Restrictive Versus Liberal Thresholds for RBC Transfusion in ECMO

NCT06560164 | Recruiting DMC

• 5 other identifiers: NL84295.018.2384295B32220220012582023-07691-0110390032310031
• Study Type: interventional
• Target: 526
• Locations: 3 countries
• Sites: 12

Brief Summary

Rationale: In patients supported with extracorporeal membrane oxygenation (ECMO), transfusion of red blood cells (RBC) is very common. This is possibly due to the application of liberal thresholds and the lack of evidence-based guidelines. Although RBC transfusion can be lifesaving, it is also a risk-bearing intervention with substantial risk for morbidity and mortality in this critically ill population. Also, with increasing scarcity, RBC transfusions are becoming more expensive. Furthermore, in the past decades it has been shown in several critically ill patient populations - not on ECMO - that maintaining a restrictive hemoglobin (Hb) threshold for RBC transfusion is non-inferior, including in cardiothoracic surgery, acute myocardial infarction and septic shock. Therefore, the investigators hypothesize that a restrictive transfusion threshold for RBC is safe to apply in patients on ECMO in comparison with a liberal transfusion threshold. Objective: The primary objective of this trial is to study in a prospective randomized comparison whether a restrictive RBC transfusions strategy is non-inferior compared to a liberal strategy in patients on ECMO with respect to 90-day mortality. Study design: Prospective multi-center randomized controlled non-inferiority trial. Study population: Patients, 18 years or older, receiving ECMO. Intervention: Restrictive RBC transfusion threshold: in case the Hb transfusion trigger of 7.0 g/dL (4.3 mmol/L) is reached, 1 RBC unit at a time will be transfused. The aimed Hb target range of the restrictive/intervention group will be 7.1 - 9.0 g/dL (4.3 - 5.6 mmol/L). Liberal RBC transfusion threshold: in case the Hb transfusion trigger of 9.0 g/dL (5.6 mmol/L) is reached, 1 RBC unit at a time will be transfused. Target range of the liberal group is defined as Hb 9.1 - 11.0 g/dL Main study parameters/endpoints: The primary outcome parameter is 90-day all-cause mortality. Secondary outcomes include: 1) proportion of patients on ECMO exposed to allogeneic RBC transfusion; 2) RBC volume infused per patient during ECMO; 3) reasons for RBC transfusion other than Hb triggers; 4) transfusion reactions; 5) time on ECMO; 6) length of hospital- and ICU-stay; 7) in-ICU morbidity; 8) quality of life (QoL), iMTA Medical Consumption Questionnaire (iMCQ) and Productivity Cost Questionnaire (iPCQ) at 3, 6, 9, and 12 months; 9) costs related to a) transfusion, b) hospital admission and c) transfusion-related sequelae.

Conditions

Transfusion; Red Blood Cell; Extracorporeal Membrane Oxygenation; Anemia; ECMO

Keywords

Transfusion; Red Blood Cell; Extracorporeal Membrane Oxygenation; Anemia; ECMO

Outcome Measures

Primary Outcomes (1)

• 90-day all-cause mortality

  The primary outcome measure is all-cause mortality within 90 days, i.e. the proportion of patients who die from any cause during this 90-day period following ECMO support.

  90 days

Secondary Outcomes (7)

• In-hospital mortality

  30 days

• Duration

  30 days

• Red blood cell transfusion exposure

  30 days

• Adherence

  30 days

• EQ-5D-5L

  3, 6, 9, and 12 months

Other Outcomes (4)

• In-ICU morbidity

  30 days

• Transfusion reasons

  30 days

• Exposure to other transfusion products

  30 days

Study Arms (2)

Restrictive strategy

ACTIVE COMPARATOR

The restrictive strategy will consist of a transfusion Hb threshold of 7.0 g/dL, with a target Hb range of 7.1 - 9.0 g/dL. These thresholds are based on previous non-inferior trials in the patient populations in which VV ECMO (comparable to sepsis) and VA ECMO (cardiac surgery, acute myocardial infarction) are often applied.

Other: Red Blood Cell transfusion

Liberal strategy

ACTIVE COMPARATOR

The liberal strategy will consist of a transfusion Hb threshold of 9.0 g/dL, with a target Hb range of 9.1 - 11.0 g/dL. These Hb thresholds are based on thresholds that are currently used in ECMO.

Other: Red Blood Cell transfusion

Interventions

Red Blood Cell transfusion OTHER

When the appropriate Hb threshold is reached, patients in each group will have one unit of RBC administered at a time. Within 3 hours after the transfusion, a repeat Hb concentration will be measured. Each group will only be transfused when their Hb level falls below the transfusion threshold. In case of a outlier measurement, clinicians are advised to repeat the measurement. The RBC transfusion must take place within 4 hours when the Hb trigger was measured.

Also known as: RBC transfusion, pRBCs, packed Red Blood Cells

Liberal strategy; Restrictive strategy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient is aged 18 years or older;
• Is receiving ECMO;
• (Deferred) informed consent.

You may not qualify if:

• Not expected to survive for 24 hours when assessed;
• Inability to receive blood products;
• (Known) decline to blood transfusions (e.g., Jehovah's Witnesses);
• Extracorporeal carbon dioxide removal (ECCO2R) using low blood flow devices or pumpless devices (i.e., MINILUNG ®, PrismaLung+);
• Received ECMO over 48h before screening for eligibility.

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (12)

Hôpital Erasme Brussels

Brussels, Brussels Capital, 1070, Belgium

RECRUITING

KU Leuven, medical IC

Leuven, Flemish Brabant, 3000, Belgium

RECRUITING

KU Leuven, surgical IC

Leuven, Flemish Brabant, 3000, Belgium

RECRUITING

CHU Charleroi

Charleroi, Hainaut, 6000, Belgium

RECRUITING

Medisch Spectrum Twente (MST)

Enschede, Drenthe, 7512 KZ, Netherlands

RECRUITING

Maastricht Universitair Medisch Centrum+ (MUMC+)

Maastricht, Limburg, 6229 HX, Netherlands

RECRUITING

Amsterdam UMC, location AMC

Amsterdam, North Holland, 1105 AZ, Netherlands

RECRUITING

Universitair Medisch Centrum Groningen (UMCG)

Groningen, Provincie Groningen, 9713 GZ, Netherlands

RECRUITING

Leids Universitair Medisch Centrum (LUMC)

Leiden, South Holland, 2333 ZA, Netherlands

NOT YET RECRUITING

Erasmus MC

Rotterdam, South Holland, 3015 GD, Netherlands

NOT YET RECRUITING

St. Antonius Ziekenhuis

Nieuwegein, Utrecht, 3435 CM, Netherlands

RECRUITING

Karolinska Universtiy Hospital

Stockholm, Stockholm County, 171 76, Sweden

NOT YET RECRUITING

Related Publications (23)

• Gattinoni L, Carlesso E, Langer T. Clinical review: Extracorporeal membrane oxygenation. Crit Care. 2011;15(6):243. doi: 10.1186/cc10490. Epub 2011 Dec 8.

  PMID: 22188792 BACKGROUND

• Makdisi G, Wang IW. Extra Corporeal Membrane Oxygenation (ECMO) review of a lifesaving technology. J Thorac Dis. 2015 Jul;7(7):E166-76. doi: 10.3978/j.issn.2072-1439.2015.07.17.

  PMID: 26380745 BACKGROUND

• Vlaar AP, Oczkowski S, de Bruin S, Wijnberge M, Antonelli M, Aubron C, Aries P, Duranteau J, Juffermans NP, Meier J, Murphy GJ, Abbasciano R, Muller M, Shah A, Perner A, Rygaard S, Walsh TS, Guyatt G, Dionne JC, Cecconi M. Transfusion strategies in non-bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. Intensive Care Med. 2020 Apr;46(4):673-696. doi: 10.1007/s00134-019-05884-8. Epub 2020 Jan 7.

  PMID: 31912207 BACKGROUND

• de Bruin S, Scheeren TWL, Bakker J, van Bruggen R, Vlaar APJ; Cardiovascular Dynamics Section and Transfusion Guideline Task Force of the ESICM. Transfusion practice in the non-bleeding critically ill: an international online survey-the TRACE survey. Crit Care. 2019 Sep 11;23(1):309. doi: 10.1186/s13054-019-2591-6.

  PMID: 31511083 BACKGROUND

• Martucci G, Grasselli G, Tanaka K, Tuzzolino F, Panarello G, Schmidt M, Bellani G, Arcadipane A. Hemoglobin trigger and approach to red blood cell transfusions during veno-venous extracorporeal membrane oxygenation: the international TRAIN-ECMO survey. Perfusion. 2019 Apr;34(1_suppl):39-48. doi: 10.1177/0267659119830526.

  PMID: 30966906 BACKGROUND

• Aubron C, DePuydt J, Belon F, Bailey M, Schmidt M, Sheldrake J, Murphy D, Scheinkestel C, Cooper DJ, Capellier G, Pellegrino V, Pilcher D, McQuilten Z. Predictive factors of bleeding events in adults undergoing extracorporeal membrane oxygenation. Ann Intensive Care. 2016 Dec;6(1):97. doi: 10.1186/s13613-016-0196-7. Epub 2016 Oct 6.

  PMID: 27714705 BACKGROUND

• Raasveld SJ, Karami M, van den Bergh WM, Oude Lansink-Hartgring A, van der Velde F, Maas JJ, van de Berg P, de Haan M, Lorusso R, Delnoij TSR, Dos Reis Miranda D, Mandigers L, Scholten E, Overmars M, Silvio Taccone F, Brasseur A, Dauwe DF, De Troy E, Hermans G, Meersseman P, Pappalardo F, Fominskiy E, Ivancan V, Bojcic R, de Metz J, van den Bogaard B, Donker DW, Meuwese CL, de Bakker M, Reddi B, de Bruin S, Lagrand WK, Henriques JPS, Broman LM, Vlaar APJ. RBC Transfusion in Venovenous Extracorporeal Membrane Oxygenation: A Multicenter Cohort Study. Crit Care Med. 2022 Feb 1;50(2):224-234. doi: 10.1097/CCM.0000000000005398.

  PMID: 35100195 BACKGROUND

• Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002 Sep 25;288(12):1499-507. doi: 10.1001/jama.288.12.1499.

  PMID: 12243637 BACKGROUND

• Bosboom JJ, Klanderman RB, Zijp M, Hollmann MW, Veelo DP, Binnekade JM, Geerts BF, Vlaar APJ. Incidence, risk factors, and outcome of transfusion-associated circulatory overload in a mixed intensive care unit population: a nested case-control study. Transfusion. 2018 Feb;58(2):498-506. doi: 10.1111/trf.14432. Epub 2017 Dec 13.

  PMID: 29238981 BACKGROUND

• Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-17. doi: 10.1056/NEJM199902113400601.

  PMID: 9971864 BACKGROUND

• Mazer CD, Whitlock RP, Fergusson DA, Hall J, Belley-Cote E, Connolly K, Khanykin B, Gregory AJ, de Medicis E, McGuinness S, Royse A, Carrier FM, Young PJ, Villar JC, Grocott HP, Seeberger MD, Fremes S, Lellouche F, Syed S, Byrne K, Bagshaw SM, Hwang NC, Mehta C, Painter TW, Royse C, Verma S, Hare GMT, Cohen A, Thorpe KE, Juni P, Shehata N; TRICS Investigators and Perioperative Anesthesia Clinical Trials Group. Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017 Nov 30;377(22):2133-2144. doi: 10.1056/NEJMoa1711818. Epub 2017 Nov 12.

  PMID: 29130845 BACKGROUND

• Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, Reeves BC; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015 Mar 12;372(11):997-1008. doi: 10.1056/NEJMoa1403612.

  PMID: 25760354 BACKGROUND

• Ducrocq G, Gonzalez-Juanatey JR, Puymirat E, Lemesle G, Cachanado M, Durand-Zaleski I, Arnaiz JA, Martinez-Selles M, Silvain J, Ariza-Sole A, Ferrari E, Calvo G, Danchin N, Avendano-Sola C, Frenkiel J, Rousseau A, Vicaut E, Simon T, Steg PG; REALITY Investigators. Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial. JAMA. 2021 Feb 9;325(6):552-560. doi: 10.1001/jama.2021.0135.

  PMID: 33560322 BACKGROUND

• Kracalik I, Mowla S, Basavaraju SV, Sapiano MRP. Transfusion-related adverse reactions: Data from the National Healthcare Safety Network Hemovigilance Module - United States, 2013-2018. Transfusion. 2021 May;61(5):1424-1434. doi: 10.1111/trf.16362. Epub 2021 Apr 20.

  PMID: 33880771 BACKGROUND

• Holst LB, Haase N, Wetterslev J, Wernerman J, Aneman A, Guttormsen AB, Johansson PI, Karlsson S, Klemenzson G, Winding R, Nebrich L, Albeck C, Vang ML, Bulow HH, Elkjaer JM, Nielsen JS, Kirkegaard P, Nibro H, Lindhardt A, Strange D, Thormar K, Poulsen LM, Berezowicz P, Badstolokken PM, Strand K, Cronhjort M, Haunstrup E, Rian O, Oldner A, Bendtsen A, Iversen S, Langva JA, Johansen RB, Nielsen N, Pettila V, Reinikainen M, Keld D, Leivdal S, Breider JM, Tjader I, Reiter N, Gottrup U, White J, Wiis J, Andersen LH, Steensen M, Perner A. Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial. Trials. 2013 May 23;14:150. doi: 10.1186/1745-6215-14-150.

  PMID: 23702006 BACKGROUND

• Hayden SJ, Albert TJ, Watkins TR, Swenson ER. Anemia in critical illness: insights into etiology, consequences, and management. Am J Respir Crit Care Med. 2012 May 15;185(10):1049-57. doi: 10.1164/rccm.201110-1915CI. Epub 2012 Jan 26.

  PMID: 22281832 BACKGROUND

• Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi D, Doree C, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2016 Oct 12;10(10):CD002042. doi: 10.1002/14651858.CD002042.pub4.

  PMID: 27731885 BACKGROUND

• Docherty AB, Turgeon AF, Walsh TS. Best practice in critical care: anaemia in acute and critical illness. Transfus Med. 2018 Apr;28(2):181-189. doi: 10.1111/tme.12505. Epub 2018 Jan 25.

  PMID: 29369437 BACKGROUND

• Spinelli E, Bartlett RH. Anemia and Transfusion in Critical Care: Physiology and Management. J Intensive Care Med. 2016 Jun;31(5):295-306. doi: 10.1177/0885066615571901. Epub 2015 Feb 18.

  PMID: 25693602 BACKGROUND

• Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD, Christiani DC. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med. 2005 Jun;33(6):1191-8. doi: 10.1097/01.ccm.0000165566.82925.14.

  PMID: 15942330 BACKGROUND

• Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, MacIntyre NR, Shabot MM, Duh MS, Shapiro MJ. The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States. Crit Care Med. 2004 Jan;32(1):39-52. doi: 10.1097/01.CCM.0000104112.34142.79.

  PMID: 14707558 BACKGROUND

• Vlaar APJ, Toy P, Fung M, Looney MR, Juffermans NP, Bux J, Bolton-Maggs P, Peters AL, Silliman CC, Kor DJ, Kleinman S. A consensus redefinition of transfusion-related acute lung injury. Transfusion. 2019 Jul;59(7):2465-2476. doi: 10.1111/trf.15311. Epub 2019 Apr 16.

  PMID: 30993745 BACKGROUND

• Wiersum-Osselton JC, Whitaker B, Grey S, Land K, Perez G, Rajbhandary S, Andrzejewski C Jr, Bolton-Maggs P, Lucero H, Renaudier P, Robillard P, Santos M, Schipperus M. Revised international surveillance case definition of transfusion-associated circulatory overload: a classification agreement validation study. Lancet Haematol. 2019 Jul;6(7):e350-e358. doi: 10.1016/S2352-3026(19)30080-8. Epub 2019 May 9.

  PMID: 31080132 BACKGROUND

Related Links

• Extracorporeal Life Support Organization. Extracorporeal Life Support Organization ECLS Registry Report Overall Outcomes. 2019
• Additional study information and progress overview

MeSH Terms

Conditions

Anemia

Interventions

Erythrocyte Transfusion

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Blood Component Transfusion; Blood Transfusion; Biological Therapy; Therapeutics

Study Officials

• Alexander P.J. Vlaar, PhD

  Amsterdam UMC, location AMC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alexander P.J. Vlaar, PhD

CONTACT

020 566 9111; a.p.vlaar@amsterdamumc.nl

Stefan F. van Wonderen, MD

CONTACT

020 566 9111; s.vanwonderen@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: Study design: This is a non-inferiority, randomized controlled trial in patients receiving ECMO. Study population: Patients, 18 years or older, receiving ECMO (see additional details below). Randomization will be stratified by: * Center; * ECMO mode, divided by: * VV ECMO (or triple cannulation methods with primarily a pulmonary indication); * VA ECMO (or triple cannulation methods with primarily a cardiac indication or extracorporeal cardiopulmonary resuscitation \[ECPR\]). Intervention: 1. Restrictive RBC transfusion threshold: in case the Hb transfusion trigger of 7.0 g/dL (4.3 mmol/L) is reached, 1 RBC unit at a time will be transfused. 2. Liberal RBC transfusion threshold: in case the Hb transfusion trigger of 9.0 g/dL (5.6 mmol/L) is reached, 1 RBC unit at a time will be transfused.

Study Record Dates

• First Submitted: August 13, 2024
• First Posted: August 19, 2024
• Study Start: November 26, 2024
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2029
• Last Updated: April 8, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: The protocol will be available after publication, expected within 1 year after the start of all participating centers.
• Access Criteria: Open access.

Locations

SE (1); NL (7); BE (4)