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Ann Thorac Surg 1998;66:535-540
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Hematologic and economic impact of aprotinin in reoperative pediatric cardiac operations

^a Department of Anesthesiology, Emory University School of Medicine and Egleston Children’s Hospital at Emory University, Atlanta, Georgia, USA
^b Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and Egleston Children’s Hospital at Emory University, Atlanta, Georgia, USA

Accepted for publication March 27, 1998.

Address reprint requests to Dr Miller, Department of Anesthesiology, Egleston Children’s Hospital at Emory University, 1405 Clifton Rd, NE, Atlanta, GA 30322

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Aprotinin consistently reduces blood loss and transfusion requirements in adults during and after cardiac surgical procedures, but its effectiveness in children is debated. We evaluated the hemostatic and economic effects of aprotinin in children undergoing reoperative cardiac procedures with cardiopulmonary bypass.

Methods. Control, low-dose aprotinin, and high-dose aprotinin groups were established with 15 children per group. Platelet counts, fibrinogen levels, and thromboelastographic values at baseline and after protamine sulfate administration, number of blood product transfusions, and 6-hour and 24-hour chest tube drainage were used to evaluate the effects of aprotinin on postbypass coagulopathies. Time needed for skin closure after protamine administration and lengths of stay in the intensive care unit and the hospital were recorded prospectively to determine the economic impact of aprotinin.

Results. Coagulation tests performed after protamine administration rarely demonstrated fibrinolysis but did show significant decreases in platelet and fibrinogen levels and function. The thromboelastographic variables indicated a preservation of platelet function by aprotinin. Decreased blood product transfusions, shortened skin closure times, and shortened durations of intensive care unit and hospital stays were found in the aprotinin groups, most significantly in the high-dose group with a subsequent average reduction of nearly $3,000 in patient charges.

Conclusions. In children undergoing reoperative cardiac surgical procedures, aprotinin is effective in attenuating postbypass coagulopathies, decreasing blood product exposure, improving clinical outcome, and reducing patient charges.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Aprotinin has been shown repeatedly to reduce blood loss and transfusion requirements after cardiopulmonary bypass (CPB) in adults by multiple mechanisms, which include inhibition of fibrinolysis and preservation of platelet function through its antagonism of the actions of plasmin and kallikrein [1–3]. Its effects are especially notable in patients considered at increased risk of bleeding such as those receiving aspirin, those with infective endocarditis, and those undergoing repeat sternotomy [4–6]. Studies of the effects of aprotinin in children have not demonstrated consistent results, with improved hemostasis and reduced transfusion requirements noted in some [7–10] and no beneficial effects found in others [11, 12]. Reasons for these inconsistencies could involve patient selection, increased complexity of coagulopathies after CPB in children, and variability of dosage regimens. Because of this ongoing debate, we prospectively evaluated the hemostatic effects of two aprotinin doses in children undergoing reoperative cardiac surgical procedures using routine coagulation tests, including the Thrombelastograph coagulation analyzer (Haemoscope Corp, Skokie, IL), and recorded the effects of aprotinin on subsequent chest tube drainage, blood product use, and costs accumulated during the hospital stays.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
After we received approval from our human investigations committee and informed the patients’ parents, 45 children (aged 5.5 months to 14.5 years and weighing 5.6 to 42.5 kg) undergoing elective cardiac surgical procedures through a repeat sternotomy were studied. Exclusion criteria included preoperative use of heparin sodium, Coumadin (crystalline warfarin sodium; DuPont Pharmaceuticals, Wilmington, DE), or platelet-inhibiting medications or prior exposure to aprotinin. Anesthesia management included the initial use of inhalation anesthetics followed by the administration of fentanyl, midazolam hydrochloride, and pancuronium bromide. A bolus of 400 U/kg of bovine lung heparin (The Upjohn Co, Kalamazoo, MI) was administered, and kaolin-activated clotting time values exceeding 480 seconds were confirmed prior to the commencement of CPB. Hourly heparin boluses of 100 U/kg were administered throughout CPB, even when kaolin-activated clotting time values exceeded 480 seconds, to ensure adequate heparinization. A Cobe VPCML Plus membrane oxygenator (Cobe Cardiovascular, Inc, Arvada, CO) was used during CPB, and packed red blood cells were added to the circuit volume as needed to maintain an acceptable hematocrit for the temperature necessitated by the complexity of the planned surgical procedure. At the conclusion of CPB, 4 mg/kg of protamine sulfate was administered to neutralize the effect of heparin.

Three patient groups comprising 15 patients each were established: control, low-dose aprotinin, and high-dose aprotinin. The control group received no aprotinin. The low-dose group received an aprotinin loading dose of 20,000 kallikrein inhibiting units (KIU) (2.8 mg) per kilogram before skin incision, 20,000 KIU/kg in the pump prime, and an infusion of 10,000 KIU · kg^-1 · h^-1 beginning with completion of the loading dose and terminating with skin closure. This regimen was derived from work defining dosage requirements in adults to maintain plasma aprotinin levels high enough to inhibit both plasmin and kallikrein [13]. The high-dose group received a loading dose of 40,000 KIU/kg, 40,000 KIU/kg in the pump prime, and an infusion of 20,000 KIU · kg^-1 · h^-1 after the loading dose to the end of skin closure. Assignment of children to the control and low-dose groups was random and was designed to maintain parity between these groups in regard to demographic variables. Because our investigation was begun on the introduction of aprotinin at our institution, the high-dose group was added later as ongoing studies reporting higher dosage regimens in children were published [10, 14]. For this group, our low-dose regimen was doubled, providing a dosage that was in the range of the higher reported dosage schedules, and patients were again selected to maintain similarity between groups with respect to demographic data.

Baseline platelet count, fibrinogen level, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombelastogram (TEG), and creatinine level were obtained before skin incision and aprotinin administration. Five values were measured from the TEG and used to characterize clot formation and stability: R, K, , MA, and A-60. The R value (reaction time) represents the time necessary for initial clot formation and reflects the function of the intrinsic coagulation pathway. The K value (coagulation time) and the value of the tracing both appraise the rapidity of fibrin buildup and cross-linking as the clot forms. The maximum amplitude (MA) is a measure of the maximum strength of the fibrin clot. The K, , and MA values are all influenced by the level and function of platelets and fibrinogen. The A-60 value is the amplitude of the TEG 60 minutes after the MA value has been reached. This value is useful in measuring clot retraction or destruction by comparing it with the MA value. An A-60/MA ratio of less than 0.85 has been used to define fibrinolysis [15]. Other calculated TEG indices include the shear modulus [16] and the coagulation index (Thrombelastograph Operations Manual and CTEG User’s Guide, Haemoscope Corp). These indices are sensitive measures of actual clot strength and the entire scope of the coagulation process.

Ten minutes after protamine administration and restoration of baseline activated clotting time values but before transfusion of hemostatic products, platelet count, fibrinogen level, and the TEG were repeated. The need to administer coagulation products in the operating room (OR) was then based on the appearance of the surgical field, as results of these coagulation tests were not available in a timely fashion. This need was determined jointly by the anesthesia and surgical teams with the surgical team unaware of aprotinin usage or dosage. On the basis of previous work in this area by our group [17], platelets were initially transfused if intervention was deemed necessary. Pheresed platelet units were used to minimize donor exposures. Cryoprecipitate was the preferred component given next if hemostasis in the surgical field remained inadequate after platelet administration; however, the availability of donor-directed fresh frozen plasma mandated its use at this point in some patients. On arrival of the patient in the intensive care unit (ICU), measurements of platelet count, fibrinogen level, PT, aPTT, and creatinine level were repeated. Blood product administration in the ICU was determined by the intensivists, who were also unaware of patient grouping, and was recorded for the initial 24 postoperative hours, as was chest tube drainage. Platelet count, PT, aPTT, creatinine level, and weight were obtained on the first postoperative day.

The total dose of aprotinin, the number of coagulation products used during the first 24 hours postoperatively, the time spent in the OR for chest closure after protamine administration, and the lengths of the ICU stay and the remainder of the hospital stay after transfer out of the ICU were recorded for each patient. Economic data were then generated for each patient on the basis of patient charges for the amount of aprotinin, blood bank products, and OR time used and for moderate acuity ICU and private room charges.

Analysis of variance was used to determine whether differences existed in demographic data, CPB data, laboratory variables, duration of OR and hospital stays, and patient charges between the three groups. Comparisons between groups were then made using two-sided t tests, assuming unequal variances, with Bonferroni’s correction for multiple comparisons. Comparisons within the same group at different time intervals were made using analysis of variance with repeated measures. Fisher’s exact test was employed to determine differences between groups in blood product use.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
The results of our study are compiled in the tables and are expressed as the mean ± the standard deviation. Demographic variables, duration of CPB, and lowest temperatures reached during CPB were not different between groups, and the surgical procedures performed were also similar (Table 1). Baseline platelet count, fibrinogen level, and TEG variables as well as PT and aPTT values (not shown) were also not different between the three groups (Tables 2, 3).

On the arrival of the patient in the ICU, PT and aPTT values were significantly prolonged compared with baseline in all groups. Whereas these PT values did not differ between groups (control, 15.8 ± 1.5 seconds; low-dose, 18.0 ± 2.5 seconds; and high-dose, 18.4 ± 4.7 seconds; p = 0.08), aPTT values were significantly longer in both aprotinin groups compared with the control group (control, 40.8 ± 12.3 seconds; low-dose, 70.9 ± 20.3 seconds; and high-dose, 87.9 ± 17.1 seconds; p 0.00006). This difference persisted for the high-dose aprotinin group into the first postoperative day. Only in the control group were creatinine levels significantly elevated on patient arrival in the ICU compared with baseline (0.54 ± 0.17 mg/dL versus 0.40 ± 0.18 mg/dL; p = 0.035). This elevation continued into the first postoperative day but was not significant compared with baseline (p = 0.06). Renal failure did not develop in any patient. In neither aprotinin group did creatinine levels rise significantly postoperatively. Patient weights on the first postoperative day were not different among groups or within groups compared with baseline.

None of the patients required mediastinal reexploration for bleeding. Patients receiving aprotinin had transfusion of less coagulation products in the OR than the control group (Table 5). In addition, less time was required for skin closure after protamine administration in these patients (Table 6). Similar amounts of coagulation products were subsequently transfused in each group during the first 24 postoperative hours in the ICU. However, 8 children in each aprotinin group required no coagulation products during the entire 24-hour study period, whereas this occurred in only 3 children in the control group (p = 0.13, each aprotinin group versus control). Time to extubation and lengths of ICU and total hospital stays were reduced in patients receiving aprotinin, especially in the high-dose group (see Table 6). No significant difference was seen in chest tube drainage between groups at 6 hours (control, 13.0 ± 8.6 mL/kg; low-dose, 14.1 ± 6.8 mL/kg; and high-dose, 16.3 ± 14.5 mL/kg; p = 0.68) or 24 hours (control, 28.9 ± 17.2 mL/kg; low-dose, 31.6 ± 23.1 mL/kg; and high-dose, 36.0 ± 26.4 mL/kg; p = 0.69) postoperatively.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Aprotinin is thought to exert its beneficial hemostatic effects by multiple mechanisms including inhibition of fibrinolysis and preservation of platelet function as it antagonizes the actions of plasmin and kallikrein [1–3]. Several studies [3, 7, 8, 18] have shown laboratory evidence of activation of the fibrinolytic system during CPB, but this activation appears to resolve quickly after the termination of bypass [18]. Thus, lysis of a newly forming clot is not believed to play a major role in bleeding after CPB [19, 20]. Indeed, TEG-defined fibrinolysis after CPB in children has been found to occur infrequently, even without administration of antifibrinolytic agents [17]. However, the activation of the fibrinolytic system during CPB has been shown to impair platelet function after CPB probably through the hydrolysis of platelet adhesive receptors [8]. Abnormalities of TEG variables ( and MA) and indices (shear modulus) that are dependent on platelet function as well as platelet numbers and fibrinogen levels have been documented after CPB in children [17]. The maintenance of higher TEG , MA, and shear modulus values after CPB that is seen with aprotinin administration in this study must reflect preservation of platelet adhesive function, platelet-fibrinogen aggregatory interactions, or both, as fibrinolysis after CPB was again an uncommon occurrence in each of our three patient groups and as the quantitative deficiencies in platelets and fibrinogen after CPB are not altered by aprotinin administration. Therefore, TEG data indicate that aprotinin’s beneficial effects in children are related to its attenuation of platelet dysfunction after CPB.

Our study extends several observations that have previously been reported concerning the use of aprotinin in children. First, aprotinin exerts beneficial hemostatic effects in children undergoing repeat, versus primary, sternotomy [10, 14]. Several pediatric studies [11, 12] indicating ineffectiveness of aprotinin have specifically excluded from their protocols children having reoperations. Second, higher doses of aprotinin are needed for maximal hemostatic effects in children. The only pediatric investigation [7] to measure plasma aprotinin levels found that a loading dose of 30,000 KIU/kg, with the same amount added to the pump prime, produced levels only half of those needed for aprotinin to inhibit both kallikrein and plasmin and thus to exert its maximal effects. Therefore, larger doses of aprotinin would be expected to be more efficacious.

Third, a considerable reduction in patient charges results from the use of aprotinin in reoperative pediatric cardiac operations, even with the substantial charge for aprotinin included in the calculations [10]. Reductions in coagulation product transfusions, OR time, and postoperative ICU and hospital stays accounted for this decrease. Additional charges such as those from the laboratory, pharmacy, and radiology services that were saved as a result of the considerable shortening of ICU and hospital stays in patients receiving aprotinin cannot be quantified, and therefore, the monetary savings we calculated substantially underestimate the true economic impact of the administration of aprotinin. Finally, we saw no adverse effects from the administration of aprotinin to children. Previous exposure to aprotinin was an exclusion criterion for our study, thereby markedly decreasing the chances of allergic reactions. No evidence of renal dysfunction was encountered even with exposure to deep hypothermic circulatory arrest, a situation that has been associated with postoperative renal dysfunction in adults [21]. This finding can be inferred from previous pediatric studies [7].

Our study provides additional practical information on the use of aprotinin in children. First, a dosage schedule based on weight, rather than body surface area, that will attenuate coagulopathies after CPB, reduce operating time and hospital stays, decrease exposure to banked blood products, and reduce patient charges has been identified. This allows easier calculation of aprotinin doses in a simple manner used routinely to determine drug doses in children. Second, hemostatic and economic benefits of aprotinin are evident in a dose-dependent manner. It is apparent from our data that both aprotinin doses attenuate coagulopathies after CPB, reduce blood product requirements, improve clinical outcomes, and reduce patient charges and that these benefits are considerably greater with the high-dose regimen (see Tables 3–7).

The finding that postoperative chest tube drainage was not diminished in the aprotinin groups should not be misinterpreted as lack of hemostatic effectiveness of aprotinin. Consideration of the interventions necessary to control bleeding after CPB must also be included in this evaluation. In the OR, patients receiving aprotinin had transfusion of significantly less coagulation products than the control group. Twelve (80%) of 15 control patients received coagulation products during the study period compared with only 7 (47%) of 15 children in each aprotinin group. Therefore, 6-hour and 24-hour chest tube drainage was similar for the control and aprotinin groups only because of the increased coagulation product transfusions to limit bleeding in the control group.

Systemic effects of aprotinin are also demonstrated by several of our findings. A shortened duration of mechanical ventilation and a reduction in ICU and hospital stays were seen with the use of aprotonin and were most pronounced in the high-dose group. Aprotinin has been found to attenuate the humoral and cellular components of the inflammatory response to CPB [22, 23]. This is logical because the coagulation and inflammatory pathways share many of the same triggers, amplifiers, and humoral components. Therefore, these clinical findings may result, in part, from aprotinin’s antiinflammatory actions.

In conclusion, aprotinin is effective in attenuating coagulopathies after CPB and improving clinical outcome in children undergoing cardiac procedures through a repeat sternotomy. Thromboelastographic data indicate preservation of platelet function to be the primary hemostatic benefit of aprotinin. The use of higher doses of aprotinin is more effective and results in significant reductions in coagulation product transfusions and considerable monetary savings. Further investigation is required to determine the aprotinin dose that will yield optimal plasma levels. In the meantime, we recommend the use of our high-dose regimen for children undergoing reoperative cardiac surgical procedures.

	References

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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): Vincent K.H. Tam Kirk R. Kanter Jerrold H. Levy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, B. E. Articles by Levy, J. H. Search for Related Content PubMed PubMed Citation Articles by Miller, B. E. Articles by Levy, J. H.