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Ann Thorac Surg 1998;66:153-158
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Aprotinin in pediatric cardiac operations: a benefit in complex malformations and with high-dose regimen only

^a Clinic for Cardiovascular Surgery, University Hospital, Zürich, Switzerland

Address reprint requests to Dr Carrel, Clinic for Thoracic and Cardiovascular Surgery, University Hospital, CH-3010 Berne, Switzerland
e-mail: (thierry.carrel{at}insel.ch)

Presented at the Poster Session of the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. The benefits and the current indications of aprotinin in congenital operations are not well defined. At present there are only a few studies available that have investigated a small number of patients in several heterogeneous groups of malformations.

Methods. We investigated efficacy and safety of aprotinin in three groups of children <15 kg, presenting with isolated ventricular septum defect (n = 60), tetralogy of Fallot (n = 52), and transposition of the great arteries (n = 56). Low-dose aprotinin regimen A1 (500,000 KIU in pump prime only) and high-dose aprotinin A2 (50,000 KIU/kg during induction of anesthesia, 50,000 KIU/kg in pump prime, and 20,000 KIU/h continuous infusion) were compared to a control group A0 (without aprotinin) regarding perioperative blood loss, transfusion requirements, and effects on the coagulation system.

Results. The most common coagulation tests of aprotinin-treated patients and the platelet numbers were comparable with those of control patients preoperatively and 15 minutes after protamine administration. A significant dose-dependent reduction in fibrin–fibrinogen split products was observed at the end of cardiopulmonary bypass in the majority of aprotinin-treated patients with transposition. In patients with ventricular septum defect and Fallot, no significant difference in blood loss and transfusion requirements could be observed between patients with or without aprotinin and no difference was observed between low- and high-dose regimen. In transposition of the great arteries, high-dose aprotinin led to significant reduction of blood loss (p = 0.02) and postoperative blood transfusion (p = 0.003). Severe side effects as a result of administration of aprotinin were not observed.

Conclusions. High-dose aprotinin reduces blood loss and transfusion requirement only in complex congenital cardiac operations; therefore aprotinin cannot be recommended as a blood conservation agent in routine pediatric operations.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The use of cardiopulmonary bypass (CPB) during cardiac operations causes a significant impairment of the coagulation system. Preoperative coagulation disorders in the newborn, perioperative hemodilution, and systemic heparinization, as well as complement and platelet activation in the extracorporeal circuit are some of the most important factors that may influence postoperative hemostasis [1, 2]. Early and aggressive pharmacologic treatment may reduce postoperative bleeding, but surgical reexploration is still required in approximately 2% to 5% of patients because of persistent bleeding [2–5].

Aprotinin is a nonspecific serine protease inhibitor that is able to inhibit various proteases involved in the coagulation, fibrinolytic, and complement cascades [6]. Another target is the preservation of glycoprotein Ib receptors on platelet membrane. Further, aprotinin develops a similar antiinflammatory effect to that of methylprednisolone in blunting CPB-induced systemic tumor necrosis factor release and neutrophil upregulation [7]. In the current literature, there is discrepancy between dosage recommendations and theoretic calculations that try to allow estimation of plasma concentration necessary to inhibit individual enzymes [6]. However, these concentrations may differ depending on the activating state of the various enzymes and the local concentration of aprotinin.

Although the beneficial effects of aprotinin in the adult population undergoing cardiac operations have been extensively discussed [8, 9], there is still controversy about indications and dosage in congenital operations. The main studies available in the pediatric group are dealing with a relatively small number of patients presenting with a large spectrum of malformations [10–14].

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
After approval by the University Hospital Board, we conducted a prospective, nonrandomized open study with low-dose and high-dose aprotinin regimen and compared perioperative blood loss (at 6 and 24 hours), transfusion requirements (at 24 and 48 hours), main coagulation parameters, liver and renal tests with those of a control group of patients who underwent similar surgical interventions without aprotinin. Three distinct groups of children weighing less than 15 kg were evaluated: isolated ventricular septum defect (VSD, n = 60), tetralogy of Fallot (TOF, n = 52), and transposition of the great arteries (TGA, n = 56).

For each lesion, the patients were assigned either to group A0 (control group without aprotinin), low-dose aprotinin regimen A1 (= 50,000 KIU/kg in pump prime only), and high-dose aprotinin A2 (= 50,000 KIU/kg during induction of anesthesia, 50,000 KIU/kg in pump prime, and 20,000 KIU/kg/h continuous infusion). All patients were included serially into one of the three dose regimen, following the sequence A0, A1, and A2. Inclusion criteria were defined as follows: elective repair, no anticoagulant during the last 10 days before operation, no previous use of aprotinin, and normal blood urea and creatinine values.

No child with VSD underwent pulmonary artery banding before definitive repair. In Fallot tetralogy, there was a comparable incidence of systemic–pulmonary shunts procedure before definitive repair (3 in A0 group, 2 in A1 group, and 3 in A2 group). The following spectrum was observed in children with TGA: TGA with intact ventricular septum in 34, TGA with VSD in 18, and TGA–VSD with coarctation (n = 2), and with double outlet right ventricle (n = 2). All operations were performed through a median sternotomy. Perioperative anticoagulation was achieved with 300 U/kg bovine heparin given 5 minutes before starting CPB with the aim of reaching an activated clotting time (determinated with cellite) more than 400 seconds. The priming volume of the extracorporeal circuit consisted in 700 mL of Ringer lactate solution with either whole blood or 100 mL of 20% human albumin solution, depending on the calculated hematocrit value on bypass, which was targeted to be around 0.20. The majority of patients underwent operation under moderate hypothermic CPB at a flow of 2.4 L · m^-2 · min^-1. In 4 patients with transposition, deep hypothermic circulatory arrest was performed. Myocardial protection included antegrade, cold blood cardioplegia, and hot shot before reperfusion. After weaning from extracorporeal circulation, heparin was reversed with protamine sulfate in a 1:1 ratio.

Blood samples were collected during induction of anesthesia, 15 minutes after starting CPB, and 15 minutes after administration of protamine sulfate. Coagulation studies included activated clotting time, platelet count, partial thromboplastin time, thrombin time, and fibrinogen. Additional samples were taken 2 to 3 hours after termination of operation and on the first postoperative day. In patients with TGA, fibrinogen–fibrin split products were tested routinely. In case of persisting or increasing tendency to postoperative bleeding, a heparin–protamine titration test was performed and clotting factors were determined. In addition, routine laboratory examination including serum electrolytes, and renal and liver values was performed. Assessment of postoperative bleeding was performed soon after arrival in the intensive care unit and on the first postoperative day. Assessment of intraoperative bleeding was realized in the operating theater until completion of sternotomy closure as well as in the intensive care unit. Total mediastinal blood drainage was assessed after 6 and 24 hours. In case of severe postoperative low cardiac output (defined when several of the following factors developed: arterial hypotension and increased filling pressures despite adequate inotropic support, decreased urine output [0.5 mL · kg^-1 · h^-1], and metabolic acidosis) confirmed by clinical signs of centralization with increased temperature difference between central and peripheral temperature, a peritoneal catheter was introduced in the abdominal cavity and dialysis was started immediately, using alternatively 2.5% and 4.5% dialysis solutions.

Postoperative transfusion of fresh blood or red cell concentrates was performed when the hematocrit value was lower than 0.25 to 0.28. Platelets were substituted when the count was less than 50,000/µL. Fresh frozen plasma was administered when prothromin time was lower than 50% or when an individual clotting factor was below 30%.

Aprotinin efficacy was evaluated by the antihemorrhagic and the blood-saving effects in the three groups of patients: total quantity of blood loss in milliliters per kilogram as well as transfusion of fresh blood, red packed cells, fresh frozen plasma, and platelet concentrates in milliliters per kilogram during the first 24 hours were registered. The split products were measured by two independent immunoassays, based on monoclonal antibodies to D-dimers (Boehringer, Mannheim, Germany) and to fibrin (Organon, Heidelberg, Germany). The total degradation products of fibrinogen (Organon) were determined by enzyme-linked immunoadsorbent assay using both monoclonal and polyclonal antibodies.

Statistical analysis
Statistical analysis was performed using Stat View (Los Angeles, CA). All values are expressed by mean value ± standard deviation. Difference between A0, A1, and A2 aprotinin regimen in the same congenital malformation was calculated by unpaired Student’s t test. A p value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Demographic and perioperative data are summarized in Table 1. Between patients presenting with the same congenital anomaly, no significant difference was observed when preoperative factors and intraoperative data were compared. Mean CPB time was not significantly different between the three groups A0, A1, and A2 within the same cardiac anomaly.

Coagulation tests of aprotinin-treated patients (fibrinogen, partial thromboplastin time, and thrombin time) as well as platelet count were comparable to those of control patients, preoperatively, 15 minutes after CPB was started, and 30 minutes after heparin reversal. Postoperatively, platelet count was similar in patients with VSD and Fallot tetralogy, independently of the aprotinin regimen administered but there was a significant decrease of platelets after the arterial switch operation for repair of TGA. Within this last group, a trend to improved platelet preservation was observed after high-dose aprotinin (Table 2). Figure 1 depicts the concentration of total degradation products (split products of fibrinogen and fibrin) and D-dimers in 56 consecutive patients with transposition. There was a dose-dependent reduction of all split products at the end of CPB, indicating a reduced fibrinolytic activity with increasing aprotinin dosage.

View larger version (20K): [in this window] [in a new window]   Fig 1. Concentrations of total degradation products of fibrin-fibrinogen and D-dimers 15 minutes after cardiopulmonary bypass. A dose-dependent reduction was observed under high-dose aprotinin compared with low-dose and control patients.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Blood conservation has emerged as a major topic in surgical practice and is now a real issue in the overall risk/benefit analysis of surgical procedures. Actually, blood and packed cells required for perioperative transfusion in a child not infrequently come from different adult donors, increasing the risk of blood-transmitted diseases. Overall perioperative blood loss in pediatric cardiac patients varies considerably [2, 15, 16]. Factors that have been associated with increased bleeding in pediatric cardiac operations are age less than 2 years, the complexity of the operation, and the duration of CPB [2, 14, 16]. Children less than 10 kg suffering from cardiac disease usually have reduced preoperative platelet aggregation and those with severe preoperative cyanosis present often with preoperative thrombopenia [17]. Other situations associated with an increased risk of mediastinal bleeding include impaired preoperative coagulation (neonates and prematures), hepatic congestion from right ventricular failure, as well as complex redo-operation and surgical repair using profound hypothermia with circulatory arrest.

The major hemostatic defect after CPB is thought to be related to altered platelet function [6]. Inhibition of plasmin with low-dose aprotinin may also spare platelet glycoproteins Ib receptors, which are responsible for platelet adhesion and damaged by plasmin during CPB [18, 19]. Because the platelets seem to be affected soon after the onset of CPB, it seems reasonable to protect these platelets before starting CPB by adding aprotinin in the pump prime [20].

As shown by the results observed by van Oeveren and colleagues [20], systemic aprotinin administration to the patient just before initiating CPB probably does not achieve superior protection of the blood elements before initial exposure than when aprotinin is added only to the pump prime.

Mössinger and colleagues [21] observed an attenuation of hemostatic activation during CPB with less plasmin formation and less thrombin generation with aprotinin treatment, thus the thrombotic–thrombolytic balance seems to be more stable after CPB. The present study looked at a patient population that was relatively homogenous in terms of age and size and included only three distinct malformations from increasing surgical complexity.

No beneficial effect of aprotinin could be demonstrated in patients after VSD closure, in terms of blood loss and transfusion requirements. In patients with TOF, a trend to decreased blood loss (p = 0.15) and transfusion requirement (p = 0.34) was observed between patients with and without aprotinin, but there was no difference between low-dose and high-dose regimen. In complex surgical repair (TGA) high-dose aprotinin only led to a significant reduction of blood loss (p = 0.02) and postoperative fresh blood, red cells, and platelets transfusion.

Given the conflicting results reported in the literature, at present it is still impossible to draw definitive recommendations regarding the efficacy and the optimal dosage of aprotinin in pediatric cardiac operations.

In some studies, the potential beneficial effect of aprotinin may have been biased—even when the study was double-blinded and randomized—because many patients underwent operation necessitating only a minor surgical trauma (eg, all interventions performed through a right atriotomy). Unfortunately the majority of studies investigating aprotinin efficacy have included a highly heterogeneous collection of cardiac malformations [10–13]. Therefore, it appeared interesting to compare three groups of patients with a well-defined surgical approach of increasing complexity (atriotomy alone, atriotomy + incision of the right ventricular outflow tract, and finally vascular anastomoses including coronary translocation). The reason why low-dose aprotinin is less effective in children than in adults may be attributable to the dilution effect through a highly different relation between blood volume and priming volume in this population. Even in miniaturized circuits with a pump-prime volume of less than 500 mL, the pediatric group is particularly susceptible to a significant dilution during CPB.

Using a drug that can prevent bleeding leads to the question whether this drug will increase the risk of thromboembolic events. From the present experience, the thromboembolic risk cannot be neglected but appears to be reasonably low, when aprotinin is used at concentrations high enough to inhibit also kallikrein [3]. The risk of thrombosis after aprotinin exposure has not been reported higher than 1% to 2%. This complication has been reported in patients after deep hypothermic circulatory arrest but not in neonates and children after complete surgical repair. However, we observed a somewhat higher incidence of venous thrombosis in aprotinin-treated patients, but the cause is most probably multifactorial (very small superior vena cava diameter, pursestring suture after decannulation, intravenous line).

Recent data suggest that the incidence of severe allergic reactions to the drug in patients undergoing primary cardiac operation is very low, whereas it may reach 2.8% after repeated exposure [22]. We did not observe allergic reaction in the present study. From the experience observed in redo-operations with repeated administration of aprotinin, one can expect that careful initial application of the drug allows to recognize very rapidly those patients who might develop a more severe systemic response.

In conclusion, in the present study, a beneficial hemostatic effect of aprotinin was observed in patients undergoing a complex surgical intervention (eg, the arterial switch procedure for repair of TGA). The costs per patient are acceptable (approximately $200 US). There are few contraindications and the incidence of deleterious side effects is low. However, as reported recently from the Great Ormond Street surgical group no beneficial effects of aprotinin can be demonstrated in routine pediatric operations and in cases with a limited surgical dissection [23]. The ideal dose regimen may be further optimized. From different previous reports, aprotinin might be considered in pediatric patients undergoing redo-operation and in those with profound preoperative cyanosis and preoperative coagulation disorders.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

1. Kern F.H., Morana M.J., Sears J.J., Hickey P.R. Coagulation defects in neonates undergoing cardiopulmonary bypass. Ann Thorac Surg 1992;54:541-546.[Abstract]
2. Guay J., Rivard G.E. Mediastinal bleeding after cardiopulmonary bypass in pediatric patients. Ann Thorac Surg 1996;62:1955-1960.[Abstract/Free Full Text]
3. Hartstein G., Janssens M. Treatment of excessive mediastinal bleeding after cardiopulmonary bypass. Ann Thorac Surg 1996;62:1951-1954.[Abstract/Free Full Text]
4. Janssens M., Hartstein G., David J.L. Reduction in requirements for allogeneic blood products: pharmacologic methods. Ann Thorac Surg 1996;62:1944-1950.[Abstract/Free Full Text]
5. Terrell M.R., Walenga J.M., Koza M.J., Pifarré R. Efficacy of aprotinin with various anticoagulant agents in cardiopulmonary bypass. Ann Thorac Surg 1996;62:506-512.[Abstract/Free Full Text]
6. Emerson T.E. Pharmacology of aprotinin and efficacy during cardiopulmonary bypass. Cardiovasc Drug Rev 1989;7:127-140.
7. Hill G.E., Alonso A., Spurzem J.R., Stammers A.H., Robins R.A. Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass-induced inflammation in humans. J Thorac Cardiovasc Surg 1995;110:1658-1662.[Abstract/Free Full Text]
8. Bidstrup B.P., Harrison J., Royston D., Taylor K.M., Treasure T. Aprotinin therapy in cardiac operations: a report on use in 41 cardiac centers in the United Kingdom. Ann Thorac Surg 1993;55:971-976.[Abstract]
9. Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993;55:1033-1041.[Abstract]
10. Boldt J., Knothe C., Zickman B., Wege N., Dapper F., Hempelmann G. Aprotinin in pediatric cardiac operations: platelet function, blood loss and use of homologous blood. Ann Thorac Surg 1993;55:1460-1466.[Abstract]
11. Boldt J., Knothe C., Zickman B., Wege N., Dapper F., Hempelmann G. Comparison of two aprotinin dosage regimen in pediatric patients having cardiac operations: influence on platelet function and blood loss. J Thorac Cardiovasc Surg 1993;105:705-711.[Abstract]
12. Herynkopf F., Lucchese F., Pereira E., Kalil R., Prates P., Nesralla A. Aprotinin in children undergoing correction of congenital defects; a double blind pilot study. J Thorac Cardiovasc Surg 1994;108:517-521.[Abstract/Free Full Text]
13. Elliott M.J., Allen A. Aprotinin in pediatric cardiac surgery. Perfusion 1990;5(Suppl):73-76.
14. Urban A.E., Popov-Cenic S., Noa G., Kulzer R. Aprotinin in open heart surgery of infants and children using the heart-lung machine. Clin Ther 1984;6:425-433.[Medline]
15. Manno C.S., Hedberg K.W., Kim H.C., et al. Comparison of the hemostatic effects of fresh whole blood, stored whole blood and components after open-heart surgery in children. Blood 1991;77:930-936.[Abstract/Free Full Text]
16. Seear M.D., Wesworth L.D., Rogers P.C., Sheps S., Ashmore P.G. The effect of desmopressin acetate on postoperative blood loss after cardiac operation in children. J Thorac Cardiovasc Surg 1989;98:217-219.[Abstract]
17. Whitten C.W., Allison P.M., Latson T.W., Bossard R.F., Rosenberg J.A., Ring W.S. Management of the thrombocytopenic cardiac surgical patient. A role for aprotinin?. Anesth Analg 1994;79:796-800.[Abstract/Free Full Text]
18. Huang H., Ding W., Su Z., Zhang W. Mechanism of the preserving of aprotinin on platelet function and its use in cardiac surgery. J Thorac Cardiovasc Surg 1993;106:11-18.[Abstract]
19. Tabuchi N., de Haan J., Boonstra P.W., Huet R.C.G., van Oeveren W. Aprotinin effect on platelet function and clotting during cardiopulmonary bypass. Eur J Cardiothorac Surg 1994;8:87-90.[Abstract]
20. Van Oeveren W., Harder M.P., Roozendaal K.J., Eijsman L., Wildevuur C.R. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:788-797.[Abstract]
21. Mössinger H, Dietrich W, Spannagel M, Henze R, Barankay A, Richter JA. High-dose aprotinin reduces not only fibrinolytic, but also clotting activation in pediatric cardiac surgery. 15th Annual Meeting of Cardiovascular Anesthesiology, 1993:249.
22. Dietrich W., Späth P., Ebell A., Richter J.A. Incidence of anaphylactic reactions to aprotinin—analysis of 248 reexposures to aprotinin [Abstract]. Anesthesiology 1995;83:A104.
23. Davies M.J., Allen A., Kort H., et al. Prospective, randomized double-blind study of high-dose aprotinin in pediatric cardiac operations. Ann Thorac Surg 1997;63:497-503.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Thierry P. Carrel Paul R. Vogt Marko I. Turina Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carrel, T. P. Articles by Turina, M. I. Search for Related Content PubMed PubMed Citation Articles by Carrel, T. P. Articles by Turina, M. I.