Sachin Talwar and Shiv Kumar Choudhary All India Institute of Medical Sciences, New Delhi, India Over the last few decades, surgical mortality associated with repair of all types of congenital heart defects has shown a declining trend. This is coupled with an increasing number of open‐heart surgeries being performed in neonates, infants, and children of varying age, spectrum of disease, and lesions [1]. This therefore necessitates a thorough understanding of the principles and practice of myocardial protection across various age groups and the application of this understanding to the environment of the individual center. It must also be understood that failure to apply appropriate myocardial protection techniques may result in significant myocardial damage that can occur as early as 20 minutes after the aorta has been cross‐clamped [2, 3]. Nearly 90% of autopsy specimens of patients who die early after open‐heart surgery show a combination of gross, microscopic, and histochemical myocardial necrosis, which is most severe in the subendocardium of the chamber affected by the underlying cardiac lesion. This necrosis has been documented to occur even in patients who do not have obstructive lesions in the coronary arteries [4]. An ideal myocardial protection strategy is not just about cardioplegia but encompasses multiple strategies that include temperature control, hypothermia, adequate venting of the heart, and precise surgical correction with minimal resection and dissection. Pediatric hearts are not small adult hearts and thus extrapolating strategies of adult myocardial protection to pediatric hearts is not useful and can be detrimental to the outcome [5]. Understanding the differences between the pediatric and adult myocardium is necessary to tailor these strategies to achieve an optimal outcome. In this chapter, we will discuss the differences between the adult and pediatric myocardium, various strategies for optimal myocardial protection in the pediatric heart, and some controversies and recent developments in the field. In some parts of this chapter studies in adults have been quoted, because often the congenital surgeon has to be involved in the care of older patients with congenital heart disease (grown‐up congenital heart disease or GUCH). Cardiac surgery started with closed operations such as ligation of the patent arterial duct and shunt palliation of tetralogy of Fallot. The use of hypothermia for myocardial protection was first proposed by Bigelow [6]. The first open‐heart surgery to repair an atrial septal defect was performed using surface cooling and inflow occlusion by Lewis and Taufic [7]. However, it was the development of the heart–lung machine by Gibbon that heralded the era of open‐heart surgery in 1953 [8]. Lillehei and Varco in 1955 reported correction of a variety of intracardiac defects using normothermic, low‐flow, controlled cross‐circulation based on the azygous flow principle and using a human adult as an oxygenator [9]. This method was unique in that the aorta was not cross‐clamped for the conduct of the open‐heart surgical procedures; hence there was no myocardial ischemia. The first “elective cardiac arrest” was described by Melrose in 1955, who coined the term “cardioplegia” [10]. Later Gott and associates [11] used retrograde perfusion of the heart via the coronary sinus using warm blood with the Melrose solution. During aortic valve surgery, Lillehei also used retrograde perfusion of the coronary sinus with blood [12]. It was however soon realized that these patients suffered from myocardial injury [13, 14], leading to abandonment of these techniques. In the late 1950s and early 1960s Shumway [15] described hypothermic methods to protect the heart, and intermittent ischemia combined with hypothermia gained widespread popularity as a method of myocardial protection in this era. Ongoing work by Bretschneider [16] resulted in the development of an intracellular cardioplegia that was shown to reduce the transmembrane gradients along with cardiac arrest. Buckberg also developed the idea of buffering the cardioplegia solution as an important adjunct to myocardial protection [17]. The work on cardioplegia continued and soon problems associated with the Melrose solution were identified, including “citrate toxicity” resulting from a high ionic concentration of potassium citrate. Continued work in this field led to the development of the St. Thomas solution in 1976. Following this, cardioplegia became the standard method of myocardial protection. Gerald Buckberg introduced the use of blood cardioplegia in the late 1970s [18]. Later, he reported the use of warm‐blood cardioplegia for cardiac arrest and to replenish high‐energy phosphates in energy‐depleted hearts before giving cold cardioplegia. Buckberg is also credited for reporting the use of amino acids in cardioplegia to provide substrates for the Krebs cycle [19]. In the 1990s at the University of Pittsburgh, Dr. Pedro del Nido and colleagues developed a cardioplegia solution that they thought would specifically address the needs of myocardium in neonates and infants. The aim of myocardial protection is to conserve cellular energy in the form of adenosine tri‐ or diphosphate (ATP or ADP) and to provide adequate levels of substrate for production of ATP before onset of cardioplegic arrest. It is also necessary to keep low levels of intracellular calcium, which is the main trigger for cell destruction during reperfusion. Minimum free radical generation along with an efficient scavenging system during reperfusion also reduces the chances of reperfusion injury. We will highlight here only those differences between the mature and the immature myocardium that affect these factors. To understand the various strategies of myocardial protection in a neonate and infant, it is of vital importance to understand the differences between the mature adult heart and the immature heart of a neonate and infant [20]. These are listed in Tables 10.1 and 10.2 and are briefly discussed below [21]. The heart of a neonate and infant is smaller in size and its interstitial tissue contains more water and collagen compared with the adult heart. As a result, the contractile mass of the heart is small [22, 23]. Pediatric myocardial cells contain a larger mass of noncontractile elements and a poorly developed sarcoplasmic reticulum. There is a lower number of mitochondria in the infant heart, but cytochrome c activity is higher than in adults. As a result of the larger mass of noncontractile elements and higher water and collagen content, the immature heart exhibits poor response to inotropes, exhibits poor preload reserve, and has poor tolerance to afterload. In addition, there is a relative abundance of polyunsaturated fatty acids in the membranes of cellular and subcellular organelles. Additional sites of oxidative damage therefore result, making the immature cyanotic heart more vulnerable to oxidative insult [24, 25]. On the positive side, pediatric hearts have normal coronary arteries and a myocardium that is not scarred (with the exception of patients with anomalous left coronary artery arising from the pulmonary artery, who may have myocardial infarcts and scarring). As a result, antegrade administration of cardioplegia results in its uniform distribution. Because of smaller body size, miniaturization of hardware and reduction in priming volume become essential. Table 10.1 Uniqueness and vulnerability of the pediatric myocardium. Source: Reproduced with permission from Talwar S et al. Indian J Thorac Cardiovasc Surg 2013;29:114–123. Table 10.2 Physiologic differences between pediatric and adult myocardium and potential effect of these differences on ischemic tolerance of the pediatric heart. Source: Reproduced with permission from Doenst T et al. Ann Thorac Surg. 2003;75:1668–1677. The pediatric heart is a metabolic omnivore and efficiently and equally utilizes glucose, ketones, glycogen, amino acids, and fatty acids (Figure 10.1). Thus, although the pediatric heart is very efficient at handling energy compared with the adult heart, it preferentially utilizes glucose as a principal metabolic fuel. The immature heart has a greater capacity for anaerobic metabolism and is therefore dependent on glycolysis with glucose as the substrate [26]. The glycogen content and glycogenolytic activity are very high. With its efficient energy utilization, the pediatric heart exhibits more tolerance to ischemia. This can potentially be enhanced by the addition of various substrates. Figure 10.1 Schematic drawing of the key aspects of myocardial energy substrate metabolism. Glucose and fatty acids (FFA) are supplemented by lactate and ketone bodies (β‐OH) as substrates. Oxidation of FFA and β‐OH produces reducing equivalents (NADH) in the Krebs cycle for adenosine triphosphate (ATP) production, and metabolism of glucose yields additional (substrate‐level) ATP during glycolysis. During ischemia, ATP and adenosine diphosphate (ADP) are degraded to adenosine monophosphate (AMP), which is phosphorylated to adenosine by 5’nucleotidase (5’NT) and the adenine nucleotide pool (ATP + ADP + AMP) is decreased. CPT1, carnitine palmitoyl transferase, the rate‐limiting step for fatty acid oxidation; FoF1, ATP‐generating ATP‐ase driven by the proton gradient of the respiratory chain; G6P, glucose 6‐phosphate; PDH, pyruvate dehydrogenase, the rate‐limiting step for glucose oxidation; TG, triglycerides. Source: Reproduced with permission from Doenst T et al. Ann Thorac Surg. 2003;75:1668–1677. In a normal heart, cardiac contractility is initiated by sarcolemma depolarization. This activates the voltage‐gated channels present in the sarcolemma with release of calcium from the intracellular stores [27]. In the adult human cardiac myocyte, L‐type calcium channels are responsible for calcium entry into the cell [28]. In an embryonic myocyte, T‐type calcium channels are present. L‐type calcium channels get activated with depolarization, and influx of calcium occurs, leading to activation and contraction with ionized calcium. In comparison to T‐type calcium channels present in the fetal stage, L‐type calcium channels present in adults are more efficient in maintaining optimum calcium balance [29]. As the sarcoplasmic reticulum is the major site for intracellular release and uptake of calcium, there exists a close structural relationship between the sarcoplasmic reticulum and L‐type calcium channels located in sarcolemma T‐tubules [30]. In neonates there is a lack of differentiation of sarcoplasmic reticulum, weak coupling of sarcoplasmic reticulum with L‐type calcium channels, and decreased activity and efficiency of the sarcoplasmic variant of the calcium ATPase. With growth, there is development and differentiation of sarcoplasmic reticulum along with its calcium‐releasing and ‐trapping receptors and efficient coupling with sarcolemma L‐type channels, leading to lesser dependence on extracellular calcium for contraction [31]. Therefore, low calcium‐containing cardioplegia solutions are preferred for the immature myocardium to decrease the intracellular calcium pool. Conversely, the pediatric heart is more dependent on extracellular calcium for proper functioning. Hence, the pediatric heart is also susceptible to calcium channel blockers. The pediatric myocardium is deficient in superoxide dismutase, catalase, and glutathione reductase, particularly in patients with cyanotic congenital heart disease [32]. Upon reoxygenation, there is overproduction of oxygen free radicals, particularly in cyanotic patients. Therefore, the cyanotic heart is more prone to reperfusion injury not only following release of the aortic cross‐clamp, but also at the time of institution of cardiopulmonary bypass (CPB), particularly if a hyperoxic bypass strategy is used. Reoxygenation injury manifests as decreased cardiac output, myocardial dysfunction, contracture, increased pulmonary vascular resistance, and alveolar damage [33–35]. Thus, means to minimize free radical generation should be implemented during CPB. Commonly used methods are incorporation of leukocyte filters in the CPB circuit, maintaining normo‐oxemic perfusate after aortic cross‐ clamp release, and adding mannitol to the cardioplegic solution, which also acts as a free radical scavenger. The pediatric heart also has decreased 51‐nucleotidase activity that results in a maintained nucleic acid pool, which is essential for recovery of energy debt when perfusion is removed. This is beneficial to the heart, as there is an abundance of ADP available from conversion. In comparison, the adult myocardium loses around 50% of adenosine during ischemia. This property makes the pediatric myocardium more tolerant to ischemia [36], but only partially affects the susceptibility to reperfusion [37]. At birth, the c‐AMP functions normally. However, there is reduced coupling of myocardial beta receptors to adenyl cyclase [38]. Therefore, catecholamines have a poorer effect on the immature myocardium compared with adults, whereas response to vasodilators, particularly phosphodiesterase inhibitors like milrinone, is good. Therefore, in pediatric hearts, adrenaline and nor‐adrenaline are less effective whereas milrinone elicits a better response [39]. Compared with an adult, the pediatric heart has an equivalent ventricular mass, but it has a poor diastolic and ionotropic reserve and exhibits poor tolerance to afterload [22]. Children also have a more reactive pulmonary vasculature and in addition there are intra‐ or extracardiac shunts that are patent [34]. As a result, residual lesions and ventricular distention are tolerated very poorly in this age group and there is a greater negative inotropic response to anesthetic drugs and poor response to inotropes. In addition, there is more interventricular dependence in the pediatric heart, and fluctuations in heart rate affect the cardiac output to a greater degree compared with the adult heart. Because of the presence of intra‐ and extracardiac shunts as described above, there may be diastolic steal of blood during CPB that further affects myocardial perfusion and protection. This is a well‐described defense mechanism against ischemia in adults. However, it has been found to be deficient in newborn animal models. It is possible that mechanisms responsible for ischemic preconditioning are already active in the immature heart [4, 25, 40–42]. The standard components of an ideal myocardial protection strategy are hypothermia, cardioplegia, adequate venting of the heart to prevent ventricular distension and dysfunction, adequate venous drainage, and precise surgical correction. Hypothermia was the first strategy to be adopted for myocardial protection. It has been thought to suppress cardiac metabolism, blunt the response to CPB, prevent calcium accumulation in the mitochondria, reduce the permeability of the sarcolemma membrane, and thus reduce reperfusion injury. However, its role as the sole strategy for myocardial protection is a matter of debate, with some studies demonstrating that it is the single most important modality of myocardial protection in infants and neonates, and may even render the use of cardioplegia unnecessary (Figure 10.2) [21, 43]. Some studies have also shown that there is equivalent or better myocardial protection with hypothermia alone compared to a combination of hypothermia and cardioplegia (Table 10.3) [43–66]. It has been proposed that hypothermia should not be used alone, but rather as an adjunct to cardioplegia [5]. The suggested mechanism is that the energy requirement of a cold heart, when allowed to work, increases 8–10 times [67]. In addition, experimental studies have shown that hypothermia alone is effective at systemic temperatures of 15 °C or less, above which the addition of cardioplegia is advantageous [21, 50, 54, 57]. Hypothermia can, however, allow reduction in the dose of potassium in the cardioplegia solution and may thus prevent against the adverse effects of systemic hyperkalemia. In addition, when cardioplegia is administered below 20 °C, the safe duration of ischemic cardiac arrest can be prolonged. However, if the cardioplegic perfusate is below 10 °C, ischemic anaerobic metabolism may be hampered and there is an increased risk of rouleaux formation in the coronary microcirculation that can lead to uneven distribution of cardioplegia and inadequate myocardial protection [64]. In addition, it has been shown that once mammalian tissue is frozen, it is irreversibly damaged, thereby limiting the benefits of hypothermia. It has been shown that electromechanical cardiac arrest has the potential to decrease the myocardial oxygen demand by 90%, and a reduction of temperature to 11 °C produces only a 5% reduction in the oxygen demand. It is therefore a common practice to administer crystalloid cardioplegia at 4 °C and blood cardioplegia at 8–10 °C. Coupled with constant washout and rewarming from noncoronary collaterals, this may prevent the harmful effect of very low temperatures. Topical saline at 4 °C or ice slush also helps in myocardial cooling and has beneficial effects. However, in patients with ventricular hypertrophy, uneven cooling may result. Figure 10.2 Benefit of cardioplegia over establishment of the same temperature by a noncardioplegic method (e.g., topical cooling, blood perfusion, perfusion with crystalloid buffer) as a function of myocardial temperature during ischemia. The percentage values were obtained by calculating the difference of the highest recovery value (mostly cardiac output) with cardioplegia and the highest value obtained without cardioplegia. Recovery in the noncardioplegia group was set to be 100%. The numbers at the data points refer to the studies used for calculating the value. A positive value indicates that cardioplegia was better than the noncardioplegic method for myocardial protection. A negative value indicates that the noncardioplegic method was better than cardioplegia for myocardial protection. Source: Reproduced with permission from Doenst T et al. Ann Thorac Surg. 2003;75:1668–1677. Table 10.3 Synopsis of comparative studies on protection of the pediatric heart during ischemia. a Evidence‐based medicine score is the modified American Heart Association/American College of Cardiology score (J Thorac Cardiovasc Surg. 2002;124:20–27). BCP, blood cardioplegia; CCP, crystalloid cardioplegia; CP, cardioplegia. Source: Reproduced with permission from Doenst T et al. Ann Thorac Surg. 2003;75:1668–1677. In addition, hypothermia is not at all a benign strategy. Due to cooling, the pH becomes alkaline, which may hamper enzyme function. Enzyme disruption and impaired anaerobic metabolism lead to poor utilization of glucose. Myocardial and tissue edema results from impaired osmotic homeostasis. There is a shift of the oxygen hemoglobin dissociation curve to the left that decreases the oxygen release to the tissues, translating into reduced tissue uptake of oxygen, decreased function of the membrane enzymes, and poor oxygen utilization by the tissues. It has been shown that cooling the patient to 32 °C reduces whole‐body oxygen consumption by 45% [6]. The oxygen consumption of the heart is below 1% of normal at 12 °C with cessation of contractile function [68]. As has been mentioned in the previous edition of this book [69], in Siberia economic constraints and limited equipment availability have led surgical teams to use hypothermic circulatory arrest without CPB. In such a situation, patients have been packed in ice with temperature drifting to 24–26 °C and the repair has been accomplished within 70 minutes. Acceptable results have been reported with mortality less than 10% [51]. Cardioplegia remains the gold standard for optimal myocardial protection across all ranges of temperature. After the aorta is cross‐clamped, varying types and doses of cardioplegia solutions help to achieve rapid cardiac arrest, resulting in a still and bloodless field while preventing detrimental effects of periods of zero myocardial blood supply. In the past, an empty beating heart and fibrillatory arrest have been used, but their use has gradually declined because the energy requirements of the heart using either strategy are considerably higher than when cardioplegia is used. Upon induction of diastolic arrest, oxygen consumption of the myocardium decreases from 8–10 mL/100 g/min to 1 mL/100 g/min at normothermia. Cardioplegia solutions produce depolarization or hyperpolarization of the myocardial cell membranes, leading to a state of mechanical arrest of the heart [69]. The addition of cardioplegia to a strategy of myocardial protection enhances the efficacy of the latter. The use of cardioplegia achieves complete cessation of all contractile and electrical activity of the heart. As a result, the myocardial oxygen consumption is significantly reduced even without hypothermia [70]. A wide variety of cardioplegia solutions are in use by different groups and, as cited in the earlier edition of this book, more than 150 cardioplegic solutions are in use clinically for cardiac transplantation in the United States [71, 72]. However, the unifying features of all cardioplegia solutions are membrane stabilizers, substrates, osmolar agents, buffers, and special additives. The characteristics of an ideal cardioplegia solution are listed in Table 10.4. During the period of aortic cross‐clamping, the myocardial subcellular structure is at risk of irreversible damage. To address this, lidocaine and procaine (which are local anesthetic drugs) are commonly used for membrane stabilization as well as preclusion of dysrhythmias. Lidocaine has the additional property of being a sodium channel blocker, which prevents sodium influx across the sarcolemma membranes that have been depolarized by the potassium‐rich cardioplegia solutions [58]. In addition, lidocaine has a longer duration of action than procaine and therefore offers a longer period of cardioplegic arrest. Substrates are needed in a cardioplegia solution to support the basal metabolism that occurs in myocytes even at low temperatures. In addition, they provide citric acid cycle intermediaries during immediate reperfusion to maintain the ATP pool. Traditionally, glucose has been the preferred agent and it acts both as a substrate and as an oncotic agent. However, the addition of glucose leads to significant lactate accumulation during anaerobic glucose metabolism. The only way to prevent this lactate accumulation is to repeat cardioplegia at frequent intervals. This, in combination with noncoronary collateral blood flow, can wash away the acidic metabolites and allow glycolysis to continue at a near physiologic pH. Repeated cardioplegia dosing, however, has the potential to produce tissue edema. Amino acids aspartate and glutamate also enter the citric acid cycle and have been shown to be promising substrates, especially during terminal warm infusion administered just prior to removal of the aortic cross‐clamp [73]. Aspartate may have a much more significant protective role than glutamate [74]. Glutamate has been shown to protect against endothelial injury caused by hyperosmolar cardioplegic solutions [75]. On the contrary, amino acid rich cardioplegia reperfusate has not been shown to confer any additional advantage in adults undergoing coronary artery bypass grafting or valve replacement [76]. In an experimental study on normal and preconditioned isolated rat hearts, Lofgren and colleagues showed that L‐glutamate transamination may play an important role in myocardial protection [40]. Using glutamate‐enriched cardioplegia solution, Lazar and associates found increased rates of contraction and relaxation, improved stroke work index, and improved recovery of ATP [77]. Using glutamate‐ and aspartate‐enriched solution during reperfusion, Engelman and colleagues found a reduction in infarct size and improved levels of ATP and acetyl coenzyme A in a swine model of ischemic reperfusion injury [78]. It has also been shown that the addition of adenosine to cardioplegia solution or administration during reperfusion may help to build up ATP stores during recovery from ischemia. In addition, adenosine reduces the myocardial oxygen demand by its negative chronotropic, inotropic, and dromotropic action. It also produces coronary vasodilation and is a free radical scavenger [79–81]. It has been shown to replenish energy stores by increasing glycolytic flux and providing substrate [41]. Table 10.4 Characteristics of an ideal cardioplegia (the Ten Commandments). Myocardial ischemia produces significant damage to cell membranes. This increases intracellular ionic concentrations and produces cellular edema that is further aggravated by repeated administration of cardioplegia, inflammatory response to CPB, and impaired lymphatic drainage [82]. To minimize myocardial ischemia, sufficient oncotic pressure of the cardioplegic solution is needed so that the fluid remains in the intravascular space. At the same time the oncotic pressure should not be too high, otherwise cellular dehydration may result. The ideal osmolarity of a cardioplegia solution is unknown. However, it appears that an osmolarity of 370 mOsm/L seems to be ideal. An osmolarity >400 mOsm/L may produce myocardial damage [4]. The commonly used agent to maintain adequate osmolarity of the cardioplegia is mannitol, which has been known to possess oxygen free radical scavenging properties. However, it is structurally similar to glucose, and when used for prolonged periods it can inhibit glucose uptake by competitive inhibition [42]. Albumin and glucose also have oncotic effects and are used often in combination with corticosteroids and insulin. In a study on isolated rat hearts, the addition of mannitol did not provide any added protection [42]. To the contrary, superior myocardial protection was achieved by adding albumin along with insulin, ATP, pyruvate, and corticosteroids. This was believed to be a result of inhibition of peroxidation, decreased lipoxygenase activity, antioxidant action, and the role of albumin as a coenzyme for tissue repair enzymes. Potassium is an integral component of almost all cardioplegia solutions. Upon administration, an increase in extracellular potassium produces depolarization of the myocardial membrane. This inactivates the voltage‐dependent fast sodium channels and produces arrest of the heart in diastole. However, high levels of potassium can produce direct endothelial toxicity and may also lead to myocardial stunning, tissue edema, free radical production, and “stone heart” contracture at the time of reperfusion due to a rapid influx of calcium into the myocardial cells [83, 84]. Hence, over time there has been a reduction in the concentration of potassium in cardioplegia solutions and most solutions contain around 20 mEq/L of potassium. In a randomized controlled trial, Liu and associates reported that cardioplegia containing low amounts of potassium (10 mmol/L) was associated with better myocardial protection compared to conventional high‐potassium cardioplegia [85]. The immature myocardium is more vulnerable to calcium influx‐mediated cell injury because the sarcoplasmic reticulum is less well developed. In patients with acyanotic congenital heart diseases, both normocalcemia and hypocalcemia are associated with similar outcomes. However, in cyanotic (hypoxic) hearts, hypocalcemic solutions are associated with better myocardial preservation. In patients with cyanotic congenital heart disease, normocalcemic solutions may lead to increased cellular injury that manifests as depression in post‐bypass myocardial and endothelial cell function [86]. In addition, following administration of depolarizing potassium‐rich cardioplegia solution, the sarcolemma membrane attains a leaky and depolarized state that makes the myocardial cells vulnerable to an influx of calcium with depletion of ATP reserves. Magnesium is known to inhibit the entry of calcium into the cells. This action is achieved by displacing the calcium from its binding sites on the sarcolemma membranes. It also prevents sodium influx during reperfusion and prevents its exchange with calcium. In addition, magnesium possesses membrane‐stabilizing properties and may reduce the incidence of arrhythmias after reperfusion. Incorporating magnesium into the cardioplegia solution allows a reduction in the potassium content in the cardioplegia, thus attenuating the side effect of hyperkalemia. The benefits of magnesium in the cardioplegia solution become apparent in hypoxic (cyanotic) hearts. In these hearts, hypocalcemic cardioplegia may offer good myocardial preservation even in the absence of magnesium. However, when a normocalcemic solution is used in the hypoxic (cyanotic) heart, the addition of magnesium protects the heart from cellular injury due to prevention of calcium influx and by the preservation of vascular endothelial function [86]. Buffers are essential for maintenance of an optimal pH to allow myocardial metabolism to continue irrespective of temperature. Commonly used buffers are THAM (tris‐hydroxymethyl aminomethane), histidine, and bicarbonate, the latter being the most commonly used buffer. However, excessive bicarbonate may elevate the sodium content of the cardioplegia solution, which may interfere with the transport mechanism across the cell membranes. From the above discussion, it is apparent that intracellular influx of calcium is largely responsible for myocardial cell injury. It therefore seems logical to add calcium channel blockers to prevent the calcium influx‐mediated cellular injury [87]. These drugs have been used mainly in adult patients. However, calcium channel blockers do not exhibit the same efficacy In pediatric patients as in the adult population. Because of their long duration of action, they may produce depression of the myocardial function; hence, there is less enthusiasm about their use in pediatric patients. Esmolol is a short‐acting beta blocker and offers an attractive nonhyperkalemic alternative to potassium‐based cardioplegia solutions [5]. However, its use is not widespread. It is known that some energy‐dependent processes are still active during depolarization arrest. These are the membrane ion pumps, and their energy requirements may contribute to ischemic injury. Hyperpolarizing agents keep the cell membranes close to the resting membrane potential. In a study in rabbits, Cohen and colleagues compared hyperpolarization with the K+‐ATP channel blocking agent aprikalim with traditional potassium depolarization, and found improved myocardial function with the use of hyperpolarizing cardioplegia. They concluded that pharmacologic activation of ATP‐sensitive potassium channels results in a predictable and sustained hyperpolarized cardiac arrest that is reversible by reperfusion. In this study, use of aprikalim was found to fully preserve cardiac electromechanical function after a 20‐minute period of global normothermic ischemia. In addition, hyperpolarized arrest significantly prolonged the period to the development of contracture [88]. In another study, He and colleagues compared the effect of hyperpolarizing cardioplegia and hyperkalemic cardioplegia on the endothelium of porcine coronary arteries. In this study, relaxation mediated by endothelium‐derived hyperpolarizing factor was used as an index of endothelial function. The results of this study led them to conclude that the endothelium‐derived hyperpolarizing factor–mediated coronary endothelial function was maximally preserved by hyperpolarizing cardioplegia, but impaired by depolarizing (hyperkalemic) cardioplegia [89]. Pinacidil is a cyanoguanidine drug that is known to open ATP‐sensitive potassium channels and produce arteriolar vasodilatation. It has been shown to improve ventricular performance and coronary blood flow following ischemic arrest [90]
CHAPTER 10
Pediatric Myocardial Protection
Historical Aspects
Uniqueness of the Infant Myocardium
Structural Differences
Smaller cells with decrease in volume of contractile elements per cell
Fewer mitochondria and poorly developed sarcoplasmic reticulum and T‐ tubules, thereby making the cell more vulnerable to calcium influx‐mediated injury
Preferential utilization of glucose over free fatty acids for energy needs under aerobic and anaerobic conditions
Increased susceptibility to intracellular lactate accumulation due to decreased coronary washout and poor noncoronary collaterals
Increased susceptibility to reperfusion injury due to suboptimal function of superoxide dismutase and catalase enzymes that degrade reactive oxygen species
Relative abundance of membrane‐bound organelles that are substrates for free radicals
Parameter
Pediatric
heart
Adult
heart
Potential effect on the ischemic tolerance in the pediatric heart
1
Preferred substrate for ATP [adenosine triphosphate] production
Glucose
Fatty acids
Increased
2
Glycogen content
High
Low
Increased
3
Insulin sensitivity
Impaired
Normal
?
4
Calcium handling (intracellular)
Impaired
Normal
?
5
Calcium sensitivity
Increased
Normal
Decreased?
6
Antioxidant defense
Low
High
Decreased
7
51 Nucleotidase
Low
High
Increased
8
Catecholamine sensitivity
Low
Normal
?
9
Ischemic preconditioning
Absent
Present
?
Metabolic Differences
Calcium Metabolism
Enzymatic Activity
Catecholamine Sensitivity
Functional and Physiological Differences
Ischemic Preconditioning
Principles of Myocardial Protection
Hypothermia
Year of study
Authors
Species of study
Age
Cardioplegia vs. hypothermia alone, comments
Evidence‐based medicine score*
1984
Bull & colleagues [43]
Children
No statement available
CCP better than fibrillation
3
1986
Bove & Stammers [48]
Rabbits
1, 4, 18 weeks
Neonatal hearts show greater ischemia tolerance than adults
4
1987
Corno & colleagues [49]
Pigs
1–5 days
Hypothermia better than CCP; BCP better than CCP
4
1987
Bove & colleagues [50]
Rabbits
1 week
CCP better than hypothermia
4
1988
Litasova & colleagues [51]
Children + adults
15 months– 44 years
Congenital heart surgery without CPB
3
1988
Ganzel & colleagues [52]
Pigs
Neonatal
CCP slightly better than hypothermia
4
1988
Magovern & colleagues [47]
Rabbits
4, 24 weeks
Hypothermia better than CCP
4
1988
Lynch & colleagues [53]
Rabbits
Neonatal
CP effective at normothermia
3
1989
Avkiran & Hearse [54]
Rats
3–5 years & 3–4 months
Hypothermia better than CCP
4
1989
Konishi & Apstein [55]
Rabbits
Neonatal
CP better than hypothermia
4
1990
Baker & colleagues [44]
Rabbits
1 week
Hypothermia better than CP
4
1990
Diaco & colleagues [56]
Rabbits
Neonatal
CP better than hypothermia
4
1991
Julia & colleagues [57]
Dogs
6–8 weeks
Metabolic support with amino acids effective
4
1991
Fujiwara & colleagues [58]
Lambs
Neonatal
CCP slightly better than BCP
4
1991
Kofsky & colleagues [59]
Dogs
6–8 weeks
Adult CP works well in children
4
1992
Hosseinzadeh & colleagues [46]
Pigs
1 week
Hypothermia better than CCP, rapid cooling is the best
4
1993
Baker & colleagues [45]
Rabbits
1 week
pH 6.8 better than hypothermia, hypothermia better than CCP
4
1993
Pearl & colleagues [60]
Pigs
1–2 days
CCP equal to BCP, normal calcium better than low calcium
4
1995
Baker & colleagues [61]
Rabbits
1–8 weeks
Hypoxic hearts more ischemia tolerant, CP protective effect increases with age
4
1996
Karck & colleagues [62]
Rats
4 weeks
Hypothermia better than CP
4
1996
Bolling & colleagues [63]
Pigs
5–18 days
Normal calcium detrimental in hypoxic hearts only
4
1997
Bolling & colleagues [64]
Pigs
Neonatal
BCP better than CCP in hypoxic states
4
1997
Young & colleagues [65]
Children
1 year to 15 years
No difference between CCP and BCP
2
2001
Imura & colleagues [66]
Children
1 month, 10 years
Hypoxic heart less ischemic tolerant
3
Cardioplegia
Membrane Stabilizers
Substrates
Osmolar Agents
Ions
Potassium
Calcium
Magnesium
Buffers
Special Additives
Calcium Channel Blockers
Esmolol
Hyperpolarizing Agents
Pinacidil
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