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CARDIOVASCULAR ANESTHESIOLOGY

The Efficacy of Aprotinin in Arterial Switch Operations in Infants

From the Department of Anesthesiology, Narayana Hrudayalaya Institute of Medical Sciences, Bangalore, India.

Abstract

BACKGROUND: In the present study we assessed whether aprotinin at a total dose (40,000 kallikrein inhibitor units (KIU)/kg) is effective in reducing postoperative blood loss and blood product requirement after arterial switch operations in infants.

METHODS: A prospective, double-blind, randomized study, evaluated 50 infants who underwent arterial switch operations for transposition of great arteries. Patients were randomized into a placebo group, 25 patients who received normal saline and a treatment group, 25 patients who received 20,000 KIU/kg of aprotinin after induction of anesthesia, followed by 20,000 KIU/kg of aprotinin added to pump prime. Postoperative blood loss through the thoracic chest tubes and blood product requirements (mL/kg/24 h) were measured for the first 24 h in the intensive care unit.

RESULTS: Postoperative blood loss in the first 24 h was significantly (P < 0.0001) higher in the placebo group (49.7 ± 11.9 mL/kg/24 h) as compared to the aprotinin group (37.1 ± 3.5 mL/kg/24 h). Requirements for fresh frozen plasma (mL/kg/24 h) and use of platelet concentrate transfusion (mL/kg/24 h) were significantly less in patients who received aprotinin (P < 0.0001), but did not reduce the proportion of patients transfused with blood products. The number of total donor exposures to all allogenic blood products was less in the aprotinin group [range (median) = 2–4 (3)] than the placebo group [range (median) = 7–14 (10)]. The re-exploration for excessive bleeding was significantly less with aprotinin group (16% vs 32%) (P = 0.01).

CONCLUSION: Our study concludes that aprotinin decreased the postoperative blood loss and requirement of transfusion of fresh frozen plasma and platelets (mL/kg/24 h) during the early postoperative period. Further, it reduced the number of donor exposures and re-exploration for excessive bleeding in the treatment population.

Increased postoperative bleeding after arterial switch operation (ASO) is a major concern during the early postoperative period. This excessive postoperative bleeding after cardiopulmonary bypass (CPB) is multifactorial in this patient population.1 Several studies in children suggest that aprotinin is beneficial for pediatric patients during cardiac surgery.2,3 Aprotinin is a broad-spectrum drug that inhibits serine proteases, such as trypsin, plasmin, and kallikrein.4 By 1984, the benefits of aprotinin in pediatric CPB were studied and decreased postoperative blood loss was demonstrated2 with multiple dose regimens. Studies involving high dose aprotinin in patients with different types of congenital heart diseases5 and transposition of great arteries6 (TGA) who underwent cardiac operations have consistently shown a decrease in postoperative blood loss. However, the benefit of lower doses of aprotinin (30,000 kallikrein inhibitor units (KIU)/kg in divided doses) in reducing postoperative blood loss has been less obvious.5 The aim of the present study was to assess whether aprotinin at a particular dose (40,000 KIU/kg) is effective in reducing bleeding and transfusion requirements in a homogenous study population undergoing ASO.

METHODS

After obtaining approval from the institute ethics committee and informed consent from the infant’s parents, we conducted a prospective, double-blind, randomized study in 50 consecutive patients who underwent ASOs (January 2006 to March 2007) for TGA with intact ventricular septum (IVS) or with ventricular septal defect (VSD). All patients who were enrolled completed study. Patients with sepsis, renal failure, liver failure, bleeding disorder, and metabolic disorders were excluded from the study. Patients were randomized by sealed envelope technique into two groups. The placebo group was comprised of 17 patients with TGA with VSD and eight patients with TGA with IVS. The aprotinin group was comprised of 15 patients with TGA with VSD and 10 patients with TGA with IVS. The attending anesthesiologists who were blinded to the study group conducted anesthesia. The placebo group included 25 patients who received normal saline as placebo. The aprotinin group included 25 patients who received 20,000 KIU/kg of aprotinin after induction of anesthesia, followed by 20,000 KIU/kg of aprotinin added to pump prime. Anesthetic and surgical management were standardized in both groups. All operations were performed by the same surgical team who were blinded to study population, eliminating variation of surgical techniques resulting in varying postoperative blood loss.

Patients were premedicated with oral atropine 0.02 mg/kg and anesthesia was induced with an inhaled technique using oxygen and sevoflurane, 0.05 mg/kg of midazolam, 2–5 µg/kg fentanyl and 0.1 mg/kg pancuronium to facilitate tracheal intubation. Anesthesia was maintained with oxygen and isoflurane (0.5%–1%), incremental doses of fentanyl up to 10 µg/kg were used. Before CPB, heparin 400 U/kg, was administered into the functioning central vein, 100 U/kg of heparin was added to the pump prime. Kaolin activated clotting time (ACT) was maintained above 600 s as per the hospital’s protocol by actalyke K-Act tube (Actalyke, Activated clotting time system, Beaumont, TX). The ACT was measured every 30 min during CPB, and after reversal with protamine. The CPB system included a Jostra (CSL 15-146, JOSTRA AB, LUND SWEDEN) pump with membrane oxygenator (Capiox RX 05, TERUMO corporation, Tokyo, Japan). The CPB circuit was primed with 400 mL of fresh whole blood (harvested with <24 h), 0.5gm/kg (w/v) mannitol (20%), 1 mL/kg (w/v) sodium bicarbonate (7.5%), 5 mL/kg of albumin (20%). Hence the total volume of pump prime was about 420–430 mL. Fresh whole blood was used in all patients in both groups. In addition, packed red blood cells (PRBC) about 50 to 100 mL were added on-pump during CPB, to maintain the hematocrit (HCT) about 30% on CPB. During CPB, patients were cooled to 18°C to 24°C. Deep hypothermic circulatory arrest (DHCA) was used for patients with TGA with VSD. Myocardial protection was achieved by using blood cardioplegia solution with a cardioplegia delivery system (MYO therm XP, Medtronic, Inc., Minneapolis, MN). Pump flows were maintained between 150–200 mL · kg^–1 · min^–1. The flow rate was adjusted to maintain an online oxygen saturation of 80% ± 5% in the superior vena cava. Modified ultrafiltration was performed in both groups at the end of CPB to achieve the target HCT of 40%. Later, protamine sulfate was administered at a dose of 1.3/1.0 mg of heparin to antagonize the effects of heparin after separation from CPB. An additional dose of protamine 0.2 mg/kg was administered if the ACT was more than 130 s. All patients received 0.1 U/kg of platelet transfusion for hemostasis after separation from CPB (as per our hospital’s protocol). Skin closure time was calculated from the time of coming off bypass to skin closure, which was an index of duration of securing hemostasis. Pediatric intensivists, who were blinded to patient groups, provided postoperative care. Postoperative blood loss through the thoracic chest tubes and blood product requirements were measured every hour for the first 24 h from the time of admission to the intensive care unit (ICU). Mediastinal shed blood was not re-transfused. Coagulation variables including HCT, prothrombin time (PT), partial thromboplastin time, and platelet counts were estimated when the patients were received in the ICU. Postoperative transfusion criteria included maintaining the HCT-35% with transfusion of PRBC. Platelets were transfused at a dose of 0.1 U/kg if the platelet count decreased to less than 100 x 10⁹/L; platelet count was re-assessed every 6 h. If the PT was >1.5 times or activated partial thromboplastin time was >1.5 times, fresh frozen plasma (FFP) was administered at the dose of 15 mL/kg. PT and activated partial thromboplastin time were checked again every 6 h. Patients who were re-explored for increased mediastinal drainage were noted. The following criteria were used to re-explore the patients for excessive drainage. If postoperative bleeding was 13 mL/kg in the first hour, or 10 mL/kg in two consecutive hours, or 8 mL/kg in three consecutive hours, it was an indication for re-exploration. If the total bleeding at the end of 4 or 5 h was 25 mL/kg, 30 mL/kg, respectively, it was again an indication of re-exploration.

All the re-explorations were performed in the operating room. Physicians involved in the re-exploration were also blinded to the study group. The total number of units of blood and blood products, which were used during the primary operation and in the first 24 h of ICU stay, were counted as donor exposures.

Results expressed as mean ± sd were analyzed by Student’s t-test and ² test between groups. A value of P < 0.05 was considered significant.

RESULTS

This study was conducted on 50 patients with TGA who underwent ASOs. Both groups were comparable in all demographics. The age of patients ranged from 2 days to 5 mo. Male infants were predominantly more affected than female infants in both groups. The demographic data are shown in Table 1. Intraoperative data are shown in Table 2. Even though time taken for skin closure in the placebo group (70 ± 28.5 min) was prolonged compared to the aprotinin group (60.6 ± 22 min), statistically there was no significance (P = 0.19) between groups. The dose of protamine used in both groups was comparable (placebo 15.3 ± 3.6 mg versus aprotinin 14.1 ± 3.9 mg).

Postoperative data are shown in Table 3. Postoperative blood loss (mL/kg/24 h) in the first 24 h in the ICU was significantly (P < 0.0001) higher in the placebo group (49.7 ± 11.9 mL/kg/24 h) than the aprotinin group (37.1 ± 3.5 mL/kg/24 h), use of PRBC was similar in both groups. FFP requirements (mL/kg/24 h) were significantly (P < 0.0001) less in the aprotinin group as compared to the placebo group. Use of platelet concentrate transfusion (mL/kg/24 h) was significantly (P < 0.0001) less in the aprotinin group. In the aprotinin Group 76% of patients required platelet transfusion postoperatively as opposed to 96% in the placebo group (P < 0.1). However, our study showed that this dose of aprotinin did not reduce the proportion of patients transfused with blood products (P = 0.1).

The re-exploration for excessive bleeding through chest tubes was significantly (P = 0.01) less in the aprotinin group (16% vs 32%). The number of total donor exposures to all allogenic blood products was less in the aprotinin group (Table 4). Postoperative blood and blood products use in patients who were re-explored for excessive bleeding are shown in Table 5. However, the proportion of patients who required inotropic support in the postoperative period, mean ICU stay (placebo versus aprotinin = 11.2 ± 3 vs 11.7 ± 3, P = 0.57), and mortality (placebo versus aprotinin = 12% vs 8%, P = 1.0) were similar in both groups.

DISCUSSION

ASO is a complex pediatric cardiac surgical procedure performed in neonates and infants. It requires meticulous dissection and multiple suture lines on great arteries and is usually associated with prolonged CPB times. Increased postoperative blood loss is a major concern after ASO. Aprotinin is a broad-spectrum serine protease inhibitor that protects platelets by preventing their activation on CPB.7 Different dose regimens of aprotinin were studied in pediatric cardiac surgeries to reduce postoperative blood loss and requirement of blood products. Studies involving high dose aprotinin in patients with different types of congenital heart diseases5 and TGA,6 who underwent cardiac operations, have consistently shown a decrease in postoperative blood loss. However, the benefits of low dose aprotinin (30,000 KIU/kg) in reducing postoperative blood loss have not been demonstrated.5 Our study found that aprotinin (40,000 KIU/kg in divided doses) decreased postoperative blood loss and transfusion requirement of FFP and platelets (mL/kg/24 h) in infants undergoing ASO for TGA.

We chose to conduct this prospective study to evaluate the efficacy of aprotinin in this particular dose (40,000 KIU/kg) in a homogenous group of patients with TGA who underwent corrective procedures. In comparison with the Hammersmith regimen, the total dose of aprotinin used in our study was in the range of an intermediate dose regimen based on the calculation of body weight. This particular dose was adopted in our study since our patients were to undergo DHCA during CPB and, further, to reduce the incidence of renal dysfunction.

The age of the patients in our study, ranged from 2 days to 5 mo with a mean age of 38 ± 1.5 days (median, 12 days) in the placebo versus 40 ± 1.8 days (median, 12 days) in the aprotinin group and weighing <5 kg, who underwent similar procedures. However, we assume that these data cannot be extrapolated to use in younger infants (younger mean age) presenting for similar procedures because our study patients were cyanotic for a longer period before surgical repair.

The risk of a hypersensitivity reaction is low after primary exposure to aprotinin.8 We did not encounter anaphylaxis in our study. A more important consideration than anaphylaxis in the use of aprotinin is the transient increase in serum creatinine and the potential for renal dysfunction.9 We did not notice any transient elevation of creatinine in our patients who received aprotinin. The potential for thrombosis when aprotinin is administered to patients undergoing DHCA remains controversial.10 Excessive mortality and complication rates have been reported only in clinical series in which the adequacy of heparinization is questionable.11 In our study 15 of 25 patients in the aprotinin group had no clinical evidence of thrombo-embolic events in the postoperative period for infants who underwent a period of DHCA. This may be related to the fact that kaolin ACT was maintained above 600 s throughout CPB. However, the sample size was not large enough to reach a definitive conclusion regarding the association of aprotinin and thrombosis. The risk of aprotinin- associated thrombosis after CPB remains undefined because European institutions with considerable experience with aprotinin during pediatric surgery report no evidence of increased thrombosis.12

In addition to aprotinin, fresh whole blood transfusions may also contribute to decreasing postoperative blood loss in infants post-CPB.13 In our study, fresh whole blood (harvested <24 h) was used for priming the CPB circuit. The present study showed that the number of total donor exposures to all allogenic blood products could be reduced with this dose of aprotinin, which can be easily extrapolated in terms of reduction in morbidity associated with multiple donor exposures. However, our study showed that this dose of aprotinin did not reduce the proportion of patients transfused with blood products.

Herynkopf et al.14 noted that donor blood exposure decreased by about half in patients who received low dose aprotinin. Children undergoing repair of Tetralogy of Fallot showed a significant decrease in the total volume of blood loss and blood transfused.15 Penkoske16 et al. found a similar decrease in blood loss, volume of transfusion, and number of units transfused. In this study, the authors demonstrated that transfusion requirements (donor) were decreased in aprotinin-treated patients (4.2 ± 3.4 vs 6.7 ± 5.2). This study had a nonhomogenous group of children, which included re-operations, neonates, extremely cyanotic children, and complex repairs. However, our study population comprised of a homogenous group of patients with TGA who underwent corrective procedures with a mean CPB time of 215 ± 31.3 vs 207.3 ± 36.5 min in the placebo and aprotinin groups respectively, showed increased postoperative blood loss and donor exposures as compared to previous study.16 Mössinger17 et al. studied high dose aprotinin for attenuating hemostatic and inflammatory activation in 60 patients weighing <10 kg. They found a significant reduction in postoperative chest drainage and postoperative ventilation in the aprotinin group.

Tranexamic acid may be as effective as low-dose aprotinin in cyanotic heart disease.18 However, there are few published reports about its use in ASOs. The platelet-sparing effect19 with aprotinin, but not with tranexamic acid, is well established. Hence we chose to use aprotinin in our study. A plasma aprotinin concentration of about 137 KIU/mL is needed to inhibit plasmin.18 However, in the present study the aprotinin dose was determined according to body weight, plasma levels were not measured.

The literature suggests that aprotinin is safe in pediatric patients undergoing cardiac surgery.20 In a cohort study of pediatric patients undergoing CPB, there was no association between the use of aprotinin and acute renal failure, need for dialysis, neurological complication, and operative or late mortality. In summary, we found that aprotinin in a dose of 40,000 KIU/kg was effective in decreasing postoperative blood loss (mL/kg/24 h) in infants undergoing ASO for TGA. Further, it reduced the requirement for transfusion of FFP and platelets (mL/kg/24 h) during the early postoperative period. We also observed that aprotinin in ASOs reduced the number of total donor exposures to all allogenic blood products and re-exploration for excessive bleeding.

Footnotes

Accepted for publication April 29, 2008.

Address for correspondence and reprint requests to Dr. C. Murugesan, Department of Anesthesiology, Narayana Hrudayalaya Institute of Medical Sciences, No.258/A, Bommasandra Industrial Area, Anekal Taluk, Bangalore, India. Address e-mail to murugesanhosur{at}gmail.com.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Murugesan, C. Articles by Muralidhar, K. Search for Related Content PubMed PubMed Citation Articles by Murugesan, C. Articles by Muralidhar, K. Related Collections Cardiovascular Coagulation Pediatrics Pharmacology