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Right arrow Myocardial protection

Ann Thorac Surg 2003;75:1668-1677
© 2003 The Society of Thoracic Surgeons

Review

Cardioplegia in pediatric cardiac surgery: do we believe in magic?

Torsten Doenst, MDa*, Christian Schlensak, MDa, Friedhelm Beyersdorf, MDa

a Department of Cardiovascular Surgery, Albert-Ludwigs University of Freiburg, Freiburg I Br, Germany

* Address reprint requests to Dr Doenst, Department of Cardiovascular Surgery, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg I Br, Germany
e-mail: doenst{at}ch11.ukl.uni-freiburg.de


   Abstract
Top
 Abstract
Introduction
 Clinically relevant mechanisms...
 Physiologic differences between...
 Cardioplegic techniques for the...
 Conclusions
 Acknowledgments
 References
 
Cardioplegia has become the gold standard of myocardial protection for practically every type of heart surgery during which the ascending aorta must be clamped. Although there is little doubt about the efficacy of cardioplegia in the adult heart, there are few studies on the pediatric heart and their results are contradictory. The physiology of pediatric heart muscle differs considerably from that of the adult myocardium. The pediatric heart distinguishes itself from that of the adult most impressively in its greater tolerance for ischemia. This ischemia tolerance is enhanced by the use of hypothermia. Considering that hypothermia is a powerful tool to prolong ischemia tolerance and that most pediatric cardiac surgeons report similar results using different types of cardioplegia, some surgeons are tempted to suspect that the contribution of the cardioplegia composition to protecting the pediatric heart may be overestimated. This provocative statement is critically discussed in this article. We examine the protective potential of cardioplegia (in various compositions), or of hypothermia, or of both in pediatric cardiac surgery. We pay special attention to several key differences between the physiologies of the pediatric myocardium and the adult myocardium and attempt to relate them to the available surgical methods of myocardial protection. We conclude that the composition of cardioplegia indeed is an important component of successful operative management in pediatric heart surgery. We provide evidence that the benefit of cardioplegia over hypothermia alone is minor at low temperatures (below 15°C), but becomes substantial when the temperature increases.


   Introduction
Top
 Abstract
 Introduction
Clinically relevant mechanisms...
 Physiologic differences between...
 Cardioplegic techniques for the...
 Conclusions
 Acknowledgments
 References
 
The main principles of myocardial protection are the reduction of metabolic activity by hypothermia and the therapeutic arrest of the contractile apparatus and all electrical activity of the myocytes by administering cardioplegic solution (eg, depolarizing of the membrane potential by high potassium blood cardioplegia) [1–3]. Both principles are unequivocally accepted and result in the decrease of energy consumption. By reducing energy consumption and thus oxygen demand, ischemia tolerance of the heart can be significantly prolonged. Without such measures, irreversible ischemic damage begins to occur in the human heart after only 20 min [4, 5], whereas when current techniques of myocardial protection are used, arrest times of more than 4 or 5 hours may be tolerated without irreversible damage (eg, 4 to 5 hours of myocardial ischemia is not uncommon during heart transplantation [6]). In addition to these two major principles, other means of extending the heart’s ischemia tolerance have been advanced, tested, and applied, but are discussed much more controversial. These approaches consist of buffering the cardioplegic solution, increasing osmolality, decreasing calcium content [2, 7], adding substrate to enhance recovery [8, 9], or incorporating leukocyte filters in the cardiopulmonary bypass circuit [10].

In 1984, Bull and colleagues [11] presented a landmark study demonstrating the efficacy of cardioplegia in pediatric cardiac surgery. Since then the achievements in this field have been tremendous and have set the ground for current practices in pediatric cardiac surgery with outstanding results. If these results are so clear, why is the efficacy of cardioplegia questioned for the heart in development? Doubts are based on several reasons: (1) Poor myocardial protection is still considered a significant cause for in-hospital mortality in children [11–13]. (2) the neonatal heart has a significantly greater tolerance for ischemia [14]. (3) the results on the efficacy of cardioplegia in the pediatric population are contradictory (Table 1). (4) hypothermia alone (by lowering perfusate temperature below 15°C) results in the arrest of contractile activity [15]. (5) most pediatric cardiac surgeons report similar results using different strategies of myocardial protection as adjunct to hypothermia [16–19]. The last reason, which also applies to the adult heart, is impressively documented by the fact that 167 different cardioplegic solutions are clinically used for heart transplantation in the United States alone [20].


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  		Table 1. Synopsis of Comparative Studies on Protection of the Pediatric Heart During Ischemia

 
There are relatively few studies on pediatric myocardial protection, and comparing them is complicated by inconsistencies in the terminology used. Many studies address differences between adult myocardium and that of newborns, neonates, or children. Thus many of the differences observed in these studies may not be comparable with each other, because they represent different stages in the respective development. The dynamic nature of heart development and the differences described may be expressed to a greater or lesser extent depending on the respective stage of the heart in its development. Therefore we have tried to specify the developmental stages of the discussed observations whenever possible.


   Clinically relevant mechanisms prolonging ischemia tolerance
Top
 Abstract
 Introduction
 Clinically relevant mechanisms...
Physiologic differences between...
 Cardioplegic techniques for the...
 Conclusions
 Acknowledgments
 References
 
The best understood and most frequently applied mechanisms in practice to increase the ischemia tolerance of the heart are hypothermia or cardioplegia, or both. In humans cooled to 32°C, whole body oxygen consumption is decreased by 45% [21], whereas the arterial oxygen saturation increases or remains the same. Although oxygen has a higher affinity to hemoglobin at low temperatures, the solubility of oxygen in the blood is also increased, and oxygen delivery to the tissues always matches the demand. In the absence of cardiac arrest, no adverse effects of hypothermia on the organism have been detected [22]. Although the heart continues to beat down to temperatures of 20°C and below, its tendency to fibrillate increases. Oxygen consumption of the heart is below 1% of normal at a temperature below 12°C, and contractile function seizes [15]. The therapeutic potential of hypothermia is impressively displayed in a study from Novosibirsk, in which a group of surgeons performed various forms of repair for congenital heart lesions at all ages in hypothermic circulatory arrest without using cardiopulmonary bypass [23]. Over 400 patients were sedated with morphine and ether and hypothermia was brought about by packing the patients in ice. At 24°C to 26°C, circulatory arrest was imposed and the required repair was completed within 70 minutes. Resumption of contractile activity took an average of 7 minutes. The results of these surgeons are remarkable. Operative mortality stayed below 10% and the neurologic complications and sequelae (at 13%) were unexpectedly low.

Cardioplegia is the second mainstay of myocardial protection for open-heart surgery on both pediatric and adult patients. Almost all mechanisms of the different cardioplegic solutions described so far include depolarizing or hyperpolarizing the membrane and arresting mechanical activity of the heart. A significant reduction in energy consumption can be reached even at normal temperatures [7]. In addition to mechanical arrest, different cardioplegic strategies aim to address other mechanisms involved in ischemia-reperfusion injury. These strategies include elevated osmotic pressure to prevent or reduce edema formation, addition of buffering solutions to blunt acidosis, addition of free radical scavengers, controlling oxygenation during cardiopulmonary bypass or supplementation of the solution with substrates to improve energy production during reperfusion (eg, warm terminal reperfusion) [8, 12, 24–26]. Although it is accepted that cardioplegia is the gold standard of myocardial protection, there is still no consensus on the type of cardioplegia to be used. The studies addressing this issue in the pediatric heart are far less numerous than those in the adult heart, but they are just as contradictory [13, 27–31].

Table 1 summarizes the main studies addressing the efficacy of cardioplegia and highlights the controversial areas. All studies demonstrate protective effects of hypothermia or cardioplegia, or both. However, there is inconsistency whether cardioplegia is superior to hypothermia alone. It is interesting to note that the studies that did not demonstrate a benefit of cardioplegia over hypothermia alone were performed at the lowest temperatures. Figure 1 is a graphical presentation of the benefit afforded by cardioplegia versus establishment of the same temperature by a noncardioplegic method (eg, topical cooling, blood perfusion, perfusion with crystalloid buffer) as a function of myocardial temperature during ischemia. Most of these studies were performed in neonatal hearts. Thus the benefit of cardioplegia in the neonatal heart appears to be directly related to myocardial temperature. One might speculate that cardioplegia would not be needed in cardiac surgery on neonates. Thus, based on the conclusions of Figure 1, the answer to the question posed in the title, whether we believe in magic by applying cardioplegia, may be answered with a yes because there is no evidence-based consensus in the literature. This magic seems to be age-dependent, because Baker and colleagues [32] demonstrated in rabbits (aged 7 to 56 days) that the importance of cardioplegia in addition to hypothermia increases with age. However it is difficult to guarantee the maintenance of deep myocardial hypothermia in clinical practice. Figure 2 illustrates the quick rewarming of hearts from piglets subjected to cold intermittent cardioplegia [33]. This rewarming mechanism would especially hold true in the small hearts of pediatric patients. Knowledge of this fact has led to the development of different strategies to maintain hypothermia during a corrective procedure (among them systemic hypothermia, "cooling blankets" for the heart, cold saline drip). The most frequently used technique is the reinfusion of cold cardioplegia.



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  		Fig 1. Benefit of cardioplegia over establishment of the same temperature by a noncardioplegic method (eg, topical cooling, blood perfusion, perfusion with crystalloid buffer) as a function of myocardial temperature during ischemia. The percentage values were obtained from the referenced studies 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.

 


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  		Fig 2. Mean cardiac septal temperatures (A) and mean rectal temperatures (B) in piglets undergoing surgery with cardiopulmonary bypass (CPB) and 1 hour of aortic cross-clamping. Piglets in group 1 were subjected to deep systemic hypothermia (15°C). Piglets in group 2 were subjected to moderate systemic hypothermia (28°C) and cold (4°C) intermittent infusions of crystalloid cardioplegia into the aortic root. Piglets in group 3 were subjected to deep systemic hypothermia (15°C) and cold (4°C) intermittent infusions of crystalloid cardioplegia into the aortic root. (Note the quick rewarming of the septum in group 2, despite the short reinfusion intervals.) (Reproduced from Ganzel et al, J Thorac Cardiovasc Surg; 1988;96:414–22 [33], with permission.)

 
Because the main goal of this approach is to cool the heart, the potassium concentration is often lowered [12]. After evidence-based medicine criteria, it is not clear why cold reinfusion of cardioplegia is the most frequently used method to maintain myocardial hypothermia. It is likely that the cardioplegic solution used may provide additional protection in certain cases, something that could be missed in large, generalized overviews. However, currently it is not possible to determine what type of cardioplegia is best for which operative procedure or clinical condition [34]. Nevertheless, we believe that cardioplegia is an important component of myocardial protection and provides an important margin of safety in successfully performing the desired procedure. In the pediatric heart, certain differences to the adult heart, and the lack of experimental and clinical studies, make it even harder to assess this problem for pediatric heart surgery. In an attempt to tackle this problem, a review of the specific peculiarities in the physiology of the pediatric heart is in order.


   Physiologic differences between pediatric and adult myocardium
Top
 Abstract
 Introduction
 Clinically relevant mechanisms...
 Physiologic differences between...
Cardioplegic techniques for the...
 Conclusions
 Acknowledgments
 References
 
Among the many differences between the pediatric and adult myocardium, there are specific differences considered important for understanding either the greater ischemia tolerance of the pediatric heart, the regulation of contractile function, or other peculiarities that require special attention for the safe conduct of pediatric cardiac surgery. These differences are listed in Table 2 and are reviewed as follows.


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  		Table 2. Physiologic Differences Between Pediatric and Adult Myocardium and Potential Impact of These Differences on Ischemia Tolerance of the Pediatric Heart

 
Substrate metabolism
The heart is a metabolic omnivore [35]. The energy needed for adenosine triphosphate (ATP) production is derived from the oxidation of fatty acids, glucose, lactate, ketone bodies, and even amino acids. The heart is also able to use some of its endogenous substrates, glycogen, and triglycerides. Figure 3 shows a schematic drawing of the key aspects of myocardial energy substrate metabolism. In adult myocardium, up to 90% of ATP production is derived from the oxidation of fatty acids [36]. In contrast, the main substrate for the neonatal heart is glucose [37]. This shift in substrate reliance occurs within the first few weeks after birth and is caused by upregulation of 5'-adenosine monophosphate-activated protein kinase [38]. Simultaneously, the heart’s sensitivity to insulin is diminished [39] and serum insulin levels fall. The structural correlate for this functional observation is found on the cellular level at which the insulin-sensitive glucose transporter (GLUT4) is much less expressed than in adult hearts, whereas the noninsulin sensitive transporter (GLUT1) is expressed to a higher degree [40]. In addition, the fetal heart has a much greater capacity to store glycogen, which occupies significantly more space in the cells [41].



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  		Fig 3. Schematic drawing of the key aspects of myocardial energy substrate metabolism. Glucose and fatty acids (FFA) are supplemented by lactate and ketone bodies (ß-OH) as substrates. Oxidation of FFA and ß-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.)

 
Neither the physiologic nor the clinical relevance of this different pattern of substrate oxidation is fully understood. However, after a period of ischemia in adult hearts, fatty acid oxidation rapidly normalizes while glucose oxidation remains depressed, as does contractile function [42]. In patients undergoing coronary artery revascularization, a positive correlation between enhanced glucose uptake and the return of contractile function was demonstrated [43]. In addition, the activation of glucose oxidation during or after ischemia under different experimental settings enhanced the functional recovery of the heart muscle [44, 45]. There are several possible explanations for these observations. First, because carbohydrates carry more of their own oxygen, glucose is used as substrate more efficiently. This reasoning is supported by convincing experimental evidence from studies in the isolated working rat heart [36]. Second, the oxidation of glucose at the pyruvate dehydrogenase step consumes protons generated during ischemia [42, 45]. Third, glycolytically generated ATP may support the function of key ion pumps and calcium homeostasis [46]. Fourth, glycogen metabolism may be associated with the maintenance of function of the sarcoplasmic reticulum [47]. Based on this reasoning, it is conceivable that some or all of these mechanisms are already present in hearts using glucose as the major substrate, such as the pediatric (especially the neonatal) myocardium, and thereby may contribute to the prolonged ischemia tolerance.

Insulin sensitivity
Insulin has been used to support the postischemic adult myocardium [48–51] and occasionally has been used in children with a presumable beneficial effect [52]. Due to the commonly described "insulin resistance" of the fetal heart, applying insulin for postischemic support of the neonatal heart may not appear reasonable. However, two factors argue against this reasoning. First, we demonstrated a direct positive inotropic effect of insulin on the postischemic adult rat myocardium [53]. At the same time, insulin was not able to increase glucose uptake (ie, the hearts were insulin resistant for glucose uptake). Second, treating patients with glucose-insulin-potassium infusion after surgery improves recovery [50, 51], although there is severe insulin resistance after surgery as documented by postoperative hyperglycemia. Although it is not known whether the beneficial effects of insulin in the adult myocardium can also be observed in the pediatric heart, the lack of effect of insulin on glucose uptake is not necessarily a sign of its inefficacy. The spectrum of insulin action is manifold and it appears to shift with ischemia [54].

Calcium metabolism
The sensitivity of the pediatric myocardium to extracellular calcium is a well-known phenomenon. There are three main differences between the adult heart and the pediatric heart that may explain this sensitivity. The sarcoplasmic reticulum is underdeveloped in the pediatric heart and has a reduced storage capacity for calcium [55]. The activity of the sarcoplasmic CaATPase (the enzyme responsible for calcium re-uptake into the sarcoplasmic reticulum) is lower than in the adult heart [56]. Therefore the ability to release calcium upon stimulation of the ryanodine receptor is significantly lower than in adult hearts and its re-uptake into the sarcoplasmic reticulum is also diminished. In adults, the bulk of the required calcium for contraction is provided by the sarcoplasmic reticulum [57, 58]. In pediatric hearts, this calcium is mainly provided by influx from the extracellular space [55]. Considering this difference makes it clear why pediatric hearts are so much more responsive to calcium channel blockers than adult hearts. It is also understandable that postischemic calcium overload may be caused by providing a perfusion medium with normal or high calcium. Several reports describe detrimental effects of cardioplegic solutions for the pediatric heart containing normal or high calcium concentrations, and the use of solutions containing subphysiologic levels of calcium is recommended [12, 59, 60]. However, other studies investigating the effects of different concentrations of calcium in the perfusate and reperfusate resulted in contradictions [30, 31, 61, 62]. In clinical practice, most cardioplegic solutions (pediatric or adult) contain subphysiologic concentrations of calcium [7, 24].

Enzyme activities
Many enzyme systems are not fully developed in the growing organism. There are two enzyme systems in the heart that seem to be relevant in the context of ischemia tolerance. The first of these is the antioxidant defense system, which includes enzymes such as superoxide dismutase, catalase, and glutathion reductase [63]. This enzyme system scavenges free radicals and protects the cells from their damaging effects. Due to a markedly elevated generation of free radicals during reperfusion after a sufficient period of ischemia, the lack of this defense system would render the heart more likely to suffer free radical injury than normally. Glutathione reductase is significantly reduced in children with tetralogy of Fallot [63–65], who are therefore at greater risk to suffer from free radical injury when they undergo surgical repair. Subsequently, strategies to reduce the amount of free radical generation by incorporating a leukocyte filter into the cardiopulmonary bypass circuit have been developed. Although studies investigating the efficacy of these filters in infants, children, and neonatal lambs have yielded mixed results [10, 66, 67], this enzyme system requires further investigation in order to precisely determine the clinical relevance of the apparent differences between the pediatric heart and the adult heart.

The other enzyme is 5'nucleotidase, which is bound to the plasma membrane and catalyzes the reaction of adenosine monophosphate to adenosine (Fig 3). Whereas adenosine monophosphate (as a phosphorylated adenine nucleotide) cannot pass the plasma membrane, adenosine is easily lost into the extracellular space. With the production of adenosine, the adenine nucleotide pool (the sum of ATP, adenosine diphosphate, and adenosine monophosphate) becomes depleted and re-synthesis is a time-consuming process. Whereas the ATP content of the heart is not a predictor of postischemic recovery [68], the size of the adenine nucleotide pool is important [35, 68]. If this pool is depleted too far (more than 50%), immediate full recovery of contractile function is impossible, presumably because the required ATP turnover cannot be provided by the remaining moieties [35, 70, 71]. The inhibition of 5'nucleotidase, or the lack of its activity, as in the newborn rabbit heart (7 to 10 days), has been demonstrated to improve ischemic tolerance [72–74].

Finally, the sensitivity of pediatric hearts to catecholamines is decreased. In vitro studies suggest that a decreased coupling of the myocardial beta-adrenergic receptor to adenylate cyclase at birth is responsible for this phenomenon [75]. Those investigators also demonstrated that the kinetics of cyclic adenosine monophosphate hydrolysis and the inhibitory potential of phosphodiesterase inhibitors (eg, milrinone) are not affected by age. Thus it is easy to understand that postoperative catecholamine support may be more complicated than in adults and that phosphodiesterase inhibitors may find a more frequent use. However, the question as to whether this "immaturity" of the heart alters its ischemic tolerance is difficult to answer at this time.

Unresolved issues
Less clear is the practical relevance of other known differences between pediatric and adult myocardium with respect to ischemia tolerance and strategies of myocardial protection. For instance it is striking to observe that ischemic preconditioning is without effect in the newborn rat heart (less than 7 days old), although it is protective for older age groups [76]. This protective effect has been demonstrated in practically every animal model as well as in humans (for review see reference [77]). Although the mechanism for this observation is not currently clear, it is tempting to speculate that the adult heart preserves a mechanism to extend its ischemia tolerance during times of stress. The lack of a preconditioning effect in the newborn heart may be caused by the fact that the mechanisms activated by preconditioning still would be operational and active at this developmental stage.

As described previously, many of the physiologic differences in the pediatric heart compared with the adult heart work in favor of the surgeon, subjecting the heart to ischemia and expecting recovery of function afterwards. However, under certain conditions the benefit of the heart’s immaturity may be compromised. This is the case for example in patients with cyanotic heart lesions in which ischemic tolerance seems to be less pronounced than in acyanotic lesions [12, 78]. The physiologic basis for this observation is not yet understood, but the observation of a decreased antioxidant defense system in infants with tetralogy of Fallot (as previously described) may provide initial insights. In contrast, Baker and colleagues [32] demonstrated that myocardial tolerance to ischemia is increased in hypoxemic rabbits from birth.

In summary, the pediatric heart possesses several clinically relevant mechanisms for the conduct of pediatric heart surgery. The preference for glucose, the ample stores of glycogen, and the low activity of 5'nucleotidase contribute to the extensive ischemia tolerance of the pediatric heart. In contrast, the reduced enzyme activity of the free radical scavenging system, the increased calcium sensitivity, and unknown factors associated with the presence of cyanotic heart defects may decrease ischemia tolerance and make the heart more prone to damage during reperfusion. The most important practical aspects in protecting the pediatric heart versus the adult heart are the calcium content (as previously described) and the amount of cardioplegia delivered (see as follows).


   Cardioplegic techniques for the immature heart
Top
 Abstract
 Introduction
 Clinically relevant mechanisms...
 Physiologic differences between...
 Cardioplegic techniques for the...
Conclusions
 Acknowledgments
 References
 
Different techniques have been described for the delivery of either blood or crystalloid cardioplegia to the pediatric heart. As for adults, these techniques comprise single shot or multi-dose protocols and the direction of cardioplegia application. Whereas some centers prefer the application of a single dose of cardioplegia, most surgeons use repetitive application, whereby cold cardioplegia is given every 20 minutes during the aortic clamp time.

If the aortic valve is competent, the initial infusion is generally administered into the aortic root. Subsequent re-infusions are either given into the aortic root (antegrade) or through a catheter that is placed into the coronary sinus (retrograde), as described by Drinkwater and colleagues [79]. Surgeons preferring antegrade re-infusion argue that the distribution of retrograde cardioplegia is inhomogeneous [80] and that the extra catheter is cluttering the operative field. Advocates of retrograde cardioplegia plead that air may collect in the aortic root between reinfusions, causing air embolisms during antegrade delivery. These surgeons address the crowded operating field by placing and removing the coronary sinus catheter each time cardioplegia is administered. Detailed descriptions of individual techniques are given in various review articles [12, 17, 81]. The main aspects for blood cardioplegia are generally as follows. The initial infusion rate is 30 mL/kg of body weight. The rate of re-infusion is 10 mL/kg of body weight. This rate is severalfold the volume used for cardioplegia of the adult heart in which infusion is based on time rather than body weight. Infusion pressure is not to exceed 80 mm Hg for antegrade delivery and 50 mm Hg for retrograde delivery.

It is important to state again that despite the many possible variations and differences in the opinions of surgeons, clinical outcome does not support the superiority of one technique to another. It seems reasonable to assume that one technique may work in the hands of one surgeon, although it does not give the same results for another surgeon. Differences in operative techniques, operating times, and quality of postoperative care may further camouflage possible differences. Because of these factors it is also reasonable to conclude that the effects of these variations and technical peculiarities are minor with respect to extending ischemia tolerance. However at the current level of sophistication, and judging the quality of the results, minor differences assume greater importance. It is therefore required to establish closer links between basic mechanisms and clinical practice and evaluate these links with large, randomized trials. In addition, parameters are missing that allow assessment of the quality of myocardial protection on-line during surgery.


   Conclusions
Top
 Abstract
 Introduction
 Clinically relevant mechanisms...
 Physiologic differences between...
 Cardioplegic techniques for the...
 Conclusions
Acknowledgments
 References
 
The ischemia tolerance of the pediatric heart is significantly greater than that of the adult heart. During cold cardioplegic arrest of the pediatric heart, ischemia tolerance is primarily prolonged by hypothermia. The degree of this time frame’s extension is maximal at myocardial temperatures under 15°C. The use of cardioplegia is of great importance to the safe conduct of pediatric cardiac surgery because it is difficult to guarantee continuous deep hypothermia of the myocardium under practical conditions. Cardioplegia contributes to the protection of the heart at higher temperatures and older age. Therefore it provides an important margin of safety for every cardiac operation with cardiac arrest. The ability to improve the current techniques of myocardial protection is intimately linked to the understanding of the underlying basic mechanisms. ([69, 92])


   Acknowledgments
Top
 Abstract
 Introduction
 Clinically relevant mechanisms...
 Physiologic differences between...
 Cardioplegic techniques for the...
 Conclusions
 Acknowledgments
References
 
This article was supported by a grant to Dr Doenst from the Emmy Noether-Programm of the Deutsche Forschungsgemeinschaft (grant no.: Do-602/2-1). The authors wish to thank Brigitte Volk-Zeiher, MD, Wolfgang Bothe, MD, and Wilhelm Bone, PhD, for their criticial comments and helpful suggestions.


   References
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 Abstract
 Introduction
 Clinically relevant mechanisms...
 Physiologic differences between...
 Cardioplegic techniques for the...
 Conclusions
 Acknowledgments
 References
 

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