TransfusionTRECNCT06560164
Restrictive Versus Liberal Thresholds for RBC Transfusion in ECMO
A study testing Red Blood Cell transfusion in people with Transfusion and Red Blood Cell, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 14 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Transfusion, Red Blood Cell, Extracorporeal Membrane Oxygenation
- What is being tested?
- Red Blood Cell transfusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 526 participants
- Where
- 14 sitesin 4 countries
- Study dates
- 26 Nov 2024to 1 Oct 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patient is aged 18 years or older;
- Is receiving ECMO;
- (Deferred) informed consent.
Who cannot join
- 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.
Trial locations and contacts
14 sites in 4 countries. Contact the study team or a site near you to ask about taking part.
14 sites in 4 countries
Netherlands8 sites, 8 recruiting
- Recruiting
Amsterdam UMC, location AMC
Amsterdam, North Holland, 1105 AZ
Alexander P.J. Vlaar, PhD, 020 566 9111, a.p.vlaar@amsterdamumc.nl
- Recruiting
Medisch Spectrum Twente (MST)
Enschede, Drenthe, 7512 KZ
Wytze Vermeijden, PhD, 053 487 2000, j.vermeijden@mst.nl
- Recruiting
Universitair Medisch Centrum Groningen (UMCG)
Groningen, Provincie Groningen, 9713 GZ
Walter van den Bergh, PhD, 050 361 6161, w.m.van.den.bergh@umcg.nl
- Recruiting
Leids Universitair Medisch Centrum (LUMC)
Leiden, South Holland, 2333 ZA
Carlos Elzo Kraemer, MD, 071 526 9111, c.v.elzo_kraemer@lumc.nl
- Recruiting
Maastricht Universitair Medisch Centrum+ (MUMC+)
Maastricht, Limburg, 6229 HX
Marcel van de Poll, PhD, 043 387 6543, marcel.vande.poll@mumc.nl
- Recruiting
St. Antonius Ziekenhuis
Nieuwegein, Utrecht, 3435 CM
Erik Scholten, MD, 088 320 3000, e.scholten@antoniusziekenhuis.nl
- Not yet recruiting
Radboudumc
Nijmegen, Gelderland, 6525 GA
Tim Frenzel, PhD, 024 361 1111, Tim.Frenzel@radboudumc.nl
- Recruiting
Erasmus MC
Rotterdam, South Holland, 3015 GD
Christiaan Meuwese, PhD, 010 704 0704, c.meuwese@erasmusmc.nl
Belgium4 sites, 4 recruiting
- Recruiting
Hôpital Erasme
Brussels, Brussels Capital, 1070
Fabio Taccone, PhD, +32 2 555 31 11, Fabio.Taccone@ulb.be
- Recruiting
CHU Charleroi
Charleroi, Hainaut, 6000
Michaël Piagnerelli, PhD, 071 92 11 11, michael.Piagnerelli@ulb.be
- Recruiting
KU Leuven, medical IC
Leuven, Flemish Brabant, 3000
Greet Hermans, PhD, +32 16 33 22 11, greet.hermans@uzleuven.be
- Recruiting
KU Leuven, surgical IC
Leuven, Flemish Brabant, 3000
Dieter Dauwe, PhD, +32 16 33 22 11, dieter.dauwe@uzleuven.be
Austria1 site, 1 recruiting
- Recruiting
MedUni Wien
Vienna, State of Vienna, 1090
Nina Buchtele, PhD, +43 1 401600, nina.buchtele@meduniwien.ac.at
Sweden1 site, 1 recruiting
- Recruiting
Karolinska Universtiy Hospital
Stockholm, Stockholm County, 171 76
Lars M. Broman, PhD, +46 8 123 70 000, lars.broman@regionstockholm.se
About this study
Official title: Restrictive Versus Liberal Thresholds for Red Blood Cell Transfusion in ExtraCorporeal Membrane Oxygenation - the TREC Study
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.
Read more
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.
Read the detailed description
Extracorporeal membrane oxygenation (ECMO) is used as a supportive method in case of temporary and potentially reversible cardiac or respiratory failure, refractory to conventional therapies. Over the past decades, application of ECMO has been increasing worldwide. As ECMO is generally used as a 'last resort' therapy, the population is vulnerable, and many complications can occur. Anemia occurs in >90% of the patients on ECMO, caused by many different patient-related, disease-related, and ECMO-related factors. Nevertheless, rationale for the recommended hemoglobin (Hb) thresholds for red blood cell (RBC) transfusion in this patient population is limited. This was recently confirmed by the members of the European Society of Intensive Care Medicine (ESICM), who concluded in their clinical practice guideline that no recommendation on transfusion thresholds can be made, since solid evidence is missing. The panel stated that this area is a research priority.
This lack of evidence-based guidelines may explain the high variance in Hb thresholds applied, as well as the thresholds in use being relatively liberal. As a result, transfusion of RBC is very common. Observational studies describe that almost 9 out of 10 patients receiving ECMO receive at least one RBC transfusion, and the total amount is very high. These numbers are even more remarkable when comparing to other patient populations in the Intensive Care Unit (ICU), in which 1 out of 4 patients receives RBC with way lesser amounts. One of the main arguments for using a liberal transfusion threshold in ECMO is the hypothesis that in patients receiving ECMO, tissue hypoxemia can develop due to decreased pulmonary oxygen intake (e.g., in pneumonia as indication for veno-venous [VV] ECMO), or decreased cardiac output (e.g., in myocardial infarction as indication for veno-arterial [VA] ECMO). By providing a larger Hb buffer, it is assumed that the oxygen delivery (DO2) will be preserved and the incidence of tissue hypoxemia will be reduced. However, evidence to either confirm or refute this hypothesis is lacking. Since ECMO ensures oxygenation and can provide a blood flow of up to 7 L/min, it can be assumed that ECMO fully compensates for the possible decrease in DO2.
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. In similar patient populations without ECMO, maintaining a restrictive RBC transfusion strategy (Hb 7.0 g/dL) has been proven non-inferior to a more liberal practice (Hb 9.0 g/dL). This includes randomized controlled trials (RCTs) in septic shock patients (comparable to patients on VV ECMO), cardiothoracic surgery patients, and even patients suffering from acute myocardial infarction and anemia (comparable to patients on VA ECMO). Although these conclusions are promising, they cannot directly be translated to patients supported by ECMO, although underlying conditions are similar. Moreover, RBC transfusions are expensive and donors are becoming more scarce. In this vulnerable critically ill patient population with an enhanced risk for transfusion related complications, it is of utmost importance to only administer a RBC transfusion when the benefits outweigh the risks.
As both anemia and transfusion are associated with poor outcomes, observational studies cannot answer the question whether a restrictive Hb threshold is non-inferior to a liberal strategy. There is a need to define general thresholds to improve the efficiency of indications for RBC transfusion in ECMO. Since one of the most commonly used triggers for RBC transfusion is Hb concentration, this forms the basis for our study to investigate whether it is non-inferior to maintain a restrictive transfusion threshold (intervention group: Hb 7 g/dL) compared to the current standard of 9 g/dL in patients on ECMO, independent of the mode.
This study is funded by ZonMW (Zorgonderzoek Medische Wetenschappen), part of the NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek; the Dutch Organization for Scientific Research, Den Haag, the Netherlands), reference number 10390032310031.
- Conditions
- Transfusion, Red Blood Cell, Extracorporeal Membrane Oxygenation, Anemia, ECMO
- Being tested
- Red Blood Cell transfusion
- Keywords
- Transfusion, Red Blood Cell, Extracorporeal Membrane Oxygenation, Anemia, ECMO
- Medical subject headings
- Anemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Red Blood Cell transfusionOther
Also called RBC transfusion, pRBCs, packed Red Blood Cells
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: Red Blood Cell transfusion |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 90 days
Secondary outcomes (7)
In-hospital mortality
All-cause mortality during the hospital stay refers to the proportion of patients who died from any cause while they were still admitted to the hospital.
Measured: 30 days
Duration
The duration of ECMO support, along with the length of ICU and hospital stays, are key metrics that quantify the total time a patient receives ECMO treatment, is in the intensive care unit, and remains in the hospital, measured in both days and hours.
Measured: 30 days
Red blood cell transfusion exposure
The proportion of patients on ECMO who receive allogeneic red blood cell (RBC) transfusions.
Measured: 30 days
Adherence
The number of adherence and non-adherence transfusion events.
Measured: 30 days
EQ-5D-5L
A quality of life questionnaire assessing various domains including mobility, self-care, daily activities, and pain/discomfort, as well as emotional states like fear/sadness. Each domain is rated on a 5-point scale, where 1 indicates no problems and 5 indicates severe problems. Additionally, the questionnaire includes a EuroQol Visual Analogue Scale (EQ-VAS), which is a vertical scale ranging from 100 (best imaginable health) to 0 (worst imaginable health).
Measured: 3, 6, 9, and 12 months
Medical Consumption
The iMTA Medical Consumption Questionnaire (iMCQ) will be used to assess medical consumption and associated costs during the first year following ECMO support. This questionnaire collects detailed information on healthcare utilization, such as hospital visits, medications, medical procedures, and other related services, enabling an analysis of the overall costs incurred during the recovery period. The iMCQ does not include an outcome scale but focuses solely on quantifying the extent and cost of medical resources used.
Measured: 3, 6, 9, and 12 months
Productivity Cost
The Productivity Cost Questionnaire (iPCQ) will be utilized to assess productivity loss during the first year following ECMO support. This questionnaire captures data on absenteeism, reduced efficiency at work, and lost productivity due to health-related issues. The iPCQ focuses exclusively on quantifying the extent of productivity loss without including an outcome scale, providing a clear picture of the economic impact associated with recovery in the first year post-ECMO.
Measured: 3, 6, 9, and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Aug 2024
- Study start26 Nov 2024
- Primary completion1 Oct 2027 (estimated)
- Study completion1 Oct 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for TransfusionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 526 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, A.P.J. Vlaar, Amsterdam UMC, location AMC
- Investigators
- Alexander P.J. Vlaar, PhD, Principal investigator, Amsterdam UMC, location AMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06560164
- Sponsor's protocol ID
- NL84295.018.23
- Other IDs
- NL84295.018.23, 84295, B3222022001258, 2023-07691-01, 10390032310031, 2023
- Acronym
- TREC
- Status last verified
- Aug 2026
- First submitted
- 13 Aug 2024
- Last updated
- 14 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The study protocol will be submitted for publication in a prominent journal.
Publications
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.
PubMed 22188792Makdisi 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.
PubMed 26380745Vlaar 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.
PubMed 31912207de 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.
PubMed 31511083Martucci 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.
PubMed 30966906Aubron 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.
PubMed 27714705Raasveld 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.
PubMed 35100195Vincent 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.
PubMed 12243637Bosboom 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.
PubMed 29238981Hebert 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.
PubMed 9971864Mazer 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.
PubMed 29130845Murphy 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.
PubMed 25760354Ducrocq 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.
PubMed 33560322Kracalik 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.
PubMed 33880771Holst 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.
PubMed 23702006
Study at a glance
From the registry record, last updated by the sponsor on 14 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Restrictive Versus Liberal Thresholds for Red Blood Cell Transfusion in ExtraCorporeal Membrane Oxygenation - the TREC Study
- ClinicalTrials.gov ID
- NCT06560164
- Acronym / sponsor ID
- TREC / NL84295.018.23
- Conditions
- Transfusion, Red Blood Cell, Extracorporeal Membrane Oxygenation, Anemia, ECMO
- Keywords
- Transfusion, Red Blood Cell, Extracorporeal Membrane Oxygenation, Anemia, ECMO
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 526 participants (estimated)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- 26 Nov 2024 (actual)
- Primary completion
- 1 Oct 2027 (estimated)
- Study completion
- 1 Oct 2028 (estimated)
- First posted
- 19 Aug 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Extracorporeal membrane oxygenation (ECMO) is used as a supportive method in case of temporary and potentially reversible cardiac or respiratory failure, refractory to conventional therapies. Over the past decades, application of ECMO has been increasing worldwide. As ECMO is generally used as a 'last resort' therapy, the population is vulnerable, and many complications can occur. Anemia occurs in >90% of the patients on ECMO, caused by many different patient-related, disease-related, and ECMO-related factors. Nevertheless, rationale for the recommended hemoglobin (Hb) thresholds for red blood cell (RBC) transfusion in this patient population is limited. This was recently confirmed by the members of the European Society of Intensive Care Medicine (ESICM), who concluded in their clinical practice guideline that no recommendation on transfusion thresholds can be made, since solid evidence is missing. The panel stated that this area is a research priority.
This lack of evidence-based guidelines may explain the high variance in Hb thresholds applied, as well as the thresholds in use being relatively liberal. As a result, transfusion of RBC is very common. Observational studies describe that almost 9 out of 10 patients receiving ECMO receive at least one RBC transfusion, and the total amount is very high. These numbers are even more remarkable when comparing to other patient populations in the Intensive Care Unit (ICU), in which 1 out of 4 patients receives RBC with way lesser amounts. One of the main arguments for using a liberal transfusion threshold in ECMO is the hypothesis that in patients receiving ECMO, tissue hypoxemia can develop due to decreased pulmonary oxygen intake (e.g., in pneumonia as indication for veno-venous [VV] ECMO), or decreased cardiac output (e.g., in myocardial infarction as indication for veno-arterial [VA] ECMO). By providing a larger Hb buffer, it is assumed that the oxygen delivery (DO2) will be preserved and the incidence of tissue hypoxemia will be reduced. However, evidence to either confirm or refute this hypothesis is lacking. Since ECMO ensures oxygenation and can provide a blood flow of up to 7 L/min, it can be assumed that ECMO fully compensates for the possible decrease in DO2.
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. In similar patient populations without ECMO, maintaining a restrictive RBC transfusion strategy (Hb 7.0 g/dL) has been proven non-inferior to a more liberal practice (Hb 9.0 g/dL). This includes randomized controlled trials (RCTs) in septic shock patients (comparable to patients on VV ECMO), cardiothoracic surgery patients, and even patients suffering from acute myocardial infarction and anemia (comparable to patients on VA ECMO). Although these conclusions are promising, they cannot directly be translated to patients supported by ECMO, although underlying conditions are similar. Moreover, RBC transfusions are expensive and donors are becoming more scarce. In this vulnerable critically ill patient population with an enhanced risk for transfusion related complications, it is of utmost importance to only administer a RBC transfusion when the benefits outweigh the risks.
As both anemia and transfusion are associated with poor outcomes, observational studies cannot answer the question whether a restrictive Hb threshold is non-inferior to a liberal strategy. There is a need to define general thresholds to improve the efficiency of indications for RBC transfusion in ECMO. Since one of the most commonly used triggers for RBC transfusion is Hb concentration, this forms the basis for our study to investigate whether it is non-inferior to maintain a restrictive transfusion threshold (intervention group: Hb 7 g/dL) compared to the current standard of 9 g/dL in patients on ECMO, independent of the mode.
This study is funded by ZonMW (Zorgonderzoek Medische Wetenschappen), part of the NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek; the Dutch Organization for Scientific Research, Den Haag, the Netherlands), reference number 10390032310031.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Restrictive strategy | Active comparator | Other: Red Blood Cell transfusionThe 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. |
| Liberal strategy | Active comparator | Other: Red Blood Cell transfusionThe 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Patient is aged 18 years or older;
- Is receiving ECMO;
- (Deferred) informed consent.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Red Blood Cell transfusionAlso: RBC transfusion, pRBCs, packed Red Blood CellsWhen 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. | Other | Liberal strategy, Restrictive strategy |
Primary outcome
90-day all-cause mortality
Time frame: 90 days
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.
7 secondary outcomes
In-hospital mortality
Time frame: 30 days
Duration
Time frame: 30 days
Red blood cell transfusion exposure
Time frame: 30 days
Adherence
Time frame: 30 days
EQ-5D-5L
Time frame: 3, 6, 9, and 12 months
Medical Consumption
Time frame: 3, 6, 9, and 12 months
Productivity Cost
Time frame: 3, 6, 9, and 12 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Aug 2026.
- Background: PubMed 22188792Gattinoni L, Carlesso E, Langer T. Clinical review: Extracorporeal membrane oxygenation. Crit Care. 2011;15(6):243. doi: 10.1186/cc10490. Epub 2011 Dec 8.
- Background: PubMed 26380745Makdisi 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.
- Background: PubMed 31912207Vlaar 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.
- Background: PubMed 31511083de 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.
- Background: PubMed 30966906Martucci 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.
- Background: PubMed 27714705Aubron 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.
- Background: PubMed 35100195Raasveld 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.
- Background: PubMed 12243637Vincent 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.
- Background: PubMed 29238981Bosboom 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.
- Background: PubMed 9971864Hebert 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.
- Background: PubMed 29130845Mazer 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.
- Background: PubMed 25760354Murphy 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.
- Extracorporeal Life Support Organization. Extracorporeal Life Support Organization ECLS Registry Report Overall Outcomes. 2019Link provided by the sponsor.
- Additional study information and progress overviewLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. The study protocol will be submitted for publication in a prominent journal.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Alexander P.J. Vlaar, PhD principal investigator
Amsterdam UMC, location AMC
14 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Red Blood Cell transfusion in people with Transfusion and Red Blood Cell, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 14 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 14 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in Netherlands, Belgium, Austria, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Alexander P.J. Vlaar, PhD (020 566 9111, a.p.vlaar@amsterdamumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
90-day all-cause mortality (time frame: 90 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06560164, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2026.