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Ann Thorac Surg 2003;75:1261-1266
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

Aprotinin reduces operative closure time and blood product use after pediatric bypass

John M. Costello, MDa, Carl L. Backer, MDb*, Alberto de Hoyos, MDb, Helen J. Binns, MD, MPHc, Constantine Mavroudis, MDb

a Division of Cardiology and Critical Care Medicine, Chicago, Illinois, USA
b Division of Cardiovascular Thoracic Surgery, Chicago, Illinois, USA
c Division of General Academic Pediatrics, Child Health Research Core, Children’s Memorial Institute for Education and Research, Children’s Memorial Hospital and Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA

Accepted for publication October 18, 2002.

* Address reprint requests to Dr Backer, Division of Cardiovascular Thoracic Surgery, Children’s Memorial Hospital, 2300 Children’s Plaza, m/c 22, Chicago, IL 60614, USA
e-mail: cbacker{at}childrensmemorial.org


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
BACKGROUND: The use of aprotinin in children undergoing cardiopulmonary bypass is controversial. We hypothesized that aprotinin would reduce blood product use and operative closure time in selected pediatric patients.

METHODS: For a 6-month period starting in October 1999, consecutive cardiopulmonary bypass patients 6 months of age or less (n = 18) or having a repeat sternotomy (n = 18) received aprotinin. Similar consecutive patients from the preceding 6 months served as controls (n = 35 and 41, respectively). Data extracted from medical records included preoperative clinical characteristics, operative and postoperative procedures, and total blood product use.

RESULTS: Patients in the aprotinin and control groups were well matched with regard to preoperative and intraoperative variables. Patients 6 months of age or less who received aprotinin required less operative closure time when compared with controls (median, 93 vs 127 minutes, p = 0.004), and trended toward requiring fewer red blood cell unit exposures (median, three vs five exposures, p = 0.07). Patients undergoing repeat sternotomy who received aprotinin required less operative closure time when compared with controls (mean, 126 vs 159 minutes, p = 0.007), fewer red blood cell unit exposures (median three vs four exposures, p = 0.002), and fewer fresh-frozen plasma unit exposures (median, zero vs one exposure, p = 0.007).

CONCLUSIONS: Aprotinin reduced operative closure time and blood product exposure in pediatric patients undergoing cardiopulmonary bypass who were 6 months of age or less or underwent a repeat sternotomy.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Cardiopulmonary bypass (CPB) is associated with a diffuse inflammatory response that can lead to subtle or overt end-organ damage and a predisposition to bleeding [1]. Several serine protease enzymes are key mediators in the initiation and amplification of this inflammatory response [2]. Contact of patient blood with the foreign surface of the CPB circuit activates factor XII, which in the presence of high–molecular weight kininogen, converts prekallikrein to kallikrein [3]. Kallikrein then stimulates other serine proteases, including bradykinin, certain complement system enzymes, factor XIIa of the coagulation cascade, and plasmin [2]. In turn, kinins are produced, leading to inflammation, and the complement, coagulation, and fibrinolytic systems are all activated [4–6]. White blood cells and platelets are also activated by the CPB circuit, which leads to further release of inflammatory mediators and proteolytic enzymes [7, 8].

Aprotinin is a nonspecific serine protease inhibitor [2]. In addition, it limits contact activation of neutrophils and platelets [9]. The beneficial effects of aprotinin on bleeding in adults undergoing coronary artery bypass graft surgery have been well documented [10, 11]. However, the use of this drug in pediatric patients remains controversial [12, 13]. The hypothesis of this study was that aprotinin, by decreasing intraoperative bleeding, decreases blood product use and operative closure time in selected pediatric patients undergoing CPB.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
This was a single-institution, retrospective, nonrandomized, controlled study. Two patient groups thought to be at high risk for perioperative bleeding were studied. For a 6-month period starting in October 1999, consecutive CPB patients who were 6 months of age or less or undergoing a repeat sternotomy received aprotinin. Similar consecutive patients from the proceeding 6 months served as controls for both groups. The rationale for administering aprotinin to patients 6 months of age or less was to include all neonates undergoing complex repair or palliation, as well as most symptomatic infants with intracardiac shunting and congestive heart failure who were referred for complete repair.

The following high-dose regimen was used for patients receiving aprotinin: after induction of general anesthesia and placement of arterial and central venous lines, an intravenous test dose (1.4 mg) of aprotinin was administered followed by a bolus of 240 mg/m2 (maximum, 280 mg). An additional 240 mg/m2 (maximum, 280 mg) was added to the CPB prime solution [14]. A 56-mg/m2/h (maximum, 70 mg/h) continuous infusion of aprotinin was then administered during the entire procedure until 1 hour after skin closure.

Anesthesia was generally induced with ketamine hydrochloride or fentanyl. Maintenance anesthesia consisted of a combination of fentanyl (50 to 100 µg/kg/min), pancuronium bromide (100 µg/kg/dose), and an inhalational agent (halothane or isoflurane). All patients received decadron (1 mg/kg; maximum dose, 10 mg) before CPB [15]. Heparin was administered (300 µ/kg) before commencing CPB, and additional doses were given as needed to keep the activated clotting time above 450 seconds. Protamine was given after CPB.

The CPB circuit consisted of a roller pump (Sarns 9000 [Sarns–Ternumo, Ann Arbor, MI]), an oxygenator (Terumo SX; Terumo Cardiovascular Systems, Ann Arbor, MI), and an arterial filter (Amicon Minntech minifilter for patients weighing < 5 kg; Minntech HPH 400-m filter for patients weighing > 5 kg; Minntech, Minneapolis, MN). The priming solution consisted of plasmalyte-A (Baxter Healthcare Corp., Deerfield, IL), 50 mL of 25% albumin, 3 mL/kg of mannitol, 3,000 U of heparin, 30 mEq sodium bicarbonate, 3 mL of calcium gluconate, and, for patients weighing less than 45 kg, packed red blood cells as necessary to raise the hematocrit value of the circuit after initiation of CPB to 25%. Cardiopulmonary bypass (CPB) was initiated with a flow rate of 2.5 L/min/m2 and decreased to 2.0 L/min/m2 during cooling. Cold-blood cardioplegia (6°C to 8°C; 4:1 blood-to-crystalloid ratio; 600 mL/m2) was given every 20 minutes. Modified ultrafiltration was used after bypass in all patients unless inadequate circuit volume or hypothermia prohibited its use. All operations were performed by one of two pediatric cardiac surgeons (CM, CLB).

The intraoperative post-CPB transfusion policy was to administer packed red blood cells to acyanotic patients with a hematocrit of less than 30% and cyanotic patients with a hematocrit of less than 45%. Platelets and fresh-frozen plasma were administered empirically when the surgeon judged that there was excessive bleeding in the surgical field. The transfusion protocol in the postoperative period for packed red blood cells was similar to the intraoperative strategy. Platelets were administered if the platelet count was less than 50,000/µL or if there was excessive bleeding at the chest tube, incision, or central line sites. Fresh-frozen plasma was administered when the prothrombin time was greater than 25 seconds or for excessive bleeding. Excessive bleeding was defined as bloody drainage from the chest tubes more than 3 mL/kg/h for 3 hours or more than 5 mL/kg/h during any single hour. The two cardiac surgeons directed postoperative management, with consultation from the pediatric cardiology and critical care services.

Medical records were reviewed and data were extracted, including patient preoperative clinical characteristics, operative and postoperative procedures, and total blood product use. Operative closure time was defined as the time from the end of CPB until the patient left the operating room.

This retrospective study was approved by the institutional review board, who waived the requirement of obtaining informed consent.

Analyses for each cohort (<= 6 months of age, repeat sternotomy) were conducted separately using SPSS for Windows, version 10.2 (SPSS, Inc., Chicago, IL). One subject who received aprotinin and 3 control subjects fit criteria for both cohorts, and therefore were included in both sets of analyses. Categorical data were analyzed using {chi}2 tests. Normally distributed data were analyzed using t tests and are reported as mean plus or minus standard deviation. Data not normally distributed were analyzed using Mann-Whitney tests and are reported as medians (range).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
In the subgroup of patients 6 months of age or less, there were 18 patients who received aprotinin and 35 patients served as controls. Primary surgical procedures are listed in Table 1. The two groups did not differ regarding the preoperative and intraoperative variables shown in Table 2. Patients 6 months of age or less receiving aprotinin required significantly less operative closure time (median, 93 [range, 62 to 383] vs 127 [range, 86 to 309] minutes; p = 0.004) (Fig 1), and trended toward requiring fewer red blood cell unit exposures throughout the total hospitalization (median, 3 [range, 3 to 8] vs 5 exposures [range, 3 to 16] exposures; p = 0.07) (Fig 2). When aprotinin patients were compared with controls, there was no difference in platelet (median, 1 [range, 0 to 4] vs 1 [range, 0 to 8] U; p = 0.11) or fresh-frozen plasma unit exposures (median, 1 [range, 0 to 3] vs 1 U [range, 0 to 22]; p = 0.19). However, patients receiving aprotinin (n = 18) required fewer ventilator days when compared with controls (n = 34; 1 control patient required long-term home mechanical ventilation related to chronic lung disease and thus was excluded from this analysis) (median, 3 [range, 1 to 22] vs 5 [range, 2 to 70] days; p = 0.025). There was no significant difference between groups with regards to survival, reoperation for bleeding, infection, days of chest tube drainage, intensive care unit stay, or hospitalization (data not shown). There was no significant difference between groups with regards to hemoglobin level on postoperative days 1, 2, or 3 (data not shown). There were no allergic reactions to aprotinin or thrombotic complications in either group.


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  		Table 1. Primary Operations for Patients 6 Months of Age or Younger

 

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  		Table 2. Preoperative and Intraoperative Variables for Patients 6 Months of Age or Less

 


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  		Fig 1. Operative closure times for aprotinin-treated patients (hatched bars) who were 6 months of age or younger (n = 18) or had a repeat sternotomy (n = 18) were significantly less than control patients (filled bars) (n = 34, n = 41, respectively). Median, 93 versus 127 minutes (p = 0.004); mean, 126 ± 30 versus 159 ± 47 minutes (p = 0.007).

 


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  		Fig 2. Aprotinin-treated patients (hatched bars) who were 6 months of age or younger (n = 18) or underwent a repeat sternotomy (n = 18) required fewer red blood cell unit exposures compared with control patients (filled bars) (n = 35, n = 41, respectively). Median, three versus five exposures (p = 0.07); median, three versus four exposures (p = 0.002).

 
In the repeat sternotomy group, there were 18 patients who received aprotinin and 41 controls. Primary surgical procedures are listed in Table 3. These patients did not differ regarding the pre and intraoperative variables outlined in Table 4, except that an aortic cross-clamp was used in a higher percentage of control patients. When compared with controls, those patients undergoing repeat sternotomy who received aprotinin required significantly less operative closure time (mean, 126 ± 30 vs 159 ± 47 minutes; p = 0.007) (Fig 1), and fewer red cell blood unit exposures throughout the total hospitalization (median, 3 [range, 1 to 7] vs 4 exposures [range, 2 to 19]; p = 0.002) (Fig 2). In addition, repeat sternotomy patients who received aprotinin required fewer fresh-frozen plasma unit exposures when compared with controls (median, 0 [range, 0 to 3] vs 1 U [range, 1 to 7]; p = 0.007). There was no significant difference between groups for platelet unit exposures (median, 1 [range, 0 to 12] vs 1 U [range, 0 to 7]; p = 0.081), days of mechanical ventilation, chest tube drainage, intensive care, hospitalization, infection, or survival (data not shown). There was no significant difference between groups regarding postoperative hemoglobin levels on postoperative days 1 and 3; however, there was a difference in hemoglobin level on postoperative day 2 (aprotinin group vs control: 11.5 ± 1.7 vs 12.5 ± 1.7 gm/dL, respectively; p = 0.043). No reoperations for bleeding were required and no allergic reactions to aprotinin were noted. No thrombotic events occurred in patients receiving aprotinin; however, 1 control patient developed occlusion of a coronary artery bypass graft.


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  		Table 3. Primary Operations for Repeat Sternotomy Patients

 

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  		Table 4. Preoperative and Intraoperative Variables: Repeat Sternotomy Patients

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
In this study, we found that aprotinin was well tolerated and its use was associated with reduced operative closure time and blood product exposure in patients 6 months of age or less and in those undergoing a repeat sternotomy when compared with control patients.

The existing literature regarding the use of aprotinin in pediatric patients undergoing CPB is controversial. Some studies have used "low-dose" aprotinin (defined as <= 120-mg/m2 boluses to CPB prime and patient, and <=28-mg/m2/h continuous infusion). We used "high-dose" aprotinin (defined as 240-mg/m2 [maximum, 280-mg] boluses to CPB prime and patient, and 56-mg/m2/h [maximum 70-mg/h] continuous infusion). The results of several studies do not support the use of low-dose aprotinin in this patient population. In a series of randomized studies reported by Boldt and colleagues, low-dose aprotinin provided no clinical benefit for patients of varying weights undergoing primary sternotomy [16–18]. Davies and associates performed a prospective, randomized, double-blind, placebo-controlled clinical trial of low-dose aprotinin involving 42 patients divided into three groups: those less than 1 year of age, those between 1 and 5 years of age, and patients greater than 1 year of age undergoing repeat sternotomy [19]. These investigators were unable to detect any difference between groups regarding blood loss or transfusion requirements.

Although our strategy of using high-dose aprotinin for all patients 6 months of age or less has not specifically been reported, two centers have reported favorable experiences with aprotinin in infants and small children. In a study of 60 patients weighing less than 10 kg, Dietrich and associates reported a dose-dependent decrease in intraoperative fibrinolytic activity and postoperative bleeding at 6 hours [20]. In a large, prospective, nonblinded study of patients with ventricular septal defect (VSD), tetralogy of Fallot (TOF), or transposition of the great arteries (TGA) weighing less than 15 kg, Carrel and colleagues found that the TGA patients undergoing arterial switch operation had a dose-dependent reduction in fibrinolysis, blood loss, and postoperative transfusion, whereas no such benefits were noted in the TOF or VSD patients [21].

Although an exact explanation for the reduction in days of mechanical ventilation required for patients six months of age or less receiving aprotinin cannot be determined from this study, this phenomenon may be related to the antiinflammatory properties of this drug. A prospective study designed to examine the effect of aprotinin on gas exchange after CPB in children with acyanotic heart disease would best address this issue.

Our results are in agreement with several prior studies that evaluated aprotinin use in pediatric patients undergoing a repeat sternotomy. In a prospective, randomized, double-blind, placebo-controlled study limited to pediatric patients having a repeat sternotomy, D’Errico and associates found that the use of aprotinin was cost effective and resulted in a dose-dependent reduction in the administration of packed red blood cells, platelets, and fresh-frozen plasma during the first 24 postoperative hours [22]. Penkoske and associates reported in a retrospective, case control study of 80 pediatric patients and 55 controls at higher risk for bleeding, most of whom had a repeat sternotomy, that low-dose aprotinin was effective for reducing operative closure time, transfusion requirements, and donor exposure [23]. However, an increased rate of thrombosis and mediastinitis were noted in the aprotinin group, complications not noted in our patient population. Finally, in a randomized study of pediatric patients requiring repeat sternotomy, Miller and associates found a dose-dependent favorable effect of aprotinin on operative closure time, transfusion requirements, and intensive care unit and hospital days [24].

This study is limited by the retrospective design and use of historical controls. Surgical teams were not blinded to the use of aprotinin, and thus, medical practice could have been influenced by preheld beliefs related to drug performance. The higher number of control patients in this study is solely reflective of the surgical referral pattern during the 6-month time periods used in this study. In the repeat sternotomy analysis, control patients had a higher incidence of aortic cross-clamp application than those receiving aprotinin, which may be a confounding variable. The heterogeneous patient population is typical of that seen in most pediatric cardiovascular programs. Larger numbers of patients undergoing nearly identical operations would best be studied in multicenter, prospective, randomized, double-blinded, placebo-controlled, clinical trials. We found in our retrospective study that high-dose aprotinin was associated with reduced operative closure time and blood product exposure in pediatric patients undergoing CPB who were 6 months of age or less or underwent a repeat sternotomy.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

  1. Butler J., Rocker G.M., Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552-559.[Abstract]
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  4. Mainwaring R.D., Lamberti J.J., Hugli T.E. Complement activation and cytokine generation after modified Fontan procedure. Ann Thorac Surg 1998;65:1715-1720.[Abstract/Free Full Text]
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  6. Tanaka K., Takao M., Yada I., Yuasa H., Kusagawa M., Deguchi K. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth 1989;3:181-188.[Medline]
  7. Butler J., Parker D., Pillai R., Westaby S., Shale D.J., Rocker G.M. Effect of cardiopulmonary bypass on systemic release of neutrophil elastase and tumor necrosis factor. J Thorac Cardiovasc Surg 1993;105:25-30.[Abstract]
  8. Kondo C., Tanaka K., Takagi K., et al. Platelet dysfunction during cardiopulmonary bypass surgery: with special reference to platelet membrane glycoproteins. ASAIO J 1993;39:M550-553.[Medline]
  9. Wachtfogel Y.T., Kucich U., Hack C.E., et al. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993;106:1-10.[Abstract]
  10. Bidstrup B.P., Royston D., Sapsford R.N., Taylor K.M. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989;97:364-372.[Abstract]
  11. Levy J.H., Pifarre R., Schaff H.V., et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236-2244.[Abstract/Free Full Text]
  12. D’Errico C.C., Munro H.M., Bove E.l Pro: the routine use of aprotinin during pediatric cardiac surgery is a benefit. J Cardiothorac Vasc Anesth 1999;13:782-784.[Medline]
  13. Williams G.D., Ramamoorthy C. Con: the routine use of aprotinin during pediatric cardiac surgery is not a benefit. J Cardiothorac Vasc Anesth 1999;13:785-788.[Medline]
  14. Elliott M.J., Allen A. Aprotinin in paediatric cardiac surgery. Perfusion 1990;5(Suppl):73-76.
  15. Bronicki R.A., Backer C.L., Baden H.P., Mavroudis C., Crawford S.E., Green T.P. Dexamethasone reduces the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg 2000;69:1490-1495.[Abstract/Free Full Text]
  16. Boldt J., Knothe C., Zickmann 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]
  17. Boldt J., Zickmann B., Schindler E., Welters A., Dapper F., Hempelmann G. Influence of aprotinin on the thrombomodulin/protein C system in pediatric cardiac operations. J Thorac Cardiovasc Surg 1994;107:1215-1221.[Abstract/Free Full Text]
  18. Boldt J., Knothe C., Zickmann B., Wege N., Dapper F., Hempelmann G. Comparison of two aprotinin dosage regimens in pediatric patients having cardiac operations: influence on platelet function and blood loss. J Thorac Cardiovasc Surg 1993;105:705-711.[Abstract]
  19. 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]
  20. Dietrich W., Mossinger H., Spannagl M., et al. Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations. J Thorac Cardiovasc Surg 1993;105:712-720.[Abstract]
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