Ann Thorac Surg 1998;65:S71-S73
© 1998 The Society of Thoracic Surgeons
Use of Aprotinin in Pediatric Organ Transplantation
Thomas L. Spray, MDa
a Department of Cardiothoracic Surgery, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Address reprint requests to Dr Spray, Department of Cardiothoracic Surgery, Children’s Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104
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. Pediatric thoracic organ transplantation is associated with an increased risk of perioperative bleeding. Many of these patients are undergoing repeat surgical procedures and in general require cardiopulmonary bypass.
Methods. This article reviews the efficacy and safety of the serine protease inhibitor aprotinin in improving hemostasis in pediatric transplantation.
Results. A review of the literature and investigations from Children’s Hospital of Philadelphia suggest that aprotinin is beneficial in pediatric lung transplantation: high-risk patients do as well as low-risk patients. Aprotinin also appears to be of benefit in redo heart transplantations, particularly in patients who have had previous sternotomy or previous transplantation. Repeat use of aprotinin appears to be safe and does reduce blood loss in retransplantation patients. Use in the pump prime and a maintenance dose of aprotinin may be the most effective protocol. At this time, however, it is uncertain whether aprotinin is valuable in primary heart transplantation in low-risk patients.
Conclusions. Current practice at Children’s Hospital of Philadelphia is to use aprotinin in all lung and heart-lung transplantations and in all redo transplantations: lung, heart-lung, and heart. The use of aprotinin in primary heart transplantations is limited to patients who have had previous sternotomies or thoracotomies.
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Introduction
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Pediatric patients present a unique challenge in organ transplantation. In lung transplantation, for example, many children have had previous thoracotomies or sternotomies for palliation or repair of congenital heart lesions. Those with cystic fibrosis have dense chest-wall adhesions. The chest wall may have numerous mediastinal or venous arterial channels, particularly in cyanotic children. Cardiopulmonary bypass is used for most children undergoing transplantation. A significant number of children who require lung transplantation may be on extracorporeal membrane oxygenator support. Retransplantation may be necessary in patients in whom late complications develop after initial transplantation.
In heart transplantation, the challenges are similar. Many of these patients are cyanotic or have had previous sternotomies; collateral vessels may be present, particularly in cyanotic children; cardiopulmonary bypass is used; and retransplantation may be necessary.
All of the above factors significantly increase the risk of bleeding at operation and in the intensive care unit. They further potentially increase bypass time, chest-tube drainage, time from end of implantation to closure of the chest and transport to the intensive care unit, incidence of renal dysfunction, the need for clotting factors, and reexploration for hemorrhage.
Results from several studies suggest that aprotinin reduces the numerous risks associated with pediatric transplantation and is beneficial in high-risk as well as in low-risk patients. Aprotinin may be of particular benefit in redo heart transplantation, ie, in those who have had a previous sternotomy or previous transplantation. Repeat use of aprotinin in retransplantation is generally safe and appears to decrease bleeding. Optimal benefit may be achieved through use of aprotinin in the pump prime and an additional maintenance dose.
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Pediatric lung transplantation
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In a 4-year study that my colleagues and I [1] conducted in 42 children who had undergone 44 lung transplantations, outcome was the same for both high-risk and low-risk patients, suggesting the benefit of aprotinin on the pediatric population. Thirty-nine of the procedures were bilateral sequential transplantations, five were single-lung procedures. Patients were divided into a low-risk (control) group and a high-risk (aprotinin) group, based on the risk of hemorrhage. The majority of single-lung patients were assigned to the low-risk group because we believe the potential for hemorrhage is low in these patients. All transplantations were done by transverse thoracosternotomy, and all used cardiopulmonary bypass.
The aprotinin group included 25 patients, whose average age was 11 to 12 years; the average age of patients in the control group was 7 to 8 years. The average weight of patients in the aprotinin group was 28 kg; the average in the control group was 19 kg. Thirty-two percent of patients in the aprotinin group had had a previous operation versus 37% of patients in the control group. Previous operations in the aprotinin group included pleurodesis, lobectomy, bilateral lung transplantation, open lung biopsy, single-lung transplantation, ventricular septal defect closure, and arterial switch procedure. Previous operations in the control group were less extensive and included open lung biopsies and exploratory thoracotomy. Four percent of patients in the aprotinin group had single-lung transplantation versus 21% for patients in the control group. Diagnoses in the aprotinin group included cystic fibrosis, pulmonary fibrosis, and pulmonary hypertension and congenital heart defects. Diagnoses in the control group included pulmonary fibrosis, bronchiolitis obliterans, surfactant protein B deficiency, unrepaired congenital heart defect with pulmonary hypertension, and bronchopulmonary dysplasia.
Protocol for aprotinin was loading dose, pump prime, and maintenance dose. Dosage was based on patient body surface area*:
- Infants up to 1.16 m2 body surface area:
- Loading dose = 240 mg/m2 (1.7 x 106 U) over 20 minutes
- Pump prime = 240 mg/m2 (1.7 x 106 U)
- Loading dose = 56 mg · m-2 · h-1 (0.4 x 106 U)
- Older children greater than 1.16 m2 body surface area:
- Loading dose = 280 mg/m2 (2 x 106 U) over 20 to 30 minutes
- Pump prime = 280 mg/m2 (2 x 106 U)
- Loading dose = 70 mg · m-2 · h-1 (0.5 x 106 U)
- Heparin levels measured, activated coagulation time equals 480 seconds by dose-response (Hepcon) before aprotinin given
- Hematocrit >30% in children <10 kg, >25% in children >10 kg
Limitations to the study included the following: (1) patients in the control group were younger and smaller and therefore required more blood replacement; (2) chest-tube output is not all blood; therefore, it is difficult to accurately determine blood loss; and (3) the study was nonrandomized and retrospective. Nevertheless, results showed the benefit of aprotinin use in high-risk patients undergoing lung transplantation (Table 1).
Need for a maintenance dose
Gu and associates [2] also stratified patients into high-risk and low-risk groups in terms of blood loss. They found that high-risk patients receiving aprotinin had no greater loss of blood than low-risk patients. They noted that low-dose aprotinin in the pump prime reduced clotting and fibrinolytic activity only in the early phase of bypass during transplantation and that fibrinolytic activity increased later during bypass. This finding suggests the need to administer a maintenance dose throughout the procedure, a protocol that we had followed in our patients.
Aprotinin and cardiopulmonary bypass
In a study of 33 patients undergoing single-lung transplantation, of whom 15 needed cardiopulmonary bypass and 11 of these 15 received aprotinin, Kesten and associates [3] found that blood loss was significantly lower in children on cardiopulmonary bypass who had received aprotinin (1,777 ± 253 mL with aprotinin versus 3,000 ± 500 mL without; p < 0.05). Similarly, the need for packed red blood cells was lower in those on bypass who had received aprotinin (3.1 ± 0.7 U with aprotinin versus 8.0 ± 0.7 U without; p < 0.05). Kesten and associates noted, however, that aprotinin conferred no benefit in patients not on cardiopulmonary bypass.
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Pediatric heart transplantation
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In one of the few randomized studies of the use of aprotinin in heart or lung transplantation, Prendergast and colleagues [4] found that aprotinin offered no significant benefit in reducing blood loss or blood requirements in patients who had not had a previous operation: - 70 patients
- Group A (n = 20): no aprotinin, no prior sternotomy
- Group B (n = 18): aprotinin, no prior sternotomy
- Group C (n = 16): no aprotinin, redo
- Group D (n = 20): aprotinin, redo
- Randomized
- No difference between groups A and B
- Significant differences between groups C and D in blood use, total fluid balance, alveolar-arterial oxygen tension gradient, and mean pulmonary artery pressures
However, in those patients who had had a previous operation, significant benefits were evident in patients who had received aprotinin, as seen in blood requirements, total fluid balance, alveolar-arterial oxygen tension gradient, and mean pulmonary artery pressure. It could be argued that total fluid balance can be altered by use of modified ultrafiltration, that there may be an inflammation response involved in alveolar-arterial oxygen tension gradient, and that mean pulmonary artery pressure may or may not be directly related to aprotinin use. Nevertheless, these findings are rather intriguing and warrant further examination.
Goldstein and colleagues [5] evaluated the use of aprotinin in patients during left ventricular assist device insertion and, subsequently, heart transplantation. Twenty-three patients received aprotinin during both procedures. Blood replacement was minimal. Anaphylaxis developed in 1 patient who had secondary exposure to the drug. Although 30% of patients experienced renal dysfunction, this may have been the result of cyclosporine use, which is associated with significant early renal dysfunction after transplantation. It is therefore difficult to attribute renal dysfunction specifically to aprotinin use.
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Use of aprotinin at Children’s Hospital of Philadelphia
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Our practice at Children’s Hospital of Philadelphia is to use aprotinin in all lung and heart-lung transplantations. We have not found any disadvantage in its use, and it does offer several advantages, particularly in reducing blood loss and blood requirements. We also use aprotinin in all redo transplantations: lung, heart-lung, and heart. We have committed ourselves to retransplantation when possible in patients in whom late complications develop after primary transplantation. However, we limit use of aprotinin in primary heart transplantations to patients who have had previous sternotomies or thoracotomies. We have cursorily examined the incidence of rejection in either primary or secondary transplantation, which is extremely high in pediatric patients, and there appears to be no significant difference in incidence between patients who have received aprotinin and those who have not.
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What is the risk of repeat aprotinin administration?
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We have used aprotinin in several repeat lung and heart-lung transplantations. From October 1994 to April 1997, we repeated administration of aprotinin in 5 children, ranging in age from 4 months to 19 years. One patient had had heart transplantation and required a second transplantation, 1 patient had heart-lung transplantation and then required bilateral lung transplantation, and 3 patients had had bilateral lung transplantation and required redo procedures. Retransplantations were undertaken as early as 1 month after primary transplantation and, in 1 patient, as late as 2 years after primary transplantation. Most redo procedures were done within the first 6 months after the original operation, primarily because of graft failure, a common complication (because of viral infection) associated with lung transplantation in children.
Although certainly there is a risk associated with repeat administration of aprotinin early after previous exposure to the drug, we found no complications attributable to aprotinin in our patients. Perhaps the lack of allergic complications after retransplantation may actually derive from the fact that these patients are immunosuppressed. This is an area that warrants further investigation.
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Conclusion
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My review of the literature and our own investigations suggest that aprotinin is beneficial in pediatric lung transplantation: high-risk patients do as well as low-risk patients. Aprotinin also appears to be of benefit in redo heart transplantation, particularly in patients who have had previous sternotomy or previous transplantation. The repeat use of aprotinin appears to be safe and does reduce blood loss in retransplantation patients. We have found that use in the pump prime and a maintenance dose of aprotinin may be the most effective protocol. At this time, however, it is uncertain whether aprotinin is valuable in primary heart transplantation in low-risk patients.
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Footnotes
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* Reprinted with permission from Jaquiss RD, Huddleston CB, Spray TL. Use of aprotinin in pediatric lung transplantation. J Heart Lung Transplant 1995;14:302–7. 
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References
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- Jaquiss R.D., Huddleston C.B., Spray T.L. Use of aprotinin in pediatric lung transplantation. J Heart Lung Transplant 1995;14:302-307.[Medline]
- Gu Y.J., de Haan J., Brenken U.P., de Boer W.J., Prop J., van Oeveren W. Clotting and fibrinolytic disturbance during lung transplantation: effect of low-dose aprotinin. J Thoracic Cardiovasc Surg 1996;112:599-606.[Abstract/Free Full Text]
- Kesten S., de Hoyas A., Chaparro C., Westney G., Winton T., Maurer J.R. Aprotinin reduces blood loss in lung transplant recipients. Ann Thorac Surg 1995;59:877-879.[Abstract/Free Full Text]
- Prendergast T.W., Rurukawa S., Beyer A.J., III, Eisen H.J., McClurken J.B., Jeevanandam V. Defining the role of aprotinin in heart transplantation. Ann Thorac Surg 1996;62:670-674.[Abstract/Free Full Text]
- Goldstein D.J., Oz M.C., Smith C.R., et al. Safety of repeat aprotinin administration for LVAD recipients undergoing cardiac transplantation. Ann Thorac Surg 1996;61:692-695.[Abstract/Free Full Text]
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Abstract
Introduction
