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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.
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 22 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 240 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Indication-based red blood cell transfusion strategy | Active Comparator | 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. |
|
| Center-specific hemoglobin/hematocrit threshold-based red blood cell transfusion strategy | Other | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Red blood cell transfusion | Other | 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. |
| 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) |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lynn A. Sleeper, ScD | Boston Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Phoenix Children's Hospital | Phoenix | Arizona | 85016 | United States | ||
| Arkansas Children's Hospital |
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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
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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.
|
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 blood stream Infection | Hospital-acquired blood stream 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) |
| 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 |
| 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) |
| Number of Donor Exposures | Number of Donor Exposures for RBC transfusion | Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) |
| Recannulation for ECMO < 48 hours and < 72 hours after decannulation | No: of patients recannulated for ECMO within 48 hours and 72 hours post-decannulation | From ECMO decannulation hour to 72 hours following ECMO decannulation |
| ECMO duration | ECMO duration in hours: Time period from ECMO cannulation to first successful ECMO decannulation in hours. Time accrued during ECMO for additional ECMO runs (i.e. those cannulated within 36 hours following first decannulation) will be included as total ECMO duration | During Hospitalization: From ECMO cannulation to ECMO decannulation, death, transition to Ventricular Assist Device (VAD) or 365 days post-randomization, whichever is earliest |
| Duration of mechanical ventilation post-randomization | Duration of mechanical ventilation post-randomization in hours: Randomization to first successful extubation from mechanical ventilation hours; for patients with tracheostomy that require mechanical ventilatory support at the time of ICU discharge: time of ICU discharge to compute mechanical ventilation duration. | During Hospitalization: From Randomization to Extubation from Mechanical Ventilation, death, hospital discharge, or 365 days post-randomization, whichever is earliest |
| Occurrence of Seizures | Occurrence of electroencephalographic evidence of seizure prior to hospital discharge or within 90 d post randomization, whichever is earliest | Randomization to Hospital Discharge or 90 days post-randomization, whichever is earliest |
| Stroke or Intracranial Hemorrhage during ECMO | Occurrence of brain infarction, intracranial hemorrhage, or ischemic injury during ECMO (composite) confirmed using head ultrasound and Computed Tomography (CT) during ECMO | Time of ECMO cannulation to ECMO decannulation, death or 30 days post-randomization, whichever occurs first |
| Stroke or Intracranial Hemorrhage prior to Hospital Discharge | Proportion of patients with brain infarction, intracranial hemorrhage, or ischemic injury (composite) confirmed using head ultrasound, CT, or Magnetic Resonance Imaging (MRI) prior to hospital discharge or within 90 d post randomization, whichever is earliest | ECMO cannulation to 90 days post-randomization or hospital discharge, whichever occurs first |
| Pediatric Overall Performance Category (POPC) | Pediatric Overall Performance (POPC; score range 0 to 6; Unit: categories on a scale; value: lower is better) at Hospital Discharge, 3, 6, 9, 12 months post-randomization. | Randomization to study completion (completion of 12 month neurodevelopment assessment) |
| Functional Status Score (FSS) | Functional Status Score (FSS; score range 6 to 30; Unit: numerical value on a scale; lower is better) at hospital discharge, 3, 6, 9, 12 months post-randomization | Randomization to study completion (completion of 12 month neurodevelopment assessment) |
| ICU Length of Stay among survivors during index hospitalization | Duration of hospitalization in the ICU among survivors in days during index hospitalization. For ICU readmissions only the only days in the first 2 ICU readmissions will be included | ICU Admission to ICU discharge, death or 365 post-randomization, whichever occurs first |
| Hospital length of stay among survivors during index hospitalization | Duration of hospitalization among survivors in days during index hospitalization | Hospital Admission to discharge death, or 365 days post-randomization, whichever occurs first |
| Pediatric Cerebral Performance Category (PCPC) | Pediatric Cerebral Performance Category (POPC; score range 0 to 6; Unit: categories on a scale, lower is better) at Hospital Discharge, 3, 6, 9, 12 months post-randomization. | Randomization to study completion (completion of 12 month neurodevelopment assessment) |
| Number of ICU admissions prior to discharge from index hospitalization among survivors | Number of ICU admissions during index hospitalization. ICU admissions are defined as number of ICU admissions following discharge from the first ICU admission. | Index ICU discharge to Hospital discharge or 365 days post-randomization, whichever occurs first |
| Proportion of ECMO days meeting moderate - severe bleeding criteria | Number of days meeting criteria for moderate or severe bleeding during ECMO | Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient) |
| Little Rock |
| Arkansas |
| 72202 |
| United States |
| Children's Hospital Los Angeles | Los Angeles | California | 90027 | United States |
| Lucile Packard Children's Hospital | Palo Alto | California | 94304 | United States |
| Children's Hospital Colorado | Aurora | Colorado | 80045 | United States |
| Children's Healthcare of Atlanta | Atlanta | Georgia | 30322 | United States |
| Lurie Children's Hospital | Chicago | Illinois | 60611 | United States |
| Riley Children's Hospital | Indianapolis | Indiana | 46202 | United States |
| Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
| University of Michigan Medical Center | Ann Arbor | Michigan | 48109 | United States |
| Children's Hospital of Michigan | Detroit | Michigan | 48201 | United States |
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| MUSC Shawn Jenkins Children's Hospital | Charleston | South Carolina | 29425 | United States |
| Monroe Carell Jr. Children's Hospital at Vanderbilt | Nashville | Tennessee | 37232 | United States |
| Children's Health Dallas University of Texas Southwestern | Dallas | Texas | 75235 | United States |
| Texas Children's Hospital - Baylor College of Medicine | Houston | Texas | 77030 | United States |
| Primary Children's Hospital | Salt Lake City | Utah | 84132 | United States |
| Inova Children's Hospital | Falls Church | Virginia | 22042 | United States |
| Seattle Children's Hospital | Seattle | Washington | 98105 | United States |
| The Children's Hospital at Westmead | Westmead | New South Wales | Australia |
| The Hospital for Sick Children | Toronto | Ontario | M5G 1X8 | Canada |
| ID | Term |
|---|---|
| D009102 | Multiple Organ Failure |
| ID | Term |
|---|---|
| D012769 | Shock |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D017707 | Erythrocyte Transfusion |
| ID | Term |
|---|---|
| D016913 | Blood Component Transfusion |
| D001803 | Blood Transfusion |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
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