Red Blood Cell Transfusion in ECMO - A Feasibility Trial

Study Overview
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Brief Summary
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Extracorporeal Membrane Oxygenation (ECMO) is an invasive and resource intense treatment used to support critically ill patients who have suffered severe cardiac arrest, cardiac failure or respiratory failure (including severe cases of COVID-19). ECMO acts as a mechanical circulatory support temporarily replacing the function of the heart or lungs by oxygenating blood and removing carbon dioxide, allowing time for these organs to recover. Many critically ill patients, including those on ECMO, have an increased risk of bleeding and reduced production/increased destruction of red blood cells (RBCs). This can lead to anaemia (haemoglobin levels <120 g/l), a condition where the body lacks enough healthy RBCs to carry enough oxygen to the body's tissues. Therefore, patients on ECMO frequently require RBC transfusion, with clinicians having to decide if administering an RBC transfusion (with its associated risks) is higher than tolerating complications of anaemia. ROSETTA is a feasibility study that aims to determine the safety and feasibility of randomizing patients on ECMO to a restrictive RBC transfusion strategy (maintain Hb concentration above 70g/L) or to a more liberal transfusion strategy (maintain Hb concentration above 90g/L). Feasibility is defined as the ability to achieve a mean separation of at least 10g/L between the average lowest daily haemoglobin values in the two study groups.

Detailed Description
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A recent Cochrane analysis recommended a transfusion strategy that minimises the use of RBC transfusions in critically ill patients (by tolerating anaemia to avoid the adverse effects of an RBC transfusion). However, the analysis acknowledges that the degree of anaemia which can be tolerated by such patients is unknown, especially in patients suffering from conditions that limit oxygen delivery to the organs (like cardiac disease). As a result, the Australian Blood Authority's guidelines recommend an RBC transfusion to a patient at an Hb concentration of less than 70 g/L, while a transfusion at a Hb between 70 and 90 g/L should be based on the need to relieve clinical signs and symptoms of anaemia. However, this range is broad, and many studies in the general critically ill cohort have shown lower transfusion triggers are non-inferior to higher transfusion triggers. No studies have been completed directly evaluating transfusion triggers in the ECMO patient cohort. ECMO patients differ to the general critically ill cohort as they have different physiological requirements, are at higher-risk for poor outcomes, and have an increased requirement for transfusions. Hb is a key driver of oxygen delivery (DO2), and critically ill ECMO patients are more commonly exposed to low DO2 due to low cardiac output and borderline oxygenation. Therefore, studies must be done to evaluate the optimal transfusion trigger/s (as determined by Hb concentration) that optimise mortality and long-term outcomes of ECMO patients.

Official Title
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Red Blood Cell Transfusion in ECMO - A Feasibility Trial

Conditions
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Blood Loss Anemia, Extracorporeal Membrane Oxygenation Complication

Intervention / Treatment
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* Other: Red Blood Cell Transfusion
* Other: Red Blood Cell Transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients receiving ECMO Age: 18 years or older Exclusion Criteria: Contraindication to RBC transfusion (including known patient preference) Limitations of care put in place either through patient wishes or the treating medical teams ECMO treatment for more than 12 hours. The start of ECMO is defined as the time of initiation of extracorporeal blood flow unless ECMO was initiated during a surgical intervention in which case the start is defined as the arrival time into the initial ICU. The treating physician anticipates that ECMO treatment will cease before the end of tomorrow Where the treating physician deems the study is not in the patient's best interest Where the treating physician has concern regarding patient ability to tolerate restrictive or liberal transfusion trigger thresholds Patients actively listed for a solid organ transplant Patients who are suspected or confirmed to be pregnant Previous ECMO treatment during the same hospital admission

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Restrictive Transfusion Trigger Group<br>if a patient's Hb concentration reads ≤ 70g/L, one unit of RBC will be transfused. Additional units can be prescribed if required to raise the Hb concentration to above 70g/L. | Other: Red Blood Cell Transfusion<br>* Following randomisation, if a patient's Hb concentration reads ≤ 70g/L, one unit of RBC will be transfused within 12 hours of the result becoming available. Additional units can be prescribed if required to raise the Hb concentration to above 70g/L. A transfusion above the restrictive threshold of 70g/L is discouraged.<br>|
| Active Comparator: Liberal Transfusion Trigger Group<br>if a patient's Hb concentration reads ≤ 90g/L, one or more units of RBC will be transfused. Additional units can be prescribed to raise the Hb concentration to greater than 90g/L | Other: Red Blood Cell Transfusion<br>* Following randomisation, if a patient's Hb concentration reads ≤ 90g/L, one or more units of RBC will be transfused in order to raise the Hb concentration to greater than 90g/L within 12 hours of the result becoming available. A decision not to transfuse below the threshold of 90g/L is discouraged.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in average lowest daily Hb concentration | Primary Outcome Measure | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Enrolment Rate | Feasibility Outcome | through study completion, an average of 2 years | 
| Reasons for not entering eligible patients into the study | Feasibility Outcome | through study completion, an average of 2 years | 
| Mean pre-transfusion Hb concentration immediately prior to an RBC transfusion | Feasibility Outcome | through study completion, an average of 2 years | 
| Proportion of RBC transfusions given according to allocated trigger | Feasibility Outcome | through study completion, an average of 2 years | 
| Time from measured Hb trigger value to transfusion | Feasibility Outcome | through study completion, an average of 2 years | 
| Number of RBC transfusions given prior to randomization | Feasibility Outcome | through study completion, an average of 2 years | 
| Frequency for not transfusing a patient who has reached a transfusion trigger | Feasibility Outcome | through study completion, an average of 2 years | 
| Reason/s for not transfusing a patient who has reached a transfusion trigger | Feasibility Outcome | through study completion, an average of 2 years | 
| Number of protocol deviations | Feasibility Outcome | through study completion, an average of 2 years | 
| Number and nature of Serious Adverse Events (SAEs) | Safety and effectiveness outcome | through study completion, an average of 2 years | 
| Total blood products used | Safety and effectiveness outcome | through study completion, an average of 2 years | 
| Major bleeding events (defined by ISTH criteria) | Safety and effectiveness outcome | through study completion, an average of 2 years | 
| Clinically relevant non-major bleeding events: GI haemorrhage, peripheral cannulation site bleeding, mediastinal cannulation site bleeding, surgical site bleeding | Safety and effectiveness outcome | through study completion, an average of 2 years | 
| Venous and arterial thromboembolic events | Safety and effectiveness outcome | through study completion, an average of 2 years | 
| New onset renal replacement therapy (RRT) during ECMO | Safety and effectiveness outcome | through study completion, an average of 2 years | 
| ECMO free days at day 60 | Safety and effectiveness outcome | 60 days | 
| ICU free days at day 60 | Safety and effectiveness outcome | 60 days | 
| Patient Reported Outcome Measure - WHODAS 2.0 | Disability Safety and effectiveness outcome | 6 months | 
| Patient Reported Outcome Measure - IADL | Independent Activities of Daily Living Safety and effectiveness outcome | 6 months | 
| Patient Reported Outcome Measure - ADL | Activity of Daily Living Safety and effectiveness outcome | 6 months | 
| Patient Reported Outcome Measure - MoCA BLIND | Cognitive Function Safety and effectiveness outcome | 6 months | 
| Patient Reported Outcome Measure - EQ-5D-5L | Quality of Life Safety and effectiveness outcome | 6 months | 
| Patient Reported Outcome Measure - mRS | Degree of Disability Safety and effectiveness outcome | 6 months |