Red Blood Cell Transfusion Strategies for ECMO Patients

(TITRE Trial)

Recruiting in Palo Alto (17 mi)

+23 other locations

Overseen by Lynn A. Sleeper, ScD

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Boston Children's Hospital

Disqualifiers: Gestational age < 37 weeks, Congenital bleeding disorders, Hemoglobinopathies, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

TITRE - Trial of Indication-based Transfusion of Red Blood Cells in ECMO, is a multicenter, prospective, randomized clinical trial. The overarching goal of TITRE is to determine whether restricting red blood cell (RBC) transfusion according to an indication-based strategy for those with bleeding and/or deficit of tissue oxygen delivery, compared with transfusion based on center-specific hemoglobin or hematocrit thresholds, can reduce organ dysfunction and improve later neurodevelopment in critically ill children receiving Extracorporeal Membrane Oxygenation (ECMO) support.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of red blood cell transfusion as a treatment for ECMO patients?

The research highlights the need for careful consideration of red blood cell transfusion in ECMO patients due to potential risks and costs, suggesting that while it may help with oxygen delivery, it also carries significant risks. Establishing optimal transfusion criteria is important to balance benefits and adverse outcomes. ^{1 2 3 4 5}

Is red blood cell transfusion generally safe for humans?

Red blood cell transfusions can carry risks, including adverse reactions and complications, especially if the blood is stored improperly or irradiated. However, restrictive transfusion protocols have been shown to be safe in some patient groups, though practices and safety can vary. ^{2 6 7 8 9}

How is red blood cell transfusion different from other treatments for ECMO patients?

Red blood cell transfusion for ECMO patients is unique because it focuses on optimizing oxygen delivery in critically ill patients with low hemoglobin (a protein in red blood cells that carries oxygen). Unlike other treatments, it involves directly increasing the number of red blood cells to improve oxygen levels, but it requires careful consideration of risks and benefits due to potential adverse outcomes. ^{1 2 3 4 6}

Research Team

Lynn A. Sleeper, ScD

Principal Investigator

Boston Children's Hospital

Eligibility Criteria

This trial is for critically ill children under 6 years old on their first ECMO run with veno-arterial mode. It's not for kids expected to have care limitations within 48 hours, those with congenital bleeding disorders or hemoglobinopathies, non-residents of the US/Canada, or those on short-term ECMO.

Inclusion Criteria

Veno-arterial (VA) mode of ECMO

First ECMO run during the index hospitalization

I was younger than 6 years old when I received ECMO treatment.

Exclusion Criteria

I was put on ECMO at a different hospital and then moved to a trial site.

I have a blood disorder affecting my hemoglobin.

Veno-venous (VV) mode of ECMO

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive red blood cell transfusion based on indication-based or center-specific threshold strategies while on ECMO support

Up to 30 days

Daily monitoring during ECMO

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neurodevelopmental assessments

12 months

Assessments at 3, 6, 9, and 12 months post-randomization

Long-term follow-up

Participants' neurodevelopmental outcomes and health-related quality of life are assessed one year post-randomization

1 year

Treatment Details

Interventions

• Red blood cell transfusion (Blood Product)

Trial Overview The TITRE study tests if limiting red blood cell transfusions based on specific needs (like bleeding or low tissue oxygen) is better than using set hemoglobin levels. The goal is to see if this can reduce organ dysfunction and improve neurodevelopment in these children.

Participant Groups

Group I: Center-specific hemoglobin/hematocrit threshold-based red blood cell transfusion strategy Experimental Treatment 1 Intervention

Red blood cell transfusion will occur according to each study center's standard of care strategy, typically based on a particular hemoglobin threshold or hematocrit threshold. When hemoglobin or hematocrit decrease to the threshold, red blood cell transfusion is administered.

Group II: Indication-based red blood cell transfusion strategy Active Control 1 Intervention

Red blood cell transfusion will occur if the center-specific hemoglobin/hematocrit threshold for transfusion is met AND at least one of the following conditions is present: a) moderate or severe bleeding; b) reduced tissue oxygen delivery, defined as serum lactate \>5 mmol/L or 2 serum lactate levels \> 3 mmol/L measured 2 hours apart; or c) hemoglobin \< 8 g/dL or hematocrit \< 25%, except for neonates (age =\< 28 d) and children with single ventricle congenital heart disease (age \< 1 y) RBC transfusion for hemoglobin \< 10g/dL or hematocrit \<30% is allowed.

Who Is Running the Clinical Trial?

Boston Children's Hospital

Lead Sponsor

Trials

801

Recruited

5,584,000+

Dr. Kevin B. Churchwell

Boston Children's Hospital

Chief Executive Officer since 2021

MD from Vanderbilt Medical School

Dr. Sarah Pitts

Boston Children's Hospital

Chief Medical Officer since 2019

MD from Harvard Medical School

Findings from Research

In a study of 419 patients on venoarterial extracorporeal membrane oxygenation (VA ECMO), 89% received red blood cell (RBC) transfusions, with a median of eight units transfused during a median ECMO run of 5 days, indicating that transfusions are a common practice in this setting.

Factors such as lower hemoglobin levels before ECMO, longer ECMO duration, and hemorrhage were associated with increased RBC transfusions, but no significant differences in overall survival were found based on transfusion status or regimens, suggesting a need for further research on transfusion guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transfusion of red blood cells in venoarterial extracorporeal membrane oxygenation: A multicenter retrospective observational cohort study. Raasveld, SJ., Karami, M., Schenk, J., et al.[2023]

In a study of 281 patients receiving ECMO support, it was found that transfusing packed red blood cells (RBCs) when hemoglobin (HGB) levels were above 10 g/dL did not improve in-hospital survival, leading to a revised transfusion threshold of ≤10 g/dL.

Implementing this new threshold resulted in a significant reduction of 1.2 units of RBC transfusion per patient without negatively impacting mortality rates, demonstrating a successful approach to optimize transfusion practices in ECMO patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A value-based approach to optimize red blood cell transfusion in patients receiving extracorporeal membrane oxygenation. Shudo, Y., Cheng, N., He, H., et al.[2023]

In a study of 201 patients undergoing extracorporeal membrane oxygenation (ECMO), red blood cell transfusion was linked to a higher risk of in-intensive care unit mortality, with each additional unit increasing the odds of death by 7%.

Transfusions were also associated with increased rates of severe complications, including acute renal failure, thromboembolic events, and sepsis, suggesting that while transfusions may be necessary, they could indicate a poorer prognosis rather than directly causing these outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of red blood cell transfusion and its association with prognosis in patients undergoing extracorporeal membrane oxygenation. Lo Pinto, H., Allyn, J., Persichini, R., et al.[2018]

In a study of 484 patients receiving ECMO support, higher volumes of red blood cell (RBC) transfusions were linked to increased mortality risk, particularly in patients with non-cardiac conditions, where each additional 10 mL/kg/day of transfusion raised the odds of in-hospital death by 24%.

Patients requiring ECMO for cardiac and CPR indications received significantly more RBC transfusions (105 mL/kg/day and 66 mL/kg/day, respectively) compared to those with non-cardiac indications (20 mL/kg/day), suggesting that the reason for ECMO support influences transfusion needs and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Red blood cell transfusion volume and mortality among patients receiving extracorporeal membrane oxygenation. Smith, A., Hardison, D., Bridges, B., et al.[2022]

In a study involving pediatric patients under 19 years old receiving extracorporeal membrane oxygenation (ECMO) across eight institutions, higher volumes of red blood cell (RBC) transfusions were linked to increased hospital mortality, with each additional 10 mL/kg/d of transfusion raising the odds of death by 9%.

Despite maintaining average hematocrit levels at 36.8%, the high RBC transfusion volume (29.4 mL/kg/d) suggests a need for further research to determine optimal transfusion thresholds to improve outcomes in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RBC Transfusion Practice in Pediatric Extracorporeal Membrane Oxygenation Support. Muszynski, JA., Reeder, RW., Hall, MW., et al.[2023]

In a study of 208 patients receiving venovenous extracorporeal membrane oxygenation (ECMO), 88% received at least one red blood cell (RBC) transfusion, indicating a high transfusion rate even among nonbleeding patients.

Despite the high rate of transfusions, there were no significant differences in survival or complication rates between patients with liberal and restrictive transfusion thresholds, suggesting that the current guidelines may need reevaluation for optimal RBC transfusion practices in ECMO patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RBC Transfusion in Venovenous Extracorporeal Membrane Oxygenation: A Multicenter Cohort Study. Raasveld, SJ., Karami, M., van den Bergh, WM., et al.[2023]

In a study involving four dogs that experienced acute hemolytic transfusion reactions, two dogs died and one was euthanized due to complications likely caused by improper storage of red blood cell (RBC) products.

The investigation revealed that RBC units from two blood banks were hemolyzed after being stored incorrectly, highlighting the importance of proper storage and monitoring of blood products to prevent life-threatening transfusion reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro lysis and acute transfusion reactions with hemolysis caused by inappropriate storage of canine red blood cell products. Patterson, J., Rousseau, A., Kessler, RJ., et al.[2021]

A restrictive transfusion protocol, which only allows red blood cell transfusions for patients with hemoglobin levels below 6 g/dL or between 6 to 8 g/dL with specific conditions, was safely implemented in a study of 409 cardiac surgery patients across 30 centers.

The protocol resulted in excellent patient outcomes, with a low mortality rate of 0.49% and a significant portion (65.0%) of patients avoiding transfusions altogether, suggesting that this approach can effectively reduce unnecessary transfusions while maintaining safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safe application of a restrictive transfusion protocol in moderate-risk patients undergoing cardiac operations. Song, HK., von Heymann, C., Jespersen, CM., et al.[2014]

In a study analyzing 149,052 units of transfused red blood cells (RBCs) over 5.5 years, irradiated RBCs were found to significantly increase the frequency of non-allergic transfusion reactions, with an odds ratio of 1.89.

Prolonged storage of irradiated RBCs was specifically linked to a higher incidence of these non-allergic reactions, suggesting that both irradiation and storage duration may impact the safety of RBC transfusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irradiation and prolonged storage of red cells are associated with increased adverse events. Chen, J., Biller, E., Losos, M., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Transfusion of red blood cells in venoarterial extracorporeal membrane oxygenation: A multicenter retrospective observational cohort study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

A value-based approach to optimize red blood cell transfusion in patients receiving extracorporeal membrane oxygenation. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Predictors of red blood cell transfusion and its association with prognosis in patients undergoing extracorporeal membrane oxygenation. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Red blood cell transfusion volume and mortality among patients receiving extracorporeal membrane oxygenation. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

RBC Transfusion Practice in Pediatric Extracorporeal Membrane Oxygenation Support. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

RBC Transfusion in Venovenous Extracorporeal Membrane Oxygenation: A Multicenter Cohort Study. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

In vitro lysis and acute transfusion reactions with hemolysis caused by inappropriate storage of canine red blood cell products. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Safe application of a restrictive transfusion protocol in moderate-risk patients undergoing cardiac operations. [2014]

9. England pubmed.ncbi.nlm.nih.gov

Irradiation and prolonged storage of red cells are associated with increased adverse events. [2019]