Inflammation, Organ Failure, Multiple, Sepsis
Conditions
Brief summary
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
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).
Interventions
DEVICErejuvesol Solution
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.
OTHERStandard Care
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.
Sponsors
National Health Service, United Kingdom
Zimmer Biomet
British Heart Foundation
University of Leicester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult cardiac surgery patients (≥18 years) undergoing cardiac surgery with cardiopulmonary bypass. 2. 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
1. Emergency or salvage procedure 2. 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. 3. Patients who are prevented from having blood and blood products according to a system of beliefs (e.g. Jehovah's Witnesses). 4. 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. 5. Pregnancy. 6. Patients who are participating in another interventional clinical study. 7. Patients requiring irradiated blood. 8. Sickle cell anaemia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal injury | baseline to 96 hours postoperatively | measurement of serum creatinine |
| Myocardial injury | baseline to 72 hours postoperatively | measurement of serum troponin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Protocol compliance measured through protocol deviations | from date of randomisation through to study completion (3 months) | protocol deviations will be aggregated based on pre-defined codes |
| Recruitment | from date of randomisation through to study completion (3 months) | measured through recruitment figures |
| Event rates | from date of randomisation through to study completion (3 months) | measured through serious adverse event (SAE)/ serious unexpected serious adverse reaction (SUSAR) reporting |
| Blinding | from date of randomisation through to study completion (3 months) | measured through protocol deviations |
| Urinary neutrophil gelatinase associated lipocalin (NGAL) | baseline to 48 hours postoperatively | measured through urine collection |
| Serum creatinine | at 6 weeks postoperatively | measured to assess renal function |
| eGFR | at 6 weeks postoperatively | measured to assess renal function |
| Sepsis-related Organ Failure Assessment (SOFA) Score | at baseline, 24, 48, 72 and 96 hours postoperatively | Sepsis will be defined as suspected or documented infection and an acute change in total SOFA score ≥2 points consequent to the infection. |
| Arterial serum lactate | 24 hours postoperatively until time of resolution of hyperlactataemia | — |
| Lung injury | baseline to 96 hours postoperatively | arterial alveolar oxygen ratios |
| GI tract injury | at baseline, 24, 48, 72, and 96 hours postoperatively | serum amylase and liver function tests |
| Transfusion reactions | from date of randomisation through to study completion (3 months) | measured as part of standard care to assess transfusion safety |
| 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) | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| transferrin saturation | baseline to 96 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| non-transferrin bound iron | baseline to 96 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| Acute lung injury | from date of randomisation through to study completion (3 months) | To inform the design of a subsequent efficacy trial |
| Acute kidney injury | from date of randomisation through to study completion (3 months) | To inform the design of a subsequent efficacy trial |
| Low cardiac output | from date of randomisation through to study completion (3 months) | To inform the design of a subsequent efficacy trial |
| Acute brain injury | from date of randomisation through to study completion (3 months) | To inform the design of a subsequent efficacy trial |
| Acute liver or gut injury | from date of randomisation through to study completion (3 months) | To inform the design of a subsequent efficacy trial |
| Sepsis | from date of randomisation through to study completion (3 months) | To inform the design of a subsequent efficacy trial |
| Organ injury, sepsis or death (a composite of sepsis, acute kidney injury, acute lung injury, acute brain injury, low cardiac output syndrome, gut or liver injury or death) | from date of randomisation through to study completion (3 months) | To inform the design of a subsequent efficacy trial |
| Endothelial function, tissue hypoxia and p50 of circulating red cells | baseline and 24 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| Recipient platelet, monocyte and endothelial activation in whole blood as determined using flow cytometry | baseline to 48 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| Bronchial aspirate neutrophil and protein concentration | 4-6 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| free haem | baseline to 96 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| hepcidin | baseline to 96 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| pulmonary leucocyte haem oxygenase-1 expression | baseline to 96 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| serum protein carbonylation and lipid peroxidation | baseline to 96 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
| serum bilirubin | baseline to 96 hours post-op | To be measured in a sub-study of mechanisms in 80 participants |
Countries
United Kingdom
Outcome results
None listed