Ann Thorac Surg 1998;65:S45-S51
© 1998 The Society of Thoracic Surgeons
Activation of Hemostasis During Cardiopulmonary Bypass and Pediatric Aprotinin Dosage
Hansjörg Mössinger, MDa,
Wulf Dietrich, MDa
a Department of Anesthesiology, German Heart Center, Munich, Germany
Address reprint requests to Dr Mössinger, German Heart Center, Lazarettstr 36, 80636 Munich, Germany
Presented at Risk Assessment of Major Perioperative Issues in Pediatric Cardiac Surgery, Washington, DC, May 7, 1997.
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Abstract
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Background. Cardiopulmonary bypass results in inappropriate activation of the coagulation and fibrinolytic systems. Factors such as a greater degree of hemodilution, use of deep hypothermic circulatory arrest, the impact of cyanosis on coagulation, and the immature coagulation system of the newborn will increase the risk of problematic perioperative bleeding.
Methods. This article describes the characteristics of the hemostatic system in children undergoing cardiac operations and addresses the effect of aprotinin on hemostasis. Hemostatic parameters were measured in 96 pediatric patients using three different doses of aprotinin. The high-dose group (group 1) received 30,000 KIU/kg (4.2 mg/kg) of aprotinin after induction of anesthesia and an additional bolus of 30,000 KIU/kg (4.2 mg/kg) into the pump prime. In the low-dose group (group 2), both the initial bolus and the pump-prime dose of aprotinin were halved to 15,000 KIU/kg (2.1 mg/kg). Group 3 received the high dose with an additional bolus of aprotinin to the pump prime.
Results. Plasma levels of aprotinin in both groups 1 and 2 were lower than the 200 KIU/mL (0.03 mg/mL) value usually reached in adults with high-dose aprotinin treatment. Group 3 patients had levels greater than 200 KIU/mL (0.03 mg/mL) throughout the procedure. Biochemical indices of fibrinolysis (fibrin[ogen] degradation products, D-dimers) revealed significant and dose-dependent inhibition at all three aprotinin concentrations. In contrast, significant changes in coagulation activation markers (prothrombin fragments F1.2, thrombin-antithrombin III complex, and fibrin monomers) were found only in group 3.
Conclusions. The inverse relationship between a small patient’s blood volume and the large pump-prime volume requires additional aprotinin to be added to the prime to achieve plasma levels sufficient to inhibit activation of the coagulation cascade.
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Introduction
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The hemostatic derangement caused by cardiopulmonary bypass (CPB) is of particular significance in pediatric cardiac surgery and may result in a more pronounced bleeding tendency than that seen in adult patients. Specific influences include the immature coagulation system of the neonate, the influence of cyanosis on hemostasis and coagulation, a greater degree of hemodilution, and the use of deep hypothermic circulatory arrest.
This presentation will discuss three aspects relevant to the conduct of CPB in the pediatric patient population: (1) the hemostatic system in children, (2) the efficacy of aprotinin in improving hemostasis and minimizing blood loss, and (3) the optimal dose of aprotinin for use in pediatric practice.
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The hemostatic system in children undergoing cardiopulmonary bypass
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Cardiopulmonary bypass results in exposure of the blood to a large artificial, nonendothelialized surface. This unphysiologic state provokes the activation of many cascade systems, which have been described as the inflammatory response of the body (Fig 1).
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Fig 1. Cellular and plasmatic systems involved in the inflammatory response induced by cardiopulmonary bypass-induced contact activation.
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One aspect is the inappropriate activation of the coagulation and fibrinolytic systems that leads to an increased postoperative bleeding tendency. Contact activation of the blood stimulates urokinase plasminogen activator, which in turn activates plasminogen, starting fibrinolysis by a mechanism that does not occur in physiologic hemostasis [1]. Thrombin is simultaneously activated via factor XII and factor XI, and both thrombin and plasmin are strong platelet activators and are mainly responsible for platelet dysfunction caused by previous activation, thereby contributing significantly to the postbypass bleeding tendency [2, 3].
Factors affecting hemostasis in children
Systemic inflammatory response seems intensified in children, the balance between coagulation and fibrinolysis even more delicate and susceptible to exogenous stimulation. Specific factors affecting hemostasis in pediatric patients include the following:
- Hemostatic factors
- Neonates: lower concentrations of hemostatic factors
- Cyanosis: thrombocytopenia, increased fibrin split products, reduced factors
- Reduced antithrombin III activity but decreased an tithrombin III/prothrombin ratio
- Reduced platelet aggregation
- Decreased von Willebrand factor
- Technical factors
- Pronounced hemodilution
- Hypothermia, frequent deep hypothermic circula tory arrest
- Complex intracardiac procedures (patches, sutures, ventricolotomy)
- Multiple redos
- Heparin plasma concentrations mainly depend on varying prime load
Two groups of young patients are at particular risk. First are infants younger than 6 months with maturational differences in the hemostatic system. Plasma concentrations of the vitamin K-dependent clotting factors (II, VII, IX, X), proteins S and C, and the components of the contact system (Hageman factor, prekallikrein, high-molecular-weight kininogen, and factor XI) are all lower in neonates, probably because of decreased hepatic synthesis and accelerated clearance caused by increased metabolic rates [4]. The second group comprises cyanotic patients who demonstrate impaired and accelerated clearance caused by increased metabolic rates. These patients demonstrate impaired hemostasis related to polycythemia, low platelet count and abnormal platelet function, decreased concentrations of factors V, VII, and VIII, and increased fibrinolysis, changes that directly correlate with the degree of cyanosis [5]. As in both groups many inhibiting factors are equally diminished, hemostasis seems to be balanced at a lower level.
The conduct of CPB, including extensive cooling and in many cases circulatory arrest, and the complex intracardiac surgical procedures performed also disadvantage the pediatric population compared with the adult population. The adverse size relationship between the patient and the heart-lung machine dictates that more profound hemodilution occurs, with undesirable dilution of often already low clotting factors. Doses of heparin vary widely between pediatric cardiac centers. Differences often encountered relating to heparin sensitivity are illustrated by data from the German Heart Center (Fig 2). Although 25% of pediatric patients had antithrombin III values lower than 80% compared with only 7% in the adult population, additional heparin was needed more often during bypass in the adult operations, presumably because of a higher sensitivity to heparin in children.
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Fig 2. Comparison of antithrombin III (AT-III) activity and heparin sensitivity in children and adults undergoing cardiopulmonary bypass. (*Difference p < 0.05.)
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Effect of aprotinin on hemostasis and blood loss
As a pharmacologic means to attenuate hemostatic activation, the protease inhibitor aprotinin has shown its capacity to block fibrinolysis in low doses, and to attenuate contact activation in higher doses (plasma levels > 200 kallikrein inhibiting units [KIU] [0.03 mg]). A prospective, randomized study at the German Heart Center investigated the effect of aprotinin in 60 children undergoing cardiac surgery who weighed less than 10 kg [6]. Patients were randomly assigned to one of three dose groups. The low-dose group (group 1) received 15,000 KIU/kg (2.1 mg/kg) of aprotinin after induction of anesthesia and an additional bolus of 15,000 KIU/kg (2.1 mg/kg) into the pump prime. In the high-dose group (group 2), both the initial bolus and the pump-prime dose of aprotinin were doubled to 30,000 KIU/kg (4.2 mg/kg). No continuous infusion was given during the procedure. Patients without aprotinin therapy served as controls. The mean age (less than 1 year), body weight (approximately 6 kg), operating time (about 3 hours), and bypass time (about 90 minutes) were comparable between groups.
Blood samples were drawn at time periods throughout the procedure to determine the effect of aprotinin on biochemical indices of fibrinolysis (fibrin[ogen] degradation products, D-dimers) and coagulation (prothrombin fragments F1.2, and thrombin-antithrombin III complex fibrin monomers). After 60 minutes of CPB, parameters of fibrinolysis were significantly lower in the two aprotinin groups compared with the control group, with the lowest concentrations in the high-dose aprotinin group (Fig 3A). However, there was only a tendency toward a reduction in coagulation activation, with thrombin-antithrombin III complexes and F1.2 fragments unaffected by either dose of aprotinin, although a significant reduction in fibrin monomer formation was seen in the high-dose aprotinin group (Fig 3B).
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Fig 3. Effect of aprotinin on (A) fibrinolysis (illustrated by fibrin degradation products) and (B) coagulation activity (illustrated by F1.2 and fibrin monomer concentrations. (*Difference p < 0.05 versus control.) (Data taken from reference 6.)
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The lack of effect of aprotinin on coagulation in this pediatric population was in contrast with the results from aprotinin studies in adults (Table 1) [7]. One possible explanation for these discrepancies was the lower plasma concentrations of aprotinin measured in the pediatric study [6]. Neither group had concentrations greater than 100 KIU/mL (0.014 mg/mL), approximately half of the level reached with high-dose aprotinin treatment in adults and the level suggested as necessary to inhibit kallikrein and contact-phase activation. The reason for this difference is probably the adverse relationship between the patients’ small blood volume and the large volume of the pump prime, essentially leading to a greater dilution of the drug during bypass in pediatric patients.
This finding prompted a complementary study to investigate patients treated with much higher doses of aprotinin (group 3) [8]. Patients less than 10 kg were given the high-dose bolus dose before CPB, ie, 30,000 KIU/kg (4.2 mg/kg), but with a total of at least 500,000 KIU (70 mg) added to the pump prime. This regimen was estimated based on the dilution effect of the pump-prime volume, which is at least 500 mL in our institution. Measurements of blood levels of aprotinin with this regimen found peak concentrations greater than 400 KIU/mL (0.06 mg/mL), and the levels remained elevated above those found in adults throughout the operation (Fig 4). Analysis of the biochemical markers of coagulation and fibrinolysis showed a significant reduction in thrombin generation with this higher dose of aprotinin compared with the other three groups, and suppression of fibrinolysis demonstrated a dose-related effect with further attenuation at the highest dose (Fig 5).
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Fig 4. Plasma concentrations of aprotinin achieved with varying dose regimens in pediatric patients undergoing operations with cardiopulmonary bypass (CPB). Adult levels are shown for comparison. (Adults = full-dose Hammersmith regimen; Dose 1 = 15,000 KIU/kg [2.1 mg/kg] loading dose, 15,000 KIU/kg [2.1 mg/kg] pump prime; Dose 2 = 30,000 KIU/kg [4.2 mg/kg] loading dose, 30,000 KIU/kg [4.2 mg/kg] pump prime; Dose 3 = 30,000 KIU/kg [4.2 mg/kg] loading dose, 500,000 KIU/kg [70 mg/kg] pump prime; Op = operation.)
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Fig 5. Effect of aprotinin on (A) fibrinolysis (illustrated by fibrin degradation products) and (B) coagulation activity (illustrated by thrombin-antithrombin III, prothrombin fragment F1.2, and fibrin monomer). (*Difference p < 0.05 versus control; **difference p < 0.05 versus dose 1; ***difference p < 0.05 versus dose 2.)
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Despite the proven efficacy of aprotinin to reduce bleeding and the need for blood and blood-product transfusions in adult cardiac surgery [7, 9–13], the results in pediatric cardiac surgery are conflicting [6, 8, 14–24]. A few authors did not see any saving effect of chest tube drainage, but most studies found a moderate reduction of about one third. Results from studies based on large patient groups attained statistical significance (Fig 6). All of these studies are not well matched with patient populations, varying considerably in age, type of operation, duration of bypass and operation, and in particular, the control levels of chest-tube drainage in the first 24 hours postoperatively. Individual centers varied from more than 50 mL/kg to as little as 5 mL/kg (Table 2).
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Optimal dosage of aprotinin
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An additional, possibly important, reason for the wide variability in aprotinin efficacy in the studies discussed above is the significantly differing doses and administration protocols used by individual centers [6, 8, 14–24]. The majority of centers base their dosing schedule on the originally described Hammersmith protocol [13], some adjusting for body weight and others for body surface area. A comparison between the actual amounts of aprotinin calculated either from the child’s surface area or from weight are very dependent on the age of the child (Fig 7). This discrepancy is highest in the youngest patients, with the ratio of surface-area dose/weight dose being 2.4 to 1 in the newborn; this discrepancy does not become insignificant until adolescence.
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Fig 7. Aprotinin dose based on body surface area as a ratio of dose based on body weight as a function of patient age.
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Although calculation based on surface area will result in a larger dose of aprotinin given to the patient, the use of a weight-based dose is acceptable provided the concentration of aprotinin in the pump-prime remains high and stable as observed with the new higher-dose regimen detailed in the study reported above [8].
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Conclusions
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Neonates and children undergoing cardiac operations with CPB are at higher risk of hemostatic derangement. Aprotinin’s actions to inhibit fibrinolysis in a dose-dependent manner, to attenuate contact activation and thrombin generation when reaching high concentrations, and to preserve a more physiologic hemostatic pattern after CPB are very similar to those observed in adults.
Clinical studies on the use of aprotinin in pediatric practice are difficult to interpret because of wide variations in dose regimens, patient age, type of operation, and other factors. Although findings concerning blood loss and allogeneic blood requirements are not as convincing as in adults, a moderate reduction in blood loss was found in most studies and was statistically significant in those studies with larger patient groups. In addition, a drier operating field and shorter chest-closure times were observed.
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Discussion
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DR GLYN D. WILLIAMS (Seattle, WA): I was wondering whether in pediatric surgery the extrinsic coagulation system has more of a part to play than we are giving it credit for, and whether your high-dose aprotinin administration regimen may be important in terms of that.
DR MÖSSINGER: Well, it can block fibrinolysis at the end of the cascade, but as far as I know, it cannot act on extrinsic activation earlier.
DR WILLIAMS: On a separate point, are you recommending that we should have a dose for the pump prime, based on the total volume of the prime, so that the amount per millimeter of aprotinin given will be the same? Is that what you are recommending?
DR MÖSSINGER: We just add quite a high dose so you need not adjust the dose for every different prime volume, but that is another possibility. The French group is doing it like that. But I think it is easier just to put one bottle, which is 500,000 KIU (70 mg) into the prime. We have measured the levels, so we are quite sure they are high enough.
DR WULF DIETRICH (Munich, Germany): May I comment on the first part of Dr Williams’s question, concerning the intrinsic and extrinsic systems? Aprotinin has no influence on the extrinsic activation of hemostasis, because it acts on the kallikrein level, which has nothing to do with the extrinsic system. On the other hand, there is ongoing debate about what is activated first, the intrinsic or the extrinsic system, and which is more important. As we now know, there are many interactions between these two systems. For instance, the extrinsic system is activated by the activation of monocytes, which are activated by complement and also thrombin. In addition, there is an interaction at the level of factor XII, which is activated from the intrinsic side as well as from the extrinsic side.
So I think it is difficult to differentiate what is the result of intrinsic activation and what is the result of extrinsic activation. However, we are sure that aprotinin inhibits the intrinsic pathway of hemostasis. That means kallikrein is inhibited if you have a level, let us say, greater than 200 KIU (0.03 mg) per milliliter of plasma. And it also inhibits the fibrinolytic pathway, which means the conversion of single-chain urokinase plasminogen activator into its active two-chain form. On the other hand, the plasminogen-plasmin interaction is also inhibited. So it is a double inhibitor of coagulation and fibrinolysis. But it does not inhibit the extrinsic pathway of coagulation directly.
DR WILLIAM J. GREELEY (Philadelphia, PA): I have just a comment: One has to wonder, if you did a metaanalysis of the 13 studies and their outcome, would you now see efficacy in either chest-tube drainage or blood loss? Certainly, if you look at the experience with the antithrombotic agents in adults (for example, the CAST study and others like it) we would have known 10 years ago some details of the efficacy if we had actually done a metaanalysis of those series of small studies; you know, my stamp collection versus your stamp collection type of approach. When you look at it in aggregate, you would probably see effects, and we would see effects earlier.
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Abstract
Introduction
