ECMO Hemostatic Transfusions in Children (ECSTATIC)

Weill Medical College of Cornell University, University of Utah, National Heart, Lung, and Blood Institute (NHLBI), Columbia University, Virginia Commonwealth University, University of Rochester, Children's Hospital and Health System Foundation, Wisconsin, Duke University, Johns Hopkins All Children's Hospital, University of Iowa, Emory University, Schneider Medical Children's Center, Israel

Critically ill children supported by extracorporeal membrane oxygenation (ECMO) receive large volumes of prophylactic platelet transfusions to prevent bleeding. However, mounting evidence has demonstrated significant morbidity and mortality associated with these transfusions. The ECmo hemoSTAtic Transfusions In Children (ECSTATIC) pilot trial will test two different platelet transfusion strategies, based on two different platelet counts thresholds, one high (higher platelet transfusion strategy) and one low (lower platelet transfusion strategy). The pilot will gather the necessary information to perform a full trial which will provide a better understanding of how to transfuse platelets to children supported by ECMO and reduce the associated morbidity.

Due to coagulopathy and thrombocytopenia induced by hemodilution and the extracorporeal circuit itself, children supported by extracorporeal membrane oxygenation (ECMO) are at significant risk of bleeding. In order to prevent bleeding, pediatric intensivists often prescribe prophylactic platelet transfusions. However, in observational studies, prophylactic platelet transfusions to children on ECMO have been independently associated with increased thrombosis, mortality, and paradoxically, increased bleeding. Guidelines to direct platelet transfusions in this patient population are limited by the lack of evidence and therefore based on expert opinion alone. Given the significant associated risks, it is crucial to provide evidence to guide clinicians. The ECSTATIC pilot, a randomized controlled trial endorsed by BloodNet, PediECMO, the Extracorporeal Life Support Organization (ELSO), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI), will be conducted in ten sites (9 in the US and 1 in Israel). The investigators will enroll an anticipated 50 consecutive critically ill children (0 to <18 years of age), admitted to a participating pediatric, neonatal, or cardiac intensive care unit (PICU/NICU/CICU), on ECMO, and who have either no bleeding or minimal bleeding. Non-bleeding children 0 to less than 18 years of age will be randomized 1:1 to either a platelet transfusion threshold of 90 x10e9/L (higher platelet transfusion strategy) or 50 x10e9/L (lower platelet transfusion strategy). Participants will be followed until progression to severe bleeding and/or severe thrombosis, decannulation from ECMO, or reach 21 days. In this pilot, the investigators will test the separation between the lower and higher transfusion strategies. The primary outcomes will be the separation between pre-transfusion platelet counts, and the total platelet dose (in mL/kg/run). Secondary outcomes will be feasibility of patient enrollment and ability for an adjudication committee to determine the severity of bleeding and thrombotic outcomes. The purpose of this pilot study is to determine the feasibility of the transfusion strategies, intervention parameters, subject availability, and other information regarding outcomes that are essential to complete the design of a large randomized controlled trial. The large future trial will evaluate the efficacy of the two transfusion strategies, in terms of progression to severe bleeding and/or severe thrombosis. To adequately calculate the sample size, the investigators need to know the difference between the pre-transfusion platelet counts, the screening and inclusion rates, the proportion of patients who are consented within the first 24 hours after cannulation, the proportion of transfusions that are compliant with each arm's strategy, and the number of temporary suspensions. The proposed pilot trial is innovative in that it is focused on children supported by ECMO, a population in whom transfusion strategies have never been tested previously; it involves the largest separation between the two arms of any platelet transfusion trial conducted in the past; and it involves two newly developed definitions of bleeding and thrombosis particularly applicable to children supported by ECMO. The pilot trial will provide necessary and sufficient information to proceed with the definitive ECSTATIC Randomized Controlled Trial (RCT) to evaluate the impact of a lower prophylactic platelet transfusion threshold on the clinical outcomes in children on ECMO. ECSTATIC has the potential to optimize efficacy, to reduce platelet transfusion exposure and to decrease mortality and morbidity of these extremely ill infants and children.

Extracorporeal Membrane Oxygenation Complication, Hemorrhage, Thromboembolism, Transfusion Adverse Reaction

Subjects will be randomized in a 1:1 ratio to either arm. Subjects will be stratified by type of extracorporeal membrane oxygenation (ECMO) support (Veno-Arterial vs Veno-Venous), by site, and by age (≤28 days vs >28 days).

Investigators and Outcome Assessors will be masked to the intervention, but the clinical team at the bedside will need to know the allocation to be able to prescribe platelet transfusion according to the randomized threshold.

Participants will be transfused according to the assigned threshold for each group, with a transfusion dose of 10 mL/kg, up to one adult unit.

The total dose (in ml/kg/run) will be computed by the research team, by dividing the total platelet transfusion volume by the patient's weight at admission.

Feasibility assessed by the number of informed consents signed in the first 24 hours post cannulation.

Feasibility will be assessed by the number of participants that sign consent within the first 24 hours after ECMO cannulation.

The proportion of transfusions that were given for platelet counts below the arm threshold will be computed to assess compliance.

The investigators will collect the proportion of participants who progress to a composite outcome of severe bleeding and/or severe thrombosis. The outcome will be adjudicated by an external review committee, blinded to the allocation arm.

Inclusion Criteria: Critically ill children (0 to <18 years of age) Admitted to a participating pediatric, neonatal, or cardiac intensive care unite (PICU/NICU/CICU) On extracorporeal Membrane Oxygenation (ECMO) Who have either no bleeding or minimal bleeding, within 24 hours of cannulation. Minimal bleeding is defined as: streaks of blood in endotracheal tube or during suctioning only streaks of blood in nasogastric tube macroscopic hematuria subcutaneous bleeding (including hematoma and petechiae) < 5 cm in diameter quantifiable bleeding < 1mL/kg/hr (e.g., chest tube) bloody dressings required to be changed no more often than each 6hr, or weighing no more than 1mL/kg/hr if weighed, due to slow saturation Exclusion Criteria: Post-conception age < 37 weeks at time of screening Underlying oncologic diagnosis (defined as receipt of chemotherapy or radiation in the last six months) or recipient of bone marrow transplant in the last year Congenital bleeding disorder Pregnant or admitted post-partum Decision to withdraw or withhold some critical care or interventions Known objection to blood transfusions On ECMO for > 24 hours at time of enrollment

The proposed research will include data from 50 critically ill subjects who are on extracorporeal life support (ECMO) enrolled at ten participating sites. The final dataset will include demographic and medical information, as well as laboratory data. After our proposed research is complete, each participating site will destroy the key linking this data to protected health information (PHI). Thus, the data will then be completely de-identified. However, we believe that there remains the possibility of deductive disclosure of subjects with unusual characteristics, considering the variety of rare conditions leading to ECMO.

We reserve the right to embargo the data for as long as two years after completion of the project (i.e. fall 2027) in order to give our research team an opportunity to publish additional observations from the data.

We will make the data and associated documentation available to users only under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying the data after analyses are completed.