[en] [en] BACKGROUND: Although life-saving in selected patients, ECMO treatment still has high mortality which for a large part is due to treatment-related complications. A feared complication is ischemic stroke for which heparin is routinely administered for which the dosage is usually guided by activated partial thromboplastin time (aPTT). However, there is no relation between aPTT and the rare occurrence of ischemic stroke (1.2%), but there is a relation with the much more frequent occurrence of bleeding complications (55%) and blood transfusion. Both are strongly related to outcome.
METHODS: We will conduct a three-arm non-inferiority randomized controlled trial, in adult patients treated with ECMO. Participants will be randomized between heparin administration with a target of 2-2.5 times baseline aPTT, 1.5-2 times baseline aPTT, or low molecular weight heparin guided by weight and renal function. Apart from anticoagulation targets, treatment will be according to standard care. The primary outcome parameter is a combined endpoint consisting of major bleeding including hemorrhagic stroke, severe thromboembolic complications including ischemic stroke, and mortality at 6 months.
DISCUSSION: We hypothesize that with lower anticoagulation targets or anticoagulation with LMWH during ECMO therapy, patients will have fewer hemorrhagic complications without an increase in thromboembolic complication or a negative effect on their outcome. If our hypothesis is confirmed, this study could lead to a change in anticoagulation protocols and a better outcome for patients treated with ECMO.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04536272 . Registered on 2 September 2020. Netherlands Trial Register NL7969.
Disciplines :
Anesthesia & intensive care
Author, co-author :
van Minnen, Olivier ; Department of Critical Care, University Medical Center Groningen, Room R3.904, PO BOX 30001, 9700, RB, Groningen, The Netherlands. o.van.minnen@umcg.nl
Oude Lansink-Hartgring, Annemieke; Department of Critical Care, University Medical Center Groningen, Room R3.904, PO BOX 30001, 9700, RB, Groningen, The Netherlands
van den Boogaard, Bas; Department of Intensive Care, OLVG, Amsterdam, The Netherlands
van den Brule, Judith; Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
Bulpa, Pierre; Department of Intensive Care, CHU UCL Namur site Mont-Godinne, Yvoir, Belgium
Bunge, Jeroen J H; Department of Intensive Care Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Delnoij, Thijs S R; Department of Intensive Care Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
Elzo Kraemer, Carlos V; Department of Intensive Care Medicine, Leiden University Medical Center, Leiden, The Netherlands
Kuijpers, Marijn; Department of Intensive Care Medicine, Isala Clinics, Zwolle, The Netherlands
Lambermont, Bernard ; Centre Hospitalier Universitaire de Liège - CHU > > Service des soins intensifs
Maas, Jacinta J; Department of Intensive Care Medicine, Leiden University Medical Center, Leiden, The Netherlands
de Metz, Jesse; Department of Intensive Care, OLVG, Amsterdam, The Netherlands
Michaux, Isabelle; Department of Intensive Care, CHU UCL Namur site Mont-Godinne, Yvoir, Belgium
van de Pol, Ineke; Department of Intensive Care Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands
van de Poll, Marcel; Department of Intensive Care Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
Raasveld, S Jorinde; Department of Intensive Care Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
Raes, Matthias; Department of Intensive Care, University Hospital Brussels, Brussels, Belgium
Dos Reis Miranda, Dinis; Department of Intensive Care Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Scholten, Erik; Department of Intensive Care Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands
Simonet, Olivier; Department of Intensive Care, Centre Hospitalier de Wallonie Picarde (CHwapi), Tournai, Belgium
Taccone, Fabio S; Department of Intensive Care, Hôpital Erasme Bruxelles, Brussels, Belgium
Vallot, Frederic; Department of Intensive Care, Centre Hospitalier de Wallonie Picarde (CHwapi), Tournai, Belgium
Vlaar, Alexander P J; Department of Intensive Care Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
van den Bergh, Walter M; Department of Critical Care, University Medical Center Groningen, Room R3.904, PO BOX 30001, 9700, RB, Groningen, The Netherlands
ZonMw - Nederlandse Organisatie voor Gezondheidsonderzoek en Zorginnovatie
Funding text :
This trial is funded by ZonMw (project number: 848018014). The funder provided research funding but had no role in the design or execution of the trial.
Oude Lansink-Hartgring A, de Vries AJ, Droogh JM, van den Bergh WM. Hemorrhagic complications during extracorporeal membrane oxygenation – the role of anticoagulation and platelets. J Crit Care. 2019;54:239–43. DOI: 10.1016/j.jcrc.2019.09.013
Ontaneda A, Annich GM. Novel Surfaces in Extracorporeal Membrane Oxygenation Circuits. Front Med (Lausanne). 2018;5:321. https://doi.org/10.3389/fmed.2018.00321.
Sklar MC, Sy E, Lequier L, Fan E, Kanji HD. Anticoagulation practices during venovenous extracorporeal membrane oxygenation for respiratory failure a systematic review. Ann Am Thoracic Soc. 2016;13:2242–50. DOI: 10.1513/AnnalsATS.201605-364SR
Mazzeffi MA, Tanaka K, Roberts A, Rector R, Menaker J, Kon Z, et al. Bleeding, thrombosis, and transfusion with two heparin anticoagulation protocols in venoarterial ECMO patients. J Cardiothorac Vasc Anesth. 2019;33(5):1216–20. Available from. 10.1053/j.jvca.2018.07.045. DOI: 10.1053/j.jvca.2018.07.045
Shah A, Pasrija C, Kronfli A, Essien E-O, Zhou Y, Brigante F, et al. A comparison of anticoagulation strategies in veno-venous extracorporeal membrane oxygenation. ASAIO J. 2022;68(5):738–43. https://doi.org/10.1097/MAT.0000000000001560. Epub 2021 Aug 20.
Krueger K, Schmutz A, Zieger B, Kalbhenn J. Venovenous extracorporeal membrane oxygenation with prophylactic subcutaneous anticoagulation only: an observational study in more than 60 patients. Artif Organs. 2017;41(2):186–92. DOI: 10.1111/aor.12737
Chung YS, Cho DY, Sohn DS, Lee WS, Won H, Lee DH, et al. Is stopping heparin safe in patients on extracorporeal membrane oxygenation treatment? ASAIO J. 2017;63(1):32–6. DOI: 10.1097/MAT.0000000000000442
ELSO. Anticoagulation guideline; 2014.
Merli G, Spiro TE, Olsson CG, Abildgaard U, Davidson BL, Eldor A, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134(3):191–202. DOI: 10.7326/0003-4819-134-3-200102060-00009
Lazrak HH, René É, Elftouh N, Leblanc M, Lafrance JP. Safety of low-molecular-weight heparin compared to unfractionated heparin in hemodialysis: a systematic review and meta-analysis. BMC Nephrol. 2017;18(1):1–13. DOI: 10.1186/s12882-017-0596-4
EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199–208. https://doi.org/10.1016/0168-8510(90)90421-9.
Thiagarajan RR, Barbaro RP, Rycus PT, Mcmullan DM, Conrad SA, Fortenberry JD, et al. Extracorporeal life support organization registry international report 2016. ASAIO J. 2017;63(1):60–7. DOI: 10.1097/MAT.0000000000000475
NFU. Guideline quality assurance of research involving human subjects; 2020.
Panigada M, Iapichino E, Brioni M, Panarello G, Protti A, Grasselli G, et al. Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study. Ann Intensive Care. 2018;8(1):7. https://doi.org/10.1186/s13613-017-0352-8.
Delmas C, Jacquemin A, Vardon-Bounes F, Georges B, Guerrero F, Hernandez N, et al. Anticoagulation monitoring under ECMO support: a comparative study between the activated coagulation time and the anti-Xa activity assay. J Intensive Care Med. 2018;1:885066618776937.
Annich GM, Zaulan O, Neufeld M, Wagner DRM. Thromboprophylaxis in extracorporeal circuits: current pharmacological strategies and future directions. Am J Cardiovasc Drugs. 2017;17(6):425–39. DOI: 10.1007/s40256-017-0229-0
Kreyer S, Muders T, Theuerkauf N, Spitzhuttl J, Schellhaas T, Schewe JC, et al. Hemorrhage under veno-venous extracorporeal membrane oxygenation in acute respiratory distress syndrome patients: a retrospective data analysis. J Thorac Dis. 2017;9(12):5017–29. DOI: 10.21037/jtd.2017.11.05
Bolliger D, Zenklusen UTK. Point-of-care coagulation management algorithms during ECMO support: are we there yet? Minerva Anestesiol. 2016;82(9):1000–9.
Ranucci M, Baryshnikova E, Cotza M, Carboni G, Isgro G, Carlucci CBA. Coagulation monitoring in postcardiotomy ECMO: conventional tests, point-of-care, or both? Minerva Anestesiol. 2016;82(8):858–66.
Cunningham D, Besser MW, Giraud K, Gerrard CVA. Agreement between ACT and aPTT during extracorporeal membrane oxygenation shows intra- and inter-individual variation. Perfusion. 2016;31(6):503–7. DOI: 10.1177/0267659116637420
Chu DC, Abu-Samra AG, Baird GL, Devers C, Sweeney J, Levy MM, et al. Quantitative measurement of heparin in comparison with conventional anticoagulation monitoring and the risk of thrombotic events in adults on extracorporeal membrane oxygenation. Intensive Care Med. 2015;41(2):369–70. DOI: 10.1007/s00134-014-3574-3
Esper SA, Levy JH, Waters JHWI. Extracorporeal membrane oxygenation in the adult: a review of anticoagulation monitoring and transfusion. Anesth Analg. 2014;118(4):731–43. DOI: 10.1213/ANE.0000000000000115
Gratz J, Pausch A, Schaden E, Baierl A, Jaksch P, Erhart F, et al. Low molecular weight heparin versus unfractioned heparin for anticoagulation during perioperative extracorporeal membrane oxygenation: a single center experience in 102 lung transplant patients. Artif Organs. 2020;44(6):638–46. DOI: 10.1111/aor.13642
