Antithrombin III Supplementation for Cardiopulmonary Bypass in Neonates

Summary

A prospective, randomized, placebo-controlled, double-blinded pilot study is planned. Neonates undergoing surgeries requiring cardiopulmonary bypass will receive antithrombin III (ATIII) supplementation or placebo in addition to standard anticoagulation with heparin as currently practiced at Children's Hospital of Wisconsin. We plan to enroll the first 60 sequential patients meeting criteria who consent to inclusion. The primary outcomes will be rates of adverse events to monitor safety. Secondary outcomes include volume of postoperative blood loss and packed red blood cell transfusion during the first 24 postoperative hours, and ATIII levels during and after bypass to determine pharmacokinetics.

Timeline

Start

2011-08

Primary completion

2013-12

Completion

2013-12

Publications

• Background Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007 Nov 27;116(22):2544-52. doi: 10.1161/CIRCULATIONAHA.107.698977. Epub 2007 Nov 12.
• Background Engoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002 Oct;74(4):1180-6. doi: 10.1016/s0003-4975(02)03766-9.
• Background Spiess BD, Royston D, Levy JH, Fitch J, Dietrich W, Body S, Murkin J, Nadel A. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion. 2004 Aug;44(8):1143-8. doi: 10.1111/j.1537-2995.2004.03322.x.
• Background Chambers LA, Cohen DM, Davis JT. Transfusion patterns in pediatric open heart surgery. Transfusion. 1996 Feb;36(2):150-4. doi: 10.1046/j.1537-2995.1996.36296181928.x.
• Background Petaja J, Lundstrom U, Leijala M, Peltola K, Siimes MA. Bleeding and use of blood products after heart operations in infants. J Thorac Cardiovasc Surg. 1995 Mar;109(3):524-9. doi: 10.1016/S0022-5223(95)70284-9.
• Background Evans DA, Holder RL, Brawn WJ, Sethia B. Post-operative blood loss following cardio-pulmonary bypass in children. Eur J Cardiothorac Surg. 1994;8(1):25-9. doi: 10.1016/1010-7940(94)90128-7.
• Background Bick RL. Alterations of hemostasis associated with cardiopulmonary bypass: pathophysiology, prevention, diagnosis, and management. Semin Thromb Hemost. 1976 Oct;3(2):59-82. doi: 10.1055/s-0028-1086129.
• Background Rosenberg RD. Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism. Am J Med. 1989 Sep 11;87(3B):2S-9S. doi: 10.1016/0002-9343(89)80523-6.
• Background Villaneuva GB, Danishefsky I. Evidence for a heparin-induced conformational change on antithrombin III. Biochem Biophys Res Commun. 1977 Jan 24;74(2):803-9. doi: 10.1016/0006-291x(77)90374-6. No abstract available.
• Background Despotis GJ, Levine V, Joist JH, Joiner-Maier D, Spitznagel E. Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation. Anesth Analg. 1997 Sep;85(3):498-506. doi: 10.1097/00000539-199709000-00005.
• Background Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P. Development of the human coagulation system in the healthy premature infant. Blood. 1988 Nov;72(5):1651-7.
• Background Odegard KC, Zurakowski D, Hornykewycz S, DiNardo JA, Castro RA, Neufeld EJ, Laussen PC. Evaluation of the coagulation system in children with two-ventricle congenital heart disease. Ann Thorac Surg. 2007 May;83(5):1797-803. doi: 10.1016/j.athoracsur.2006.12.030.
• Background Hakacova N, Laluhova-Striezencova Z, Zahorec M. Disturbances of coagulation in neonates with functionally univentricular physiology prior to the first stage of surgical reconstruction. Cardiol Young. 2008 Aug;18(4):397-401. doi: 10.1017/S1047951108002400. Epub 2008 Jun 18.
• Background Odegard KC, Zurakowski D, DiNardo JA, Castro RA, McGowan FX Jr, Neufeld EJ, Laussen PC. Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through Fontan completion. J Thorac Cardiovasc Surg. 2009 Apr;137(4):934-41. doi: 10.1016/j.jtcvs.2008.09.031. Epub 2009 Feb 23.
• Background Avidan MS, Levy JH, Scholz J, Delphin E, Rosseel PM, Howie MB, Gratz I, Bush CR, Skubas N, Aldea GS, Licina M, Bonfiglio LJ, Kajdasz DK, Ott E, Despotis GJ. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology. 2005 Feb;102(2):276-84. doi: 10.1097/00000542-200502000-00007.
• Background Avidan MS, Levy JH, van Aken H, Feneck RO, Latimer RD, Ott E, Martin E, Birnbaum DE, Bonfiglio LJ, Kajdasz DK, Despotis GJ. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005 Jul;130(1):107-13. doi: 10.1016/j.jtcvs.2004.10.045.
• Background Koster A, Chew D, Kuebler W, Habazettl H, Hetzer R, Kuppe H. High antithrombin III levels attenuate hemostatic activation and leukocyte activation during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2003 Sep;126(3):906-7. doi: 10.1016/s0022-5223(03)00392-1. No abstract available.
• Background Lemmer JH Jr, Despotis GJ. Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2002 Feb;123(2):213-7. doi: 10.1067/mtc.2002.119060.
• Background Rinder CS, Rinder HM, Smith MJ, Fitch JC, Tracey JB, Chandler WL, Rollins SA, Smith BR. Antithrombin reduces monocyte and neutrophil CD11b up regulation in addition to blocking platelet activation during extracorporeal circulation. Transfusion. 2006 Jul;46(7):1130-7. doi: 10.1111/j.1537-2995.2006.00861.x.
• Background Jaggers J, Lawson JH. Coagulopathy and inflammation in neonatal heart surgery: mechanisms and strategies. Ann Thorac Surg. 2006 Jun;81(6):S2360-6. doi: 10.1016/j.athoracsur.2006.02.072. No abstract available.
• Background Agati S, Ciccarello G, Salvo D, Turla G, Undar A, Mignosa C. Use of a novel anticoagulation strategy during ECMO in a pediatric population: single-center experience. ASAIO J. 2006 Sep-Oct;52(5):513-6. doi: 10.1097/01.mat.0000242596.92625.a0.

Drugs

Indications

No indication recorded.