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 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 the outer one-fourth (subepicardial layer) in normal hearts with intact circulation is maintained at 1.0 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. Circulating vasoactive agents also affect coronary vascular resistance during CPB (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.

In most patients undergoing cardiac surgery, coronary blood supply or the myocardium, or both, are not normal and are particularly susceptible to ischemic and reperfusion damage. Hypertrophied ventricles have long been known to be 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 the elaboration of oxygen-derived free radicals. Superoxide dismutase levels are markedly decreased, reducing the natural defenses against oxygen-derived free radicals. Also, the 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.

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 also pertain 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 cardiogenic shock is highly sensitive to the damaging effects of global myocardial ischemia.

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.

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 diminished contractility for a time, a perfusion/contractility mismatch. ²

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 result from 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 results from 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 partly caused by an ischemia-induced increase in calcium influx 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 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 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 occur 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, 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 more rapidly out of the cell, as do cytoplasmic proteins and enzymes; these appear in the cardiac interstitium and 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 endpoint 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 versus blood-perfused preparations. The appearance of contracture indicates that the ATP content 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.

As with 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. 3.3 ). 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. 3.3 ). 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 in poor mechanical function (see Fig. 3.3 ). 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, 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 ).

(A) Hypoxic endothelial cell activation. Hypoxia stimulates Weibel-Palade bodies to release P-selectin and activates nuclear factor (NF)-κB. NF-κB is translocated to nucleus, where it promotes transcription of E-selectin, ICAM, tissue factor, interleukin (IL)-8, and IL-1. IL-1 feeds back to promote more endothelial cell activation through activation of NF-κB. (B) Neutrophil adhesion is a multistep process that involves contact between neutrophils and members of the selectin family of adhesion molecules (P-selectin, E-selectin) expressed on activated endothelium. These low-affinity bonds result in rolling and slowing of leukocytes. As this occurs, neutrophils become activated, and a firm bond forms between integrins on the leukocyte surface (i.e., CD 11/18) and adhesion molecules on the endothelium (i.e., ICAM-1, vascular cell adhesion molecule, platelet-endothelial cell adhesion molecule). (C) No-reflow phenomenon. Hypoxia results in activation of endothelial cell layer, which promotes leukocyte adhesion and degranulation, endothelial swelling, platelet activation, microthrombosis, and increased vasomotor tone. This contributes to impaired microcirculatory flow, despite what appears to be adequate perfusion through the large epicardial arteries. Adherent neutrophils infiltrate underlying myocardium and promote lipid peroxidation, enzymatic degradation of membranes, calcium overload, and excitation-contraction uncoupling. Collectively, these events result in impaired myocardial function. LPS, Lipopolysaccharide.

(From Boyle EM Jr, Pohlman TH, Cornejo CJ, Verrier ED. Ischemia-reperfusion injury. Ann Thorac Surg. 1996;62:S24.)

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.

The specialized conduction cells become nonfunctional early during global myocardial ischemia in humans. It may be speculated that their recovery takes longer than 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.

The response of myocardial cells to uncontrolled reperfusion depends largely on the time-related point along the pathway to cell death reached during the ischemic period. Yet the critical point at which the “explosive cellular response” to uncontrolled reperfusion can be expected is uncertain.

When uncontrolled reperfusion is initiated after limited periods of 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. The most severe reperfusion damage is evidenced by the rigid 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.

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 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 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 (especially hydrogen peroxide) and 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.

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 is due to delayed closure of coronary arterioles and capillaries and 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 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.

Little specific information is available about reperfusion injury to the specialized conduction cells.

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 are important. ^{, ,} The minimal effective hematocrit level in the reperfusate is 0.15 to 0.20. The buffering capacity of blood proteins, especially their histidine and imidazole groups, is also advantageous.

There is little doubt that activated leukocytes play an important role in reperfusion damage. Depletion of leukocytes from the blood reperfusate (by filtration) reduces reperfusion injury considerably. Leukocyte filters are commercially available for pediatric and adult CPB circuits.

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.

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. ^{, ,}

During reperfusion, perfusate calcium content should be low to minimize calcium influx 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.

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. ^,

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) improved myocardial function with no more myocardial edema than from normokalemic reperfusion and rapid resumption of cardiac activity. The importance of maintaining sufficient coronary perfusion pressure at this stage has been well documented in the canine hearts arrested in diastole exhibiting maximal coronary vasodilation. 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. 3.6 ). 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. ^,

Information obtained from an isolated blood-perfused canine model, with heart arrested in diastole and with maximal coronary vasodilation. Variation in coronary perfusion pressure is along horizontal axis, coronary flow rate (or inner/outer flow ratio) is along vertical axis, and columns represent endomyocardial, midmyocardial, and epimyocardial flow rates, and the inner/outer flow ratio. Note that as coronary perfusion pressure was reduced, perfusion of subendocardium progressively declined out of proportion to decline in other layers. Accordingly, the inner/outer ratio fell. Also, heterogeneity of flow increased with decreasing perfusion pressure (increased height of vertical bars).

(From Aldea GS, Austin RE Jr, Flynn AE, Coggins DL, Husseini W, Hoffman JI. Heterogeneous delivery of cardioplegic solution in the absence of coronary artery disease. J Thorac Cardiovasc Surg. 1990;99:345.)

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.

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.

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 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.

Reperfusion with the aorta clamped, as previously described, has been called “warm terminal reperfusion” (or “hot shot”). This routinely performed period of warm terminal reperfusion is done for 3 minutes, after which the aortic clamp is removed, and normal contractility of the myocardium has been achieved.

Some centers use a prolonged controlled normokalemic reperfusion with adequate aortic root pressure. This should be continued until the heart beats forcefully and is in sinus rhythm. This stage usually occurs 10 to 20 minutes after the beginning of reperfusion. The rational for this approach is the assumption that 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. In an experimental study, this length of time (10-20 min) 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 can 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).

In practice, this prolonged controlled reperfusion with the aorta clamped may not be necessary; reperfusion by pump flow supported by pharmacologic manipulation may be adequate.

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 Kin 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.

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.

Use of intermittent cardiac ischemia with moderate cardiac hypothermia requires conducting CPB with the perfusate temperature at 25°C to 30°C. The surgeon works intermittently on or in the heart for 10 to 15 minutes, during which time the ascending aorta is clamped (to stop coronary perfusion), or individual perfusion into the coronary ostia is interrupted. The aortic clamp is released (or individual coronary perfusion resumed) between these periods for 3 to 5 minutes. When the technique is used optimally, the heart is made to beat (not fibrillate) during this interval. This method was most commonly used during the 1960s and early 1970s but is used by some surgeons today.

Positive clinical results, published in the late 1970s to 1990s, were demonstrated by McGoon and by Bonchek and colleagues. ^{, ,} McGoon’s analysis of one group of patients, those receiving valved extracardiac conduits, indicated no relationship between the proportion of non-survivors in the experience and cumulative aortic clamp time. However, because 35% of the 468 patients in the group had low cardiac output postoperatively (in which subset the mortality was 52%), the method must have been producing myocardial damage. Reduto and colleagues in 1981 found no difference in left ventricular performance early after CABG, regardless of whether this or cold cardioplegic myocardial protection was used.

The method does not provide optimal exposure for operations inside the heart but does provide reasonable working conditions for CABG. Unless the heart is electrically fibrillated just before aortic clamping, it continues to beat during much of the ischemic period, making precise repair difficult. Each time coronary perfusion is recommenced, coronary (and perhaps systemic) air embolization may occur despite precautions against it. A considerable amount of blood comes into the heart during periods of coronary perfusion, stressing the intracardiac sucker systems and thereby increasing blood damage and interfering with the smooth and efficient flow of the operation. Moreover, each time the coronary arteries are perfused in this uncontrolled manner, a reperfusion injury may occur.

The heart may be profoundly cooled by the perfusate, by filling the pericardium with very cold saline solution, or by both, after which the aorta is clamped. The cardiac operation is done during a single period of aortic clamping. ^{, ,} In clinical practice, myocardial temperature is generally about 22°C with these methods.

In addition, filling the pericardium with very cold saline solution, with or without ice slush, results in a high percentage of phrenic nerve palsy. ^, A randomized study of patients undergoing aortic valve replacement showed that this technique results in as much myocardial necrosis as does continuous individual coronary perfusion.

Both β-adrenergic receptor blocking and calcium channel blocking drugs, in conjunction with one of the other methods, have been used as part of myocardial management by some groups. ^, The calcium channel blocking agents verapamil and diltiazem have seemed particularly advantageous because of their prevention of calcium influx into cells and their coronary vasodilatory effects. However, these drugs are potent negative inotropes and produce prolonged electromechanical quiescence, at least when used clinically in cardioplegic solutions. ^,

Particularly good results have been obtained by giving lidoflazine intravenously just before CPB and using moderately hypothermic intermittent cardiac ischemia. ^, Lidoflazine is believed to be a nucleotide transport inhibitor, which results in increased myocardial accumulation of endogenous adenosine during ischemia, increased lactate extraction during reperfusion, and improved postischemic function. The basic action of lidoflazine is complex and appears different from that of β-blocking and calcium channel blocking drugs.

Certain drugs have been shown in experimental studies to reduce reperfusion damage related to oxygen-derived free radicals (see “Advantageous Conditions during Reperfusion” earlier in this chapter). However, when using blood cardioplegia and pressure-controlled, initially hyperkalemic, blood reperfusion, incorporation of free radical scavengers has not been demonstrated to provide additional protection.

The underlying principles of all cardioplegic solutions are listed in Box 3.1 . Inducing chemical arrest to conserve energy during the period of myocardial ischemia can be accomplished by two basic mechanisms :

• 1.

  Inhibition of the fast sodium current to prevent conduction of the myocardial action potential by one or more of the following methods:

  • a.

    Extracellular hyperkalemia

  • b.

    Sodium channel blockers (e.g., lidocaine)

  • c.

    KATP channel openers (e.g., adenosine)

• 2.

  Inhibition of calcium activation of myofilaments to prevent myocyte contraction by one or more of the following methods:

  • a.

    Zero extracellular calcium

  • b.

    L-type calcium channel blockers (e.g., magnesium)

  • c.

    Direct myofilament inhibition with agents such as 2, 3 butanedione monoxime (BDM)

There are both asanguinous solutions and those that are mixed with blood (at a 2:1 or 4:1 blood-to-solution ratio), and extracellular solutions and intracellular solutions as distinguished by their potassium concentrations. Some believe that the components of the solution, particularly K ⁺ concentrations, should be altered according to solution temperature, timing of infusion (initial, maintenance, and terminal), and presumed energy state of the myocardium. In general, K ⁺ concentration is lowered for maintenance, and substrates are added for energy-depleted hearts. Delivery can be intermittent (multidose) or continuous; in the latter case, the K ⁺ concentration is lower than for intermittent delivery ( Box 3.2 ).

Hyperkalemic cold sanguinous cardioplegia is advantageous ^, and is preferred, although asanguinous cardioplegia may work equally well. The Buckberg formulation (cold, oxygenated, hyperkalemic blood-crystalloid mixture, with lowered free calcium concentration, added glucose, and added buffering capacity) may be preferable to simple hyperkalemic blood. With all special applications (see later), the use of Buckberg’s cardioplegia has the best scientific basis and safety of most blood-based solutions, and effectiveness has been proven in all situations in cardiac surgery (i.e., routine, complex cases, acute coronary occlusions, second cross-clamp period, energy-depleted hearts, long cross-clamp time, and low ejection fraction).

In recent years, the del Nido cardioplegic solution has also been used for adult cardiac surgery. This solution has been used extensively in congenital heart surgery at Children’s Hospital Boston since 1994 and was developed at the University of Pittsburgh in the early 1990s. The main components are lidocaine (a sodium channel blocker that reduces intracellular sodium and calcium accumulation), histidine, low calcium, and additives such as potassium and adenosine. This limitation of sodium and calcium influx into the cardiac myocytes is especially suited for pediatric cardiac surgery, as immature myocardium is especially susceptible to reperfusion injury. ^, A single dose is administered without the need for redosing for up to 90 minutes. ^, The single application technique in routine operations reduces extracorporeal circulation, cross-clamp time, and total operation time.

In studies comparing del Nido cardioplegia (1:4 ratio of blood to crystalloid) with other blood-based cardioplegic solutions in routine and/or more complex adult cardiac surgical procedures, there were almost no statistically significant differences in the majority of parameters. ^{, ,} However, a major problem with many studies comparing the different cardioplegic solutions is that non-standardized solutions (modifications) were used.

Uncertainties regarding del Nido cardioplegia in adult patients have been described in the following areas:

• •

  Is it safe for prolonged cross-clamp time, and when should redosing be performed? ^{, , ,} This is important because many studies have focused on isolated CABG or valve operations, where a single dose will suffice for the entire operation.

• •

  Is it effective in patients with reduced right ventricular function, low ejection fraction, and energy-depleted hearts? Several publications have raised concerns about the lack of evidence for del Nido cardioplegia in these patients, and some randomized trials have excluded them. ^{, ,}

• •

  What should be done in cases where a second cross-clamp time with additional cardioplegia is needed?

• •

  To avoid hemodilution, hemoconcentration has been recommended. Ultrafiltration has been reported to be used in 83.7% of all cases where del Nido has been used. To avoid the problem of hemodilution, micro del Nido cardioplegia was suggested.

For pediatric application, see later under “Neonates and Infants.”

In the belief that control of all aspects of the reperfusion may be even more important than details of cold cardioplegia and that acutely ill patients coming to the operating room require a special form of myocardial management, the technique described in this section may be used. During reperfusion, the heart is separated from the ongoing events in the remainder of the body for a brief time. The technique is surgically convenient, prolongs the operation only mildly, is essentially devoid of ventricular fibrillation, minimizes myocardial stunning and myocardial necrosis, and appears to result in better postoperative cardiac performance than methods previously used. ^, Yet the proof of its advantages has remained as difficult to obtain as for other techniques, which probably accounts for the fact that it is not yet widely used in its entirety (see also “Introduction”).

Some may wish to use simpler methods for routine operations and restrict the use of this method for more complex high-risk operations. The problems with such a plan are the usual operational disadvantages of a surgical method that is infrequently used rather than routinely (see “ Human Error ” in Chapter 7 ), and the fact that even routine operations have a small mortality and occasionally considerable morbidity, which may be nearly eliminated by more perfect myocardial management.

Possible species and experimental model differences pose a major problem in generating inferences regarding myocardial management during cardiac surgery in human subjects. For example, extensive myocardial edema is frequently observed after ischemia and reperfusion in experimental studies of many different types in many different animal models. Yet in clinical experience, it has been rarely evident, except for instances of prolonged and severe damage and of some operations in young patients. In support of this, a careful study in humans using two-dimensional echocardiography failed to disclose any increase in left ventricular mass (a reasonably sensitive indicator of increased myocardial water) after uncomplicated cardiac operations in which cardioplegia was used. By contrast, the same study in a dog model showed a marked sudden increase in left ventricular mass.

Inferences from studies in isolated supported heart models, usually rat heart, are generally transferred to human cardiac surgery with some difficulty. This difficulty is considerably increased when the isolated heart models are perfused with a crystalloid solution because such models behave differently from blood-perfused models.

Inferences from studies of immature hearts in animal models are transferred with difficulty to cardiac surgery in neonates and infants because the relationship of age-defined cardiac immaturity in one species to that in another is uncertain.

These considerations emphasize that confirmation of the applicability of inferences derived from animal models to humans must continually be sought.

Several important differences between the immature and mature myocardium warrant review in any discussion of neonatal myocardial protection. While some of these differences render the immature myocardium more susceptible to injury, overall, these differences confer a protective effect during the course of cardiac surgery. ^, The transition from fetal life to antenatal circulation and the drastic changes in loading conditions stimulate a period of rapid myocyte growth and development, but parallel increases in angiogenesis permit a balance of myocardial demand with coronary microvasculature supply. This balance of coronary circulation and myocardial demand persists throughout infancy, and the immature myocardium rarely has any impediments to uniform delivery of coronary blood flow (and therefore cardioplegia delivery), with notable exceptions being coronary cameral fistulae and congenital coronary ostial atresia. Despite this rapid growth and luxurious coronary blood flow, the immature myocardium remains limited in its contractility and does not tolerate distension. Preventing ventricular distension during the course of neonatal cardiac surgery is of supreme importance to optimize myocardial preservation.

Certain unique cellular and metabolic characteristics of the immature myocardium must also be considered. In contrast to the adult heart, which preferentially uses fatty acid oxidation and aerobic metabolism to generate ATP, the neonatal heart preferentially uses glucose as its energy substrate.

Certain enzymes that facilitate glycolysis, such as hexokinase, pyruvate kinase, and phosphofructokinase, are upregulated in the immature cardiomyocyte. ^, As such, the immature myocardium can tolerate periods of hypoxia and ischemia while still generating adequate ATP for cellular metabolism. ^{, ,} Larger stores of amino acids in neonatal hearts also contribute to their increased capacity for anaerobic metabolism, including ATP production, which persists throughout infancy. This anaerobic ATP production appears to be for the transamination and substrate level phosphorylation of glutamate and pyruvate. This may be expected to result in better maintenance of cellular integrity during ischemia and, thereby, better functional recovery after ischemia than experienced by adult hearts. These considerations also help explain the demonstrated value of amino acid supplementation for improving tolerance of the immature heart to ischemia and hypoxia. ^, However, some have found the immature myocardium (less than about 18 months old) to be deficient in cytosolic 5′-nucleotidase and thereby less able than mature myocardium to convert cyclic AMP and inosine back to ATP.

Differences in calcium metabolism and homeostasis between the immature and mature myocardium play an important role, not just in myocardial protection but also in the myocyte response to injury and ischemia-reperfusion. The sarcoplasmic reticulum of the immature myocardium is incompletely developed and has decreased expression of the sarcoendoplasmic reticulum calcium-ATPase, which is critical for the reuptake of calcium into the sarcoplasmic reticulum from the cytosol. ^, Because of this, the immature cardiomyocyte is less able to regulate intracellular calcium levels, cannot store calcium as effectively, and is, therefore, more dependent on extracellular calcium levels for EC coupling. For this reason, intravenous calcium can be an effective inotropic agent in the postoperative state in neonates. However, incompletely developed mechanisms of intracellular calcium regulation also place the immature myocardium at risk of calcium overload and cellular injury following ischemia and reperfusion. As such, many formulations of cardioplegia solutions in use in the pediatric population are either hypocalcemic, contain calcium antagonists such as magnesium, or utilize both strategies to decrease the risk of calcium overload and cellular injury. This vulnerability is further exacerbated by the immature myocardium’s incompletely developed antioxidant mechanisms. Ischemia-reperfusion injury is characterized by several intracellular responses, including producing ROS. Key enzymes that serve to reduce these ROS (superoxide dismutase, catalase, glutathione reductase, etc.) are not as well expressed in the immature cardiomyocyte, thus rendering these cells more susceptible to ROS-mediated damage to the sarcoplasmic reticulum, mitochondria, and key cellular functions. While the immature myocardium tolerates ischemic conditions, its reaction to cellular injury, extrinsic changes in calcium levels, and ischemia-reperfusion render it more susceptible to additional injury once injury has occurred.

The role of cyanosis.

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