Asian Cardiovasc Thorac Ann 2004;12:121-124
© 2004 Asia Publishing EXchange Ltd
Dose Comparison of Tranexamic Acid in Pediatric Cardiac Surgery
Sandeep Chauhan, MD,
Akshay Bisoi, MCh1,
Neeraj Kumar, MD,
Dinesh Mittal, MS1,
Shailaja Kale, MD,
Usha Kiran, MD,
Panangipalli Venugopal, MCh1
Department of Cardiac Anesthesia
1 Department of Cardiac Surgery, Cardiothoracic Center, All India Institute of Medical Sciences, New Delhi, India
For reprint information contact: Sandeep Chauhan, MD Tel: 91 11 2610 8115 Fax: 91 11 2658 8641 Email: sdeep61{at}yahoo.com Cardiac Anesthesia, Cardiothoracic Centre, All-India Institute of Medical Sciences, New Delhi 110029, India.
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ABSTRACT
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To compare different doses of tranexamic acid, 150 consecutive children with congenital cyanotic heart disease were randomly assigned to one of 5 groups of 30 each. Group A served as a control. Group B received 50 mg·kg–1 of tranexamic acid at induction of anesthesia. Group C received 10 mg·kg–1 at induction followed by an infusion of 1 mg·kg–1·h–1. Group D had 10 mg·kg–1 at induction, 10 mg·kg–1 on bypass, and 10 mg·kg–1 after protamine. Group E had 20 mg·kg–1 at induction and again after protamine. The control group had the longest sternal closure time, the greatest blood loss in the first 24 hours, and the highest requirements for blood and blood products. Among the 4 groups given tranexamic acid, group D (triple dose) had the best results, followed by group E (double dose). Group B (single dose) had the worst results among the groups receiving tranexamic acid.
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INTRODUCTION
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Blood conservation continues to be an important focus of interest in the field of cardiac surgery, given the increased awareness of blood-borne diseases and problems arising from the multiple donor transfusions that are a routine part of cardiac surgery.1 The search for methods and pharmacological agents to reduce blood loss after cardiac surgery is ongoing. The use of antifibrinolytic agents such as 
-aminocaproic acid or tranexamic acid (TA) to reduce blood loss after pediatric cardiac surgery has been described in several studies.2,3 These agents were found to be more effective in cyanotic rather than acyanotic patients. TA is a synthetic lysine analogue that has been used to reduce postoperative blood loss in adult patients, but very few studies have been conducted in children.4–6 The dosage of TA has varied greatly in different reports. Reichert and colleagues7 used a single dose of 50 mg·kg–1 after anesthetic induction. Isetta and colleagues8 used 15 mg·kg–1 of TA before heparin, and the same dose after protamine administration, and compared the effects with those of low dose aprotinin. Horrow and colleagues9 used a 10 mg·kg–1 loading dose followed by an infusion of 1 mg·kg–1·h–1. In view of the large variation in dosage of TA, we decided to compare the previously used regimens to assess their relative efficacy in children with cyanotic congenital heart disease undergoing corrective surgery.
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PATIENTS AND METHODS
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After approval from the institute’s ethics committee and informed consent from the parents of the children, this study was conducted over a 9-month period from September 2002 on 150 consecutive children aged 2 months to 15 years, undergoing corrective surgery for congenital cyanotic heart disease. Patients with renal dysfunction, a previous neurological event, or a congenital bleeding disorder were excluded from the study. We included patients who were on heparin or aspirin to assess any beneficial effect of TA in these patients. Preoperative blood samples were taken for platelet count, prothrombin time, and activated partial thromboplastin time. The patients were randomly assigned to one of 5 groups of 30 each, based on the dose of TA (Systopic Laboratories, New Delhi, India). Patients in group A served as controls and received no drug. Group B had a single dose of 50 mg·kg–1 given over 30 minutes after anesthetic induction. Group C received 10 mg·kg–1 of TA after anesthetic induction followed by an infusion of 1 mg·kg–1·h–1 for 8 hours. Group D received 10 mg·kg–1 of TA after anesthetic induction, 10 mg·kg–1 on cardiopulmonary bypass (CPB) and 10 mg·kg–1 after protamine administration. Group E received 20 mg·kg–1 of TA after anesthetic induction and 20 mg·kg–1 after protamine.
Conduct of anesthesia and CPB was standardized in all groups which differed only in the dose of TA given. All operations were performed by the same surgical team, ruling out variations in surgical technique as a cause of varying postoperative blood loss. Anesthesia was induced with ketamine, midazolam, and pancuronium for muscular relaxation, and maintained on air oxygen, isoflurane and fentanyl. After systemic heparinization with 3 mg·kg–1 of bovine intestinal mucosal heparin, CPB was established using a Minimax membrane oxygenator (Medtronic, Anaheim, CA, USA), nonocclusive roller pumps, and moderate hypothermia (28°C). The CPB circuit was primed with 20 mL·kg–1 lactated Ringer’s solution, 1 mL·kg–1 sodium bicarbonate 7.5% (w/v)*, 0.5 g·kg–1 mannitol 20% (w/v)*, and 100 U·kg–1 heparin. Blood remaining in the CPB circuit after bypass was processed through a cell saver for re-transfusion. Time taken for chest closure (from protamine administration to sternal closure) was recorded in all patients as an indirect assessment of coagulation status. Postoperative care was undertaken by a separate team of intensivists who were blinded to the study groups and who managed bleeding and blood product administration according to existing protocols. Packed red cells were used for transfusion if the hematocrit fell below 33%. Fresh frozen plasma was used if the hematocrit was above 33%. Platelet concentrates were used in a dose of 1 unit per 10 kg, and 5% albumin was used for volume replacement if no active bleeding was present. Postoperative cumulative blood loss was recorded at 24 hours. Use of blood and blood products was noted at 24 hours. Blood samples were collected at 6 hours for tests of coagulation including activated clotting time, fibrinogen, fibrin degradation products, and platelet count. Results are expressed as mean ± standard deviation. They were assessed by analysis of variance followed by Newman-Keul, multiple range tests. Values of p < 0.05 were considered significant.
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RESULTS
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Demographic data are shown in Table 1
. The various operations performed in the 5 groups are listed in Table 2. Although CPB times were similar in the 5 groups, sternal closure took the longest in group A (control group). Intraoperative data were comparable in the 5 groups (Table 3). Postoperatively, the control group had the greatest blood loss in the first 24 hours. Blood and blood product usage mirrored the pattern of blood loss, with group D having the lowest requirements at 24 hours among the 5 groups. Re-exploration for increased mediastinal drainage was less frequent in groups D and E. Postoperative data are shown in Table 4. Tests of coagulation at 6 hours postoperatively showed preservation of fibrinogen in the groups given TA, with highest levels of fibrinogen and lowest levels of fibrin degradation products in groups D and E, as shown in Table 5. No complication in the form of renal problems or cerebral events were noted in any of the children studied.
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DISCUSSION
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Platelet dysfunction and fibrinolysis are important causes of increased postoperative blood loss after cardiac surgery performed under CPB.10 As children with congenital cyanotic heart disease have a deranged coagulation system, with preexisting altered platelet function and enhanced fibrinolysis, they are more prone to excessive postoperative blood loss because these preexisting defects are worsened by CPB.11 Patients with congenital cyanotic heart disease are known to benefit from antifibrinolytics such as -aminocaproic acid which has been used in several studies to reduce postoperative blood loss.12,13 Tranexamic acid is 10 times more potent than -aminocaproic acid as an antifibrinolytic agent, with more effective binding to plasminogen. However, there is no agreement on the optimal dosage of TA or the timing of administration, specially in patients with congenital cyanotic heart disease. Reichert and colleagues7 studied TA in 88 children given a single dose of 50 mg·kg–1 and found no benefit in 64 non-cyanotic patients in terms of reduced bleeding or transfusion requirements.
This study found a single bolus dose to be the least effective amongst the 4 dosage regimes studied. The maximum reduction in blood loss was seen when sustained antifibrinolysis was produced by administration of TA before skin incision (after anesthetic induction), with an additional dose on CPB to compensate for decreased TA levels on CPB because of hemodilution, and another dose after weaning from CPB (group D). Group E which received a double dose on induction and another after weaning from CPB, also had sustained plasminogen inhibition as the blood loss and blood and product requirements closely matched those of group D. A study by Harrow and colleagues14 compared a full dose of TA (10 mg·kg–1 bolus followed by 1 mg·kg–1·h–1 infusion) with a half dose, quarter dose, and double dose in 65 adult patients, and found the double dose (20 mg·kg–1 bolus and 2 mg·kg–1·h–1 infusion) to be the most effective. Reid and colleagues15 conducted a study on 41 pediatric patients undergoing reoperation, however, they used a dose of 100 mg·kg–1 after induction, followed by a 10 mg·kg–1·h–1 infusion with an additional 100 mg·kg–1 in the prime. These doses are more than 10 times the recommended dosage of TA in most of the literature. This study found that all 4 groups of children with congenital cyanotic heart disease given TA benefited in terms of reduced postoperative bleeding, but the single bolus dose given at anesthetic induction was the least effective, and an infusion of 1 mg·kg–1·h–1 after the bolus dose in group C was probably not adequate to compensate for the hemodilution on CPB. The best results were found in the 2 groups where sustained plasminogen inhibition was achieved by giving an additional dose of TA during or after CPB.
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Footnotes
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* w/v: refers to weight per volume and is a standard short format used by pharmacists and pharmaceutical companies to describe the weight of a substance dissolved in the volume of the dissolving liquid. 
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ABSTRACT
INTRODUCTION
