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

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

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).

Study Overview

• Status: Withdrawn
• Conditions: Sepsis; Inflammation; Organ Failure, Multiple
• Intervention / Treatment: Device: rejuvesol Solution; Other: Standard Care

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).

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Department of Cardiovascular Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention; 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; 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.
ACTIVE_COMPARATOR: Control; 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; 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.

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute lung injury	To inform the design of a subsequent efficacy trial	from date of randomisation through to study completion (3 months)
Acute kidney injury	To inform the design of a subsequent efficacy trial	from date of randomisation through to study completion (3 months)
Low cardiac output	To inform the design of a subsequent efficacy trial	from date of randomisation through to study completion (3 months)
Acute brain injury	To inform the design of a subsequent efficacy trial	from date of randomisation through to study completion (3 months)
Acute liver or gut injury	To inform the design of a subsequent efficacy trial	from date of randomisation through to study completion (3 months)
Sepsis	To inform the design of a subsequent efficacy trial	from date of randomisation through to study completion (3 months)
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)	To inform the design of a subsequent efficacy trial	from date of randomisation through to study completion (3 months)
Endothelial function, tissue hypoxia and p50 of circulating red cells	To be measured in a sub-study of mechanisms in 80 participants	baseline and 24 hours post-op
Recipient platelet, monocyte and endothelial activation in whole blood as determined using flow cytometry	To be measured in a sub-study of mechanisms in 80 participants	baseline to 48 hours post-op
Bronchial aspirate neutrophil and protein concentration	To be measured in a sub-study of mechanisms in 80 participants	4-6 hours post-op
free haem	To be measured in a sub-study of mechanisms in 80 participants	baseline to 96 hours post-op
serum bilirubin	To be measured in a sub-study of mechanisms in 80 participants	baseline to 96 hours post-op
transferrin saturation	To be measured in a sub-study of mechanisms in 80 participants	baseline to 96 hours post-op
non-transferrin bound iron	To be measured in a sub-study of mechanisms in 80 participants	baseline to 96 hours post-op
hepcidin	To be measured in a sub-study of mechanisms in 80 participants	baseline to 96 hours post-op
pulmonary leucocyte haem oxygenase-1 expression	To be measured in a sub-study of mechanisms in 80 participants	baseline to 96 hours post-op
serum protein carbonylation and lipid peroxidation	To be measured in a sub-study of mechanisms in 80 participants	baseline to 96 hours post-op

Collaborators and Investigators

• Sponsor: University of Leicester
• Collaborators: Zimmer Biomet; British Heart Foundation; National Health Service, United Kingdom

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): December 1, 2020
• Primary Completion (ANTICIPATED): December 1, 2020
• Study Completion (ANTICIPATED): December 1, 2020

Study Registration Dates

• First Submitted: May 12, 2017
• First Submitted That Met QC Criteria: May 23, 2017
• First Posted (ACTUAL): May 30, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 29, 2021
• Last Update Submitted That Met QC Criteria: April 27, 2021
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Shock; Inflammation; Multiple Organ Failure
• Other Study ID Numbers: 0582

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No