Trial of Indication-Based Transfusion of Red Blood Cells in ECMO

Study Overview
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Brief Summary
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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.

Detailed Description
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Observational studies of children on ECMO have shown an association between large-volume RBC transfusion and mortality. However, the hematocrit (or hemoglobin) level at which optimal tissue oxygen delivery occurs is unknown. TITRE - Trial of Indication-based Transfusion of Red Blood Cells in ECMO, is a prospective, randomized clinical trial to be conducted at 18-20 study sites. The overarching goal of TITRE is to determine whether restricting 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 ECMO support. Aim 1: To test whether children < 6 years of age on ECMO support who are randomized to a strategy of indication-based versus center-specific threshold-based RBC transfusion will have greater improvement in organ function. Aim 2: To test whether survivors among children age < 6 years on ECMO support who are randomized to indication-based compared to center-specific threshold-based RBC transfusion will have better neurodevelopmental outcomes and health-related QOL at one year post-randomization. Key design features include: Randomization stratified by patient age (neonate, <28d vs. non-neonate) and by diagnosis (CHD vs. other diagnosis); and a target sample size of 228 patients. Endpoints will be evaluated during ECMO, at hospital discharge, and at 3, 6, 9, and 12 months. To ensure trial integrity, the primary outcome (pSOFA: Pediatric Sequential Organ Failure Assessment score) will be adjudicated by an independent committee and neurodevelopmental assessments will be blinded.

Official Title
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TITRE: Trial of Indication-Based Transfusion of Red Blood Cells in ECMO

Conditions
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Extracorporeal Membrane Oxygenation, Red Blood Cell Transfusion, Organ Failure, Multiple

Intervention / Treatment
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* Other: Red blood cell transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age < 6 year at ECMO cannulation Veno-arterial (VA) mode of ECMO First ECMO run during the index hospitalization Exclusion Criteria: Gestationally-corrected age < 37 weeks Veno-venous (VV) mode of ECMO Patients initially started on VV-ECMO and then transitioned to VA ECMO ECMO used for procedural support (ECMO deployed and decannulated in procedural area with no ICU ECMO care) ECMO duration expected to be < 48 h Limitation of care or withdrawal of support expected < 48 h after ECMO deployment Congenital bleeding disorders Hemoglobinopathies Primary Residence outside United States or Canada

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 6 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two independent study arms will be used: indication-based red blood cell transfusion strategy vs. a center-specific standard of care hemoglobin/hematocrit threshold-based red blood cell transfusion strategy
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Indication-based red blood cell transfusion strategy<br>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 >3 mmol/L; or c) hemoglobin < 8 g/dL or hematocrit < 25% or, for children with single ventricle heart disease, 5% lower than institutional standard hematocrit threshold for transfusion during ECMO. | Other: Red blood cell transfusion<br>* The intervention is a strategy for when red blood cell transfusion will be administered (see description of Arms). However, volume of RBC transfused in the two arms is not specified by this study. Red blood cell transfusion strategy for ECMO weaning and decannulation is not specified by this study. Red blood cell transfusion after ECMO decannulation is not specified by this study.<br>|
| Other: Center-specific hemoglobin/hematocrit threshold-based red blood cell transfusion strategy<br>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. | Other: Red blood cell transfusion<br>* The intervention is a strategy for when red blood cell transfusion will be administered (see description of Arms). However, volume of RBC transfused in the two arms is not specified by this study. Red blood cell transfusion strategy for ECMO weaning and decannulation is not specified by this study. Red blood cell transfusion after ECMO decannulation is not specified by this study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline-adjusted change in pSOFA (pediatric Sequential Organ Failure Assessment) score | The pSOFA score ranges from 0 (no organ dysfunction) through 24 (severe dysfunction in all 6 organs assessed). If death occurs during ECMO within 30 days, a score of 24 is assigned. | At randomization and at 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) | 
| Bayley Infant Scales of Development, 4th edition (Bayley-4) | Scales for Cognitive, Language (Expressive and Receptive), Motor (Gross and Fine), and Social-Emotional. For ages 16 days to 42 months. Composite score range is 40 to 160. Higher scores indicate better performance. | One year post-randomization (+/- 2 mo) | 
| Wechsler Preschool and Primary Scale of Intelligence (WPPSI - IV) | Index scores include Verbal Comprehension, Visual Spatial, Working Memory, and Full Scale Intelligence Quotient (IQ). Score range is 40 to 160. Higher scores indicate better performance. | One year post-randomization (+/-2 mo) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mixed venous oxygen saturation | Oxygen content of blood that returns to the heart after meeting tissue needs | Daily AM (6 AM - 12 AM), during ECMO (up to 30 days post-randomization, whichever is earlier) | 
| Total volume of blood products administered | Packed RBC and whole blood, cryoprecipitate, plasma, platelets | 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) | 
| Presence vs. absence of hospital-acquired Infection | Nosocomially-acquired infection that is not present or incubating at the time of admission to hospital | 30 days post-randomization (up to time of ECMO decannulation if earlier; varies according to patient) | 
| Daily renal function | Serum creatinine, blood urea nitrogen (BUN) | Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) | 
| Acute kidney injury > stage 2 | Kidney Disease Improving Global Outcomes (KDIGO) definition | 30 days post-randomization (up to time of ECMO decannulation if earlier; varies according to patient) | 
| Presence vs. absence of transfusion-related allergic reactions | Using accepted definition | 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) | 
| Presence vs. absence of transfusion-related acute lung injury (TRALI) | Using accepted definition | 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) | 
| Number of ECMO circuit component replacements | Replacement of oxygenator and/or pump | At 30 days post-randomization | 
| Presence vs. absence of hemolysis | According to plasma hemoglobin values | Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) | 
| All-cause mortality | Death from any cause | 30 days, in-hospital, and 1 year post-randomization | 
| Number of ICU-free days | Minimum value is zero, maximum value is 60 minus ICU length of stay | At 60 days post-randomization | 
| Number of hospital-free days | Minimum value is zero, maximum value is 60 minus hospital length of stay | At 90 days post-randomization | 
| Discharge location | Home vs. rehabilitation facility | At time of hospital discharge (assessed up to 1 year) | 
| Adaptive Behavior Assessment System-3 (ABAS-3) | Composite scores for overall adaptive functioning (General Adaptive Composite, GAC), Conceptual, Social and Practical domains as well as nine subscales. Higher score indicates better behavior. | 1 year post-randomization (+/- 2 mo) | 
| Child Behavior Checklist (CBCL) | Parent-report; child minimum age 1.5 years. Higher score indicates worse behavior. | 1 year post-randomization (+/- 2 mo) | 
| Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) | Parent-report; child minimum age 2.0 years. Higher score indicates better quality of life. | 9 months post-randomization (+/- 1 mo) | 
| Pediatric Quality of Life Inventory Cardiac Module | Parent-report; child minimum age 2.0 years. To be completed for participants with a congenital heart disease diagnosis. Higher score indicates better quality of life. | 9 months post-randomization (+/- 1 mo) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, children, ECMO, transfusion, neurodevelopment, TITRE