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Ann Thorac Surg 2003;75:430-437
© 2003 The Society of Thoracic Surgeons
a Department of Anesthesiology, Munich, Germany
b Department of Clinical Chemistry, Munich, Germany
c Department of Cardiac Surgery, German Heart Center, Munich, Germany
d Institute for Clinical Biochemistry, Ludwig-Maximilians-University, Munich, Germany
Accepted for publication September 5, 2002.
* Address reprint requests to Dr Mössinger, German Heart Center, Lazarettstr 36, 80636 Munich, Germany
e-mail: moessinger{at}dhm.mhn.de
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Abstract |
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METHODS: In a double-blind, randomized, and placebo-controlled study, the efficacy of aprotinin in attenuating the hemostatic and inflammatory activation during cardiopulmonary bypass in 60 patients weighing less than 10 kg was investigated. Secondary endpoints were the influence of aprotinin on the reduction of blood loss and allogeneic blood requirement, as well as postoperative oxygenation and length of mechanical ventilation. Aprotinin was administered in a high-dose of 3 x 104 KIU/kg plus a bolus of 5 x 105 KIU (not weight adjusted) added to the pump prime.
RESULTS: Aprotinin plasma concentration at the end of cardiopulmonary bypass (CPB) was with 184 ± 45 KIU/mL, within the targeted range of 200 KIU/mL. Coagulation and fibrinolysis were suppressed (F1.2 1 hour after CPB: 5.35 ± 2.9 nmol/L vs 14.5 ± 23.1 nmol/L; D-dimer 1 hour after CPB: 0.63 ± 0.6 ng/mL vs 2.3 ± 3.1 ng/mL; p < 0.05), inflammatory markers (interleukin [IL]-6, IL-8, IL-10) increased over time without significant differences between the groups, and only complement C3a activation was significantly attenuated at the end of CPB in the aprotinin group. Chest tube drainage was significantly reduced (24 hours: median 13.5 [IQR 12.2] mL/kg vs 19.4 [8.2] mL/kg; p < 0.05). All patients received one unit of packed cells to prime the heart lung machine. A second unit was needed significantly less often in the aprotinin group (13% vs 47%; p < 0.05). Postoperative oxygenation (pO2/FIO2 172 [IQR 128] mm Hg vs 127 [74]; p < 0.05) improved, and the time on ventilator was shorter in the aprotinin group (median 45 hours [IQR 94] vs 101 [IQR 74]; p < 0.05). No side effects were attributable to the use of aprotinin.
CONCLUSIONS: High-dose aprotinin effectively attenuated hemostatic activation and reduced blood loss and transfusion requirement in pediatric cardiac surgery. Postoperative ventilation was also shortened in the aprotinin group.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Despite the routine use of aprotinin in pediatric cardiac surgery at institutions internationally, no generally accepted dosing regimen for aprotinin has been established. The adaptation of dose to the needs of a small patient connected to a relatively high-volume loaded extracorporeal circuit complicates the calculation of a dosage, leading to an aprotinin plasma concentration similar to that observed in adults receiving the full-dose regimen [3].
Suppression of coagulation or fibrinolysis activated by cardiopulmonary bypass (CPB) is considered to provide a basis to determine whether an aprotinin-plasma level is effective. The influence on the inflammatory reaction and prevention of systemic inflammatory response (SIRS) is also widely discussed with conflicting results. A study in children using a low-dose aprotinin regimen essentially showed no demonstrable effect [8]. In adults, however, high-dose administration of aprotinin was shown to attenuate the SIRS reaction [9].
The aim of the present study on pediatric cardiac-surgical patients was to investigate the influence of aprotinin on hemostatic activation, bleeding tendency, and allogeneic blood requirements. Additionally, the inflammatory reaction and clinical outcome in terms of length of postoperative time on ventilator were assessed.
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Patients and methods |
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CPB and anesthetic management
Anesthesia was performed using a standard technique including a combination of sufentanil, midazolam, and pancuronium. No steroids were used to exclude an interference with the trial drug on inflammatory factors. Intra- and postoperative monitoring consisted of ECG, transcutaneous SaO2, arterial blood pressure through radial or femoral line, and central venous pressure by means of a jugular or a femoral venous line. Dopamine (3 µg/kg/min) was administered to all patients after aortic declamping. Higher doses of dopamine, as well as dobutamine, epinephrine, norepinephrine, or amrinone were given if needed according to the hemodynamic status of the patient
The extracorporeal circuit including a membrane oxygenator (Lilliput 1 or 2; Sorin Biomedica, Düsseldorf, Germany), roller pumps, a cardiotomy reservoir, and an ultrafiltration device (HFT 0.2; Sorin Biomedica), which was primed with 1 U (250 mL) packed red cells, 1 U (300 mL) fresh-frozen plasma, and 100 to 250 mL Ringer’s solution. Heparin (375 U/kg) was administered for anticoagulation (ACT > 400 seconds) and antagonized with protamine in a 1:1.5 ratio. CPB was performed in hypothermia (24°C rectal temperature), reducing usual blood flow of 2.4 L/m2/min to 1.2 L/m2/min when hypothermic. Neonates were cooled to rectal temperatures below 20°C with similarly reduced blood flow or deep hypothermic circulatory arrest (DHCA), according to surgical necessity. Within 10 to 15 minutes after bypass, pump prime volume was reduced to a minimum and hematocrit elevated by modified ultrafiltation. The remaining volume of the cardiotomy reservoir was transfused in the operating room or in the intensive care unit (ICU); additional blood products were administered if needed to maintain a stable hemodynamic and hemostatic status. A hematocrit value of 30% to 35% or even more for a cyanotic infant was considered adequate in the postoperative period after major cardiac surgery. Platelets were given if clotting was impaired to all appearances.
Measurements
Blood samples were taken from the central venous line after induction of anesthesia [1], at the lowest rectal temperature when starting to warm up [2], 5 minutes after aortic declamping [3], 5 minutes [4] and 60 minutes [5] after weaning from bypass, as well as 4 hours [6] and 24 hours after cessation of bypass [7], and the third day postoperatively [8].
Blood specimens were collected in different phlebotomy tubes (Sarstedt, Nümbrecht, Germany): EDTA tubes for blood counts and C3a; Li-Heparin tubes for creatinine, CRP, IL-6, IL-8, IL-10, and aprotinin; and citrate-tubes for D-dimers and prothrombin fragment 1.2 (F1.2). Aliquots of plasma samples were stored frozen at -80°C until assayed within batches.
D-dimers were determined using standard photometric and immunoturbidimetric (Tina-quant) assays on a Hitachi 911 analyzer (Roche Diagnostics, Mannheim, Germany). F1.2 was measured using the Enzygnost F1.2 micro-enzyme immunoassay (Dade Behring, Schwalbach, Germany).
Inflammatory response was monitored using complement C3a and interleukin (IL)-6, -8, and -10. Complement C3a was assayed with the C3a fragment enzyme-linked immunosorbent assay (ELISA; Quidel, Mountain View, CA). IL-6 and IL-8 were measured using a solid-phase, two-site chemiluminescent enzyme immunometric assay (Diagnostic Products Corporation, Los Angeles, CA), and IL-10 was assayed using solid-phase ELISA microtiter plates (PerSeptive Biosystems, Framingham, MA). For aprotinin plasma concentrations, samples were measured using a competitive ELISA according to Müller-Esterl and associates [10].
Platelet function was assessed by flow cytometry using the synthetic thrombin agonist TRAP (thrombin receptor agonist peptide) to evaluate the platelet reactivity at four time points (preoperative, beginning of rewarming, and 1 and 4 hours postoperatively). The method is described in detail by Gawaz and associates [11].
Blood loss through chest tubes was recorded after 6, 12, and 24 hours, and in total before taking off chest tubes. All blood products were registered, such as packed red cells, platelets, fresh-frozen plasma, human albumin, and prothrombin complex concentrate (PPSB).
Following a standard protocol, weaning from ventilation was started, when oxygenation was sufficiently recovered (pO2 > 70 mm Hg with FIO2 < 0.3 and positive inspiratory pressure < 20 cm H2O). To compare oxygenation ability at different FIO2, we calculated an oxygenation ratio of pO2/FIO2.
Activation of hemostasis, as measured by F1.2 and D-dimers at the end of operation, was the primary efficacy end point. Secondary end points of the study were blood loss and allogeneic blood requirements, time of postoperative ventilation, and length of stay in the ICU, as well as the attenuation of inflammatory response. Based on previous studies [3], we expected a difference in F1.2 of 5 nmol/L and a standard deviation of 4 nmol/L at the end of operation. Assuming a two-sided type I error protection of 5% and a power of 80%, we calculated that a sample size of 25 patients was required to permit the detection of a 50% reduction in thrombin generation at the end of operation, which was considered as clinically important. Because pediatric patients with congenital heart disease present a wide variation in physiologic factors, rendering statistical comparison sometimes difficult, 30 patients were enrolled into each group.
Statistical analysis
Statistics were performed by using the software package StatView 4.02 (Abacus Concepts, Inc., Berkeley, CA) for a Macintosh computer. Normally distributed data are presented as mean ± SD; skewed data as median and interquartile range (IQR, 25% to 75%). Baseline characteristics of the groups were examined using analysis of variance for continuous variables followed by Fisher’s protected least significant differences post hoc test. Analysis of variance for repeated measures was used to evaluate, within groups, the changes of the variables over time, with Bonferroni correction adjusted to the number of comparisons. 
2 analysis was used for categorical variables. For factors not normally distributed, a nonparametric test for two unpaired groups according to Mann-Whitney was applied. A p value less than 0.05 was considered statistically significant.
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Results |
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The course of routinely surveyed laboratory values such as hemoglobin, platelet count, C-reactive protein (CRP,) and others were almost identical in both groups (hemoglobin [mg/100 mL] preoperative: 12.9 ± 2.8 vs 12.60 ± 2.1; postoperative day (POD) 3: 14.2 ± 1.7 vs 13.9 ± 1.4; platelets [1,000/mL] preoperative: 348 ± 114 vs 351 ± 121; POD 1: 87 ± 39 vs 94 ± 71). Serum creatinine did not increase in either group ([mg/100 mL] POD 3: 0.7 ± 0.2 vs 0.7 ± 0.2).
The generation of prothrombin fragments F1.2 was suppressed by aprotinin, showing the greatest difference 1 hour after CPB (Table 5), whereas D-dimer formation was nearly completely hindered throughout the whole process. Surprisingly, D-dimers increased to very high concentrations in both study groups on the third postoperative day, reaching levels exceeding those of the nonaprotinin group during CPB (Fig 4).
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For IL-6, IL-8, and IL-10, a parallel increase culminating in the early postoperative phase was observed in both groups (Table 5). As the only differing finding, the elevation of complement C3a levels was significantly attenuated at 4 and 24 hours postoperatively in those patients treated with aprotinin.
Circulatory arrest was carried out in 18 patients ranging from 5 to 51 minutes. In 12 patients (5 aprotinin, 7 placebo), DHCA exceeded 20 minutes. In a subanalysis, patients with circulatory arrest obtained similar results as those of the overall calculation, admittedly without reaching statistical significance due to small numbers.
We also performed a subanalysis of the four major diagnosis groups, and found similar differences compared with the entire study population, as listed in Table 6. Again, due to the low number of cases, the analysis of the subgroups did not have enough power to achieve statistical significance.
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Side effects attributable to aprotinin, notably allergic reactions, were not seen. Thrombotic complications were monitored clinically and not suspected in any of the patients perioperatively. In-hospital mortality was 7% (4/60). One intraoperative death was recorded in each group, including one resulting from excessive surgical bleeding from the anastomosis (pulmonary vein to left atrium) in TAPVC (aprotinin group) and another after unsuccessful repair and subsequent replacement of a malformed mitral valve in partial atrioventricular septum defect (placebo group). Two further fatal courses were observed postoperatively. One patient in the aprotinin group after arterial switch operation generated massive bilateral chyleous effusions (vena cava thrombosis was excluded by echography at the onset after 1 week), and a second from the control group having TOF associated with partial trisomy 16 needed resuscitation on postoperative day 12 and did not recover.
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Comment |
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The prime end point in most studies dealing with the efficacy of aprotinin is postoperative blood loss or allogeneic blood component transfusion. A comparison of the previous studies in pediatric patients shows that due to a wide range of average blood loss and heterogeneous diagnosis, the possible beneficial effect is hard to assess and to compare [3]. In a study with predefined diagnosis groups (50 patients each for TGA, VSD, and TOF), only in the TGA group were observed significant, but not necessarily clinically relevant, differences in relative blood loss (reduction by 14%) [12]. Similar to the VSD group of this study, zero reduction of blood loss is reported in a few reports, but usually diminution varies between 10% and 56% [3]. Although obtaining statistical significance whenever a larger population is examined, the amount of reduction is not comparable to that found in adult patients treated with high-dose aprotinin [1]. The high dosage and plasma concentrations could be the causal background of the surprisingly pronounced reduction of blood loss in the present study, which furthermore was applicable to all main diagnosis subgroups. The exclusion of all patients with more than 120 minutes of CPB, still leading to a significant reduction of blood loss and allogeneic blood consumption, underlines the value of the drug even in uncomplicated procedures, although there is no doubt that patients undergoing redo operations or long pump runs are those who profit most.
Clinically, more important than blood loss, however, is the contamination with a number of different blood donors, which was significantly more frequent in the control group. This fact already advocates the application of the drug on a routine basis, at least in a setting like in our institution, where obviously the threshold between using just one and more than one units of packed cells is borderline.
The present study also showed that even in complex, yet uncomplicated cases of pediatric cardiac surgery, platelet transfusion can mostly be avoided, even without using aprotinin.
Aprotinin dosing and hemostatic activation
The dosage adjustment of aprotinin to small patients remains an issue [13]. Most dosing schedules are based on the original Hammersmith protocol for adults [6], adjusted for children either for body surface area or for body weight. As the portion of body surface area of a newborn compared with an adult is more than twice of the percentage relating to body weight, the former method usually gives higher doses in newborns and small children than weight-based calculations. Most importantly, however, the dilution of the circulating blood volume and, therefore, the dilution of the drug preponderates in small patients, where the ratio "pump prime volume–to–blood volume" is several times higher compared with the one in adult patients.
The lack of efficacy in some studies may thus be contributed to lower dosage, because dilution by the prime volume is not taken into account. For this reason, in our study, we employed a fixed dose of 5 x 105 KIU of aprotinin added to the pump prime, which had produced stable concentrations of 200 KIU and more throughout the pump run in a previous study [3]. However, as body weight is linked to the priming volume, aprotinin concentrations in this study trended towards lower levels for the older children (Fig 2). A practicable alternative, also applicable in patients weighing more than 10 kg, could be a prime volume-adapted dosage (eg, 103 KIU/mL prime). Again based on our measurements [3], we refrained from adding a continuous infusion, but our current results would rather suggest to additionally add aprotinin during bypass to avoid the decline in plasma concentrations (eg, 2 x 104 KIU/kg/h)(Fig 1).
A level of 200 KIU/mL is considered to be efficacious not only in suppressing fibrinolysis, but also inhibiting kallikrein and, consequently, attenuating the activation of coagulation by reduced thrombin generation [14]. We found prothrombin fragments F1.2 significantly reduced in our high-dose aprotinin group previously [3] and again in the present study, which was most accentuated 1 hour after CPB. This finding demonstrates that aprotinin in high concentrations has antithrombotic properties [7]. Attenuating thrombin generation and the subsequent activation of the coagulation cascade is hypothesized to be a major mechanism of diminishing postoperative bleeding tendency for aprotinin [14].
The suppression of fibrinolysis, as reported in other studies [4, 7, 12], could be confirmed in the present study. The high fibrinolytic activity found in both groups on day 3 postoperatively, however, was remarkable and unexpected, although the course of D-dimers in a study in neonates [15] was almost identical. Little is known about hemostatic disturbances during the early postoperative period. In view of the current findings, one might suspect that hemostatic derangement does not stop immediately after the end of CPB but persists during several days postoperatively. During this period, the balance of hemostasis is shifted to the procoagulatory side, and the patients are at increased risk of thrombembolic complications. Further studies should examine such a predisposition for venous thrombosis and their relation to hemostatic abnormalities.
The lack of efficacy of aprotinin regarding platelet function, as assessed by flow cytometry with and without TRAP stimulation, can be explained by the mode of action of TRAP. This agonist bypasses the activation of the protease-activated receptor 1 (PAR 1), which is inhibited by aprotinin [16]. Thus, a platelet preservation effect could not be demonstrated with this method.
Aprotinin and inflammatory response
Contradictory results regarding an attenuation of the inflammatory reaction by aprotinin have been reported in adults [9, 17]. In a pediatric population, using low-dose aprotinin (2 x 104 KIU/kg), no effect was observed regarding inflammatory response [8]. Using much higher doses, similar results not militating in favor of a pronounced systemic antiinflammatory effect were obtained in the present study, with the exception of complement C3a.
However, clinical outcome values were improved. Time on ventilator was significantly longer for the control patients. Oxygenation, as measured by the ratio of p02/FI02, was significantly improved in the aprotinin group throughout the postoperative period until extubation. It may be speculated that a reduced inflammatory response within the lung perfusion [18] could be the cause of improved ventilation. Rahman and associates [19] found an attenuation of neutrophil count in the lung parenchyme and a reduced lung perfusion injury with the use of aprotinin in coronary artery bypass graft patients. Thus, there is some evidence that lung injury caused by CPB can be attenuated by aprotinin. Other clinical values (eg, diuresis or use of diuretics), as well as a reduced inotropic support when using aprotinin [20] did not show any differences in the present study. Thus, the clinical relevance of an (assumed) antiinflammatory action of aprotinin still remains under consideration.
Being closely related to the duration of artificial ventilation, the length of ICU stay also was different between placebo and aprotinin group, but nearly missed the 0.05 threshold (Table 4). This value, however, is strongly susceptible to organizational influence, so that reasons not associated with medical need may have confounded these data. So, if these findings are reproducible, aprotinin could contribute to a shortened ICU and hospital stay, improving dramatically its cost-effectiveness [21].
Limitations of the study
Although the purpose of this study was to evaluate reliable data for a rational use of aprotinin, some difficulties in comparing patients with different pathologies and ages occur. On the other hand, a limitation to just one diagnostic subgroup would take a long time and perhaps could not be simply generalized for other populations in pediatric cardiac surgery. The mode of action of aprotinin is complex and influenced by many different factors, so that contradictory results arise. Perioperative management, especially concerning ventilation or transfusion policy, may vary considerably between different institutions, so that findings from this study may not have the same importance in other settings.
Because pediatric cardiac surgery frequently carries the risk of a second operation within a short time period, the possible occurrence of an allergic reaction in a reexposure with potentially even fatal outcome must be weighed against the benefits [22].
In conclusion, the present study demonstrated efficacy of aprotinin to reduce hemostatic activation, blood loss, and allogeneic blood requirement in pediatric cardiac patients. In comparison with other investigations, a relatively high dosage of aprotinin was applied. With this dosage, the postoperative time on ventilator was also reduced. No apparent drug-related adverse events were observed. In summary, aprotinin is recommended for the use in pediatric cardiac surgery.
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