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J Thorac Cardiovasc Surg 1998;115:475-477
© 1998 Mosby, Inc.
BRIEF COMMUNICATIONS |
Leipzig, Germany
From Pediatric Cardiology, Cardiac Center Leipzig, University Hospital,Leipzig, Germany.
Received for publication April 29, 1997 Accepted for publication Sept. 9, 1997. Address for reprints: Attila Tárnok, PhD, Pediatric Cardiology,Cardiac Center Leipzig, University Hospital, Russenstr. 19, D-04289 Leipzig,Germany.
During pediatric cardiac operations with cardiopulmonary bypass (CPB),the serum levels of various inflammatory cytokines change dramatically.
1 Recent studies in childrendemonstrate that interleukin-10 (IL-10), a cytokine that acts in animmunosuppressive manner, is liberated during 2 or after 3 pediatric cardiac operations. Theinformation provided by these authors, however, are conflicting with respect tothe amplitude and the kinetics of secreted IL-10. 2,3Seghaye and colleagues 2reported two peaks of IL-10 release, one during and a second after CPB, withmaximums at the end of CPB and 1 day after the operation, respectively. Datafrom Sugita and associates 3indicate earlier IL-10 release, with maximums during reperfusion and a few hoursafter the operation. Their data are similar to data reported for adults 4 with respect to the kinetics ofIL-10 release. In contrast, Sugita and associates 3 reported initial and peak IL-10values that were more than 10 times as high as in adults 4 and in infants until 10 months afterbirth. 2 We analyzed thekinetics of IL-10, interleukin-6 (IL-6) and tumor necrosis factor–
(TNF-) release in children undergoing cardiac operations to clarify therelease pattern of IL-10 in children.
Patients and methods. After informedconsent was obtained, 24 children with atrial septal defects (atrial septaldefect I, n = 1; atrial septal defect II, n =13) or ventricular septal defects (n = 10)undergoing cardiac operations were analyzed. The surgical procedures wereventricular septal defect closure and atrial septal defect repair, respectively.General anesthesia and myoplegia were performed with midazolam, fentanyl, andpancuronium. CPB was performed with a roller pump (Stöckert InstrumenteGmbH, Munich, Germany) and hollow-fiber oxygenator (DIDECO, Mirandola, Italy).The priming solution consisted of a crystalloid solution, mannitol (3 ml/kg bodyweight), and Iono-lactat (Fresenius, Bad Homburg, Germany). In a few cases,priming was completed with compatible erythrocyte concentrate. During CPB, thehematocrit level was kept at 22% to 30% and the flow rate wasmaintained at 2.7 to 3.5 L/m2/min. Hypothermia was induced bycooling priming solution and circulating blood with the heat exchanger. Duringthe cooling period, all patients received sodium nitroprusside (0.3 to 2.0µg/kg/min) for vasodilatation. Bretschneider's cardioplegic solution wasused for myocardial perfusion. Our perioperative antibiotic regimen consisted ofcefazolin (50 mg/kg body weight) in three separate doses. During rewarming,heated and humidified inspired gases were used and sodium nitroprusside wasadministered intravenously. At the end of CPB, all but one patient underwenthemofiltration, normal flow was reestablished, and the patients were rewarmed.The lungs were reventilated and heparin was neutralized with protamine sulfate.In all but two cases, a catecholamine (dobutamine or dopamine at 2 to 6 µg/kg/min)was infused before the patients were weaned from bypass. No corticosteroids wereapplied before, during, or after the operation.
Blood samples were collected 1 day before the operation (–1d);after the onset of anesthesia (anesthesia); 10 minutes after onset of CPB;before the end of the CPB during rewarming (CPB end); 4 to 6 hours after theoperation and protamine administration (+4h); 1, 2, and 3 days after theoperation (+1d, +2d, and +3d); and shortly before discharge (discharged). Bloodwas collected in untreated tubes (IL-10 and IL-6) or tubes treated withethylenediaminetetraacetic acid (EDTA; TNF-), and serum or EDTA-treatedplasma samples were stored within 30 to 40 minutes after sampling at –80°C until analysis. Cytokine concentrations were determined by enzyme-linkedimmunoabsorbent assay. The detection ranges were 16 to 2000 pg/ml for IL-10assay (sensitivity 1.5 pg/ml; Boehringer Ingelheim, Ingelheim, Germany), 3.13 to300 pg/ml for IL-6 (sensitivity 0.7 pg/ml, Quantikine; R&D Systems,Minneapolis, Minn.), and 15.6 to 1000 pg/ml for TNF- (sensitivity 5pg/ml; Immunotech, Hamburg, Germany). Data obtained during CPB were notcorrected for hemodilution. Statistical analysis was done with paired two-tailedStudent's t tests.
Results. Patients and surgical data are shown in Table I.The surgical and clinical outcomes were good for all children. Twelve of thechildren had minor postoperative complications such as pericardial effusion,edema, and liver swelling. Fig. 1 shows the kinetics of the analyzed serumparameters. Mean IL-10 level before the operationwas 2.3 ± 3.6 pg/ml (mean ± standard deviation; range0.0 to 14.6 pg/ml). IL-10 concentration rose, with highest values duringreperfusion (50.0 ± 71.6 pg/ml, p =0.003), remained elevated as longas 4 hours after the operation (p = 0.04), and was at baseline later on.The basal TNF- level was 16.9 ± 17.6 pg/ml (range 0.0 to 61.9pg/ml); it decreased significantly during CPB (p = 0.004 at 10 minutes ofCPB), returned to basal levels 1 day after the operation, and was notsignificantly increased after the operation. Il-6 levels were initially low (1.0 ±1.8 pg/ml; range 0.0 to 7.2 pg/ml). IL-6 increased during reperfusion (p =0.003), with a maximum 4 hours after the operation (p = 0.00005), andremained elevated after the operation (p = 0.02). There were no cleardifferences in the release patterns of IL-10, IL-6, and TNF- betweenchildren with and without catecholamine administration. Linear regressionanalysis demonstrated no correlation of peak IL-10 levels with minimal rectaltemperature during bypass and preoperative, intraoperative, or postoperativeTNF- levels (r2 <0.02). In contrast, peak IL-10 levels at reperfusion were slightly positivelycorrelated with IL-6 levels determined at the same time (r2= 0.35).
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3 for children and by Tabardel andcoworkers 4 for adults. WhereasSugita and associates 3 and wefound an immediate increase in IL-10 levels after the operation and normallevels 1 day later, Seghaye and colleagues 2reported a second, more pronounced peak 1 day after the operation. The firstpeak in the study of Seghaye and colleagues 2is similar in amplitude to our findings but a tenth that reported by Sugita andcoworkers. 3 Our preoperativeserum levels of IL-10 and TNF- are in agreement with data reported forinfants 2 and adults. 4
In contrast to the study of Seghaye and colleagues, 2 there were no increased TNF-levels during CPB. This difference between the studies potentially arises fromtwo different mechanisms underlying the IL-10 secretion. As previously shown, 5 there are two major producers ofIL-10 in human beings, monocytes and T lymphocytes. Activated monocytes secreteIL-10 after stimulation with TNF-, whereas IL-10 secretion from activatedT cells is triggered by interleukin-12, IL-6, or both. In our study, IL-10levels did not correlate with TNF- levels before or during the operation.In contrast, Il-6 levels correlated slightly with IL-10 levels duringreperfusion. From these data, we conclude that T cells were probably the majorsource of IL-10 in our patients. This hypothesis is supported by our recentfinding that monocyte activity (e.g., class II major histocompatibility complexexpression) is regulated downward immediately after the start of the surgicalprocedure. 1 Similar resultswere reported by Habermehl (Habermehl P, University of Mainz, Germany;unpublished observations). During CPB, the phenotype of T lymphocytes changesinto "naive" (CD45RA expressing) T lymphocytes. 1 "Naive" T lymphocytestend to develop into helper-2 T lymphocytes and secrete IL-10, among otherfactors, on appropriate stimulation. 6A similar response could have occurred in the patient group analyzed by us, thatanalyzed by Sugita and associates, 3and in adults. 4 In the studyof Seghaye and colleagues, 2 onthe other hand, mainly activated monocytes could have contributed to thepostoperative IL-10 secretion.
Comparison of anesthesia, medication, and surgical and postoperativeprotocols did not show major discrepancies between the study of Seghaye andcolleagues 2 and our study thatcould explain the measured differences. Although the mean durations of thesurgical procedures, CPB, and aortic crossclamping were lower and the minimaltemperature was higher than in the study of Seghaye and colleagues, 2 these values had a broadlyoverlapping distribution in the two studies. In our study, even in patients withthe longest procedures, CPB, and crossclamp time, no second IL-10 peak wasdetectable. The patient data suggest, however, that the ages of the children mayplay a crucial role in the release kinetics of IL-10 and the type of cellsinvolved. In the study of Seghaye and colleagues, 2 infants 2 to 10 months old wereanalyzed. In our study and that of Sugita and associates, 3 the children were older. Thisdifference could indicate that the mechanism of IL-10 induction by CPB inpatients with congenital heart disease is age dependent and develops from amostly monocyte-dependent to a T cell–specific response. This couldexplain why IL-10 release during cardiac operations in adults 4 follows mostly the kinetics wefound. In addition, age-related differences in surgical procedure, other type ofextracorporeal circuit, non–whole-blood priming, and hemofiltration mayhave altered the immune response. In an extended study, we have started toanalyze the release pattern of cytokines during cardiac operations in infantsand perform in vitro studies to scrutinize the source of IL-10. We believe thata clarification of the age dependency of the immune response could finally leadto more age-specific therapy.
References
. J Immunol 1996;157:12-20.[Abstract]This article has been cited by other articles:
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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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 A. J. Alcaraz, L. Sancho, L. Manzano, F. Esquivel, A. Carrillo, A. Prieto, E. D. Bernstein, and M. Alvarez-Mon Newborn patients exhibit an unusual pattern of interleukin 10 and interferon {gamma} serum levels in response to cardiac surgery J. Thorac. Cardiovasc. Surg., March 1, 2002; 123(3): 451 - 458. [Abstract] [Full Text] [PDF]
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