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Ann Thorac Surg 2002;73:601-608
© 2002 The Society of Thoracic Surgeons
a Department of Pediatric Cardiology, Aachen University of Technology, Aachen, Germany
b Department of Thoracic and Cardiovascular Surgery, Aachen University of Technology, Aachen, Germany
c Department of Anesthesiology, Aachen University of Technology, Aachen, Germany
Accepted for publication October 9, 2001.
* Address reprint requests to Dr Hövels-Gürich, Department of Pediatric Cardiology, University Hospital, Aachen University of Technology, Pauwelsstrasse 30, D-52057 Aachen, Germany
e-mail: hhoevels-guerich{at}ukaachen.de
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Abstract |
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Methods. Twenty infants (median age, 8 months) with hypoxemia owing to intracardiac right-to-left shunt (group 1, n = 10) or with heart failure because of intracardiac left-to-right shunt (group 2, n = 10), scheduled for elective primary corrective operation, were enrolled. Plasma levels of the proinflammatory cytokine interleukin (IL) 6, the natural antiinflammatory cytokine IL-10, and the markers of the acute-phase response, C-reactive protein and procalcitonin, were sequentially measured before, during, and after cardiac operation up to the 10th postoperative day. The ratio of IL-10 to IL-6 levels served as a marker for the individual’s antiinflammatory cytokine balance.
Results. Group 1 showed higher preoperative IL-6 (p < 0.001), lower IL-10 levels (p < 0.02), and lower ratio of IL-10 to IL-6 levels (p < 0.001) than group 2. Preoperative C-reactive protein and procalcitonin were not detectable. In group 1, preoperative IL-6 levels inversely correlated with preoperative oxygen saturation (Spearman correlation coefficient, -0.74, p < 0.02). During cardiopulmonary bypass, IL-6 levels were higher, whereas IL-10 and ratio of IL-10 to IL-6 levels were lower in group 1 than in group 2. In all patients, postoperative IL-6 levels were positively correlated with duration of inotropic support and serum creatinine value and inversely correlated with oxygenation index and diuresis.
Conclusions. Infants with hypoxemia show a preoperative inflammatory state with low antiinflammatory cytokine balance in contrast to those with heart failure. This in turn is associated with lower perioperative antiinflammatory cytokine balance and might contribute to postoperative morbidity.
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Introduction |
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, interleukin (IL) 6, and IL-8 play an important role in this systemic inflammatory response [3], initiating the acute-phase response (APR) and leading to the synthesis of acute phase proteins such as C-reactive protein (CRP) and procalcitonin (PCT) [4]. Acute-phase proteins and antiinflammatory cytokines such as IL-10 contribute in turn to the termination of APR [5–8]. The maintenance of normal postoperative organ function is likely to depend on the balance between proinflammatory and antiinflammatory cytokine synthesis. In the setting of sepsis, the ratio of IL-6 to IL-10 is recognized as a reliable predictor of poor outcome [9, 10]. Indeed, our previous experimental data indicate that synthesis of IL-10 during cardiopulmonary bypass (CPB) is associated with reduced postoperative organ damage [11]. The potential for antiinflammatory cytokine balance is probably multifactorial, including genetic determination, as it has been shown in the setting of sepsis [12]. As far as patients with congenital cardiac defect are concerned, the preoperative clinical condition could initiate a systemic inflammatory reaction, which could enhance the inflammatory response to cardiac operation. Whereas heart failure in adults has been shown to be related to elevated circulating levels of proinflammatory cytokines [13, 14], this has never been demonstrated in children. Furthermore, the role of chronic hypoxemia, another common clinical condition of infants undergoing cardiac operation, as a primer for cytokine-producing cells has not been addressed so far. This prospective study was therefore designed to test the hypothesis that (1) the preoperative cardiac condition of infants undergoing cardiac operation (hypoxemia versus heart failure) alters preoperative cytokine balance, and (2) this influences the relation between proinflammatory and antiinflammatory response related to cardiac operation as well as the clinical outcome.
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Clinical data
Ten infants with a regular form of a tetralogy of Fallot (group 1; median age, 9.5 months) and 10 infants with a ventricular septal defect (VSD) or a complete atrioventricular septal defect (group 2; median age, 7 months) were prospectively investigated. All group 1 patients had preoperative cyanosis (arterial oxygen saturation < 90%) or presented with hypoxic spells; 7 of them were treated with the ß-adrenergic blocker propranolol (oral dosage of 2 mg · kg-1 · d-1). All group 2 patients had clinical signs of heart failure and pulmonary hypertension at cardiac catheterization owing to left-to-right shunt (ranging from 50% to 80%) and increased pulmonary flow. They all were treated with furosemide and digoxin. Two group 2 patients had Down syndrome.
Anesthesia and antibiotic regimen
Conventional general anesthesia consisted of diazepam, fentanyl sulfate, and pancuronium bromide. After induction of anesthesia, nasotracheal intubation was performed, and central venous and peripheral arterial catheters were inserted. Perioperative antibiotic prophylaxis consisted of cefotiam hydrochloride. Dexamethasone (3 mg/m2 body surface area) was given before sternotomy.
Surgical procedure and cardiopulmonary bypass
All patients of group 1 underwent infundibulectomy and 8 of them had transpulmonary patch enlargement; 9 of them had transventricular and 1 had transatrial repair of the VSD. Nine group 2 patients underwent transatrial and 1 had transventricular VSD repair.
The CPB protocol was uniform and included a roller pump, a hollow-fiber membrane oxygenator, and an arterial filter. Cooling and rewarming were performed with a heat exchanger. The priming solution consisted of a crystalloid solution, mannitol (3 mL/kg) and packed red blood cells to obtain a hematocrit value of the circulating volume of approximately 25%. Anticoagulation was achieved with heparin sulfate (3 mg/kg). For vasodilation during the cooling and rewarming periods, a continuous infusion of sodium nitroprusside was given. Cardiopulmonary bypass was instituted with a perfusion index of 2.7 L · min-1 · m-2 body surface area. During CPB, the pH-stat method was used, correcting arterial carbon dioxide tension to the patient’s hypothermic temperature to maintain a pH value of 7.40. The aorta was cross-clamped after deep hypothermia was reached (minimal nasopharyngeal temperature averaging 15°C), and cardioplegia was induced by a single intraaortic injection of a 4°C cold Bretschneider solution (30 mL/kg). Cardiocirculatory arrest was instituted for not longer than 60 minutes. If necessary, 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 patients were reventilated when core temperature reached 30°C. Neutralization of heparin was achieved with protamine sulfate in a 1:1 ratio.
Postoperative care
Postoperative monitoring included continuous registration of heart rate and rhythm, arterial blood pressure, central venous pressure, and diuresis. Target values for mean blood pressure, central venous pressure, and diuresis during the first 72 hours postoperatively were 50 mm Hg, 5 to 7 mm Hg, and more than 1.5 mL · kg-1 · h-1, respectively. Inotropic support consisted in all cases of dopamine (5 µg · kg-1 · min-1) and, if necessary, epinephrine (0.05 to 0.2 µg · kg-1 · min-1) or dobutamine (5 to 7.5 µg · kg-1 · min-1) and vasodilatory treatment of sodium nitroprusside (0.5 to 2 µg · kg-1 · min-1). Diuretics (furosemide, single dosage 0.5 to 1 mg/kg) and volume substitution, which consisted of fresh-frozen plasma or human albumin 5%, were administered according to the hemodynamic variables. Treating intensivists were blinded to the cytokine values of the patients. Postoperative clinical end-point variables were mean blood pressure, mean central venous pressure, need for inotropic support, oxygenation index expressed as partial arterial oxygen tension to inspired oxygen fraction, minimal diuresis, maximal serum creatinine and serum glutamate oxaloacetate transaminase values during the first 72 hours after the operation, and duration of inotropic and ventilatory support.
Patients were investigated clinically and by echocardiography during the first 48 hours postoperatively twice a day by one pediatric cardiologist.
Laboratory tests
Plasma 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 of blood was taken in tubes containing ethylenediaminetetraacetic acid. The samples were immediately centrifuged for 3 minutes (3,000 rpm), and the plasma was stored at -70°C until analysis. Plasma samples were collected preoperatively, 10 minutes after the onset of CPB, at the end of the rewarming period, after protamine administration, and 4, 24, 48, and 72 hours after the end of CPB as well as 10 days postoperatively.
Cytokine determination
Interleukin 6 and IL-10 were measured by enzyme-amplified sensitivity immunoassay (EASIA, Medgenix, BioSource Europe S.A., Fleurus, Belgium) according to the manufacturer’s recommendation. It is a solid-phase enzyme-amplified sensitivity immunoassay performed on microtiter plate, based on the oligoclonal system, in which several monoclonal antibodies directed against distinct epitopes of the intact cytokine are used, allowing high sensitivity but without hypersensitivity of the assay. The minimal detectable concentration is 2 pg/mL for IL-6 and 1 pg/mL for IL-10. The range covered by the standard curve is 0 to 1,540 pg/mL for IL-6 and 0 to 1,335 pg/mL for IL-10. Normal values for healthy adults given by the manufacturer range between 0 and 8.5 pg/mL for IL-6 and average 2.5 ± 3.5 pg/mL for IL-10 (mean ± standard deviation). Our normal values for healthy infants average 4.2 ± 1.3 pg/mL (mean ± standard deviation) for IL-6, and IL-10 was found to be undetectable (unpublished data). The ratio of IL-10 to IL-6 blood levels (IL-10/IL-6) expressing individual antiinflammatory cytokine balance is expressed as the ratio of IL-10 to IL-6 blood levels determined at the same time point multiplied by 100.
C-reactive protein and procalcitonin
C-reactive protein was determined by laser nephelometry. Detection limit of the method is 5 mg/L. Procalcitonin was determined using a specific immunoluminometric assay (Lumitest PCT, Brahms Diagnostica GmbH, Berlin, Germany). The detection limit of the method is 0.1 ng/mL. Normal values for healthy adults and children are less than 0.1 ng/mL [15].
Statistical analysis
Results are expressed by the median value and interquartile range, assuming nonnormal distribution of the data. Data were analyzed with the SPSS for Windows software, version 10.0 (SPSS GmbH Software, München, Germany). Time-dependent variations of biologic variables were analyzed by the Wilcoxon test, and intergroup comparison at specific sample times by Mann-Whitney U test. Alpha-adjustment for repeated comparisons was performed according to Bonferroni-Holm. Spearman correlation coefficient was calculated for correlation analysis. Probability values less than 0.05 were considered significant, and p values between 0.05 and 0.09 were considered to have a tendency toward significance.
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Interleukin 10
Preoperative IL-10 levels were significantly lower in group 1 than in group 2 (IL-10, 0.1 pg/mL [0.1 to 1.1 pg/mL] versus 1 pg/mL [0.1 to 5 pg/mL], median [interquartile range], p < 0.02). In all patients, IL-10 rose during CPB to maximal values after protamine administration and normalized from the first postoperative day on in both groups. Preoperative IL-10 levels correlated inversely with IL-6 levels during CPB (Spearman correlation coefficient, -0.51; p < 0.05) and with epinephrine dosage on admission to the intensive care unit (Spearman correlation coefficient, -0.50; p < 0.05).
During CPB, IL-10-levels were significantly lower in group 1 than in group 2 patients (Fig 2B). In all patients, maximal IL-10 levels measured after protamine administration inversely correlated with postoperative epinephrine dosage on admission to the intensive care unit (Spearman correlation coefficient, -0.54; p < 0.02).
Ratio of interleukin 10 to interleukin 6
Preoperative rIL-10/IL-6 was significantly lower in group 1 than in group 2 (rIL-10/IL-6, 0.40 [0.25 to 0.57] versus 42.8 [8.4 to 86.4], median [interquartile range], p < 0.001) and remained lower in the former during CPB. Postoperatively, there was no difference in rIL-10/IL-6 between both groups (Fig 2C).
In all patients, preoperative rIL-10/IL-6 and rIL-10/IL-6 during CPB was inversely correlated with dosages of epinephrine on admission to the intensive care unit (Spearman correlation coefficient, -0.51; p < 0.05; and -0.69; p < 0.01, respectively) and with duration of inotropic support (Spearman correlation coefficient, -0.59; p < 0.01; and -0.67; p < 0.01, respectively).
C-reactive protein and procalcitonin
C-reactive protein levels rose significantly in all patients from normal preoperative values (0 [0 to 0] mg/L, median [interquartile range]) to elevated values of more than 5 mg/L 24 hours after CPB. At that time, CRP values were significantly lower in group 1 than in group 2 patients. C-reactive protein levels reached their peak 48 hours after CPB in both groups and remained elevated in all patients 10 days after the operation (p < 0.0001 versus preoperative values; Fig 3A).
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Comment |
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As preoperative IL-6 production was well correlated with the degree of hypoxemia in our patients with tetralogy of Fallot, our data strongly suggest that in young infants chronic hypoxemia caused by cardiac malformation induces production of IL-6. This is in line with previous reports showing that adults submitted to short-term high-altitude hypoxia have slightly increased IL-6-blood concentrations [18]. According to the literature, the mechanisms leading to hypoxemia-mediated increase of cytokine production involve at least increased responsiveness of monocytes and macrophages against an inflammatory stress [19]. The induction of IL-6 mRNA is probably the result of hypoxic activation at the nuclear factor site for IL-6 [20]. Indeed, in experimental studies, increased nuclear factor-kappa B activation has been related to increased expression of inflammatory cytokine mRNA such as tumor necrosis factor-, IL-1, and IL-1ß in alveolar rat macrophages of animals exposed to acute hypoxia [21]. Because IL-10 synthesis is independent of nuclear factor-kappa B, one could speculate on the selective effect of hypoxemia on cytokine transcription. Remarkably, patients with hypoxemia and elevated levels of IL-6 did not show increased levels of the acute-phase protein CRP. This indicates that these patients had insufficient APR [4]. Because CRP is not only a marker of APR but also an important actor in its control [22], this observation supports the view of a net proinflammatory balance in infants with hypoxemia. We did not address the mechanisms of this insufficient preoperative APR in this study. Downregulation of IL-6 receptors could, however, be proposed as being partly responsible [4].
The fact that the majority of our hypoxemic patients, but not those with heart failure, were treated with ß-adrenergic blockers preoperatively has to be discussed in this context with respect to the possible modulating role of this drug on cytokine plasma levels [23]. Recently, cytokine-mediated downregulation of propranolol receptors in adults with coronary artery disease has been suggested [24]. To our knowledge, the effects of propranolol with respect to cytokine plasma levels in clinical settings of chronic hypoxemia have not been investigated. If propranolol had influenced preoperative cytokine balance, it should have resulted in a catecholamine antagonism with depression of IL-6 rather than stimulation [25]. Moreover, within the group of hypoxemic patients, IL-6 levels in propranolol-treated patients were not found to be different from those in untreated children.
Within the heart failure group, 2 patients had Down syndrome, which is associated with upregulation of IL-6 [26]. This strengthens our view of the proinflammatory effect of hypoxia in infants as we clearly show for the first time in the present series.
As demonstrated previously [7], cardiac operations involving CPB elicited in all our patients a strong proinflammatory response with IL-6 production, and IL-6 levels peaked between 4 and 24 hours after the operation. This proinflammatory response was accompanied by an antiinflammatory reaction as indicated by IL-10 production. In this series, IL-10-plasma levels peaked at the end of CPB, after protamine administration. This early and short-lasting antiinflammatory response observed in all patients was obviously insufficient to control later IL-6 production, being responsible for the persistence of an inflammatory state at least until the 10th postoperative day. Although patients with preoperative hypoxemia had higher circulating levels of IL-6 after CPB in comparison with the patients with heart failure, postoperative cytokine balance as shown by rIL-10/IL-6 was similar in both groups.
In our series, the use of hypothermic cardiocirculatory arrest in all patients could well have influenced the inflammatory response to CPB. However, as it has recently been suggested that cardiac arrest reduces the importance of the septemic inflammatory reaction in infants (P. Tassani, personal communication), the uniform bypass modalities presented in our study are unlikely to have enhanced proinflammatory cytokine production.
Although they had higher IL-6-levels in the early postoperative period, patients with preoperative hypoxemia had lower CRP values than did patients with preoperative heart failure. In contrast to CRP, PCT levels were higher in the former patients, suggesting adequate induction of this newly recognized marker of APR [27]. Production of PCT, thought to take place in leukocytes and neuroendocrine cells [28], is probably for this reason unaffected by postoperative hepatic dysfunction. It could therefore be a better marker of inflammation after cardiac operation [29], in which hepatic dysfunction is a common complication [1]. As CRP contributes to the control of inflammation [22], its decreased intrahepatic production could have contributed to the persistence of the inflammatory state that was biologically present up to the 10th postoperative day in all patients.
In this study, we hypothesized that the preoperative condition (hypoxemia or heart failure) could influence cytokine production related to cardiac operation. It has to be considered that besides preoperative treatment and bypass modalities—as discussed above—drugs such as catecholamines administered in the early postoperative period may exert immunomodulating properties. Indeed, it is well known that exogenous catecholamines are able to increase production of proinflammatory and antiinflammatory cytokines [30]. The influences are, however, dependent on the kind of substance used and the time of administration, and the exact working mechanisms remain as yet unclear. In our study, catecholamine support was not applied before and during the operation, but only after the operation. Furthermore, catecholamine treatment was terminated within 48 hours after CPB in both groups. Therefore, an influence of exogenous catecholamines on the intraoperative cytokine balance can be excluded.
Our observation suggesting that preoperative condition could influence cytokine production related to the cardiac operation is compatible with two hypotheses: first, infants with defined congenital cardiac defects could have a genetically determined level of responsiveness against an inflammatory stress owing to cytokine gene polymorphism [31]; second, hypoxemia or heart failure could, per se, prime immune competent cells differently, leading to different cytokine production in response to an inflammatory stimulus. The negative relationship between preoperative arterial oxygen saturation and IL-6 levels speaks for the second hypothesis.
In this series, as others [32, 33] and we [2] have previously reported, higher proinflammatory cytokine levels during CPB might influence postoperative morbidity. Interleukin 6 acts as a myocardial depressant substance by inducing intramyocardial nitric oxide synthase [34]. Our data support this as IL-6 levels during CPB correlated with dosage and duration of postoperative epinephrine support.
Chronic hypoxemia might therefore be a risk factor contributing to the development of postoperative complications related to the systemic inflammatory reaction elicited by cardiac operation, and, if confirmed in a larger series, this should be taken into account for the timing of operation in cyanotic patients.
In conclusion, our data show that chronic hypoxemia because of cardiac malformations leads to an inflammatory state with imbalance between proinflammatory and antiinflammatory cytokine production and modified APR. This preoperative inflammatory state is likely to influence perioperative cytokine balance and might be associated with postoperative morbidity related to cardiac operation.
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and potentiates interleukin-10 production during human endotoxemia. J Clin Invest 1996;97:713-719.[Medline]
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]) are shown. Spearman correlation coefficient, -0.74; p < 0.02.
) with median and interquartile ranges (boxes). Differences between both groups were analyzed by Mann-Whitney U test: * p < 0.005 and ** p < 0.02 and # p < 0.1. Significant difference between preoperative and peak values in all patients analyzed by Wilcoxon test: 
p < 0.01. (B) Interleukin 10 concentrations before, during, and after cardiopulmonary bypass (CPB) in patients with preoperative hypoxemia (group 1, open boxes) and with preoperative heart failure (group 2, hatched boxes). Values expressed as mean values (