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.

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.

Inclusion Criteria:

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

Exclusion Criteria:

• 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.

The study protocol will be submitted for publication in a prominent journal.

The protocol will be available after publication, expected within 1 year after the start of all participating centers.

Open access.