Ann Thorac Surg 2006;82:172-178
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Myocardial Metabolism is Better Preserved After Blood Cardioplegia in Infants
Kerstin Åmark, MD
a
,
b
,
*
,
Håkan Berggren, MD, PhD
d
,
Kerstin Björk, CCP
d
,
Annica Ekroth, CCP
d
,
Rolf Ekroth, MD, PhD
d
,
Krister Nilsson, MD, PhD
c
,
Jan Sunnegårdh, MD, PhD
a
,
b
a Department of Pediatrics, The Queen Silvia Children's Hospital, Göteborg, Sweden
b Department of Pediatric Anesthesia, The Queen Silvia Children's Hospital, Göteborg, Sweden
c Department of Intensive Care, The Queen Silvia Children's Hospital, Göteborg, Sweden
d Department of Metabolic and Cardiovascular Research/Cardiothoracic Surgery, Göteborg University, Göteborg, Sweden
Accepted for publication January 26, 2006.
* Address correspondence to Dr Åmark, Department of Pediatrics/Cardiology, The Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden (Email: kerstin.amark{at}vgregion.se).
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Abstract
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BACKGROUND: We have previously reported improved hemodynamic function after blood cardioplegia in comparison with crystalloid cardioplegia. Furthermore, lactate was released from the heart after crystalloid cardioplegia but not after blood cardioplegia. The purpose of this study was to determine whether the difference in substrate metabolism between the two cardioplegia methods was restricted to lactate, or whether the difference in metabolic derangement was more extensive.
METHODS: Thirty consecutive infants with complete atrioventricular septal defects were included in this prospective, randomized, controlled study. Arterial and coronary sinus blood concentrations of substrates and amino acids were measured after weaning from bypass.
RESULTS: After crystalloid cardioplegia, there was a myocardial uptake of glutamate (p = 0.003), leucine (p = 0.03), lysine (p = 0.003), and beta-hydroxybutyrate (p = 0.004), whereas lactate was released (p = 0.03). After blood cardioplegia, there was a myocardial uptake of free fatty acids (p = 0.01) but no uptake of amino acids and no release of lactate.
CONCLUSIONS: There are differences in myocardial substrate metabolism between blood cardioplegia and crystalloid cardioplegia, which involve carbohydrates and amino acids. The differences may include lipids but our data in this respect are not conclusive.
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Introduction
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The relative advantage of blood cardioplegia in relation to crystalloid cardioplegia is still the subject of debate. In spite of theoretical advantages with blood cardioplegia, the research literature is equivocal and crystalloid cardioplegia remains in use at several centers. In pediatric surgery, only a few clinical reports comparing blood and crystalloid cardioplegia have been published [1–3].
Recently, we reported functional benefits from blood cardioplegia, with better left ventricular function (echocardiography) and higher cardiac output (thermodilution) early after blood cardioplegia in infants undergoing surgery for complete atrioventricular septal defects [4]. The difference also included myocardial lactate metabolism with lactate release from the heart after crystalloid cardioplegia but not after blood cardioplegia.
Previous work in adults has shown extensive changes after crystalloid cardioplegia in myocardial substrate metabolism, involving not only carbohydrates but also amino acids and lipids [5–8]. The immature heart differs in substrate preference from the adult heart and experience from middle-aged and elderly coronary patients may not apply to the operated infant. The present report on infants extends the metabolic focus in the comparison between blood cardioplegia and crystalloid cardioplegia to include all major myocardial substrates. The purpose was to describe substrate patterns and it was hypothesized that blood cardioplegia would maintain a more normal pattern than crystalloid cardioplegia due to less severe ischemic injury.
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Patients and Methods
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Ethical Considerations
The study was approved by the Ethics Committee at the Sahlgrenska Academy at the University of Göteborg (295-95) and was conducted according to the World Medical Association Declaration of Helsinki. Individual consent was obtained for every patient.
Study Inclusion-Exclusion Criteria
Consecutive infants, referred to us for elective correction of complete atrioventricular septal defect without other major anomalies, were included. Patients with a persistent left superior caval vein to the coronary sinus were excluded, because this anatomy makes coronary blood sampling invalid for evaluating myocardial effluent. Thirty-two patients qualified for participation. Two were excluded, as parental consent was not obtained. The study population was identical to the one on which we have previously reported [4]. The preoperative clinical data are shown in Table 1
[9, 10].
Anesthesia, Cardiopulmonary Bypass, and Surgical Technique
No oral intake occurred later than 4 a.m. All operations were performed in the morning session and anesthesia was induced at approximately 8 a.m. A detailed description of the perioperative and surgical techniques is given in Ref. 4.
Study Protocol
At the end of surgery, a 20 G Ohmeda HydrocathTM (Swindon, UK) polyurethane line infusing heparin (5 U mL–1 at 1 mL hour–1) was placed in the coronary sinus at direct inspection through the wound. Coronary sinus and arterial blood samples were collected simultaneously within a few minutes after the termination of cardiopulmonary bypass. Blood samples were drawn after ensuring stable patient conditions and before protamine was administered.
Cardioplegia
The crystalloid group had Plegisol (St Thomas' II crystalloid cardioplegia; Abbott Scandinavia AB, Sweden) with the following contents: K+ 16 mM, Ca2+ 2.4 mM, Na+ 120 mM, Cl– 160 mM, Mg2+ 32 mM, HCO3
– 10 mM, pH 7.8. The blood cardioplegia group had a mixture of one part potassium-enriched Plegisol (60 mmol KCl added to 1,000 mL Plegisol) and four parts of blood from the cardiopulmonary bypass circuit (final K+ concentration of 15 mM). The blood cardioplegia was given through the cardiopulmonary bypass circuit with pressure control (<200 mm Hg prior to the heat exchanger), while the crystalloid cardioplegia was administered by slow injection (<50 mL per minute). Both groups had 20 mL kg–1 of 4°C cardioplegia given antegradely through a 4F pediatric aortic root cannula (Medtronic, Inc, Minneapolis, MN) and iterated (10 mL kg–1) every 20 to 30 minutes.
Laboratory Methods
Blood gases, glucose, and lactate were analyzed immediately and kept on ice for triple analyses. Samples for plasma amino acids, fatty acids, and beta-hydroxybutyrate were spun in a cooling centrifuge and stored at –50°C for later analysis. Blood gases were analyzed with an ABL 625 analyzer (Radiometer, Copenhagen, Denmark) and lactate and glucose with a 2300 Stat Plus analyzer (YSI, Yellow Springs, OH). Individual amino acids were separated by ion exchange chromatography in a Beckman 6300 analyzer (GMI, Ramsey, MA); after reaction with ninhydrin, the amino acids were continuously measured by a photometer at 570 nm (440 nm for proline). Free fatty acids were quantified by means of an enzymatic colorimetric method using the Wako NEFA C test kit (Waco Chemicals GmbH, Neuss, Germany) and a Cobas Fara centrifugal analyzer (Roche Diagnostic Systems, Basel, Switzerland). Beta-hydroxybutyrate was analyzed by enzymatic oxidation to aceto-acetate and the resulting nicotinamide adenine dinucleotide (NADH) was measured at 340 nm by means of a Cobas Fara centrifugal analyzer.
Calculations
The blood oxygen content (mmol/L) was calculated as: hemoglobin (g/L) x hemoglobin oxygen saturations (%) x 0.00062 + p02 (kPa) x 0.01. The difference between arterial and coronary sinus blood metabolites was calculated (arterial minus coronary sinus metabolite concentrations). Positive (arterial concentration greater than coronary sinus concentration) values were defined as uptake and negative (arterial concentration less than coronary sinus concentration) values were defined as release.
Statistics
Coronary sinus concentrations of lactate were used as the primary endpoint for power calculations. The coronary sinus concentration was preferred to the arterial minus coronary sinus concentration difference, because this variable can be negative, positive, or zero, which may complicate calculations of percentage differences. Based on our previous data from adult patients after crystalloid cardioplegia [7], a calculation including the mean coronary sinus lactate concentration and standard deviation of controls indicated that 13 patients per group would be required to detect a 30% difference in coronary sinus blood lactate content between the two groups for 80% power with a 5% significance level. The children were allocated to blood or crystalloid cardioplegia by simple block randomization.
In Tables 1 and 2,
the two groups were compared using the Student t test, the Mann-Whitney U test, or the Fisher exact test where appropriate. In Tables 3 and 4,
the group factor was analyzed in two ways. First, the concentration difference (arterial minus coronary sinus concentrations) was analyzed for each group separately versus 0 with the sign test to establish significant (p < 0.05) uptake (= arterial minus coronary sinus concentration difference > 0), significant release (= arterial minus coronary sinus concentration difference < 0), or neither. Second, median values were compared between the two groups using the Mann-Whitney U test. The results are presented as means ± standard error of the mean unless otherwise specified.
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Table 4. Arterial Minus Coronary Sinus Concentrations of Carbohydrates, Lipids, Ketones, and Oxygen (mmol/L, Mean ± Standard Error of the Mean)
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Results
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Clinical Course
All patients were weaned from cardiopulmonary bypass at the first attempt (detailed hemodynamic data are presented in Ref. 4) and there was no hospital mortality. Twenty-three of 30 patients had uneventful clinical courses. Two children (one in each cardioplegia group) required a reoperation for left atrioventricular valve regurgitation at 5 and 14 days postoperatively. Five patients had a prolonged hospital stay; three due to pleural or pericardial effusions and two due to infections. Further perioperative observations are shown in Table 2.
Metabolic Data
In the crystalloid cardioplegia group, there were significant uptakes of glutamate (p = 0.003), leucine (p = 0.03), lysine (p = 0.003), and beta-hydroxybutyrate (p = 0.004), and a release of lactate (p = 0.03). Alanine release was borderline (p = 0.06). In the blood cardioplegia group, there was an uptake of free fatty acids (p = 0.01) and a release of alanine (p = 0.01). All arteriovenous differences are shown in Tables 3 and 4. The arterial levels of all metabolites are shown in Tables 5 and 6.
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Table 6. Arterial Levels of Carbohydrates, Lipids, Ketones, and Oxygen (mmol/L, Mean ± Standard Error of the Mean)
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Comment
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The principal finding in this study was the differences in amino acid and lactate metabolism between blood and crystalloid cardioplegia that were seen after weaning from bypass. This indicates that there is a protracted impairment of aerobic metabolism after crystalloid cardioplegia.
Myocardial Substrates
The heart can use a variety of substrates for oxidation. Normally, the specific choice is largely determined by availability (or arterial concentrations of substrates). Glucose is the dominant fuel after glucose ingestion, free fatty acids in the fasting state, while lactate predominates during exercise. Ketones are oxidized in diabetic ketoacidosis and during starvation. Under normoxic conditions, substrates are largely interchangeable, but during and after hypoxia and ischemia there is a definite difference between fatty acids on the one hand and glucose and amino acids on the other. Free fatty acids require more oxygen per unit of generated adenosine triphosphate (ATP) than glucose. Normally, the difference is marginal (14%), but in conditions with exaggerated catecholamine drive the difference may increase to about 40% [11]. In addition, the incomplete oxidation of fatty acids at hypoxia generates toxic metabolites [11]. As a result, glucose is preferable to fatty acids during and after ischemia. One particular advantage of glucose degradation is the capacity for the anaerobic generation of ATP. However, anaerobic glycolysis can only proceed as long as pyruvate and lactate are disposed of by the cell. This does not occur during severe ischemia and glycolysis then ceases.
In this context, amino acids obtain functional importance. Glutamate metabolism provides an alternative route for the elimination of pyruvate to alanine and by taking part in the aspartate-malate shuttle by which cytosolic NAD (necessary for glycolysis) is regenerated from NADH+. These events expand the glycolytic capacity during ischemia. In addition, glutamate enters the Krebs' cycle after transamination to 
-ketoglutarate, which is metabolized to succinate to provide ATP at substrate level without oxygen. Glutamate and other amino acids are also important for recovery after ischemia; after transamination, they replenish Krebs' cycle intermediate metabolites, which are consumed during ischemia.
The significance of glutamate metabolism is indicated by the observations that the myocardial extraction of glutamate is increased in chronic ischemic heart disease [12, 13]. Furthermore, myocardial glutamate concentrations decrease during aortic cross-clamping in pediatric heart surgery [1]. Conversely, the provision of glutamate or -ketoglutarate reduces ischemic injury and improves postischemic function in clinical trials [14, 15].
Blood Versus Crystalloid Cardioplegia
In the present study, two distinctly different metabolic patterns were observed. After crystalloid cardioplegia there was a release of lactate and an uptake of glutamate and other amino acids. In contrast, after blood cardioplegia there was no release of lactate and no uptake of amino acids. There was no difference in arterial amino acid concentrations between cardioplegia types except for leucine. Furthermore, a regression analysis of arterial versus arterial minus coronary sinus concentrations of leucine detected no significant correlations in this series (r = 0.06, p = 0.76).
It is therefore not likely that the difference in amino acid uptake is due to differences in amino acid availability. Another difference between the cardioplegia types was the greater myocardial extraction of oxygen and the lower oxygen saturation of coronary sinus blood after crystalloid cardioplegia. It is suggested that both glutamate uptake and lactate release are related to a lower oxygenation of the myocardium (Fig 1) and represent adaptation to a failing aerobic metabolism. It is noteworthy that the adaptive measures still appeared to be operational after approximately 40 minutes of reperfusion with fully oxygen-saturated blood.
The proposition that glutamate uptake represents an adaptation to a period of insufficient oxygenation would, if true, be associated with an increased efflux of alanine. The fact that there is no significant (p = 0.06) release of alanine after crystalloid cardioplegia, while this could be detected after blood cardioplegia (p = 0.01), may therefore appear confusing. However, as discussed below in "Study Limitations," our study was not powered for alanine and any conclusions related to alanine would be hazardous.
Our data are in line with the findings of Caputo and associates [2], who compared blood cardioplegia with crystalloid cardioplegia and found differences in arterial blood lactate two hours after surgery for ventricular septal defects. The same group subsequently studied myocardial glutamate content [1] and found a difference between the two cardioplegia types only in cyanotic patients and only when the arrest period was terminated with warm blood cardioplegia ("hot shot"). In contrast, our data reveal differences in noncyanotic patients and without a terminal "hot shot." Can this contradiction be explained? As the authors pointed out, the cyanotic patients had longer operations with aortic cross-clamping lasting almost twice as long (mean, 59 to 74 minutes) as their noncyanotic patients. In our study, we chose noncyanotic patients with a mean ischemic time of 88 minutes. It could be suggested that, in conjunction with shorter ischemic times, the benefit of blood cardioplegia is less or nonevident. This does not challenge the hypothesis that cyanotic patients may be more vulnerable, but it implies that cyanosis is not a prerequisite for blood cardioplegia providing superior cardioprotection.
Another finding in the present study was that after crystalloid cardioplegia (in contrast to after blood cardioplegia) there was no significant uptake of fatty acids. This difference in substrate pattern should, however, be considered with caution. As will be discussed in "Study Limitations," the reservations expressed about alanine are equally justified for fatty acids. Even so, it may be of interest to review some previous findings relating to myocardial fatty acid utilization. In a normal heart in a fasting state with arterial levels of free fatty acids equal to those in the present study, a large myocardial uptake of fat would be expected. In a previous work [7] after coronary surgery in adults with crystalloid cardioplegia, we observed that, in spite of markedly increased fatty acid levels in blood, there was no detectable uptake. Teoh and colleagues [8], also in coronary surgery, found that fat oxidation did not occur in crystalloid cardioplegia (but it did when blood cardioplegia was used). A similar finding has been made in experimental hemorrhagic shock [16] and in septic shock patients [17]. In that context, the abnormality was associated with an unfavorable clinical outcome. In future studies, it may be worthwhile to clarify this issue in pediatric cardiac surgery.
Study Limitations
One study limitation relates to the use of concentration differences between arterial and coronary sinus blood to evaluate myocardial metabolism. When this measure is positive it reflects myocardial uptake and when it is negative it indicates a release from the myocardium. In order to quantify the uptake or release, blood flow must also be determined. In this study coronary blood flow was not measured because no technique for clinical use in infants was available. The values for arteriovenous differences in oxygen in the two groups (3.02 vs 2.35 mmol/L) would correspond to a 22% difference in coronary blood flow, which is conceivable. In contrast, for lactate and glutamate the flow difference between the two groups would be 18-fold and eightfold, respectively, which is not conceivable. It can therefore be concluded that most of the differences between groups in terms of lactate and glutamate cannot be explained by blood flow differences but instead by metabolic differences.
A second limitation is statistical power. Ideally, a pre-study power analysis should include all measured variables. However, a "primary" variable of particular importance is often chosen. It is accepted that conclusions relating to other variables may be compromised due to underpowering. In this study, we chose coronary sinus lactate concentration as the variable for the power analysis and it was fully appreciated that there was a risk of type II errors for other variables. Furthermore, we based our calculations on data in adults. The relevance of these data could be questioned when calculating the necessary sample size in infants. To our satisfaction, a power analysis of the present data indicated that the power for coronary sinus lactate (>80%) and for arterial minus coronary sinus lactate (>90%) was sufficient and indicated an adequate sample size for these variables. In contrast, the power for fatty acids (arterial minus coronary sinus concentration difference) was only 22%, while it was even lower for alanine. To obtain 80% power, it would be necessary to include 76 patients in each group to detect a 30% difference in free fatty acids and 158 patients in each group for alanine. This indicates that it would be difficult to perform studies that are adequately sized in this patient category and that other approaches will be necessary to clarify the unresolved issues in this study. Whether or not we should have refrained from including these variables at all is open to discussion. We find our results worthwhile, since they provide information that may be important for future studies.
Summary and Conclusion
This prospective, controlled, randomized study compares crystalloid cardioplegia with blood cardioplegia in a homogeneous group of noncyanotic infants, all undergoing surgery for complete atrioventricular septal defects. The results indicate that blood cardioplegia maintains a more normal myocardial substrate metabolism because adaptive measures such as lactate production and glutamate uptake are not operative, in contrast to the situation after crystalloid cardioplegia. These findings may explain the early superior hemodynamic function that follows blood cardioplegia.
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Acknowledgments
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This study was conducted using donations from the Freemason Founding Asylum Direction in Göteborg (Frimurare-Barnhusdirektionen), the Göteborg Children's Clinic Research Fund, and the Swedish Heart and Lung Foundation.
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References
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|---|
- Modi P, Suleiman M-S, Reeves B, et al. Myocardial metabolic changes during pediatric cardiac surgerya randomized study of 3 cardioplegic techniques. J Thorac Cardiovasc Surg 2004;128:67-75.[Abstract/Free Full Text]
- Caputo M, Modi P, Imura H, et al. Cold blood versus cold crystalloid cardioplegia for repair of ventricular septal defects in pediatric heart surgerya randomized controlled trial. Ann Thorac Surg 2002;74:530-535.[Abstract/Free Full Text]
- Young JN, Choy IO, Silva NK, Obayashi DY, Barkan HE. Antegrade cold blood cardioplegia is not demonstrably advantageous over cold crystalloid cardioplegia in surgery for congenital heart disease J Thorac Cardiovasc Surg 1997;114:1002-1009.[Abstract/Free Full Text]
- Åmark K, Berggren H, Björk K, et al. Blood cardioplegia provides superior protection in infant cardiac surgery Ann Thorac Surg 2005;80:989-994.[Abstract/Free Full Text]
- Pietersen HG, Langenberg CJ, Geskes G, et al. Myocardial substrate uptake and oxidation during and after routine cardiac surgery J Thorac Cardiovasc Surg 1999;118:71-80.[Abstract/Free Full Text]
- Svedjeholm R, Svensson S, Ekroth R, et al. Trauma metabolism and the heartstudies of heart and leg amino acid flux after cardiac surgery. Thorac Cardiovasc Surg 1990;38:1-5.[Medline]
- Svensson S, Svedjeholm R, Ekroth R, et al. Trauma metabolism and the heart. Uptake of substrates and effects of insulin early after cardiac operations J Thorac Cardiovasc Surg 1990;99:1063-1073.[Abstract]
- Teoh KH, Mickle DA, Weisel RD, et al. Decreased postoperative myocardial fatty acid oxidation J Surg Res 1988;44:36-44.[Medline]
- Myrelid Å, Gustafsson J, Ollars B, Annerén G. Growth charts for Down's syndrome from birth to 18 years of age Arch Dis Child 2002;87:97-103.[Abstract/Free Full Text]
- Albertsson Wikland K, Luo ZC, Niklasson A, Karlberg J. Swedish population-based longitudinal reference values from birth to 18 years of age for height, weight and head circumference Acta Paediatr 2002;91:739-754.[Medline]
- Vik-Mo H, Mjos OD. Influence of free fatty acids on myocardial oxygen consumption and ischemic injury Am J Cardiol 1981;48:361-365.[Medline]
- Mudge Jr GH, Mills Jr RM, Taegtmeyer H, Gorlin R, Lesch M. Alterations of myocardial amino acid metabolism in chronic ischemic heart disease J Clin Invest 1976;58:1185-1192.[Medline]
- Thomassen A, Nielsen TT, Bagger JP, Thuesen L. Myocardial glutamate and alanine exchanges related to carbohydrate metabolism in patients with normal and stenotic coronary arteries Clin Physiol 1984;4:425-434.[Medline]
- Kjellman U, Bjork K, Ekroth R, et al. Alpha-ketoglutarate for myocardial protection in heart surgery Lancet 1995;345:552-553.[Medline]
- Svedjeholm R, Vanhanen I, Hakanson E, et al. Metabolic and hemodynamic effects of intravenous glutamate infusion early after coronary operations J Thorac Cardiovasc Surg 1996;112:1468-1477.[Abstract/Free Full Text]
- Spitzer JJ, Spitzer JA. Myocardial metabolism in dogs during hemorrhagic shock Am J Physiol 1972;222:101-105.[Free Full Text]
- Dhainaut JF, Huyghebaert MF, Monsallier JF, et al. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock Circulation 1987;75:533-541.[Abstract/Free Full Text]
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Abstract
Introduction
= blood cardioplegia; 
= crystalloid cardioplegia.)