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Low-Dose Versus Therapeutic Anticoagulation in Patients on Extracorporeal Membrane Oxygenation: A Pilot Randomized Trial

Aubron, Cécile MD, PhD1,2; McQuilten, Zoe MBBS, PhD1; Bailey, Michael PhD1; Board, Jasmin MPH3; Buhr, Heidi RN, MClinTPrac4; Cartwright, Bruce MBBS5; Dennis, Mark MBBS4; Hodgson, Carol PhD, FACP, BAppSc1; Forrest, Paul MBChB5; McIlroy, David MBBS, MClinEpi, FANZCA6; Murphy, Deirdre MD3; Murray, Lynne BAppSci, FAIMS1; Pellegrino, Vincent MBBS, MD1,3; Pilcher, David MBBS1,3; Sheldrake, Jayne RN, PGCert3; Tran, Huyen MBBS, MClinEpi7; Vallance, Shirley MClinResMeth3; Cooper, D. James AO, BMBS, MD1,3; ; endorsed by the International ECMO Network (ECMONet)

doi: 10.1097/CCM.0000000000003780
Online Clinical Investigations

Objectives: To determine whether randomization of patients undergoing extracorporeal membrane oxygenation to either therapeutic or a low-dose anticoagulation protocol results in a difference in activated partial thromboplastin time and anti-Xa.

Design: Randomized, controlled, unblinded study.

Setting: Two ICUs of two university hospitals.

Patients: Patients admitted to the ICU, who required extracorporeal membrane oxygenation (venovenous or venoarterial) and who did not have a preexisting indication for therapeutic anticoagulation.

Interventions: Therapeutic anticoagulation with heparin (target activated partial thromboplastin time between 50 and 70 s) or lower dose heparin (up to 12,000 U/24 hr aiming for activated partial thromboplastin time < 45 s).

Measurements and Main Results: Thirty-two patients were randomized into two study groups that were not significantly different in demographics and extracorporeal membrane oxygenation characteristics. There was a significant difference in the daily geometric mean heparin dose (11,742 U [95% CI, 8,601–16,031 U] vs 20,710 U [95% CI, 15,343–27,954 U]; p = 0.004), daily geometric mean activated partial thromboplastin time (48.1 s [95% CI, 43.5–53.2 s] vs 55.5 s [95% CI, 50.4–61.2 s]; p = 0.04), and daily geometric mean anti-Xa (0.11 international units/mL [95% CI, 0.07–0.18] vs 0.27 [95% CI, 0.17–0.42]; p = 0.01). We found similar results when considering only venovenous extracorporeal membrane oxygenation episodes; however, no difference in daily geometric mean activated partial thromboplastin time between groups when considering only venoarterial extracorporeal membrane oxygenation episodes.

Conclusions: Allocating patients on extracorporeal membrane oxygenation to two different anticoagulation protocols led to a significant difference in mean daily activated partial thromboplastin time and anti-Xa levels between groups. When considering subgroups analyses, these results were consistent in patients on venovenous extracorporeal membrane oxygenation. Our results support the feasibility of a larger trial in patients undergoing venovenous extracorporeal membrane oxygenation to compare different anticoagulation protocols; however, this study does not provide evidence on the optimal anticoagulation protocol for patients undergoing extracorporeal membrane oxygenation.

1Department of Epidemiology and Preventive Medicine, Australian and New Zealand Intensive Care Research Centre (ANZICRC), Monash University, Melbourne, VIC, Australia.

2Departement de Médecine Intensive Réanimation, Centre Hospitalier Régionale et Universitaire de Brest, site La Cavale Blanche, Université de Bretagne Occidentale, Brest, France.

3Department of Intensive Care, Alfred Hospital, Melbourne, VIC, Australia.

4Department of Intensive Care, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

5Department of Anaesthesia, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

6Department of Anaesthesia & Perioperative Medicine, Alfred Hospital, Melbourne, VIC, Australia

7Clinical Haematology Department, Alfred Hospital, Melbourne, VIC, Australia.

The complete list of board members for the International ECMO Network (ECMONet) is: Laurent Brochard, Daniel Brodie, Alain Combes, Eddy Fan, Niall Ferguson, John Fraser, Carol Hodgson, Alain Mercat, Thomas Mueller, Vin Pellegrino, Antonio Pesenti, Marco Ranieri, Art Slutsky, Danny McAuley, and Michael Quintel.

Drs. Aubron and McQuilten have contributed equally to this work and are co-first authors.

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This study was funded by an Australian and New Zealand College of Anaesthestists Project Grant (2015/007). This work was also supported by the Australian National Health and Medical Research Council (NHMRC) Centre of Research Excellence for Patient Blood Management in Critical Illness and Trauma (APP1040971). Dr. McQuilten is supported by a NHMRC Early Career Fellowship (APP1111485).

Dr. McQuilten disclosed that she is employed by Monash University Transfusion Research Unit that has received financial support from Alexion, Amgen, Bayer, Celgene, CSL Behring, Janssen-Cilag, Takeda, Novartis, Australian Red Cross Blood Service, New Zealand Blood Service, Department of Health Victoria (Australia), and Myeloma Foundation of Australia. None of these funding sources had any involvement the design or conduct of this study. Drs. Board’s and McIlroy’s institutions received funding from Australia and New Zealand College of Anaesthetists. Dr. Board disclosed off-label product use of heparin low-dose protocol. Dr. Buhr’s institution received funding from Alfred Health and the Intensive Care Foundation (research grant). Dr. Hodgson disclosed that she is employed by Monash University and she holds a Heart Foundation of Australia Future Leader Fellowship. Dr. Pellegrino received accommodation support for European ECMONet meetings where the work was presented during development. Dr. Tran received funding from Novartis, Shire, and Pfizer. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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