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Semin Thromb Hemost 2023; 49(07): 756-763
DOI: 10.1055/s-0043-1772838
Review Article

Anticoagulation with Intravenous Direct Thrombin Inhibitors in Pediatric Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature

Amy L. Kiskaddon
1   Department of Pharmacy, Johns Hopkins All Children's Hospital, St. Petersburg, Florida
2   Department of Pediatrics, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
,
Nhue L. Do
3   Division of Pediatric Cardiac Surgery, Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
4   Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee
,
Pamela Williams
5   Medical Library, Johns Hopkins All Children's Hospital, St. Petersburg, Florida
,
Marisol Betensky
6   Department of Pediatrics, Division of Hematology, Johns Hopkins School of Medicine, Baltimore, Maryland
7   Johns Hopkins All Children's Institute for Clinical and Translational Research, St. Petersburg, Florida
,
Neil A. Goldenberg
6   Department of Pediatrics, Division of Hematology, Johns Hopkins School of Medicine, Baltimore, Maryland
7   Johns Hopkins All Children's Institute for Clinical and Translational Research, St. Petersburg, Florida
8   Departments of Pediatrics and Medicine, Division of Hematology, Johns Hopkins School of Medicine, Baltimore, Maryland
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Abstract

Although intravenous (IV) direct thrombin inhibitors (DTI) have gained interest in pediatric extracorporeal membrane oxygenation (ECMO), dosing and safety information is limited. The objective of this systematic review was to characterize DTI types, dosing, monitoring, and outcomes (bleeding and thromboembolic) in pediatric ECMO patients managed with IV DTIs. We conducted searches of MEDLINE (Ovid) and Embase (Elsevier) from inception through December 2022. Case reports, retrospective studies, and prospective studies providing per-patients or summary data for patient(s) <18 years of age receiving IV DTI for ECMO anticoagulation were included. Study selection and data extraction were conducted independently by two reviewers. A total of 28 studies: 14 case reports, 13 retrospective studies, and 1 prospective study were included, totaling 329 patients. Bivalirudin was utilized in 318 (96.7%), argatroban in 9 (2.7%), and lepirudin in 2 (0.6%) patients. Infusion dosing included: bivalirudin 0.14 ± 0.37 mg/kg/h, argatroban 0.69 ± 0.73 µg/kg/min, lepirudin 0.14 ± 0.02 mg/kg/h. Laboratory monitoring tests utilized were the activated clotting time, activated partial thromboplastin time (aPTT), diluted thrombin time, and thromboelastography measures. The aPTT was utilized in most patients (95%). Thromboembolism, bleeding, or death were observed in 17%, 17%, and 23% of bivalirudin, argatroban, and lepirudin patients, respectively. Bivalirudin appears to be the most frequently used DTI in pediatric ECMO. Dosing and laboratory monitoring varied, and bleeding and thromboembolic events were reported in 17% of patients. Prospective studies are warranted to establish dosing, monitoring, safety, and efficacy of bivalirudin and other IV DTI in pediatric ECMO.

Keywords

ECMO - pediatrics - direct thrombin inhibitors - anticoagulation

Supplementary Material



Publication History

Article published online:
29 August 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Sakurai K, Singhal N. Extracorporeal membrane oxygenation in children: A brief review. J Paediatr Child Health 2022; 58 (09) 1525-1531
    CrossrefPubMedSearch in Google Scholar
  • 2 Vuylsteke A, Brodie D, Combes A. et al. The ECMO Circuit. Cambridge: Cambridge University Press; 2017: 25-57
    Search in Google Scholar
  • 3 Murphy DA, Hockings LE, Andrews RK. et al. Extracorporeal membrane oxygenation-hemostatic complications. Transfus Med Rev 2015; 29 (02) 90-101
    CrossrefPubMedSearch in Google Scholar
  • 4 Barton R, Ignjatovic V, Monagle P. Anticoagulation during ECMO in neonatal and paediatric patients. Thromb Res 2019; 173: 172-177
    CrossrefPubMedSearch in Google Scholar
  • 5 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70 (01) 165-172
    CrossrefPubMedSearch in Google Scholar
  • 6 Newall F, Ignjatovic V, Johnston L. et al. Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin. Thromb Haemost 2010; 103 (05) 1085-1090
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Ignjatovic V, Furmedge J, Newall F. et al. Age-related differences in heparin response. Thromb Res 2006; 118 (06) 741-745
    CrossrefPubMedSearch in Google Scholar
  • 8 Ozment CP, Scott BL, Bembea MM, Spinella PC. Pediatric ECMO (PediECMO) subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and the Extracorporeal Life Support Organization (ELSO). Anticoagulation and transfusion management during neonatal and pediatric extracorporeal membrane oxygenation: a survey of medical directors in the United States. Pediatr Crit Care Med 2021; 22 (06) 530-541
    CrossrefPubMedSearch in Google Scholar
  • 9 Zaaqoq AM, Brammer RC, Chan CM, Shorr AF. Heparin-induced thrombocytopenia in extra-corporeal membrane oxygenation: epidemiology, outcomes, and diagnostic challenges. J Thromb Thrombolysis 2022; 53 (02) 499-505
    CrossrefPubMedSearch in Google Scholar
  • 10 Petros S. Lepirudin in the management of patients with heparin-induced thrombocytopenia. Biologics 2008; 2 (03) 481-490
    PubMedSearch in Google Scholar
  • 11 Koster A, Fischer KG, Harder S, Mertzlufft F. The direct thrombin inhibitor argatroban: a review of its use in patients with and without HIT. Biologics 2007; 1 (02) 105-112
    PubMedSearch in Google Scholar
  • 12 Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Best Pract Res Clin Haematol 2004; 17 (01) 105-125
    CrossrefPubMedSearch in Google Scholar
  • 13 Knoderer CA, Knoderer HM, Turrentine MW, Kumar M. Lepirudin anticoagulation for heparin-induced thrombocytopenia after cardiac surgery in a pediatric patient. Pharmacotherapy 2006; 26 (05) 709-712
    CrossrefPubMedSearch in Google Scholar
  • 14 Hensch LA, Hui SR, Teruya J. Coagulation and bleeding management in pediatric extracorporeal membrane oxygenation: clinical scenarios and review. Front Med (Lausanne) 2019; 5: 361
    CrossrefPubMedSearch in Google Scholar
  • 15 Bingham KR, Riley JB, Schears GJ. Anticoagulation management during first five days of infant-pediatric extracorporeal life support. J Extra Corpor Technol 2018; 50 (01) 30-37
    CrossrefPubMedSearch in Google Scholar
  • 16 Deitcher SR, Topoulos AP, Bartholomew JR, Kichuk-Chrisant MR. Lepirudin anticoagulation for heparin-induced thrombocytopenia. J Pediatr 2002; 140 (02) 264-266
    CrossrefPubMedSearch in Google Scholar
  • 17 Dager WE, Gosselin RC, Yoshikawa R, Owings JT. Lepirudin in heparin-induced thrombocytopenia and extracorporeal membranous oxygenation. Ann Pharmacother 2004; 38 (04) 598-601
    CrossrefPubMedSearch in Google Scholar
  • 18 Almond CS, Harrington J, Thiagarajan R. et al. Successful use of bivalirudin for cardiac transplantation in a child with heparin-induced thrombocytopenia. J Heart Lung Transplant 2006; 25 (11) 1376-1379
    CrossrefPubMedSearch in Google Scholar
  • 19 Scott LK, Grier LR, Conrad SA. Heparin-induced thrombocytopenia in a pediatric patient receiving extracorporeal support and treated with argatroban. Pediatr Crit Care Med 2006; 7 (03) 255-257
    CrossrefPubMedSearch in Google Scholar
  • 20 Landsman IS, Karsanac CJ. Case report: pediatric liver retransplantation on an extracorporeal membrane oxygenation-dependent child. Anesth Analg 2010; 111 (05) 1275-1278
    CrossrefPubMedSearch in Google Scholar
  • 21 Latham GJ, Jefferis Kirk C, Falconer A, Dickey R, Albers EL, McMullan DM. Challenging argatroban management of a child on extracorporeal support and subsequent heart transplant. Semin Cardiothorac Vasc Anesth 2016; 20 (02) 168-174
    CrossrefPubMedSearch in Google Scholar
  • 22 Shudo Y, Wang H, Ha RV, Hayes AD, Woo YJ. Heart transplant after profoundly extended ambulatory central venoarterial extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 2018; 156 (01) e7-e9
    CrossrefPubMedSearch in Google Scholar
  • 23 Ali A, Yorsi M, Abouelwafa M. et al. One hundred forty six days on extracorporeal membrane oxygenation (ECMO): our longest ECMO run. The Egyptian Journal of Critical Care Medicine. 2018; 6 (03) 113-121
    CrossrefPubMedSearch in Google Scholar
  • 24 Pollak U, Yacobobich J, Tamary H, Dagan O, Manor-Shulman O. Heparin-induced thrombocytopenia and extracorporeal membrane oxygenation: a case report and review of the literature. J Extra Corpor Technol 2011; 43 (01) 5-12
    CrossrefPubMedSearch in Google Scholar
  • 25 Preston TJ, Dalton HJ, Nicol KK, Ferrall BR, Miller JC, Hayes Jr D. Plasma exchange on venovenous extracorporeal membrane oxygenation with bivalirudin anticoagulation. World J Pediatr Congenit Heart Surg 2015; 6 (01) 119-122
    CrossrefPubMedSearch in Google Scholar
  • 26 Wong JY, Buchholz H, Ryerson L. et al. Successful semi-ambulatory veno-arterial extracorporeal membrane oxygenation bridge to heart-lung transplantation in a very small child. Am J Transplant 2015; 15 (08) 2256-2260
    CrossrefPubMedSearch in Google Scholar
  • 27 Pollak U, Mishaly D, Kenet G, Vardi A. Heparin-induced thrombocytopenia complicating children after the Fontan procedure: single-center experience and review of the literature. Congenit Heart Dis 2018; 13 (01) 16-25
    CrossrefPubMedSearch in Google Scholar
  • 28 Kunchapudi K, Issac G, Pandian S, Jayakumar I. A case of HITT in a child on extracorporeal membrane oxygentation. Egyptian J Crit Care Med. 2018; 6 (03) 111-112
    CrossrefPubMedSearch in Google Scholar
  • 29 Ezetendu C, Jarden A, Hamzah M, Stewart R. Bivalirudin anticoagulation for an infant with hyperbilirubinemia and elevated plasma-free hemoglobin on ECMO. J Extra Corpor Technol 2019; 51 (01) 26-28
    CrossrefPubMedSearch in Google Scholar
  • 30 Potter KE, Raj A, Sullivan JE. Argatroban for anticoagulation in pediatric patients with heparin-induced thrombocytopenia requiring extracorporeal life support. J Pediatr Hematol Oncol 2007; 29 (04) 265-268
    CrossrefPubMedSearch in Google Scholar
  • 31 Ranucci M, Ballotta A, Kandil H. et al; Surgical and Clinical Outcome Research Group. Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation. Crit Care 2011; 15 (06) R275
    CrossrefPubMedSearch in Google Scholar
  • 32 Nagle EL, Dager WE, Duby JJ. et al. Bivalirudin in pediatric patients maintained on extracorporeal life support. Pediatr Crit Care Med 2013; 14 (04) e182-e188
    CrossrefPubMedSearch in Google Scholar
  • 33 Ranucci M, Baryshnikova E, Isgrò G. et al. Heparin-like effect in postcardiotomy extracorporeal membrane oxygenation patients. Crit Care 2014; 18 (05) 504
    CrossrefPubMedSearch in Google Scholar
  • 34 Teruya J, Hensch L, Bruzdoski K, Adachi I, Hui SR, Kostousov V. Monitoring bivalirudin therapy in children on extracorporeal circulatory support devices: thromboelastometry versus routine coagulation testing. Thromb Res 2020; 186: 54-57
    CrossrefPubMedSearch in Google Scholar
  • 35 Schill MR, Douds MT, Burns EL, Lahart MA, Said AS, Abarbanell AM. Is anticoagulation with bivalirudin comparable to heparin for pediatric extracorporeal life support? Results from a high-volume center. Artif Organs 2021; 45 (01) 15-21
    CrossrefPubMedSearch in Google Scholar
  • 36 Snyder CW, Goldenberg NA, Nguyen ATH, Smithers CJ, Kays DW. A perioperative bivalirudin anticoagulation protocol for neonates with congenital diaphragmatic hernia on extracorporeal membrane oxygenation. Thromb Res 2020; 193: 198-203
    CrossrefPubMedSearch in Google Scholar
  • 37 Campbell CT, Diaz L, Kelly B. Description of bivalirudin use for anticoagulation in pediatric patients on mechanical circulatory support. Ann Pharmacother 2021; 55 (01) 59-64
    CrossrefPubMedSearch in Google Scholar
  • 38 Hamzah M, Seelhammer TG, Yabrodi M. et al. Evaluation of bivalirudin dosing in pediatric extracorporeal membrane oxygenation with renal insufficiency or renal replacement therapy. ASAIO J 2022; 68 (11) e196-e203
    CrossrefPubMedSearch in Google Scholar
  • 39 Hamzah M, Jarden AM, Ezetendu C, Stewart R. Evaluation of bivalirudin as an alternative to heparin for systemic anticoagulation in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med 2020; 21 (09) 827-834
    CrossrefPubMedSearch in Google Scholar
  • 40 Kaushik S, Derespina KR, Chandhoke S. et al. Use of bivalirudin for anticoagulation in pediatric extracorporeal membrane oxygenation (ECMO). Perfusion 2023; 38 (01) 58-65
    CrossrefPubMedSearch in Google Scholar
  • 41 Lahart MA, Burns EL, Streb MM. et al. Impact of continuous renal replacement therapy on bivalirudin dosing in pediatric extracorporeal membrane oxygenation. ASAIO J 2022; 68 (11) 1393-1398
    CrossrefPubMedSearch in Google Scholar
  • 42 Machado DS, Garvan C, Philip J. et al. Bivalirudin may reduce the need for red blood cell transfusion in pediatric cardiac patients on extracorporeal membrane oxygenation. ASAIO J 2021; 67 (06) 688-696
    CrossrefPubMedSearch in Google Scholar
  • 43 Ryerson LM, Balutis KR, Granoski DA. et al. Prospective exploratory experience with bivalirudin anticoagulation in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med 2020; 21 (11) 975-985
    CrossrefPubMedSearch in Google Scholar
  • 44 Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Göttl U. Perinatal and Paediatric Haemostasis Subcommittee of the SSC of the ISTH. Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9 (09) 1856-1858
    CrossrefPubMedSearch in Google Scholar
  • 45 McMichael ABV, Ryerson LM, Ratano D, Fan E, Faraoni D, Annich GM. 2021 ELSO adult and pediatric anticoagulation guidelines. ASAIO J 2022; 68 (03) 303-310
    CrossrefPubMedSearch in Google Scholar
  • 46 Liu L, Liu F, Tan J, Zhao L. Bivalirudin versus heparin in adult and pediatric patients with extracorporeal membrane oxygenation therapy: a systematic review and meta-analysis. Pharmacol Res 2022; 177: 106089
    CrossrefPubMedSearch in Google Scholar
  • 47 Study Comparing Bivalirudin Versus Heparin in Neonatal and Pediatric ECMO. ClinicalTrials.gov identifier: NCT03318393. Accessed April 07, 2023 at: https://clinicaltrials.gov/ct2/show/NCT03318393
    PubMed
  • 48 Seelhammer TG, Bohman JK, Schulte PJ, Hanson AC, Aganga DO. Comparison of bivalirudin versus heparin for maintenance systemic anticoagulation during adult and pediatric extracorporeal membrane oxygenation. Crit Care Med 2021; 49 (09) 1481-1492
    CrossrefPubMedSearch in Google Scholar