Thank you so much for the introduction and the enthusiastic welcome. So thank you. I hope I live up to it. And thank you for the invitation to talk about the use of biomarkers to better understand neurologic injury in pediatric ECMO, and specifically to talk about where we stand with multi-center study of children on ECMO support entitled Biomarkers of Brain Injury in Children on ECMO. These are my disclosures, and none of them is commercial in nature. And to start, acute neurologic injury occurs in 15 to 36% of children on ECMO in the form of hypoxic ischemic injury, intracranial hemorrhage, and ischemic stroke. Cortical and electrographic seizures occur in 10% to 23% of patients. And brain death is typically listed in this category primarily because it's reported as such in the ELSO registry, and it occurs in 0.2% to 10% of patients. That range varies based on the age of patients, and also based on the primary indication for ECMO. Acute neurological injury is not trivial. If it occurs, mortality increases by 89%, and 10% to 50% of survivors have poor neurologic outcomes. It's also notable that even before the start of the ECMO course, the critical illness landing children onto ECMO, more than a third of patients have pre-existing neurologic disease or disability, and 40% to 42% have cardiac arrest preceding ECMO. So these patients start with a background of hypoxemia, hypotension, acidosis, impaired cerebrovascular autoregulation. And to that, we add the ECMO circuitry that enhances the inflammatory response, adds the prothrombotic surfaces of the circuit, altered blood flow. To that, we add anticoagulation to avoid clot in the circuit. There's further impaired cerebrovascular autoregulation. And in most neonates, infants, and small children, the right common carotid artery and the right IJ are ligated for cannulation. So the continuum of care starts way before the ECMO period with critical illness, where multiple risk factors have been identified, as noted before. The period that we primarily focus on, in general, in the pediatric ICU, is the on-ECMO period, when additional risk factors, also as mentioned before, land us to very closely neuromonitor these patients. If possible, we try to keep them awake. And that's easier at the extremes of ages, neonates who can't really turn and who can be easily soothed. And older school-age children and adolescents, where we can communicate and we can all understand each other and be compliant with sitting still. Otherwise, for the middle ages, there are toddlers and small school-age children. And for all patients who remain encephalopathic after cardiac arrest or due to sepsis, we employ multimodal neuromonitoring methodologies using continuous EEG, cerebral oximetry, serocranial ultrasounds, and so on. And all of these will guide neuroprotective interventions, including cooling for both asphyxia, PCAC bundles, post-cardiac arrest. And that journey doesn't stop there. In the immediate post-ECMO period, there is a period of acute rehabilitation and organ function recovery that we all participate in. And of course, after discharge from the hospital, longitudinal follow-up with ensuring services that are needed, such as physical therapy, occupational therapy, SLP, etc., are provided to these patients. So it is with that background that we started the BEAM study, now four years ago. This is a five-year NIDS-funded study that we're conducting at 11 centers that focuses on neuroimaging and also on plasma blood-based brain injury biomarkers. Brain injury biomarkers have been employed in critical care in traumatic brain injury, inflicted TBI, cardiac arrest, congenital heart defects, etc. And our group and a couple of others, primarily in Europe, are focused on the use of brain injury biomarkers and validation of these biomarkers in the ECMO population. From top to bottom, there are some examples of neuronal injury, astrocytic injury, axonal injury, and neuroinflammation. The hypotheses of the study are that neurologic injury with cell death and blood-brain barrier disruption leads to release of low-abundance but highly specific brain proteins into plasma, and that hypoxic ischemic injury pre-ECMO followed by reperfusion upon ECMO cannulation and the exacerbation of critical illness-related global inflammation by exposure to the ECMO circuit result in neuroinflammation that contributes to secondary brain injury during the ECMO course and potentially affects long-term neurodevelopmental outcomes. The overarching goals of the study are to develop simple, minimally invasive, objective, repeatable, and generalizable brain injury measures for early diagnosis of neurologic injury and classification of outcomes using plasma brain injury and imaging biomarkers, to investigate neuroinflammation as a potential mechanism for neurologic injury and for future neurologic disability, and also overall to obtain accurate, high-quality, multi-assigned data on the epidemiology and severity of neurologic injury and outcomes after ECMO support. Inclusion criteria are all children between the ages of two days and less than 18 years who are cannulated on ECMO and admitted to a PIC or PCICU in a participating institution. And exclusion criteria include ECMO cannulation at an outside institution with transport to a study site more than 24 hours after cannulation, any limitation in care, inability to speak or understand English or Spanish, and that's related to the questionnaires that we use that are validated in these two languages, and pregnancy. The primary outcome is recorded at 18 months after ECMO is survival with a score of 85 and above on the Vineland Adaptive Behavioral Scale. And just for orientation, 100 is the population mean, and the standard deviation is 15 points, so this is above minus one standard deviation below the population mean. And secondary outcomes evaluate functional status, health-related quality of life, and health care services utilization. So the study procedures include consent within 48 hours from ECMO cannulation with administration of the questionnaires mentioned earlier to obtain a pre-admission status assessment. During the ECMO course, we collect lots and lots of clinical data and adverse events that occur on a daily basis during the ECMO course. And we collect blood, urine, and ultrafiltrate samples every day for the first five days on ECMO, and then every third day thereafter, if still on support. After decannulation, within six weeks, if a brain MRI is obtained, we add research sequences, and then follow-up is done at 18 months post-ECMO decannulation, administering the same questionnaires that we administered at baseline, and all outcome evaluation is done centrally from our colleagues at the Kennedy Krieger Institute. We certainly hit a snag with the pandemic. This study was funded right before the pandemic hit. So you can see here on the bottom, I don't think I can point to this, or maybe I can, that at the parent site, the central site at Johns Hopkins, we were able to obtain RB approval, and then as the pandemic hit, everything kind of lagged behind. And that explains this long period here, where we enrolled one patient, and then we had to wait for a year for all clinical research activities to restart. But once we were able to restart in the fall of 2020, we got right back on track, and we're very excited that we completed enrollment in the fall of 2023, so within three years as planned. And we are now following the last several participants to hospital discharge. As you all know, a lot of ECMO patients do stay in the hospital for weeks and sometimes months, and then we will complete 18-month follow-up only in 2025, so still some ways to go. As is always the case, anything that is done in a multi-center fashion in clinical research takes a huge village, and we couldn't be more grateful to all of our participating sites, the site PIs, and all the research coordinators, and of course, all the families that under these very, very stressful conditions very generously agreed to participate in research studies. So I'll stop here. Thank you so much. Thank you to Polisi, PDECMA, and PNCRG for supporting this study, and of course, our funders at the NINDS. And we'll answer questions at the end. Thank you.

biomarkers

ECMO

neuroimaging

neuroinflammation

neurodevelopmental outcomes