Red Cell Rejuvenation for the Attenuation of Transfusion Associated Organ Injury in Cardiac Surgery

Study Overview
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Brief Summary
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The REDJUVENATE Trial proposes to test the hypothesis that postoperative organ injury and inflammation will be less if patients undergoing cardiac surgery who are at risk of large volume blood transfusion (defined as the administration of ≥4 units of red cells) receive rejuvenated washed cells compared to standard care (unwashed aged stored cells).

Detailed Description
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In the REDJUVENATE trial, we propose to establish whether the administration of rejuvenated red cells will reduce inflammation and organ injury in cardiac surgery patients at risk of large volume blood transfusion when compared to standard care. Organ injury and sepsis accounts for the majority of all deaths following cardiac surgery. Once organ injury is established care is primarily supportive and there are no effective treatments. Prevention is therefore a key clinical strategy to prevent death, morbidity and high healthcare costs attributable to these complications. Sepsis and inflammatory organ injury are also the principal causes of death following paediatric cardiac surgery, trauma, non-cardiac complex surgical procedures and in critical care; clinical settings that are also among the principal consumers of blood components. National and international blood management strategies are focused on these patients. Evidence of a clinical benefit attributable to the use of rejuvenated red cells in cardiac surgery patients is therefore likely to translate into more widespread benefits to patients and the National Health Service (NHS).

Official Title
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A RANDOMISED CONTROLLED TRIAL OF RED CELL REJUVENATION FOR THE ATTENUATION OF TRANSFUSION ASSOCIATED ORGAN INJURY IN CARDIAC SURGERY: The REDJUVENATE Trial

Conditions
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Sepsis, Organ Failure, Multiple, Inflammation

Intervention / Treatment
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* Device: rejuvesol Solution
* Other: Standard Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult cardiac surgery patients (≥18 years) undergoing cardiac surgery with cardiopulmonary bypass. Identified as representing a high risk group for massive blood transfusion using a modified risk score. A large volume blood transfusion (LVBT) score of >23 indicates predicted risk of receiving ≥4 units of allogeneic red cells equal to or greater than 55 per cent. Exclusion Criteria: Emergency or salvage procedure Patients with end stage renal failure defined as an estimated Glomerular Filtration rate (eGFR) <15 mL/min/1.72 m2 calculated from the Modification of Diet in Renal Disease equation, or patients who are on long-term haemodialysis or have undergone renal transplantation. Patients who are prevented from having blood and blood products according to a system of beliefs (e.g. Jehovah's Witnesses). Patients with a pre-existing sepsis or organ injury defined as documented sepsis, acute kidney injury, acute lung injury, myocardial infarction, low cardiac output, liver injury, stroke or pancreatitis within 5 days of surgery. Pregnancy. Patients who are participating in another interventional clinical study. Patients requiring irradiated blood. Sickle cell anaemia.

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Cross-matched allogeneic stored red cells will be rejuvenated using rejuvesol® Red Blood Cell Processing Solution (Citra Labs, MA, a Zimmer Biomet Company, IN, USA) with washing and re-suspension in an additive solution prior to transfusion. The rejuvenated red cells will then be administered to the patient as per standard practice and according to established institutional protocols. A maximum of 6 rejuvenated red cell units will be transfused within any 24 hour period. | Device: rejuvesol Solution<br>* The rejuvenation process involves incubation of stored red cells with a rejuvenating solution, rejuvesol Red Blood Cell Processing Solution (rejuvesol® Solution), Citra labs, MA, a Zimmer Biomet Company, IN, USA) which restores red cell adenosine triphosphate (ATP), 2,3-DPG (diphosphoglycerate), oxygen transfer characteristics and rheology. Post rejuvenation red cells are washed to remove the rejuvesol Solution, and cells are re-suspended in additive solution for transfusion.<br>|
| Active Comparator: Control<br>Standard care i.e. Cross-matched allogeneic stored non-rejuvenated, unwashed red cells will be administered to the patient as per standard practice and according to established institutional protocols. | Other: Standard Care<br>* Allogeneic red cells, harvested in citrate-phosphate-dextrose (CPD), leucocyte depleted, saline-adenine-glucose-mannitol (SAGM) stored red cell units, issued by National Health Service Blood & Transplant (NHSBT) will be administered to cardiac surgery patients as per standard practice, and according to established unit protocols.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal injury | measurement of serum creatinine | baseline to 96 hours postoperatively | 
| Myocardial injury | measurement of serum troponin | baseline to 72 hours postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protocol compliance measured through protocol deviations | protocol deviations will be aggregated based on pre-defined codes | from date of randomisation through to study completion (3 months) | 
| Recruitment | measured through recruitment figures | from date of randomisation through to study completion (3 months) | 
| Event rates | measured through serious adverse event (SAE)/ serious unexpected serious adverse reaction (SUSAR) reporting | from date of randomisation through to study completion (3 months) | 
| Blinding | measured through protocol deviations | from date of randomisation through to study completion (3 months) | 
| Urinary neutrophil gelatinase associated lipocalin (NGAL) | measured through urine collection | baseline to 48 hours postoperatively | 
| Serum creatinine | measured to assess renal function | at 6 weeks postoperatively | 
| eGFR | measured to assess renal function | at 6 weeks postoperatively | 
| Sepsis-related Organ Failure Assessment (SOFA) Score | Sepsis will be defined as suspected or documented infection and an acute change in total SOFA score ≥2 points consequent to the infection. | at baseline, 24, 48, 72 and 96 hours postoperatively | 
| Arterial serum lactate |  | 24 hours postoperatively until time of resolution of hyperlactataemia | 
| Lung injury | arterial alveolar oxygen ratios | baseline to 96 hours postoperatively | 
| GI tract injury | serum amylase and liver function tests | at baseline, 24, 48, 72, and 96 hours postoperatively | 
| Transfusion reactions | measured as part of standard care to assess transfusion safety | from date of randomisation through to study completion (3 months) | 
| Age of each unit of red cells transfused |  | day of operation | 
| Postoperative blood loss, transfusion of red cell and non-red cell allogenic blood components |  | day of operation | 
| Adverse events other than those included in the primary endpoint |  | from date of randomisation through to study completion (3 months) | 
| Length of ICU and hospital stay |  | from date of randomisation through to study completion (3 months) |