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Ann Thorac Surg 1996;61:1205-1211
© 1996 The Society of Thoracic Surgeons
Departments of Pediatric Cardiology and Thoracic and Cardiovascular Surgery, Aachen University of Technology, Aachen, Germany, and Department of Immunology, University Hospitals Brugmann and St. Pierre, Free University, Brussels, Belgium
Accepted for publication December 18, 1995.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. In an open, randomized study, 25 children undergoing cardiac operations were investigated prospectively. The treated group comprised 11 patients receiving low-dose aprotinin (20,000 kIU/kg [2.8 mg/kg]), and the control group included 14 patients. Complement activation, cytokine production, and leukocyte stimulation were analyzed before, during, and after cardiopulmonary bypass.
Results. In all children, significant C3 conversion and C5a generation, interleukin-6 synthesis, and myeloperoxidase, eosinophil cationic protein, and histamine liberation occurred in relation to cardiopulmonary bypass. This was not influenced by aprotinin treatment. In contrast, neutrophil kinetic studies at the end of cardiopulmonary bypass showed a significantly lower increase in the aprotinin as compared with the control group.
Conclusions. Our results suggest that low-dose aprotinin has little influence on the inflammatory reaction induced by cardiopulmonary bypass. Aprotinin affects neutrophil mobilization but not white blood cell degranulation related to cardiopulmonary bypass, and has no influence on complement activation and interleukin-6 synthesis.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Aprotinin is a serine protease inhibitor that is used in many cardiosurgical centers, principally to reduce blood loss after CPB [3]. The hemostatic effect of aprotinin is ascribed to its antifibrinolytic properties and preserving effect on platelet function [4–6]. Because of its nonspecific antiprotease properties, aprotinin inhibits trypsin, kallikrein, and plasmin and prevents the activation of factor Hageman [7, 8]. On the other hand, aprotinin counteracts the serine protease C1 inhibitor and thus potentiates the hemolytic activity of C1 and enhances complement system activation in vitro [9]. Indeed, enhanced C3 conversion related to aprotinin therapy has been reported in adult patients undergoing CPB [10].
Because aprotinin, due to its biologic properties, could influence the CPB-related inflammatory reaction, we analyzed the influence of low-dose aprotinin on complement activation, leukocyte stimulation, cytokine production, and the acute-phase response in children undergoing cardiac operations.
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Material and Methods |
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Anesthesia and Antibiotic Regimen
Conventional general anesthesia was performed. Cefotiam hydrochloride (25 mg/kg) and dexamethasone (3 mg/m2) given as prophylaxis for cerebral edema were administered before sternotomy.
Cardiopulmonary Bypass
The CPB protocol included a roller pump, a disposable membrane oxygenator, and an arterial filter. Cooling and rewarming were done with a heat exchanger. The priming solution consisted of a crystalloid solution, mannitol (3 mL/kg), and packed red blood cells, if necessary, to obtain a hematocrit value of the circulating volume of about 25%. We instituted CPB with a perfusion index of 2.7 L • m-2 • min-1. Heparin treatment was achieved with heparin sulfate (3 mg/kg), and anticoagulation therapy was monitored by determination of the activated clotting time, which was kept at greater than 450 seconds throughout the procedure. For vasodilation in the cooling and rewarming periods, all children received a continuous infusion of sodium nitroprusside (0.5 to 1.5 µg • kg-1 • min-1). Aortic cross-clamping was done and cardioplegia was induced by a single intraaortic injection of 4°C cold Bretschneider solution (30 mL/kg). In 3 children (2 receiving and 1 not receiving aprotinin), the operation was performed under deep hypothermia and cardiocirculatory arrest; in the remaining patients, operations were done under low-flow perfusion (25% of the calculated initial perfusion rate). The lungs of the children were reventilated when the core temperature reached 30°C. Neutralization of heparin was achieved with protamine sulfate in a 1:1 ratio. Catecholamines were administered if necessary for weaning the patients from CPB.
Postoperative Care
Postoperative monitoring included continuous registration of heart rate and rhythm, arterial and central venous pressures, and diuresis. Blood loss through the mediastinal drainages was monitored hourly up to 24 hours postoperatively, as was the administration of blood products (packed red blood cells and fresh frozen plasma), which were used if clinically indicated by the physician in charge.
Besides regular determination of arterial blood gas analysis and serum electrolytes, laboratory tests including serum glutamic oxaloacetic transaminase, serum creatinine, urea nitrogen, and coagulation tests (prothrombin time, partial thromboplastin time, fibrinogen, and antithrombin-III) were performed at least 4, 12, and 24 hours postoperatively. Creatinine clearance was calculated 24 hours postoperatively. The ratio of partial pressure of oxygen in arterial blood (mm Hg) to inspired oxygen fraction was used as an index of oxygenation in ventilated patients.
Laboratory Tests
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, 2.0 mL of blood was taken in tubes containing ethylenediamine tetraacetic 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; after heparin administration; 10 minutes after the onset of CPB; at the end of the rewarming period; after protamine administration; 4, 24, 48, and 72 hours after the end of CPB; and on the fifth and tenth postoperative days.
Urine samples were taken from the pooled urine volume collected by bladder catheterization before anesthesia, at admission to the intensive care unit, and 4 and 24 hours postoperatively.
COMPLEMENT FRACTIONS.
We determined C3 and C3d by means of standard turbidimetry using an automated procedure on the RA 1000 turbidimeter (Technicon, Brussels, Belgium). The ratio of C3d to C3 was used as an index of C3 conversion. We determined C5a by the enzyme immunoassay Enzygnost C5a, Behring (Hoechst, Brussels, Belgium). The normal range for healthy adults is 0.15 to 0.45 µg/L.
MYELOPEROXIDASE.
Myeloperoxidase was used as marker of neutrophil activation. It was determined using a double antibody radioimmunoassay (Kabi Pharmacia Diagnostics, Uppsala, Sweden). Normal values for healthy adults range from 170 to 478 µg/L.
EOSINOPHIL CATIONIC PROTEIN.
Eosinophil cationic protein, a specific marker of eosinophil degranulation, was determined using a double antibody radioimmunoassay (Kabi Pharmacia Diagnostics). Normal values for healthy adults range between 2.3 and 16 µg/L.
TUMOR NECROSIS FACTOR-
AND INTERLEUKIN-6.
Tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) were determined using an immunoenzymetric assay (enzyme amplified sensitivity immunoassay; Medgenix, Medgenix Diagnostics, Fleurus, Belgium). Normal TNF- values are lower than 20 pg/mL, and normal IL-6 values range between 3.0 and 8.5 pg/mL in healthy adults.
HISTAMINE.
Histamine, a marker of both basophil and mast cell degranulation, was determined in plasma and in urine using immunoenzymatic dosage (Immunotech International, Marseille, France) based on competition between histamine and histamine acetylcholinesterase. The dosage method allows a cross-reactivity between histamine and its principal metabolite methylhistamine of 5%. Normal plasma histamine levels in healthy adults are less than 1,000 pg/mL. Urinary histamine concentrations were adjusted for a concentration of urinary creatinine of 100 mg/dL.
BLOOD ELEMENTS.
White blood cell (WBC) counts and differential were determined by Coulter counter. Counts during CPB were corrected for hemodilution.
C-REACTIVE PROTEIN.
C-reactive protein (CRP) was determined by standard turbidimetry. The detection limit of the method was 5 mg/L.
ANTIBODIES AGAINST APROTININ.
Anti-aprotinin immunoglobulin G antibodies (Ap-AB) were measured with a solid-phase enzyme-linked immunosorbent assay using polystyrene microtiter plates passively coated with aprotinin (50 µg/mL) in bicarbonate buffer (pH 9.6) and saturated with gelatin. Samples of 1:25 diluted plasma were used for individual determinations. Binding of IgG was detected with peroxidase-labeled protein A and quantified using orthophenylenediamine photometric determination. A standard curve performed with hyperimmune preselected human sera was used for calibration, and results were expressed in arbitrary units (AU). The significant detection limit was greater than 10 AU. Values of Ap-AB measured in a randomly selected population of 55 adult blood donors were less than 30 AU. We determined Ap-AB before and 2 weeks after the operation in all children.
Statistical Analysis
Clinical results are expressed as the median value and the range, and biologic results as the mean ± standard error of the mean. Assuming non-normal distribution of the data, nonparametric statistical tests were used. For intergroup comparisons of clinical data, the nonparametric Mann-Whitney U test was applied. Repeated measures analysis of variance was performed to assess whether curves of biologic variables before, during, and immediately after CPB were different between the groups. Correction for repeated analysis was performed with the Bonferroni procedure. Spearman's rank correlation coefficient was assessed for correlation of independent variables, and Fisher's exact test was applied for analysis of contingency tables. Values of p less than 0.05 were considered significant.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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summarizes the operative data and clinical results in the aprotinin and control groups.
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shows the course of C3d/C3 before, during, and after CPB in both patient groups. Complement C5a rose significantly and similarly in both patient groups from normal baseline values (0.38 ± 0.09 µg/L and 0.30 ± 0.08 µg/L, respectively) to peak values after protamine administration (0.76 ± 0.2 µg/L and 1.1 ± 0.2 µg/L, respectively) (p < 0.001). In both groups, C5a reached prebypass values at 4 hours postoperatively.
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averaged 28 ± 4.5 pg/mL and 28.5 ± 4.7 pg/mL before CPB in the treated and control patients, respectively, and was not overtly produced during CPB in either group.
Interleukin-6 was in the normal range before CPB and averaged 7.8 ± 2.5 pg/mL and 8.6 ± 2.4 pg/mL in patients treated (n = 8) or not treated with aprotinin (n = 9), respectively. Levels of IL-6 increased tenfold during CPB, rose further after the operation, and reached peak values within the study period 4 hours postoperatively (p < 0.001 versus prebypass values). At this time, IL-6 levels averaged 285 ± 48 pg/mL and 205 ± 49 pg/mL in treated and control patients, respectively. Kinetics of IL-6 during and after CPB were similar in both patient groups. Figure 2 shows the course of IL-6 before, during, and after CPB in the aprotinin and control patients.
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Eosinophil cationic protein rose significantly and similarly from 3.8 ± 0.5 µg/L and 4.4 ± 1.1 µg/L before CPB to 11.8 ± 2.1 µg/L and 8.5 ± 1.3 µg/L after protamine administration in treated patients and controls, respectively (p < 0.001). Values normalized on the first postoperative day.
PLASMA AND URINE HISTAMINE.
Upon institution of CPB, circulating histamine averaged 67.4 ± 21 pg/mL in treated patients and 76.6 ± 21 pg/mL in the control group, respectively. It remained unchanged after protamine administration (87.7 ± 26.3 pg/mL and 60.0 ± 8.2 pg/mL, respectively). Compared with its levels after protamine administration, histamine rose significantly and similarly in treated and control patients 4 hours after CPB to 157.8 ± 19.5 pg/mL and 166.1 ± 19.0 pg/mL, respectively (p < 0.01), representing its peak values.
Urine histamine rose significantly and similarly in treated and control patients from baseline values at induction of anesthesia (23.3 ± 5.6 ng/mL and 21.7 ± 3.9 ng/mL, respectively) to 169.3 ± 42.5 ng/mL and 166.9 ± 50.5 ng/mL, respectively, at admission to the intensive care unit (p < 0.001). Urine histamine further rose similarly in both groups (p < 0.05), reaching its peak values 4 hours postoperatively (231.1 ± 51.7 ng/mL versus 421.3 ± 170.4 ng/mL in treated and control patients, respectively).
BLOOD ELEMENTS.
The course of total WBC before, during, and after CPB in the treated and control groups is depicted in Figure 3. Total WBC fell in both groups significantly and similarly upon institution of CPB (p < 0.01). Total WBC increased during CPB in both groups, showing a significant rebound after protamine administration (p < 0.01). Comparison of the evolution of WBC during CPB and after protamine administration in the aprotinin and control patients showed that the former tended to have a lower increase in the WBC count from the end of rewarming until protamine administration (p < 0.1). Neutrophils showed a course similar to that of total WBC. Analysis of neutrophil kinetics during CPB and after protamine administration showed a significantly lower increase of neutrophils from the end of rewarming until protamine administration in treated than in control patients (p < 0.05) (Fig 4).
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C-REACTIVE PROTEIN.
In all children, CRP was under the detection limit before CPB and 4 hours postoperatively. On the first postoperative day, CRP averaged 36.1 ± 8.2 mg/L in the aprotinin group and 66.0 ± 8.0 mg/L in the control group (p = not significant). Values of CRP measured on the first postoperative day correlated in both groups with the IL-6 value measured 4 hours postoperatively (Spearman's correlation coefficient, 0.73) (p < 0.05) (Fig 5).
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APROTININ ANTIBODIES.
None of the 25 patients had elevated Ap-Ab before the operation. One patient who had received aprotinin (and none who did not receive it) had elevated Ap-Ab 2 weeks after the operation (p = not significant). In the patient concerned, Ap-Ab rose from a preoperative value of 25 AU to 200 AU 2 weeks after the operation.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Aprotinin, a broad-spectrum serine protease inhibitor, has been demonstrated to potentiate complement activation in vitro, enhancing the hemolytic activity of C1 by inactivation of C1 inhibitor [9]. In our series, however, increased C3 conversion and C5a liberation were not observed in patients receiving low-dose aprotinin. This contrasts with a previous study conducted in adults undergoing cardiac operations, showing significantly higher levels of circulating C3 split-products in patients receiving high-dose aprotinin as compared with control patients [10]. The discrepancy between our results and the previous reported data is not clear. The effect of aprotinin on complement might be dose related, thus explaining the absence of enhanced complement activation with a low-dose regimen as observed in our series. On the other hand, the effect of aprotinin on complement activation in vivo could depend on its net effect on all activating or inhibiting serine proteases involved at each step of the cascade of complement activation [11]. Furthermore, a complement-activating effect of aprotinin could be counterbalanced in vivo by its inhibiting effect on the plasma contact system [8], in particular on kallikrein, which interacts with the complement system inducing C5a generation [12]. For all these reasons, a simple dose-response relation of the effect of aprotinin on complement is unlikely.
In our series, neutrophil mobilization at the end of CPB, as it is classically observed at the end of rewarming after lung reperfusion and after protamine administration [13, 14], was significantly reduced in aprotinin-treated as compared with control patients. Total WBC rebound at the end of CPB also tended to be reduced in the treated group, and the difference between the aprotinin and control patients nearly reached the significance level (p < 0.1). Although the magnitudes of C3 conversion and C5a liberation were similar in both groups, the lesser neutrophil mobilization can be interpreted in terms of lesser chemoattraction of marginated cells into the circulation. An enhanced peripheral marginalization of neutrophils in aprotinin patients cannot be strictly excluded from our data, but is unlikely because our aprotinin patients did not show any biologic evidence of increased inflammatory reaction, and aprotinin was recently shown not to influence the plasma levels of circulating adhesion molecules [15]. It has been demonstrated that aprotinin inhibits WBC migration to antigens with a dose-response dependency; this has been discussed in terms of influence on the leukocyte inhibition factor, which is produced by lymphocytes in response to antigen stimulation and mainly acts on macrophages and neutrophils to slow cell migration [16]. This effect could involve either stimulation of leukocyte inhibition factor production by WBC, reduction of leukocyte inhibition factor breakdown, or an increase of target cell responsiveness to leukocyte inhibition factor [16]. It is conceivable that in our patients, a similar effect of aprotinin on WBC migration to chemoattractants has been involved.
In contrast to the evolution of neutrophil count, the magnitude of WBC degranulation during CPB, as measured here by myeloperoxidase and eosinophil cationic protein liberation, was similar in aprotinin and control patients, in accordance with a previous study [10]. Thus, the lower neutrophil count in patients treated with aprotinin and the similar WBC degranulation in both patient groups suggest that low-dose aprotinin inhibits WBC mobilization but not degranulation, the latter involving both circulating and noncirculating (marginated) cells. A beneficial clinical effect of aprotinin related to lower neutrophil mobilization after CPB could not, however, be demonstrated in our series.
We have reported previously that histamine, principally due to basophil degranulation, is liberated into the circulation of children undergoing cardiac operations [17]. In accordance with these results, substantial histamine release was measured in the plasma of our patients from the early postoperative period on. In the urine of these patients, however, significant increases in the levels of histamine and its major urine metabolite methylhistamine between induction of anesthesia and admission to the ICU suggest that histamine is already released in large amounts during the operation. In our series, patients receiving aprotinin did not have increased plasma or urine histamine concentrations as compared with control patients, excluding aprotinin-related histamine liberation. Because of its high pH, however, aprotinin, if rapidly administered intravenously, can be responsible for histamine liberation with anaphylactoid reaction, leading to life-threatening situations [7].
Although aprotinin is considered a weak immunogen and allergic reactions are infrequent after its administration [7], aprotinin-specific antibodies developed in 1 child of 11 patients who received aprotinin in our series, 2 weeks after the operation. Despite the small number of patients investigated, this should raise some concern about the routine use of aprotinin in patients with congenital cardiac defects who are candidates for reoperations, and thus for repeated exposure to aprotinin.
In our series, proinflammatory cytokine production was unaffected by aprotinin administration. Production of TNF- during and after CPB was not observed at all in this series, most probably because of dexamethasone administration before CPB [1]. In contrast to TNF-, significant release of IL-6 was observed in all children despite dexamethasone administration, which inhibits IL-6 synthesis by monocytes in vitro [18]. Interleukin-6 is a pleiotropic cytokine synthesized by monocytes, endothelial cells, and fibroblasts during systemic inflammation, and plays a central role in the control of acute inflammation [18]. In contrast to IL-1 and TNF-, IL-6 is the major inducer of the synthesis of acute-phase proteins such as CRP by hepatocytes. We could verify the relation between IL-6 and CRP synthesis because in our series, IL-6 levels measured 4 hours after the operation correlated significantly with CRP values on the first postoperative day. This relation was demonstrated previously in patients with burn injury [19].
The clinical results of our study confirm that low-dose aprotinin has no significant blood-saving effect in pediatric patients undergoing cardiac operations [20]. Side effects related to aprotinin therapy such as renal dysfunction [4] were not observed. Our study mainly reports the absence of influence of low-dose aprotinin on complement activation, cytokine production, and WBC degranulation in children undergoing relatively simple cardiac operations. Despite the relatively small series investigated, implying that these negative results should be interpreted with caution, our data suggest that low-dose aprotinin affects only neutrophil mobilization at the end of CPB, by a mechanism that warrants further investigations.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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