Objective  To systematically assess the efficacy and safety of antifibrinolytic drugs for hemostatic efficacy in cardiac surgery for cardiopulmonary diversion in children.

Methods  A systematic search of PubMed, Embase, and The Cochrane Library was performed to collect all randomized controlled trials (RCTs) using antifibrinolytic drugs in cardiac surgery for cardiopulmonary diversion in children from January 1st, 1980 to October 14 th, 2023. Meta-analysis was performed using RevMan 5.4 software.

Results  A total of 20 studies and 23 RCTs were included, with 9 involving peptidase, 10 involving tranexamic acid, and 4 involving aminocaproic acid. The result of Meta-analysis showed that compared with the control group, all the experimental groups using antifibrinolytic drugs (peptidase, tranexamic acid, and aminocaproic acid) significantly reduced the amount of hemorrhage and transfusion in the first 24 h postoperatively (P<0.05); however, the difference of the incidence of thrombosis and death in the two groups was not statistically significant (P>0.05).

Conclusion  Antifibrinolytic drugs have hemostatic effects in cardiac surgery for cardiopulmonary bypass in children. Because of the paucity of evidence from relevant pediatric studies, a large number of comparative trials are needed to assess the safety associated with these drugs and the appropriate dosing regimen.

1.Williams GD, Bratton SL, Ramamoorthy C. Factors associated with blood loss and blood product transfusions: a multivariate analysis in children after open-heart surgery[J]. Anesth Analg, 1999, 89(1): 57-64. DOI: 10.1097/00000539-199907000-00011.

2.Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review[J]. Intensive Care Med, 2004, 30(10): 1873-1881. 10.1007/s00134-004-2388-0.

3.Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass[J]. Ann Thorac Surg, 2003, 75(2): S715-720. DOI: 10.1016/s0003-4975(02)04701-x.

4.Eaton MP. Antifibrinolytic therapy in surgery for congenital heart disease[J]. Anesth Analg, 2008, 106(4): 1087-1100. 10.1213/ane.0b013e3181679555.

5.Lu J, Meng H, Meng Z, et al. Epsilon aminocaproic acid reduces blood transfusion and improves the coagulation test after pediatric open-heart surgery: a meta-analysis of 5 clinical trials[J]. Int J Clin Exp Pathol, 2015, 8(7): 7978-7987. https://pubmed.ncbi.nlm.nih.gov/26339364/.

6.Mössinger H, Dietrich W, Braun SL, et al. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery[J]. Ann Thorac Surg, 2003, 75(2): 430-437. DOI: 10.1016/s0003-4975(02)04412-0.

7.Bulutcu FS, Ozbek U, Polat B, et al. Which may be effective to reduce blood loss after cardiac operations in cyanotic children: tranexamic acid, aprotinin or a combination?[J]. Paediatr Anaesth, 2005, 15(1): 41-46. DOI: 10.1111/j.1460-9592.2004.01366.x.

8.Chauhan S, Kumar BA, Rao BH, et al. Efficacy of aprotinin, epsilon aminocaproic acid, or combination in cyanotic heart disease[J]. Ann Thorac Surg, 2000, 70(4): 1308-1312. DOI: 10.1016/s0003-4975(00)01752-5.

9.Davies MJ, Allen A, Kort H, et al. Prospective, randomized, double-blind study of high-dose aprotinin in pediatric cardiac operations[J]. Ann Thorac Surg, 1997, 63(2): 497-503. DOI: 10.1016/s0003-4975(96)01031-4.

10.D'Errico CC, Shayevitz JR, Martindale SJ, et al. The efficacy and cost of aprotinin in children undergoing reoperative open heart surgery[J]. Anesth Analg, 1996, 83(6): 1193-1199. DOI: 10.1097/00000539-199612000-00011.

11.Herynkopf F, Lucchese F, Pereira E, et al. Aprotinin in children undergoing correction of congenital heart defects. A double-blind pilot study[J]. J Thorac Cardiovasc Surg, 1994, 108(3): 517-521. https://pubmed.ncbi.nlm.nih.gov/7521498/.

12.Miller BE, Tosone SR, Tam VK, et al. Hematologic and economic impact of aprotinin in reoperative pediatric cardiac operations[J]. Ann Thorac Surg, 1998, 66(2): 535-540, 541. DOI: 10.1016/s0003-4975(98)00469-x.

13.Murugesan C, Banakal SK, Garg R, et al. The efficacy of aprotinin in arterial switch operations in infants[J]. Anesth Analg, 2008, 107(3): 783-787. DOI: 10.1213/ane.0b013e31817f8b2c.

14.Williams GD, Ramamoorthy C, Pentcheva K, et al. A randomized, controlled trial of aprotinin in neonates undergoing open-heart surgery[J]. Paediatr Anaesth, 2008, 18(9): 812-819. DOI: 10.1111/j.1460-9592.2008.02678.x.

15.Aggarwal V, Kapoor PM, Choudhury M, et al. Utility of Sonoclot analysis and tranexamic acid in tetralogy of Fallot patients undergoing intracardiac repair[J]. Ann Card Anaesth, 2012, 15(1): 26-31. DOI: 10.4103/0971-9784.91477.

16.Chauhan S, Bisoi A, Kumar N, et al. Dose comparison of tranexamic acid in pediatric cardiac surgery[J]. Asian Cardiovasc Thorac Ann, 2004, 12(2): 121-124. DOI: 10.1177/021849230401200208.

17.Chauhan S, Bisoi A, Modi R, et al. Tranexamic acid in paediatric cardiac surgery[J]. Indian J Med Res, 2003, 118: 86-89. https://pubmed.ncbi.nlm.nih.gov/14680204/.

18.Chauhan S, Das SN, Bisoi A, et al. Comparison of epsilon aminocaproic acid and tranexamic acid in pediatric cardiac surgery[J]. J Cardiothorac Vasc Anesth, 2004, 18(2):141-143. DOI: 10.1053/j.jvca.2004.01.016.

19.Couturier R, Rubatti M, Credico C, et al. Continuous or discontinuous tranexamic acid effectively inhibits fibrinolysis in children undergoing cardiac surgery with cardiopulmonary bypass[J]. Blood Coagul Fibrinolysis, 2014, 25(3): 259-265. DOI: 10.1097/mbc. 0000000000000051.

20.Hatami F, Valizadeh N, Salehi F, et al. Topical versus low-dose systemic tranexamic acid in pediatric cardiac surgery: A randomized clinical study[J]. J Card Surg, 2020, 35(12): 3368-3373. DOI: 10.1111/jocs.15082.

21.Reid RW, Zimmerman AA, Laussen PC, et al. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery[J]. Anesth Analg, 1997, 84(5): 990-996. DOI: 10.1097/00000539-199705000-00008.

22.Shimizu K, Toda Y, Iwasaki T, et al. Effect of tranexamic acid on blood loss in pediatric cardiac surgery: a randomized trial[J]. J Anesth, 2011, 25(6): 823-830. DOI: 10.1007/s00540-011-1235-z.

23.Zonis Z, Seear M, Reichert C, et al. The effect of preoperative tranexamic acid on blood loss after cardiac operations in children[J]. J Thorac Cardiovasc Surg, 1996, 111(5): 982-987. DOI: 10.1016/s0022-5223(96)70374-4.

24.Rao BH, Saxena N, Chauhan S, et al. Epsilon aminocaproic acid in paediatric cardiac surgery to reduce postoperative blood loss[J]. Indian J Med Res, 2000, 111: 57-61. https://pubmed.ncbi.nlm.nih.gov/10824468/.

25.Sarupria A, Makhija N, Lakshmy R, et al. Comparison of different doses of ε-aminocaproic acid in children for tetralogy of Fallot surgery: clinical efficacy and safety[J]. J Cardiothorac Vasc Anesth, 2013, 27(1): 23-29. DOI: 10.1053/j.jvca.2012.07.001.

26.Jiménez JJ, Iribarren JL, Brouard M, et al. Safety and effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial[J]. J Cardiothorac Surg, 2011, 6: 138. DOI: 10.1186/1749-8090-6-138.

27.Pugh SC, Wielogorski AK. A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery[J]. J Cardiothorac Vasc Anesth, 1995, 9(3): 240-244. DOI: 10.1016/s1053-0770(05)80314-3.

28.Schouten ES, van de Pol AC, Schouten AN, et al. The effect of aprotinin, tranexamic acid, and aminocaproic acid on blood loss and use of blood products in major pediatric surgery: a meta-analysis[J]. Pediatr Crit Care Med, 2009, 10(2): 182-190. DOI: 10.1097/PCC.0b013e3181956d61.

29.Dietrich W, Mössinger H, Spannagl M, et al. Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations[J]. J Thorac Cardiovasc Surg, 1993, 105(4): 712-720. https://pubmed.ncbi.nlm.nih.gov/7682267/.