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|Year : 2010
: 13 | Issue : 2 | Page
|Comparison of three dose regimens of aprotinin in infants undergoing the arterial switch operation
Yashwant S Verma1, Sandeep Chauhan1, Akshay K Bisoi2, Parag Gharde1, Usha Kiran1, Sambhu N Das1
1 Department of Cardiac Anesthesia, AIIMS, New Delhi, India
2 Department of CTVS, AIIMS, New Delhi, India
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|Date of Submission||07-Jun-2009|
|Date of Acceptance||01-Sep-2009|
|Date of Web Publication||3-May-2010|
| Abstract|| |
To determine the most effective dose regimen of aprotinin for infants undergoing arterial switch operation for transposition of the great arteries in reducing blood loss and postoperative packed red blood cell (PRBC) requirements. A total of 24 infants scheduled for arterial switch operation for transposition of the great arteries were included in the study. The infants were randomly assigned to one of the three groups. Group I (n = 8) patients received aprotinin in a dose of 20,000 kallikrein inhibiting units (KIU)/kg after induction of anesthesia, 20,000 KIU/kg was added to the pump prime, and 20,000 KIU/kg/hour infusion for three hours after weaning from bypass; group II (n = 8) patients received aprotinin 30,000 KIU/kg after induction of anesthesia, 30,000 KIU/kg was added to the pump prime and 30,000 KIU/Kg/hour infusion for three hours after weaning from bypass; group III patients (n = 8) received aprotinin 40,000 KIU/kg after induction of anesthesia, 40,000 KIU/kg was added to the pump prime and 40,000 KIU/kg/hour infusion for three hours after weaning from bypass. Postoperatively, the cumulative hourly blood loss and PRBC requirements were noted up to 24 hours from the time of admission in the intensive care unit (ICU). Use of blood and blood products were noted. Coagulation parameters such as hematocrit, activated clotting time (ACT), fibrinogen, prothrombin time (PT), international normalized ratio (INR), platelet count, and fibrin degradation products (FDP) were investigated before cardiopulmonary bypass (CPB), after protamine administration, and at four hours postoperatively in the ICU. The number of infants reexplored for increased mediastinal drainage was recorded. Renal functions were monitored by measuring urine output (hourly) and serum urea (mg%) and serum creatinine (mg%) at 24 hours. The sternal closure time was comparable in all the three groups. Cumulative blood loss (ml/kg/24 hours) was greatest in group I (17.30 ± 7.7), least in group III (8.14 ± 3.17), whereas in group II, it was 16.45 ± 6.33 (P = 0.019 group I versus group III; (P = 0.036 group II versus group III). Postoperative PRBC requirements were significantly less in high dose group III (P = 0.008, group I versus III; p = 0.116, group II versus group III) . Tests for coagulation performed at four hours postoperatively, viz. ACT, PT, INR, FDP, and platelets were comparable in the three groups. Urine output on CPB was comparable in all the groups. Serum urea and creatinine showed no significant difference between the three groups twenty four hours postoperatively. Aprotinin dosage regimen of 40,000 KIU/kg at induction, in CPB prime and postoperatively for three hours was most effective in reducing postoperative blood loss and PRBC transfusion requirements. Aprotinin does not have any adverse effect on renal function.
Keywords: Aprotinin, infants, postoperative bleeding, transposition of great arteries
|How to cite this article:|
Verma YS, Chauhan S, Bisoi AK, Gharde P, Kiran U, Das SN. Comparison of three dose regimens of aprotinin in infants undergoing the arterial switch operation. Ann Card Anaesth 2010;13:110-5
|How to cite this URL:|
Verma YS, Chauhan S, Bisoi AK, Gharde P, Kiran U, Das SN. Comparison of three dose regimens of aprotinin in infants undergoing the arterial switch operation. Ann Card Anaesth [serial online] 2010 [cited 2020 Mar 29];13:110-5. Available from: http://www.annals.in/text.asp?2010/13/2/110/62935
| Introduction|| |
The use of cardiopulmonary bypass (CPB) for 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 by the extracorporeal circuit are some of the most important factors that may influence postoperative hemostasis. ,
Several serine protease enzymes are key mediators in the initiation and amplification of the inflammatory response.  Contact of the patient's 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.  Kallikrein, then, stimulates other serine proteases, including bradykinin, certain complement system enzymes, factor XIIA of the coagulation cascade, and plasmin.  In turn, kinins are produced leading to inflammation and the complement, coagulation, and fibrinolytic systems are all activated by the CPB circuit, which leads to further release of inflammatory mediators and proteolytic enzymes. 
Aprotinin is a nonspecific serine protease inhibitor that is able to inhibit various proteases involved in the coagulation, fibrinolytic, and complement cascade.  Another action of aprotinin is preservation of glycoprotein IIb receptor on the platelet membrane. Aprotinin has an antiinflammatory effect similar to methylprednisolone in blunting CPB-induced systemic tumor necrosis factor release and neutrophil upregulation.  Various studies have raised questions about the use of aprotinin in adults, , and this drug has been withdrawn from the US market. However, the authors did not find any contraindication to aprotinin use in pediatric patients and is still used in pediatric cardiac surgery. 
Despite the routine use of aprotinin in pediatric cardiac surgery globally, no generally accepted dosing regimen for aprotinin has been established. ,, The infant is connected to a relatively high-volume loaded extracorporeal circuit compared to it's blood volume, which, in turn, complicates the calculation of dosage, of aprotinin. 
Congenital heart disease itself has long been associated with coagulation abnormalities  including platelet abnormalities , and fibrinolysis. ,, Postoperative blood loss is a major concern after the arterial switch operation (Jatene), due to the long suture lines and preexisting coagulation abnormalities. Bleeding should be minimized as far as possible in order to avoid the associated hemodynamic instability,  prolonged surgical times, reoperation, ,, and increased need for allogeneic transfusions.  The literature on use of aprotinin in pediatric patients is significantly incomplete, and the issues of efficacy, safety, and even dosing remain unanswered.
The aim of present the study was to assess the efficacy of various doses of aprotinin in infants undergoing the arterial switch operation using parameters such as postoperative blood loss, postoperative PRBC requirements, coagulation tests including measures of fibrinolysis (fibrin degradation product titres) and platelet preservation. Renal functions were also assessed by comparing serial measurements of serum urea and creatinine and urine output.
| Materials and Methods|| |
The study was performed in 24 pediatric patients undergoing arterial switch operation after obtaining approval from the institute's ethics committee and taking informed consent from the parents of children. The children were randomly allocated to one of the three groups by computer generated sheet. Each group comprised eight patients. The consultant anesthesiologist incharge of the case administered the aprotinin. Group I patients received aprotinin in a dose of 20,000 KIU/kg by slow intravenous infusion after the induction of anesthesia, bolus dose of 20,000 KIU/kg in CPB prime and 20,000 KIU/kg/hour intravenous infusion for three hours after weaning from CPB. Group II patients received Aprotinin 30,000 KIU/kg by slow infusion after the induction of anesthesia, bolus dose of 30,000 KIU/kg in CPB prime, and 30,000 KIU/kg/hour infusion for three hours after weaning from CPB. Group III patients received aprotinin 40,000 KIU/kg by slow infusion after the induction of anesthesia, bolus dose of 40,000 KIU/kg in CPB prime, and 40,000 KIU/kg/hour infusion for three hours after weaning from CPB. During onset of CPB bolus dose of aprotinin was necessary to prevent sudden fall in blood aprotinin concentration due to hemodilution from large prime volume compared to the circulating blood volume of the child.
Exclusion criteria were, known bleeding disorders, known metabolic disorders, renal dysfunction, and earlier exposure to aprotinin.
Anesthetic and surgical management and conduct of CPB was standardized in all patients. All operations were performed by the same team Anesthesia was induced with 1 mg/kg ketamine or sevoflurane 2-5%; 0.05 mg/kg midazolam, and 0.1 mg/kg pancuronium or 1 mg/kg rocuronium to facilitate tracheal intubation. Anesthesia was maintained with incremental doses of fentanyl up to 10 μg/kg, pancuronium, and isoflurane in air and oxygen. CPB was conducted at moderate hypothermia (28°C) using a membrane oxygenator (Minimax, Meditronic, California,USA). Systemic heparinization was achieved with heparin 400 IU/kg keeping kaolin activated clotting time (ACT) more than 480 seconds as per the protocol of the center. Pump was primed with 600 ml of Ringer's Lactate. Mannitol, sodiumbicarbonate and PRBCs were added to the prime and the prime was hemofiltered before commencement of the CPB to achieve the hematocrit of around 30 percent by removing excess of prime through hemofitration. Hemofiltration was also performed during rewarming phase of CPB to achieve a hematocrit of 35-40% before separation from CPB. Deep hypothermic arrest was not used in any case. Continuous ultrafiltration was performed in all patients. Pump flows were maintained at 150 ml/kg at normothermia and 100 ml/kg during hypothermia. The children were rewarmed to a nasopharyngeal temperature of 35°C, as per institutional protocol. Heparin was neutralized with protamine in the ratio of 1:3 and additional protamine was administered if the ACT was more than 140 seconds. Platelets were transfused 0.1 mL/kg to all the patients after protamine infusion before transfer to ICU. Time taken for sternal closure after protamine administration was noted as an index of surgical hemostasis in all patients. Sternal closure time was taken as the time period between protamine administration and the last skin suture.
Postoperative care was provided by a separate team of intensivists, blinded to the dose of aprotinin, with full freedom for postoperative management as per existing protocols. Postoperatively, the cumulative hourly blood loss and PRBC requirements were noted up to 24 hours from the time of admission to the intensive care unit. Use of blood and blood products was noted. PRBC were transfused in measured amounts using 5 ml syringe and hematocrit was maintained around 35-40%. Fresh frozen plasma (FFP) was administered as volume replacement in small incremental doses to maintain the desired central venous pressure and left atrial pressure.
Coagulation parameters such as hematocrit, ACT, fibrinogen, prothrombin time (PT), platelet count and fibrin degradation products (FDP) were investigated pre-CPB, after protamine administration, and at four hours postoperatively. The number of patients reexplored for increased mediastinal drainage was recorded. The criteria for reexploration included postoperative bleeding 12 ml/kg in first hour or 10 ml/kg in two consecutive hours or 8 ml/kg in three consecutive hours following neutralization of heparin. Renal function was monitored by measuring urine output (hourly) and urea (mg%), creatinine (mg%) at 24 hours.
The data were entered in Microsoft Excel format and analyzed using SPSS50 software. Chi square test was used to compare qualitative data whereas continuous data comparison between three groups was performed by applying one way ANOVA/Kruskal-Wallis test wherever applicable followed by multiple comparison by Bonferroni method. The comparision over period of time was performed by applying repeated measures of analysis/Friedman (two-way ANOVA) wherever applicable followed by post-hoc comparison, for ordinal data the comparision was performed by Mc Nemars test; P < 0.05 was considered as significant.
| Results|| |
The study included 24 patients with transposition of the great arteries who underwent arterial switch operations. All the three groups were comparable with respect to the demographics [Table 1]. The age of the patients ranged from 18 to 61 days with the mean age being 41 days. There was male predominance in all the three groups.
Intraoperative data are shown in [Table 2]. Preoperative hematocrit and hematocrit during CPB, time taken for sternal closure, and urine output on CPB were comparable in all the three groups. There was significant difference between the amounts of hemofiltrate volume between the three groups.
Coagulation tests performed at four hours postoperatively are shown in [Table 3]. ACT, PT, INR, FDP and platelets were comparable in all the groups. Fibrinogen levels were comparable (P 0.24) in all the groups preoperatively (Group I, 1.99 ± 0.36 gm/L; Group II, 1.71 ± 0.36 gm/L; Group III, 1.78 ± 0.29 gm/L). Fibrinogen levels decreased significantly after surgery in group I (P = 0.002) as well as group II (P = 0.04). However, in group III there was no significant difference in preoperative and postoperative fibrinogen levels (P = 0.07) [Table 4].
Postoperative data are shown in [Table 5]. Cumulative blood loss (ml/kg/24 hours) was greatest in group I (17.30 ± 7.7), least in group III (8.14 ± 3.17), whereas in group II, it was 16.45 ± 6.33 (P = 0.019 group I versus group III; P = 0.036 group II versus group III).
FFP used for volume replacement was comparable in all the three groups. Postoperative PRBC requirements were significantly less in group III (P = 0.008, group I versus III; P = 0.116, group II versus group III).
Postoperative urine output was comparable among all the groups. There was a significant increase from the baseline in serum urea in group I (P = 0 .001), but no such increase was observed in groups II and III. Postoperative serum urea values were within normal range and statistically insignificant on intergroup comparision (P = 0.164). There was no significant change in pre and postoperative creatinine levels in all the three groups.
| Discussion|| |
CBP and cardiac surgery activate coagulation, inflammation, and fibrinolysis and cause platelet dysfunction. Children with congenital cyanotic heart disease already have a deranged coagulation system and new born plasma has 30% to 70% lower levels of both procoagulant and anticoagulant proteins than adult levels.  Pharmacological interventions, such as the use of protease inhibitor aprotinin are aimed at limiting the negative effect of CPB on coagulation. Aprotinin is an antifibrinolytic agent and also protects platelets by preventing their activation on CPB.
The arterial switch (Jatene) is a complex pediatric cardiac surgical procedure performed in neonates and infants requiring multiple suture lines on the great arteries with increased risk of postoperative bleeding.
Different dose regimens of aprotinin have been studied in pediatric cardiac surgery to reduce the postoperative blood loss and requirements for PRBC transfusions, however, there is no consensus among the scientific community on the most efficacious dose. ,,, The present study shows that the group III regimen (40,000 KIU after induction; 40,000 KIU in the CPB prime; and 40,000 KIU/kg/hr infusion after CPB for three hours) was the most appropriate dose regimen with regard to reduction in postoperative blood loss and reduced PRBC requirements.
Aprotinin, a protein derived from bovine lung has significant antigenic potential and fatal anaphylactic reactions have been reported.  German heart centre in a study on pediatric aprotinin exposure found an anaphylaxis rate of 0.05% in primary exposure and 1.3% in reexposure to aprotinin. None of the patients in the present study showed any evidence of anaphylatic reaction.
The authors did not observe an increased risk of thrombosis in any of the infants, a finding which has been reported earlier by Jacquiss et al,  Avoiding the use of deep hypothermic circulatory arrest could have been a contributing factor in this observation. Various studies investigating aprotinin in pediatric patients have reported renal outcomes.  Aprotinin is taken up by the brush border of the renal tubules after filtration. This has led to concerns about potential for renal toxicity. In a study by D'Errico et al.,  control patients had a transient increase in blood urea level that was not seen in the aprotinin treated groups. Miller et al.,  reported transient increase in creatinine in the placebo group patients on arrival in ICU that was not seen in aprotinin treated patients. In the present study, postoperative serum urea and serum creatinine values were within normal range and statistically insignificant on intergroup comparision. Group III patients showed maximum postoperative urine output. This is in agreement with the study of Herynkopf  who reported significantly higher diuresis in aprotinin treated patients. The amount of hemofiltrate was less in group II compared to group I and III. Prime was hemofiltered before commencement of CPB to achieve the hematocrit of around 30%. Aprotinin was added to the prime after this process. Hemofiltration during rewarming was uniform in all the patients.
The authors did not observe any difference in the coagulation parameters ACT, INR, PT, FDP, fibrinogen in intergroup comparision. The decrease in fibrinogen levels was least in group III compared to groups I and II where a significant decrease in fibrinogen levels was observed. In group I, one patient had FDP levels >20 μg/ml before CPB and during CPB. In group II, one patient had FDP levels >20 μg/ml before CPB and one had levels between 5-20 μg/ml. In group III, two patients had FDP levels between 5-20 μg/ml.
However, post-CPB FDP levels returned to <5 μg/ml (normal value) in all the patients.
We did not observe any dose dependent inhibition in FDP levels in any of the three groups. Postoperative INR levels were high but statistically comparable (P = 0.332). The most probable cause of high postoperative INR levels may have been heparin rebound phenomenon.
Earlier studies have shown decreased mediastinal drainage and hence decreased PRBC requirements, ,,, with varying dosage regimens of aprotinin in a variety of surgical procedures. Carrel et al.,  concluded that in complex surgical repair (transposition of great arteries), high dose aprotinin (50,000 KIU/kg during induction of anesthesia, 50,000 KIU/kg in pump prime, and 20,000 KIU/hr continuous infusion) led to a significant reduction of blood loss and postoperative PRBC requirements. The present study performed on a homogenous group of patients with transposition of great arteries operated by the same surgical team showed that the postoperative chest drainage was significantly less (P = 0.02) in group III compared to groups I and II. However, no difference in the postoperative blood loss was observed between groups I and II. In group I, all the patients (100%) received PRBC and four (50%) received FFP. In group II, six patients (75%) received PRBC and three (37.5%) received FFP. In group III, three patients (37.5%) received PRBC and only one (12.5%) received FFP. Postoperative PRBC transfusion requirements were significantly less in high dose group III (P = 0.008; group I versus III). FFP transfusion was comparable in all the groups.
Limitations of the study
The number of patients in each group was small as homogeneity was maintained in terms of type of surgery, age group of patients, surgery, and anesthesia team. There was no control group since it is the protocol of our institution that surgery is not performed without some sort of blood conservation measures (for example, tranexamic acid or epsilon aminocaproic acid). The difference in the hemofiltrate volume in the three groups may have influenced the results.
| Conclusion|| |
Aprotinin in the dose of 40,000 KIU/kg after the induction of anesthesia, 40,000 KIU/kg in the CPB prime and 40,000 KIU/kg/hour infusion for three hours after weaning from CPB in combination with ultrafiltration was the most effective in reducing postoperative blood loss and PRBC transfusion requirements in infants undergoing the arterial switch operation at moderate hypothermia.
Aprotinin does not have any adverse effect on renal function in these doses.
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Department of Cardiac Anesthesia, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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