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J Thorac Cardiovasc Surg 2002;124:811-820
© 2002 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease (CHD) |
From the Departments of Pediatric Cardiologya and Thoracic and Cardiovascular Surgeryb and the Institute of Biomedical Statistics,c Aachen University of Technology, Aachen, Germany, and the Department of Immunology,d Hôxopital Brugman, Brussels, Belgium.
Received for publication May 25, 2001. Revisions requested Oct 16, 2001; revisions received Nov 9, 2001. Accepted for publication Dec 10, 2001. Address for reprints: Hedwig H. Hövels-Gürich, MD, Department of Pediatric Cardiology, Aachen University of Technology, Pauwelsstr 30, D-52057 Aachen, Germany (E-mail: hhoevels-guerich{at}ukaachen.de).
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Abstract |
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Introduction |
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1-5 but its pathophysiologic mechanisms remain unclear. The systemic and intramyocardial inflammatory response has been suggested to contribute to myocardial dysfunction. 6,7
Term neonates undergoing cardiac surgery have a systemic inflammatory reaction comprising complement activation, leukocyte stimulation, and cytokine synthesis. 8,9 Proinflammatory cytokines such as interleukin (IL) 6, the regulator of the acute-phase response, and IL-8, a potent chemokine with neutrophil-stimulating properties, are involved in the systemic inflammatory response related to cardiopulmonary bypass (CPB) in children. 10-13 These cytokines may cause myocardial cell damage and consecutive myocardial dysfunction as a result of nitric oxide-independent and nitric oxide-dependent pathways 14-16 and as a result of increased leukocyte-endothelial cell interactions, with consequent capillary obstruction and impaired microcirculation in the myocardium. 17
Although the responsibility of perioperative proinflammatory cytokine production for the development of postoperative myocardial dysfunction has been suggested in adult patients after cardiac surgery, 18-21 this question has never been addressed in children or neonates. It was therefore the aim of our study to test the hypothesis that proinflammatory cytokine release during cardiac surgery in neonates is associated with postoperative myocardial cell damage and consequent myocardial dysfunction.
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Methods |
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22 All patients received prostaglandin E1 infusion (0.05 µg/[kg · min]) before the operation to maintain patency of the ductus arteriosus. Maternofetal infection or bacterial infection before the operation and preoperative organ dysfunction were cause for exclusion in all cases.
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Cardiopulmonary bypass protocol
The CPB circuit included a roller pump, a disposable membrane oxygenator, and an arterial filter. Cooling and rewarming were carried out with a heat exchanger. The priming solution consisted of a crystalloid solution, mannitol (3 mL/kg), and leukocyte-depleted packed red blood cells to obtain a hematocrit value of the circulating volume of about 25%. Heparinization was achieved with heparin sulfate (3 mg/kg). For vasodilatation in the cooling and rewarming periods, all neonates received a continuous infusion of sodium nitroprusside (SNP, 0.5-1 µg/[kg · min]). CPB was instituted with a perfusion index of 2.7 L/(min · m2), which was maintained throughout the cooling phase. During CPB the pH-stat method was used, with correction of PaO2 to the patients's hypothermic temperature to maintain a pH value of 7.40. After deep hypothermia was reached (minimal nasopharyngeal temperature averaging 15°C), aortic crossclamping was done and cardioplegia was induced with a single intra-aortic injection of a 4°C cold Bretschneider solution (30 mL/kg), and cardiocirculatory arrest was instituted for a target period of not longer than 60 minutes. The surgical procedure was continued under low-flow perfusion (25% of the calculated initial perfusion rate). Rewarming was achieved under full-flow conditions. The lungs of the neonates were reventilated when core temperature reached 30°C. Neutralization of heparin was achieved with protamine sulfate in a 1:1 ratio. Epinephrine, dopamine, and SNP were systematically administered for weaning the patients from CPB. After coronary reperfusion and at the end of the operation, intraoperative myocardial function was assessed by the cardiac surgeon, as explained here. In cases of hemodynamic instability or myocardial dysfunction at the end of the operation, sternal closure was delayed until stabilization, and sternal wounds were closed with a latex membrane.
Perioperative and postoperative care
Postoperative monitoring included continuous registration of heart rate and rhythm, arterial blood pressure, central venous pressure, and diuresis. Target values for mean arterial blood pressure, central venous pressure, and diuresis during the first 72 hours after the operation were 45 mm Hg, 5 to 7 mm Hg, and more than 1.5 mL/(kg · h), respectively. Inotropic support, vasodilation, and diuretic treatment consisting of epinephrine, dopamine, dobutamine, SNP, and furosemide were adapted accordingly, as was volume substitution, which was carried out with fresh-frozen plasma or 5% human albumin. Blood gas values, serum electrolytes, serum creatinine, aspartate aminotransferase (AST), and bilirubin were routinely measured during the first 3 postoperative days. The ratio between PaO2 and inspired oxygen fraction was used as oxygenation index for patients receiving ventilatory support.
Myocardial dysfunction was considered to be hypocontractility of one or both ventricles, as reported by the surgeon at the end of the operation or by the pediatric cardiologist from systematic transthoracic echocardiography 4 and 24 hours after the operation. Repeated routine transesophageal echocardiography was not possible in most cases. The decision to delay sternal closure or increase inotropic support was based on hemodynamic parameters, as stated previously, and was not a criterion for assignment to the myocardial dysfunction group.
Myocardial ischemia was diagnosed in the presence of discolored or demarcated myocardial areas seen by the surgeon after coronary reperfusion and before the end of the operation. It was also diagnosed on the basis of typical repolarization abnormalities in the standard electrocardiogram 4 and 24 hours after the operation.
Total inotropic support was calculated 4 and 24 hours after the operation by adding the doses of dopamine and dobutamine in micrograms per kilogram per minute and assigning an arbitrary equivalent value of 10 µg/(kg · min) inotropic agent for each 0.1 µg/(kg · min) epinephrine. 1 Dopamine was given in a dosage of 5µg/(kg · min) as basic support in all cases. Dobutamine was administered at a dosage of 5 to 10 µg/(kg · min), according to hemodynamic need, and epinephrine was given additionally, also according to hemodynamic need.
Specific laboratory examinations
Collection of samples
Venous blood was collected before and after the operation. During CPB, blood was withdrawn from the arterial line of the circuit. For each sample time, 1 mL blood was taken in tubes containing ethylenediaminetetraacetic acid. The samples were immediately centrifuged for 3 minutes (3000 rpm), and the plasma was stored at -70°C until analysis. Plasma samples were collected before the operation, at the end of CPB after protamine administration, and at 4 and 24 hours after the end of CPB.
Cardiac troponin T
Cardiac troponin T (cTnT) concentration was determined by enzyme-linked immunosorbent assay (ELISA Troponin-T Kit; Boehringer Mannheim, Division of Roche Pharmaceuticals, Mannheim, Germany), with the use of two highly specific monoclonal antibodies directed against two different epitopes of the cTnT molecule, allowing high specificity. Cross-reactivity with skeletal muscle troponin T and the influence of hemolysis and hyperbilirubinemia (bilirubin <25 mg/dL) were excluded by the manufacturer. Normal values for healthy neonates range up to 0.33 ng/mL (95th percentile according to Panteghini and associates 23).
Cytokines
IL-6 and IL-8 concentrations were measured by immunoenzymetric assay (enzyme-amplified sensitivity immunoassay; BioSource Europe [formerly Medgenix Diagnosics], Nivelles, Belgium) according to the manufacturer's recommendation. This is a solid-phase enzyme-amplified sensitivity immunoassay performed on microtiter plate that is based on the oligoclonal system in which several monoclonal antibodies directed against distinct epitopes of the intact cytokine are used, allowing high sensitivity of the assay. The minimal detectable concentrations are 2 pg/mL for IL-6 and 0.7 pg/mL for IL-8. The ranges covered by the standard curve are 0 to 2100 pg/mL for IL-6 and 0 to 750 pg/mL for IL-8. In plasma from healthy adults, values range between 0 and 70 pg/mL for IL-6 and between 0 and 47 pg/mL for IL-8. In cord venous and arterial blood from healthy neonates, mean (± SEM) values are 16 ± 2 and 40 ± 14 pg/mL, respectively, for IL-6 and 4.6 ± 1.0 and 6.1 ± 1.0 pg/mL, respectively, for IL-8 according to our previous results. 24
During the study period, cTnT, IL-6, and IL-8 plasma levels were not known to the treating physicians.
Statistical analysis
Results are expressed as the median value and interquartile range or interquartile difference, assuming nonnormal distribution of the data, or by their logarithmic values. For intergroup comparison of clinical and biologic variables at specific sample times, the nonparametric Mann-Whitney U test was used. For comparison of biologic variables at specific sample times within a group, the paired nonparametric Wilcoxon test was used. The Spearman rank correlation coefficient was assessed for correlation of independent parameters, and the Fisher exact test was used for the analysis of contingency tables. The 
adjustment for repeated measures was done according to the Bonferroni-Holm method. For multivariable analysis of risk factors for the occurrence of myocardial dysfunction within 24 postoperative hours, a logistic regression was performed with nine independent risk factors that were statistically significant in corresponding univariate analysis: VSD closure, CPB duration, aortic crossclamping duration, IL-6 blood levels 4 hours after the operation, IL-8 blood levels 4 and 24 hours after the operation, and cTnT blood levels at the end of CPB and 4 and 24 hours after the operation. Additional case-matched analysis for the durations of CPB and aortic crossclamping was performed in order to evaluate whether cytokine plasma levels were different in patients for whom CPB and aortic crossclamping durations were similar but in whom myocardial dysfunction did or did not develop. Statistical analysis was performed with the Statistical Analysis System, version 8.0 (SAS Institute, Inc, Cary, NC). The term significant was used to indicate statistical, not clinical, significance.
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Results |
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). Patients with VSD closure had significantly longer durations of CPB (median 75 min, interquartile difference 30 min, vs median 44 min, interquartile difference 14 min, P = .03) and of aortic crossclamping (median 82 min, interquartile difference 13 min, vs median 62 min, interquartile difference 7 min, P = .008) than did those without myocardial dysfunction. Myocardial dysfunction was significantly more frequent in patients with VSD closure than in those without such closure. Age at surgery tended to influence the occurrence of myocardial dysfunction. Differences in coronary artery status with respect to myocardial dysfunction could have been due to chance (Table 1).
With respect to perioperative hemodynamic data 4 and 24 hours after the operation, median arterial blood pressure, central venous pressure, and diuresis were not different in patients with and without myocardial dysfunction (P > .2 each; data not shown), whereas AST was significantly elevated 4 and 24 hours after the operation and oxygenation index tended to be lower 24 hours after the operation in patients with myocardial dysfunction. Total inotropic support was significantly higher 4 and 24 hours after the operation in patients with myocardial dysfunction than in those without myocardial dysfunction, whereas differences in SNP dosages could have been due to chance. Delayed sternal closure after severe intraoperative hemodynamic instability was more frequent and mechanical ventilation time was prolonged in patients with myocardial dysfunction (Table 2).
Cardiac troponin T
Preoperative cTnT levels were normal in all neonates except for two (0.4 and 0.9 ng/mL), in whom neither preoperative, perioperative, nor postoperative complications, nor findings of myocardial dysfunction, were present. Within the whole group as well as within the subgroups with and without myocardial dysfunction, cTnT levels rose significantly at the end of CPB, reaching peak values 4 hours after the operation (P < .001 each vs preoperative values; Figure 1). The cTnT levels fell between 4 and 24 hours after the operation (P < .001 each). The cTnT values after CPB were significantly correlated with those 4 and 24 hours after the operation (Figure 2); cTnT values after CPB, 4 and 24 hours after the operation were correlated with durations of CPB and aortic crossclamping but not DHCA (Table 3). Intergroup comparison between patients with and without myocardial dysfunction showed significantly higher cTnT levels in patients with myocardial dysfunction at the end of CPB and 4 and 24 hours after the operation than in those without myocardial dysfunction (Figure 1).
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). Significant correlations were found between IL-6 and cTnT levels after CPB (Spearman correlation coefficient 0.32, P = .02). Intergroup comparison between patients with and without myocardial dysfunction showed that IL-6 levels tended to be higher at the end of CPB and were significantly higher 4 hours after the operation in patients with myocardial dysfunction than in those without myocardial dysfunction (Figure 3).
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). Significant correlations were found between IL-8 and cTnT levels 4 hours after the operation (Spearman correlation coefficient 0.34, P = .02), between IL-8 levels 4 hours after the operation and cTnT levels 24 hours after the operation (Spearman correlation coefficient 0.46, P = .001), and between IL-8 levels and cTnT levels 24 hours after the operation (Spearman correlation coefficient 0.43, P = .003). Intergroup comparison between patients with and without myocardial dysfunction showed significantly higher IL-8 levels in patients with myocardial dysfunction 4 and 24 hours after the operation than in those without myocardial dysfunction (Figure 4).
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Additional case-matched analysis for the durations of CPB and aortic crossclamping (tolerance ±5 minutes) with respect to the predictive value of IL-6 levels 4 hours after the operation for the occurrence of myocardial dysfunction was possible for 7 pairs of patients with and without myocardial dysfunction. This analysis showed that IL-6 blood levels 4 hours after the operation tended to predict myocardial dysfunction within 24 hours after the operation (P = .07, odds ratio per 10 pg/mL 1.09, 95% confidence interval 0.992-1.200).
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Discussion |
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Release of cardiac troponin T
In recent studies, cTnT and cardiac troponin I have been evaluated as indicative of perioperative myocardial damage in adults after coronary artery bypass grafting. 25,26 In pediatric cardiovascular surgery, perioperative myocardial dysfunction depends on the surgical procedure itself as well as on intraoperative factors such as durations of CPB, aortic crossclamping, and circulatory arrest. Preliminary data indicate that cTnT values shortly after surgery for congenital heart disease are potentially useful prognostic indicators of postoperative recovery. 2-5,27 In these studies, however, data were from children at different ages and with different types of heart defects. Our study reports for the first time on correlations of cTnT values with clinical outcome in a large, homogeneous group of neonates after cardiac surgery.
Our data demonstrate that the arterial switch operation in neonates is related to myocardial cell damage, with loss of cTnT. In addition, our results clearly show that myocardial dysfunction, as assessed according to our definition, is associated with higher cTnT release, suggesting a higher degree of myocardial cell damage in these patients. On multivariable analysis, however, cTnT elevation could not be evaluated as an independent predictive variable of early postoperative myocardial dysfunction in our neonatal population. Cardiac regulator proteins cTnT and cardiac troponin I have been accepted as specific serum markers of irreversible cardiomyocyte injury, but it is not clear whether they also represent a suitable marker of subtle, reversible injury. 28 The latter is suggested by a recent animal study of our group, 7 which showed that levels of circulating cardiac troponins are not related to the percentage of necrotic or apoptotic myocardial cells. In our study cTnT values immediately after the operation were strongly correlated with those 4 and 24 hours after CPB, probably reflecting early release of the cytosolic component of troponin followed by the later increase caused by slow degradation of myocardial cell myofibrils. 29
Production of the proinflammatory cytokines interleukin 6 and 8
A main purpose of this work was to assess whether enhanced synthesis of proinflammatory cytokines is associated with postoperative myocardial dysfunction in neonates. Proinflammatory cytokines are known to be mediators of myocardial cell damage 18 and have been found to be related to postoperative damage to organs including the myocardium in a recent experimental study of our group. 30 Cytokines are highly potent endogenous peptides capable of modulating cardiovascular function through various mechanisms, such as promoting ventricular remodeling, inducing contractile dysfunction, and uncoupling myocardial ß-adrenergic receptors. 31 Tumor necrosis factor , the prototype of harmful proinflammatory cytokines, has cytotoxic effects leading to cell membrane damage with gap formation, rupture, interstitial edema, and cell necrosis, 7,32 as well as the capability of inducing apoptosis. 16 During cardiac surgery, the myocardium has been found to be not only a target organ for proinflammatory cytokines but also a local site of production of circulating cytokines such as tumor necrosis factor , IL-6, and IL-8, 20,32,33 all of which are involved in neutrophil and endothelial cell activation during CPB. In a recent experimental study of our group, higher intramyocardial tumor necrosis factor synthesis was associated with extensive myocardial lesions. 7
In clinical studies on adults, proinflammatory cytokines IL-6 and IL-8 were found to be associated with postoperative myocardial ischemia and segmental wall abnormalities 18 and with the acute-phase response accompanying myocardial infarction, reflecting the extent of early myocardial damage. 19,20 IL-6 was found to be produced in cardiac myocytes during ischemia and reperfusion in patients undergoing coronary bypass surgery. 20 In children, IL-6 levels were found to be elevated in the early postoperative period, 11,12 correlated with the duration of inotropic support. 34 IL-8 is also suggested to be produced in the ischemic myocardium. 35 In children IL-8 levels are elevated early after cardiac surgery and are correlated with the duration of CPB. 10,13
In our homogeneous group of neonates, significant elevations of IL-6 and IL-8 levels relative to preoperative values immediately and 4 and 24 hours after surgery in patients with and without myocardial dysfunction, and their correlations with duration of operation variables, confirmed the role of CPB and myocardial ischemia on the induction of these proinflammatory cytokines. In patients with myocardial dysfunction, IL-6 plasma levels tended to be higher immediately after CPB and were significantly higher 4 hours after the operation than in those without myocardial dysfunction. This fact, as well as our observation of a significant correlation between proinflammatory cytokine levels and cTnT values in the early postoperative period, support the assumption that proinflammatory cytokines may contribute to myocardial damage and therefore to depressed myocardial function. 31
Limitations
The causal relationship between uncontrolled synthesis of proinflammatory cytokines and myocardial damage and dysfunction could only be definitively demonstrated in trials with cytokine-blocking or -inhibiting agents. Therefore the association between elevated plasma levels of proinflammatory cytokines and myocardial dysfunction, as shown in this study, needs to be confirmed by further investigation.
Conclusions
Cardiac operations in neonates induce the production of the proinflammatory cytokines IL-6 and IL-8. The latter may be related to myocardial cell damage, as indicated by cTnT release, and to postoperative myocardial dysfunction. The cTnT level is a useful indicator of myocardial cell damage but does not allow prediction of the occurrence of early postoperative myocardial dysfunction in this age group.
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expression following acute global ischemia in vivo. J Mol Cell Cardiol. 1998;30:1683-9.[Medline]This article has been cited by other articles:
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  C. Schmitz, B. Esmailzadeh, U. Herberg, N. Lang, R. Sodian, R. Kozlik-Feldmann, A. Welz, and J. Breuer Hybrid procedures can reduce the risk of congenital cardiovascular surgery Eur. J. Cardiothorac. Surg., October 1, 2008; 34(4): 718 - 725. [Abstract] [Full Text] [PDF]
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 M. M Maddali, J. Valliattu, T. al Delamie, S. Zacharias, A. R Ahmed, and S. S Ganguly Arterial Switch Operation: Troponin T Does Not Predict Ventilation Requirements Asian Cardiovasc Thorac Ann, August 1, 2008; 16(4): 274 - 277. [Abstract] [Full Text] [PDF]
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 D. J. Kozik and J. S. Tweddell Characterizing the Inflammatory Response to Cardiopulmonary Bypass in Children Ann. Thorac. Surg., June 1, 2006; 81(6): S2347 - S2354. [Abstract] [Full Text] [PDF]
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J. M. Schultz, T. Karamlou, J. Swanson, I. Shen, and R. M. Ungerleider Hypothermic Low-Flow Cardiopulmonary Bypass Impairs Pulmonary and Right Ventricular Function More Than Circulatory Arrest Ann. Thorac. Surg., February 1, 2006; 81(2): 474 - 480. [Abstract] [Full Text] [PDF]
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M. Caputo, S. Bays, C. A. Rogers, A. Pawade, A. J. Parry, S. Suleiman, and G. D. Angelini Randomized Comparison Between Normothermic and Hypothermic Cardiopulmonary Bypass in Pediatric Open-Heart Surgery Ann. Thorac. Surg., September 1, 2005; 80(3): 982 - 988. [Abstract] [Full Text] [PDF]
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 I. Malagon, K. Hogenbirk, J. van Pelt, M. G. Hazekamp, and J. G. Bovill Effect of three different anaesthetic agents on the postoperative production of cardiac troponin T in paediatric cardiac surgery Br. J. Anaesth., June 1, 2005; 94(6): 805 - 809. [Abstract] [Full Text] [PDF]
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S. Dittrich, D. Aktuerk, S. Seitz, P. Mehwald, J. Schulte-Monting, C. Schlensak, and D. Kececioglu Effects of ultrafiltration and peritoneal dialysis on proinflammatory cytokines during cardiopulmonary bypass surgery in newborns and infants Eur. J. Cardiothorac. Surg., June 1, 2004; 25(6): 935 - 940. [Abstract] [Full Text] [PDF]
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 M. Qing, K. Schumacher, R. Heise, M. Woltje, J. F. Vazquez-Jimenez, T. Richter, M. Arranda-Carrero, J. Hess, G.o. von Bernuth, and M.-C. Seghaye Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2266 - 2274. [Abstract] [Full Text] [PDF]
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