and coronary surgery. Metabolic demands of the heart were reduced by approximately 85% by sustained potassium arrest, even at normothermia. Therefore, using the delivery concepts of Buckberg and Menasche, Lichtenstein and Salerno reasoned that warm continuously delivered blood cardioplegia containing minimal amounts of potassium would provide adequate oxygen, substrate, and buffer to the arrested nonworking heart. They occluded the aorta and maintained the heart quiet and flaccid, but perfused.
Need for Special Measures of Myocardial Management
Conditions during Cardiopulmonary Bypass
The heart of intact humans is perfused by blood, ejected from the left ventricle, that leaves the aorta via the right and left coronary arteries. Blood is continuously modified by the organism so as to be correct in its composition and free of damaging materials such as gaseous or particulate microemboli. The amount and distribution of myocardial blood flow (hence myocardial oxygen supply) are continuously regulated, primarily in response to myocardial oxygen demand. This flow is determined by coronary perfusion pressure (aortic pressure), tension in the various myocardial layers (related in part to ventricular wall thickness and size), and coronary vascular resistance. An appropriate coronary vascular resistance depends on proper function of the coronary endothelial cells and underlying smooth muscle. The ratio between flow to the inner one fourth of the myocardium (subendocardial layer) and that to the outer one fourth (subepicardial layer) in normal hearts with intact circulation is maintained at 1 or a little greater. Although blood flow to the subepicardial layer occurs during both systole and diastole, blood flow to the subendocardial layer occurs almost exclusively during diastole, because intramyocardial tension during systole closes the branches of the coronary arteries that pass perpendicularly through the myocardium to arborize in the subendocardium. The well-known vulnerability to ischemia of the left ventricular subendocardial layer in shock, ventricular hypertrophy, and coronary artery disease, as well as during cardiac surgery, is dependent in part on this relationship, but in part on other factors as well, including a higher rate of oxygen consumption in the subendocardial layer.
During CPB, the heart is deprived of most of these protective regulatory factors. During total CPB, blood enters the arterial system through a cannula in the ascending aorta or at a more distal point. It then passes retrogradely into the most proximal part of the aorta and is distributed through the right and left coronary ostia into the coronary arteries. Arterial pulse pressure is narrow (essentially nonpulsatile), and mean arterial blood pressure is variable. The heart is usually more or less empty and thus smaller than usual, thereby increasing intramyocardial tension and transmural and subendocardial vascular resistance, and decreasing flow to the subendocardial layer. The effect is particularly powerful in the small heart and hypothermic heart. Ventricular fibrillation increases intramyocardial tension still more. Coronary vascular resistance during CPB is also affected by circulating vasoactive agents (see “Details of the Whole-Body Inflammatory Response” in Section II of Chapter 2 ). The perfusate is diluted blood of variable composition with highly abnormal physiochemical properties. The blood may contain microemboli of several kinds, and leukocytes and platelets with altered mechanical and humoral functions.
Thus, there is little reason to assume that the empty perfused human heart on CPB, even when beating, is managed optimally. Furthermore, clinical experience refutes that view.
Vulnerability of the Diseased Heart
In most patients undergoing cardiac surgery, coronary blood supply or the myocardium, or both, are not normal and are therefore particularly susceptible to ischemic and reperfusion damage. Hypertrophied ventricles have long been known to be particularly susceptible to ischemic and reperfusion damage. This vulnerability is a result of several factors. Transmural gradients of energy substrate utilization are markedly elevated, increasing the vulnerability of the subendocardium to ischemic damage. Xanthine oxidase levels are markedly elevated, increasing the opportunity for elaboration of oxygen-derived free radicals. Superoxide dismutase levels are markedly decreased, reducing the natural defenses against oxygen-derived free radicals. Also, wall characteristics of the hypertrophied ventricle make reperfusion of the subendocardium even more difficult than under normal circumstances.
The heart of the patient with chronic heart failure is chronically depleted in energy charge 1 and is particularly susceptible to additional acute depletion and damage during ischemia and reperfusion.
1 Energy charge describes the energy-producing capacity of the particular combination of adenine nucleotides present in mitochondria and cytoplasm of myocytes of a particular heart. Normally, it is 0.85. It would be 1.0 if the nucleotides were present only as ATP, but 0.0 if they were present only as adenosine monophosphate.
The hearts of experimental animals made cyanotic have been shown to be considerably more susceptible to ischemic and reperfusion damage than are normal hearts. This may pertain also to severely ill, cyanotic patients. It is well known that the heart of a patient coming to the operating room in a hemodynamically unstable state or in cardiogenic shock is highly sensitive to the damaging effects of global myocardial ischemia.
Surgical Requirements
Cardiac operations can be performed with the heart perfused and either beating, in ventricular fibrillation, or in diastolic arrest. However, the probability of a precise and complete surgical procedure without air embolization is greatest when the heart is bloodless and mechanically quiescent. These optimal conditions are provided by global myocardial ischemia, but they necessitate appropriate myocardial management to limit the damage that would otherwise result from the period of global myocardial ischemia. The changes associated with myocardial ischemia and those associated with reperfusion are not often discussed as separate events; much of the literature does not allow interpretation of one or the other as a separate event. In contrast, the surgeon, by his or her manipulations, has a unique opportunity to control and influence each separately. Therefore, the following discussion must, for strategic purposes, attempt to distinguish the role of ischemia from that of reperfusion.
Damage from Global Myocardial Ischemia
Damage from a period of ischemia may result in a variable, and sometimes prolonged, period (many days) of both systolic and diastolic dysfunction without muscle necrosis. This condition is termed myocardial stunning . A period of ischemia may also result in irreversible damage (myocardial necrosis) . Some investigators have obtained information indicating that this can develop in the subendocardium after as little as 20 minutes of normothermic ischemia. Others have obtained evidence that at least 6 hours of normothermic myocardial ischemia is compatible with myocardial cell survival throughout the myocardium. Ischemic damage involves myocardial cells (myocytes), vascular endothelium, and specialized conduction cells (which, with many cardioplegic techniques, may be the last to recover).
Overall reviews of the damage from myocardial ischemia are available. Nayler and Elz stress the extreme heterogeneity among cells (and by implication among hearts) in the rate of progression of ischemic damage, as well as in the rapidity of the chain of events of ischemia (i.e., the switch from aerobic to anaerobic glycolysis occurs within seconds of onset of ischemia).
Although the phrase global myocardial ischemia is appropriately used to describe the situation during cardiac surgery when the aorta is clamped, some blood flow—originating in mediastinal arteries—continues from noncoronary collaterals. Generally, noncoronary collateral flow is less than 3% of total coronary flow. However, in patients with cyanotic congenital heart disease, advanced ischemic heart disease, extensive pericarditis, and other conditions, coronary collateral flow may be sufficient to initiate electromechanical activity in the heart rendered quiescent by cardioplegia, but insufficient to prevent continuing and important ischemia.
Myocardial Cell Stunning
Surgeons have long known that patients may have severely depressed cardiac function after cardiac surgery without evidence of myocardial necrosis, and that the duration of the depressed function may last minutes or days. Some instances of delayed recovery of cardiac function after cardiac surgery may be related to initially incomplete reperfusion of the microvasculature of the heart. However, myocardial stunning probably underlies at least some instances of prolonged postoperative low cardiac output. In general, stunning occurs after a state of acutely diminished myocardial blood flow followed by adequate reperfusion. After establishing “normal” blood flow, there remains for a time diminished contractility; that is, perfusion/contractility mismatch. 2
2 Myocardial hibernation vs. myocardial stunning: If stunning is characterized as a perfusion/contraction mismatch, hibernation is a perfusion/contraction match; in the latter, both are low. Generally, hibernation is a chronic, potentially reversible state of segmental (less often, global) contractile dysfunction. Theoretically, dobutamine echocardiography, thallium scintigraphy, and positron emission tomography can distinguish hibernating from nonviable myocardium. However, the difference between stunned and hibernating segments may be vague. Marban suggests that a decrease in Ca 2+ transients at a cellular level is responsible for the contractile dysfunction in hibernation, whereas a decrease in myofilament Ca 2+ responsiveness accounts for the excitation-contraction decoupling seen in stunning.
Myocardial stunning, which can follow even brief periods of myocardial ischemia, is characterized by systolic and diastolic dysfunction in the absence of myocardial necrosis. Myocardial stunning has been attributed to reduced oxygen consumption, which might protect against myocardial necrosis. This hypothesis is denied by the fact that stunned myocardium has a high, not low, oxygen consumption. Some have suggested that stunning may be a consequence of abnormal energy transduction or utilization secondary to depletion of high-energy phosphates. Stunned myocardium, however, responds to inotropic stimulation, indicating the presence of adequate ATP to produce active contraction. Myocardial stunning, then, is a form of myocardial cell damage caused by ischemia and reperfusion. Stunning, like myocardial necrosis, tends to begin in the subendocardial layers and progress outward; recovery during reperfusion proceeds in the reverse direction.
Current information makes it unlikely that stunning is the result of prolonged postischemic depletion of myocardial cell energy charge. It does not appear to be the result of a continuing postischemic impairment of coronary blood flow or coronary reserve. It may be caused in part by the release of oxygen-derived free radicals, presumably by activated neutrophils and probably occurring to a major degree during the first few minutes of reperfusion. Experimentally, introduction of superoxide dismutase and catalase (free radical scavengers) before an ischemic period results in nearly full restoration of contractile indices upon reperfusion, compared with prolonged depression in controls. Stunning may be caused in part by an ischemia-induced increase in influx of calcium into the myocardial cells. This possibility has led to the hypothesis that cardiac stunning is related to a defect in calcium-mediated excitation-contraction (EC) coupling that results from the excess calcium. This hypothesis must be reconciled with evidence that after short periods of ischemia, excess intracellular calcium that rapidly accumulates with the onset of reperfusion soon leaves the cells.
Techniques of myocardial management designed to minimize myocardial necrosis are probably effective against myocardial stunning as well. Thus, for optimal results, these techniques should be used even when the period of global myocardial ischemia is less than that anticipated to result in myocardial cell death.
Myocardial Cell Necrosis
Myocardial necrosis after cardiac surgery is the end stage of a complex process initiated by the onset of global myocardial ischemia, maintained by continuing ischemia, and aggravated by reperfusion. The final link in the chain of events, reperfusion, can be favorably modified so as to prevent necrosis, unless the duration of myocardial ischemia is excessive; “excessive” in this context has not yet been defined.
Immediately after the onset of ischemia, contractile force declines rapidly, as does myocardial pH. Oxidative metabolism, electron transport, and ATP production by oxidative phosphorylation (which take place in mitochondria) decline rapidly. Some ATP is still produced by relatively inefficient anaerobic glycolysis. Fatty acid utilization is rapidly reduced, while fatty acid acyl-CoA derivatives accumulate because of continuing uptake of fatty acids by myocardial cells. Intracellular acidosis develops because of accumulation of lactate and protons in the myocardial cytoplasm, suppressing anaerobic glycolysis. These developments contribute to damage to the cell membrane and loss of control of cell size, with consequent cell swelling, intracellular accumulation of calcium, and other disturbances of membrane ion transport. This entire process acutely diminishes myocardial energy charge and glycogen reserves, while adenosine, inosine, and other nucleotides that are the results of ATP catabolism and the building blocks for ATP repletion leave the cell. Ultrastructural changes during this early phase are limited to loss of glycogen granules and some intracellular and organelle swelling.
As the duration of ischemia lengthens, intracellular metabolic deterioration continues, still more fatty acids accumulate within the myocytes, and diastolic arrest occurs. Loss of control of sarcolemmal membrane permeability—which begins within 15 minutes of onset of ischemia —continues, and nonspecific membrane permeability increases. Adenosine, lactate, and other small molecules leak still more rapidly out of the cell, as do cytoplasmic proteins and enzymes; these appear in the cardiac interstitium and in the lymph. As macromolecules within myocardial cells are converted to smaller, more osmotically active molecules by ischemic metabolic conversion, cell swelling proceeds more rapidly. Cellular metabolism and ATP production nearly cease, and glycogen stores are depleted. As glycolysis and mitochondrial function are totally lost, cellular autolysis begins, and cell contents leak more extensively into the interstitial space and cardiac lymph.
In many laboratory preparations, as the depletion of ATP continues and finally reaches critical levels, myocardial contracture begins to occur. The classic belief has been that once contracture is completed, functional recovery is suddenly more difficult, and the time to this end point has been an important criterion in many studies in isolated rat heart preparations. However, the time to contracture (1) is highly species dependent, (2) is unknown but probably quite long in humans, and (3) in the rat heart, at least, has a greatly different implication in crystalloid vs. blood-perfused preparations. The appearance of contracture does indicate that the content of ATP has been depleted to a critically low level. Contracture first develops in the subendocardium, because of its higher metabolic rate and consequent more rapid depletion of ATP. Contracture develops more rapidly in hypertrophied than in normal hearts and is delayed in its onset by hypothermia.
Where the process becomes truly irreversible along this course of events, and cell death becomes inevitable, is not known with certainty.
Endothelial Cell Damage
As in the case of myocytes, distinguishing between ischemic endothelial cell damage and reperfusion damage is difficult. Endothelial cell swelling develops during ischemia and becomes more prominent during reperfusion, and secretion of endothelial relaxing factor, as well as of endothelin, the constricting factor, is affected. Boyle and Verrier have reviewed the role of the endothelium in events associated with ischemia and reperfusion ( Fig. 3-2 ). There is endothelial cell activation following hypoxia, anoxia, or ischemia. Activated endothelial cells express proinflammatory properties, including induction of leukocyte adhesion molecules. These result in neutrophil accumulation at the arterial wall and release of oxygen-derived free radicals. Intracellular adhesion molecules (ICAM) are upregulated (see Fig. 3-2 ). Endothelial cell selectins (E and P) are also involved in the hypoxic inflammatory response and, theoretically, may ultimately contribute to small vessel occlusion (no-reflow) occasionally seen after myocardial ischemia. Impaired microcirculatory flow, membrane degradation, and enzyme dysfunction result then in poor mechanical function (see Fig. 3-2 ). After prolonged ischemia, endothelial cell damage is marked and apparent during reperfusion with unmodified blood and without control of pressure, with sufficient endothelial cell damage that necrosis occurs and large intraluminal projections develop, some of which are cast off into the lumen. Thus, myocardial endothelial cells probably also participate, along with other endothelial cells in the body, in the “whole-body inflammatory response” to CPB (see “Details of the Whole-Body Inflammatory Response” in Section II of Chapter 2 ).
These ischemic changes in the coronary vascular endothelium play an important role in changes in coronary vascular resistance that have been observed in humans during reperfusion after global myocardial ischemia, and in the no-reflow phenomenon seen after prolonged ischemia, particularly in the inner half of the myocardium. In children, cytokines such as interleukin (IL)-8 are liberated during CPB and may contribute to neutrophil adhesion and migration. Burns and colleagues and Kilbridge and colleagues report endothelial expression of P-selectin, E-selectin, and ICAM in myocardial biopsies taken during cardioplegic ischemic arrest in infants undergoing complex repairs. However, the degree to which endothelial activation and related subsequent events contribute to impaired microcirculatory flow and myocardial dysfunction during cardiac surgery is unknown.
Specialized Conduction Cell Damage
The specialized conduction cells become nonfunctional early in the course of global myocardial ischemia in humans; it may be speculated that their recovery takes longer than does recovery of myocytes. Some support for this is that 5 or so minutes after initially hyperkalemic reperfusion, the ventricular myocardium in some patients responds well and strongly to direct ventricular pacing, although it is quiescent with atrial pacing or without pacing. Then, after 5 or so more minutes, sinus rhythm may appear. Also, when blood cardioplegia and uncontrolled normokalemic reperfusion are used, about 50% of patients have atrioventricular (AV) conduction disturbances when CPB is discontinued. This appears to be a form of specialized conduction cell stunning rather than necrosis, because these disappear by the time of hospital discharge in most of the patients in whom it had developed. Even third-degree AV block persisting as long as 2 months has been observed to give way to sinus rhythm. Validation of this speculation remains to be obtained, however. These changes might also be ascribed to variation of specialized conduction fibers’ sensitivity to chemical components of the cardioplegia infusate.
Damage from Reperfusion
The morphologic changes following normal blood reperfusion of ischemic myocardium have been authoritatively presented by Jennings and Reimer. They stress the complexity of the process, including cell swelling, contraction band necrosis, calcium loading of mitochondria, accelerated washout of creatine kinase early in reperfusion, and the particular vulnerability of the subendocardium. It is clear that there can be no reperfusion damage in the absence of prior ischemia. What is not clear is whether there can be reperfusion damage in the absence of ischemic damage . Clearly, limitation of the duration of ischemia and modification of the conditions during ischemia are fundamental to limiting reperfusion injury.
The following discussion assumes some degree of spontaneous ischemia (coronary obstructive disease) or induced ischemia (low blood flow or aortic clamping); it pertains to uncontrolled reperfusion, which is reperfusion by unmodified blood without control of pressure or flow.
Myocardial Cell Damage
The response of myocardial cells to uncontrolled reperfusion depends in large part on the time-related point along the pathway to cell death that has been reached during the ischemic period. Yet the critical point at which the “explosive cellular response” to uncontrolled reperfusion can be expected is not known with certainty. In the past, it has been defined (in the isolated rat heart) as the point at which contracture appears, a definition of little help in humans undergoing cardiac surgery, because the time to contracture—if it occurs—is unknown but probably quite long. Also, when the rat heart is blood perfused (rather than crystalloid perfused), reperfusion after contracture results in good return of function.
When uncontrolled reperfusion is initiated after global myocardial ischemia in cardiac surgery, the response may be only myocardial stunning. A more severe response consists of reperfusion arrhythmias, particularly ventricular tachycardia and ventricular fibrillation. The more prolonged and the larger the area of myocardial ischemia, the more frequent, severe, and intractable the arrhythmias. A still more severe response is the hard and fibrillating heart, sometimes termed stone heart . The stone heart phenomenon may involve only some regions of the heart, typically the basilar portion of the left ventricle and the subendocardium. This phenomenon indicates that the heart has undergone severe damage and may be considered to have approached the critical “point of no return.” It has not necessarily reached this point, because the stone heart is, at least under some circumstances, capable of recovery. The histologic features of these advanced forms of reperfusion damage include disruption of the regular myofibrillar pattern and evident contraction bands.
Clearly, the strong influx of calcium into myocytes, and particularly its accumulation in mitochondria, are obvious and fundamental features of reperfusion injury. Stiffness of cardiac muscle resulting from uncontrolled reperfusion after a period of ischemia is caused by the massive influx of calcium into mitochondria and cytoplasm of myocytes, as well as by edema and capillary disruption. However, many other types of events are ongoing, most well underway within 1 or 2 minutes of uncontrolled reperfusion.
Chemotactic factors of cardiac subcellular origin, activated endothelial cells, activated complement fragments, such as C5a, and cytokines are generated locally in ischemic myocardium. This process activates circulating neutrophils, which accumulate and play an important role in initiating and sustaining reperfusion injury. Neutrophils plug myocardial capillaries as reperfusion continues because of their large size and active adherence to ischemically damaged endothelial cells. Leukocytes, and in particular neutrophils, release large amounts of oxygen-derived free radicals in these circumstances. Activated neutrophils also release arachidonic acid metabolites that cause endothelial injury, vasoconstriction, and platelet aggregation. During reperfusion, certain leukotrienes are also released from platelets and endothelial cells.
Oxygen-derived free radicals generated during reperfusion represent one of the fundamental processes that produce damage. Oxygen-derived free radicals are characterized by presence of unpaired electrons and include superoxide (O 2 ), hydrogen peroxide (H 2 O 2 ), and the hydroxyl radical (OH). Normally, myocardial cells are constantly exposed to superoxide anions in very small amounts, produced in (1) mitochondria (where 95% of oxygen consumption occurs) during electron transport, (2) cell cytoplasm during prostaglandin synthesis and metabolism and oxidation of tissue catecholamines, (3) vascular endothelium by xanthine oxidase–catalyzed reactions, and (4) extracellular fluids by activated neutrophils. Normally, these very small amounts of oxygen-derived free radicals are well controlled. Superoxide dismutase, which is normally present in myocytes, catalyzes the transformation of superoxide anions to hydrogen peroxide and water; metabolism of hydrogen peroxide to water and oxygen is accomplished by either catalase or glutathione peroxidase, or both.
The very onset of uncontrolled reperfusion can produce large amounts of oxygen-derived free radicals because of profound alterations imposed on this exquisite system by ischemia. Ischemia progressively decreases the cellular levels of the scavenger superoxide dismutase and also increases metabolic end products of ATP catabolism, such as hypoxanthine and xanthine. These catabolites may participate in producing oxygen-derived free radicals by supplying free radical substrates to endothelial xanthine oxidase. Also, during ischemia, normally present xanthine dehydrogenase is converted to xanthine oxidase. Superoxide anions are generated at the start of uncontrolled reperfusion. Xanthine oxidase is the catalyst for reoxygenation and metabolism of the considerable amounts of hypoxanthine and xanthine generated during ischemia. A chain reaction results, leading to the generation of other free radicals and of a direct attack by them on unsaturated fatty acids within cell membranes. As part of this chain reaction, iron plays a key role in converting relatively innocuous superoxide radicals into highly damaging hydroxyl radicals. Peroxidation of membrane lipids has been shown to result in increased membrane permeability, decreased calcium transport into the sarcoplasmic reticulum, and altered mitochondrial function, setting the stage for myocardial stunning or necrosis.
Endothelial Cell Damage
Reperfusion damage to the heart involves more than the myocytes. For example, myocytes surrounding a necrotic area of myocardium may be perfectly viable and functioning 1 hour after the start of reperfusion, only to become necrotic over the subsequent few hours. This has been shown to be due to delayed closure of coronary arterioles and capillaries and to the resulting no-reflow phenomenon.
The endothelial cells of large coronary arteries appear to be little affected by the damaging effects of ischemia and reperfusion. The coronary microvasculature is profoundly affected, however, and the resultant endothelial dysfunction appears to develop rapidly with the onset of reperfusion. This damage appears to be minimal after ischemia itself but is incited almost exclusively by reperfusion. In addition to changes in endothelial cell function, the endothelial cell swells, activated neutrophils and platelets aggregate and adhere to the endothelium, and microvascular obstruction can develop.
This rapidly induced reperfusion injury to the endothelial cells severely impairs normal endothelium-dependent relaxations to neutrophils and platelets as well as to thrombin, acetylcholine, and bradykinin. These alterations could play some role in the observed progressive increase in coronary vascular resistance during reperfusion. In addition, with damage to endothelial cells, smooth muscle beneath the cells is exposed, allowing additional mediators to induce direct smooth muscle contraction.
In addition to these phenomena, coronary vessels are compressed by myocardial areas with high wall tension and hemorrhage and by myocardial cell swelling. This all may lead to inhomogeneous distribution of the uncontrolled, unmodified blood reperfusate or actual “no-flow,” further aggravating reperfusion injury in the clinical setting. These unfavorable events are particularly damaging after prolonged (>24 hours) cardiac preservation, as may eventually be required for cardiac transplantation.
Specialized Conduction Cell Damage
Little specific information is available about reperfusion injury to the specialized conduction cells.
Advantageous Conditions During Ischemia
Advantageous conditions during ischemia delay the time required for the ischemic myocardium to reach the hypothetical critical point in the course of ischemic injury. This is classically considered the point at which uncontrolled, unmodified blood reperfusion produces explosive cell damage and accelerated myocardial necrosis, rather than recovery. For this discussion, it is this critical point that must be delayed. The common denominator may be delay in severe reduction of the energy charge of the myocardium.
Circumstances that decrease the rate of ATP utilization (or its surrogate, myocardial oxygen consumption) lengthen the safe ischemic interval . These circumstances include immediate cessation of electromechanical activity and hypothermia. The interrelationships are such that a great advantage is obtained by reducing myocardial temperature from 37°C to 27°C, a lesser advantage by reducing temperature from 27°C to 17°C, and a still smaller advantage by reducing temperature further ( Fig. 3-3 ). However, for longer periods of arrest (6 hours), Rosenfeldt found an increase in protection with stepwise cooling from 20°C to 4°C. In a different experimental preparation, Balderman and colleagues found less satisfactory ventricular performance after 120 minutes of ischemia at temperatures of 6°C and 10°C compared with 14°C and 18°C.
Preoperative enhancement of cardiac substrates seems advantageous, but has been little used in cardiac surgery to date. Myocardial glycogen content can be increased by an intravenous infusion of a glucose-insulin-potassium solution during the 12 hours preceding operation. This can be combined with continuous retrograde coronary sinus infusion of a similar solution during the ischemic period.
Acute substrate enhancement before cold cardioplegia and ischemia by initial infusion of warm, hyperkalemic, modified and substrate-enriched blood has been shown to benefit hearts that have become energy depleted before the cardiac operation. Continuation of the pressure-controlled, warm, enriched blood infusion for a few minutes after the onset of asystole takes advantage of increased coronary flow and better distribution brought about by cardiac asystole.
Preischemic administration of drugs such as lidoflazine has been shown to be advantageous, although the mechanism of their favorable effect remains arguable (see “ Drug-Mediated Myocardial Protection ” later in this chapter).
Preischemic myocardial conditioning may surface as an additional tactic to limit damage during an induced ischemic interval and as an adjunct to surgical myocardial management. The concepts of both ischemic preconditioning and postconditioning are well recognized in the science of myocardial ischemia and reperfusion, but have not found general application in cardiac surgery. Ischemic preconditioning refers to brief periods of cessation of coronary blood flow prior to the longer ischemic event, and ischemic postconditioning refers to brief periods of coronary blood flow cessation during the early period of reperfusion. Ischemic preconditioning appears to stimulate potent innate cardioprotective mechanisms that attenuate ischemia-reperfusion injury. The protective mechanisms have been linked to stimulation of myocyte adenosine receptors, reduction of inflammatory responses to reperfusion, attenuation of endothelial dysfunction during reperfusion, reduction in tissue acidosis during ischemia, and prevention of ischemia-induced cell apoptosis.
Similar mechanisms have been invoked for ischemic postconditioning. Ischemia-induced cardiac preconditioning has been shown to reduce infarct size in dogs and swine. Several reports suggest that in humans, prodromal angina may limit infarct size. Adenosine activation and α 1 -adrenergic stimulation are two pathways suggested as mediators of preconditioning. Protein kinase C has been identified as at least one of the factors that when activated by adenosine or phenylephrine results in protection by myocardial preconditioning in laboratory animals ( Fig. 3-4 ). Experimentally in sheep, preconditioning has been produced by CPB alone and the response suppressed by α 1 -adrenergic blockade or adenosine receptor blocker.
Because of its simpler application to cardiac surgery, remote ischemic preconditioning is the object of numerous clinical trials. It refers to myocardial protection against ischemic injury by inducing ischemia in a distant organ, such as skeletal muscle of the arm. This, and the fact that a preconditioning factor can be transferred from animal to animal, suggests a humoral factor, although a mural component has been implicated as well. Remote ischemic preconditioning has been implemented during cardiac surgery simply by 3- to 5-minute cycles of upper-limb cuff inflation to 200 mmHg, separated by 5 minutes of cuff deflation. Clinical trials have thus far produced mixed results.
Advantageous Conditions During Reperfusion
Advantageous conditions during reperfusion (1) minimize the persistence of myocardial stunning into the post-CPB period, (2) provide for optimal recovery of function of reversibly damaged myocardium, and (3) resuscitate myocytes that would otherwise have undergone necrosis.
Buckberg and colleagues evolved the methods and demonstrated the advantages of controlling reperfusion. These ideas constitute a clinically useful body of knowledge. In essence, the advantageous conditions consist of:
- 1
Maintaining electromechanical quiescence during the first 3 to 5 minutes of reperfusion to permit more rapid repletion of myocardial energy charge, minimize regional heterogeneity of reperfusion flow, minimize myocardial energy expenditure until recovery has been established, and minimize intracellular accumulation of calcium
- 2
Combating accumulated myocardial acidosis by controlling pH of the initial reperfusate and providing a large buffering capacity to permit more prompt morphologic, biochemical, and functional recovery
- 3
Minimizing damage from oxygen-derived free radicals
- 4
Reducing ionized calcium in the initial reperfusate to help minimize intracellular accumulation of calcium
- 5
Increasing availability of substrate for repletion of myocardial energy charge
- 6
Maintaining a low perfusion pressure (≈30 mmHg) during the first 60 to 120 seconds of reperfusion to minimize endothelial cell damage and swelling, during which time reactive hyperemia, usually present, allows this low pressure to be maintained with adequate volume and distribution of flow
- 7
Maintaining a flow sufficient to encourage near-uniform myocardial distribution of the reperfusate
- 8
Continuing control of reperfusion pressure and flow until myocyte, endothelial cell, and specialized conduction cell recovery is essentially complete
Specific comments about individual items follow, and the details of establishing these advantageous conditions during clinical cardiac surgery are described in “Cold Cardioplegia, Controlled Aortic Root Perfusion, and (When Needed) Warm Cardioplegic Induction” later in this chapter. New information continues to accumulate, and current practices must be changed whenever sufficient information becomes available to indicate the possibility of improving results by modifying methods.
Blood
Blood as the reperfusion vehicle has been shown to be superior to crystalloid solutions. The advantage is due in part to the red blood cell component, although it may not relate to the oxygen transport capacity of red blood cells. Among other things, red blood cells contain abundant oxygen-derived free radical scavengers, which have been shown to be important. The minimal effective level of hematocrit in the reperfusate is 0.15 to 0.20. The buffering capacity of blood proteins, especially their histidine and imidazole groups, is also advantageous.
Leukocyte Depletion
There is little doubt that activated leukocytes play an important role in reperfusion damage. Depletion of leukocytes from the blood reperfusate (by filtration) has been shown to reduce reperfusion injury considerably. Leukocyte filters are commercially available for pediatric and adult CPB circuits.
Substrate
Addition of the amino acids l -glutamate and aspartate to solutions used to reperfuse the heart after an ischemic insult has been shown by Rosenkranz and by Buckberg and colleagues to be beneficial to metabolic and functional recovery. Their early work has been confirmed by Choong and Gavin and others.
Addition of adenosine during reperfusion was theorized to improve postischemic function; there is experimental support for its efficacy. The delay in repletion of ATP after ischemic injury may well relate to lack of availability of adenosine, an important component of the process of rebuilding ATP stores, because it presumably converted to inosine and as such is washed out of cells during reperfusion.
Hydrogen Ion Concentration
The initial reperfusate should contain adequate buffering capacity to combat the intracellular acidosis developed during the ischemic period (see “ Blood ” earlier in this section). Various buffering agents have been used, but hydroxymethyl aminomethane (Tris) and histidine have particularly favorable characteristics.
Calcium
During reperfusion, perfusate calcium content should be low to minimize the influx of calcium into potentially damaged myocytes. The special effects of calcium in the neonatal and infant myocardium are discussed under “Neonates and Infants” under Special Situations and Controversies later in this chapter.
Potassium
Hyperkalemic reperfusion permits rapid repletion of ATP and improved functional recovery, even in the face of ischemic contracture and myocardial accumulation of calcium. It also promotes better myocardial blood flow. Therefore, if controlled reperfusion is elected, the initial reperfusate should contain sufficient potassium to maintain electromechanical quiescence for at least 2 to 3 minutes, and preferably 5 to 10 minutes. The sufficient concentration is about 12 mmol · L −1 .
The advantages of hyperkalemic reperfusion in clinical cardiac surgery have been confirmed in a randomized trial by Teoh and colleagues, although these advantages may be difficult to demonstrate in low-risk patients undergoing uncomplicated CABG.
Pressure
After a period of myocardial ischemia, coronary vascular endothelial cells are in a state in which they are easily damaged by high reperfusion pressure, but that state appears to be rapidly reversed by gentle reperfusion. Therefore, in clinical cardiac surgery, it is prudent to keep reperfusion pressure at about 30 mmHg for the first 60 to 120 seconds of reperfusion. Because of reactive hyperemia present at that time, the reperfusion flow rate may nonetheless be large.
Some experimental studies have suggested that reperfusion pressure should be no higher than 50 mmHg, lest excessive myocardial edema develop; others have suggested that it may be as high as 100 mmHg. These differences may be the result of species differences. In a canine model, 1 hour of hyperkalemic reperfusion at 80 mmHg (with electromechanical quiescence) resulted in improved myocardial function with no more myocardial edema than from normokalemic reperfusion and rapid resumption of cardiac activity. The importance of maintaining a sufficient coronary perfusion pressure at this stage has been well documented in the diastolically arrested canine heart exhibiting maximal coronary vasodilatation. In that model, endocardial flow falls steeply when coronary perfusion pressure is reduced from 70 mmHg to 40 mmHg. Reduction of perfusion pressure to 20 mmHg leads to substantially increased heterogeneity of flow ( Fig. 3-5 ). Clinical experience at UAB demonstrated the efficacy and safety, after the first 60 to 120 seconds, of maintaining reperfusion pressure between 50 and 75 mmHg, or at the preoperative diastolic arterial blood pressure of the patient, whichever was lower.
Flow and Resistance
At the beginning of reperfusion, coronary resistance is very low, primarily as a result of reactive hyperemia, with additive effects from the cold temperature of the myocardium and the action of vasoactive substances, such as adenosine and lactic acid, that accumulate during the ischemic period. Thus, coronary blood flow is very high initially, even with low reperfusion pressure, but begins to fall within a few minutes of beginning reperfusion.
Subsequently, reperfusion flow is usually about 150 mL · min −1 in adults (about 100 mL · min −1 · m −2 body surface area). This is about 40 mL · min −1 · 100 g −1 of heart muscle, approximately half the value for normal hearts, but it appears to be adequate in the nonworking empty heart being reperfused under these conditions. In similar experimental models of normal hearts, flow after the initial hyperemia is higher and near control level.
Temperature
In practice, the temperature of the reperfusate is initially about 35°C because of the characteristics of the heat exchange mechanism in the reperfusion circuit. After 2 to 3 minutes, the temperature rises to 37°C. There may be advantages to this gradual return to normothermia. Normothermia is advantageous to the normal function of enzyme systems.
Suppression of Formation of Oxygen-Derived Free Radicals and Enhancement of Free Radical Scavengers
Allopurinol, a xanthine oxide inhibitor, given just before reperfusion, protects the previously ischemic isolated rat heart from reperfusion injury, presumably by slowing conversion of hypoxanthine and xanthine to superoxide ions. Deferoxamine, given just before reperfusion, is also protective in experimental models, presumably by chelating iron and slowing formation of highly damaging hydroxyl radicals from superoxide radicals. The free radical scavengers superoxide dismutase and catalase protect against reperfusion injury when given before ischemia in experimental studies. Their use during early reperfusion has also been shown to be advantageous in experimental models. However, use of blood as the reperfusate, with its naturally occurring free radical scavengers, appears to obviate need for these agents in clinical cardiac surgery.
Duration
Recovery is not complete at the end of the hyperkalemic phase of controlled reperfusion. This may be because at this time (1) cellular recovery from ischemia is incomplete, and (2) inhomogeneity of myocardial perfusion probably persists. Controlled normokalemic reperfusion with adequate aortic root pressure should be continued until the heart is beating forcefully and is in sinus rhythm. This stage is usually reached 10 to 20 minutes after the beginning of reperfusion. In an experimental study, this length of time has been shown to be required for return of normal coronary vascular resistance, myocardial oxygen consumption, myocardial lactate levels, and ventricular function. Although ATP levels have not yet returned to normal, at this stage the heart itself is able to generate an adequate coronary perfusion pressure. Controlled aortic root reperfusion can therefore be discontinued by removing the aortic clamp, with proper precautions (see “ Cold Cardioplegia, Controlled Aortic Root Reperfusion, and [When Needed] Warm Cardioplegic Induction ” later in this chapter).
Reperfusion with the aorta clamped, as described above, has been called “hot shot.” In practice, controlled reperfusion with the aorta clamped may not be necessary; reperfusion by pump flow supported by pharmacologic manipulation may be adequate.
Adenosine
Adenosine is a potent coronary vasodilator with effects that can reverse coronary artery spasm, increase flow to the myocardial microvasculature during reperfusion, replenish high-energy phosphates, and retard no-reflow effects through its antiplatelet and antineutrophil activity. Studies by Kim and colleagues, Solenkova and colleagues, and others provide supporting evidence for the beneficial effect of adenosine during reperfusion. Four adenosine receptor subtypes have been identified that, when blocked, worsen postischemic reperfusion injury. Adenosine has a short half-life, but its biological activity is likely more prolonged. Adenosine administration (1.5 mg · kg −1 ) through the arterial cannula early after aortic clamp removal has been correlated with reduction in troponin 1 release and lower inotrope requirement.
Ischemic Postconditioning
The proposed mechanisms of ischemic postconditioning are similar to ischemic preconditioning (see Advantageous Conditions During Ischemia earlier in this chapter). Although studies in cardiac surgery have shown a beneficial effect, this technique has not gained general application in clinical cardiac surgery.
Methods of Myocardial Management During Cardiac Surgery
The objective of any type of myocardial management during CPB should be limiting injury during ischemia by some combination of myocardial hypothermia, electromechanical arrest, washout, O 2 and other substrate enhancement, oncotic manipulation, and buffering.
No single method of myocardial management is unequivocally the best. Many different methods are in use by surgeons obtaining good results. Surgeons necessarily make a decision as to the method to be used each time they perform a cardiac operation, often based on “preferences” rather than on rigorous comparisons between methods. A number of factors influence the surgeon's preference:
- 1
The surgeon's specific surgical techniques or operative sequencing that influence duration of aortic clamping
- 2
Strength of the surgeon's desire to have a quiet, bloodless heart
- 3
Strength of the conviction that cardiac surgery without myocardial necrosis or residual stunning is desirable and possible despite the added complexity to achieve these goals
- 4
Institutional environment
- 5
Costs
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