Trial of Indication-Based Transfusion of Red Blood Cells in ECMO (TITRE)

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.

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.

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

Adjudicators for the primary endpoint (organ failure assessment score) will be blinded to treatment assignment. Specialists for neurodevelopmental assessment of participants will be blinded to treatment assignment. Parents/guardians completing assessment of child behavior, functioning, and health-related quality of life will be blinded to treatment assignment.

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.

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.

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.

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)

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.

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.

30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)

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 up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)

30 days post-randomization (up to time of ECMO decannulation if earlier; varies according to patient)

30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)

30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)

Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)

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.

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.

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