Yeah, it's so wonderful to be here with Mela and Ravi and Lynn and to be able to talk, have the opportunity to talk about multiple ongoing pediatric clinical studies in ECMO. And so today, as Matt said, I'm going to talk a little bit about just the timing of ECMO cannulation and how that might modify outcomes. And I just want to acknowledge, of course, like most of us here today definitely believe in the potential benefits of ECMO, have some roles here, as well as I'm studying this within our own study. And so I think as we sit at the bedside, we often think about when should we initiate ECMO for respiratory failure. And then I think we often think, did we do it too early or did we do it too late? Occasionally, we probably pat ourselves on the back and think we did it just in time. But I think as I think about this, I think that actually wherever that bend point is probably changes over time. And what I mean by that is really not just in the specific patient, because what I hope that ECMO is able to do is bend that critical illness, that exposure to critical illness by providing life support technology that delivers oxygen and blood to our tissues as we need. However, ECMO obviously also comes with negative consequences that are associated with it. And those probably also shift over time as we hone our anticoagulation strategies and our technology. And so the things that I'll talk about today, which are actually relatively older studies, maybe have somewhat waning relevance to our current moment. And so I think one of the ways that we certainly all talk about are we going early or not is early as a measure of ventilator exposure. And this is now more than a decade old, but I still think is equally as relevant. And Luke Zabrocki, but Ravi, who's going to speak later, was a part of this study when it was published. 58% roughly is kind of the number that we see for that first kind of 13 days. But then once you get to 14 days and over, that we do start to see this dip. And that's probably not just ventilator exposure. That probably has something to do with the fact that those are different kinds of patients that are going on ECMO there. But when we talk about ARDS, and we're talking about oxygenation, which is another measure of just how sick we are before we're going on ECMO, what we're talking about typically in ECMO is an OIF40, which is far beyond where we are even classifying ARDS. But these studies, again, looking back into our past, in the 90s, neonatologists decided to look at, in a randomized way, granted a small study, whether earlier ECMO might have been better or different. And they chose an OIF25 to 40 versus more than 40, that same demarcation point that was used in the UK-published neonatal trial that we'll talk about a little bit later. They didn't see any statistical benefits, and they didn't see any statistical harms either in terms of what it meant in terms of mental developmental index, which is just a measure of their neurodevelopmental outcome used year to year. I think that regardless, when you're talking about what's too early and too late in ECMO, it's really hard if you're not doing it in a clinical trial. I say that while also acknowledging that the study that we're conducting is an observational mechanism, and I'll try and draw some reasons why that might be appropriate. But the research populations looked at here, the neonatal and the adult EOLIA trials, had similar kind of definitions of oxygenation failure, PF ratios of less than 50 or 80 for adults, or OIs greater than 40. Similar kind of time frames for exposure to ventilation, obviously very different age ranges. That UK neonatal study, which was done in quite a different era of medicine and with different ECMO circuitry and anticoagulation that maybe changed the risk profile, definitely showed a pretty substantial impact in terms of its outcomes. Whereas the EOLIA trial, while I think has often been interpreted by at least folks who think about ECMO on a regular basis as potentially demonstrating some positive outcomes, didn't reach that statistical significance point as related to unanticipated crossover to the ECMO study. But within each of these, they did these kind of post hoc analyses of looking at different groups within them do better or worse. And what they showed in that UK neonatal trial is that if you look from the enrollment criteria of an OI or 40 to 60 versus greater than 60, that those kids who are less sick going on ECMO seem to have a more benefit of ECMO. And in EOLIA, again, granted, lots of grains of salt here because it wasn't a positive clinical trial necessarily. If you look at the PF ratio between the median, which was 66, up to 80, that lesser disease, in terms of hypoxemia, that's also where it seemed to benefit ECMO more as well. So maybe earlier is better. But maybe if we're delaying ECMO, maybe we're reducing unnecessary exposure to potential associated complications. And I think here, what I want to point out, both in terms of the frequency of these complications is also the disparity in terms of what our adult colleagues experience. Of course, that's multifactorial. But we're talking about, if we think of things like intracranial hemorrhage, many folds different, which brings me to ASCEND. And so I've said that I think that these studies really need to be done in an assigned way, in a clinical trial setting. We didn't feel like we could do that within pediatric ARDS and ECMO. But we did think we could take advantage of an ongoing clinical trial, the prospect clinical trial, that set an externality that said, hey, here's a protocol for how to treat pediatric ARDS as part of that protocol. Go on to ECMO support only after you've failed this protocol, which happened in terms of observing what people have done in usual practice, to be a little bit at worse OIs than what we experienced folks do in natural practice. And of course, all of this work is team science. Our team is definitely, every member is hugely necessary to our ability to move forward, but none more than our folks who are at the ground helping us execute it day to day, Kelly and Mary. And so I think that the critical questions that we were hoping to address in ASCEND were, what is the functioning and quality of life of children one year after ECMO support for pediatric ARDS? So really similar to some of the things that Mela is doing in BEAM, but focusing on a population here in ARDS where we have quite a paucity, I think, of some of the ECMO outcome data. And when should ECMO be initiated to preserve life while potentially avoiding some of those consequential adverse effects? And so we have two aims, which are similar to those things I've just said before. One is just looking at what those differences are in functional status and health-related quality of life. And then one is this comparative aim, comparing those similarly sick children who are enrolled in PROSPECT versus who are enrolled in ASCEND through usual care, and looking at that 90-day mortality as well as one-year functional status and health-related quality of life. I think one of the things that ASCEND hopefully is doing reasonably well is taking advantage of some of the efficiencies. And so the fact that all of the folks who are participating are existent within the ELSO registry, and so we don't ask for any of that data that's already input there. We just rely on it and then addend that registry with additional information that was necessary to capture what's being captured in PROSPECT. And then we centralized all of that follow-up work so that we can make sure, just like was done in BEAM, that we have a consistent approach to that follow-up. Our population of interest is, again, just children with ARDS, mirroring mostly what's done in PROSPECT, 14 days to 20 years. Pre-ECMO ventilation is going to be different here, but we go out to 10 days. Respiratory ECMO support, moderate pediatric ARDS or worse, bilateral lung disease, and absent many of the exclusion diagnoses, which I won't go over here, but I'm happy to address. What we'll end up with here, actually, is for Aim 1, that kind of just looking at what happens cohort, we'll use every patient that was enrolled into ASCEND. For Aim 2, this is our comparative aim. We'll use those patients that were enrolled in PROSPECT as well as patients who are enrolled in ASCEND. And for that short term, that 90-day mortality, we'll use all patients in PROSPECT as potential candidates. For that longer-term outcome, though, so PROSPECT doesn't follow up patients that are enrolled outside of the United States, in ASCEND we will, but we're only going to match patients that are speaking English and Spanish just to try and make sure that we have comparable approaches there. We recognize that ECMO is done incredibly heterogeneously across our centers, and so we do match for propensity that a hospital would have participated in PROSPECT. This is a way of kind of getting at, hopefully these are similar kinds of centers that we're drawing patients from, and then we also match at a patient level in terms of the likelihood that they might have received usual care. The hospital characteristics get at things that we think are probably important, so average ECMO mortality, volume, some of the adverse event rates, as well as strategies for putting on and maintaining patients on ECMO, and then patient characteristics really. A lot of the things that maybe help us think about how we think our patients might do or what maybe pushed us towards going on ECMO in the first place, as well as some of their treatment characteristics in case PROSPECT demonstrates that a particular arm was more beneficial than another, that we have that as a aspect. And so we, like BEAM, certainly got the opportunity to encounter rolling out a study at the outset of a pandemic, which was lots of fun. And so differently, perhaps, is that we learned during the COVID pandemic is that masking certainly helped to prevent some of our pediatric patients from developing ARDS or other viral syndromes, and so we did have also a slow period as a result of just exposure. But we currently have 94 sites open to enrollment, 270 patients enrolled, and 76 sites that have enrolled some patients. We had to re-imagine our enrollment target, but once we've done that, we've stayed on target. Haven't quite had that catch-up that BEAM has had, but we're happy to be where we are. And then we're really grateful to the families, just as was said before. They all universally just say that their thank you for the care that they receive, grateful for the care they receive in your centers, and because of that are really grateful to participate and give back. And so that's a reflection on the care that's delivered from the folks that are in this room, and then really grateful to all of our centers that make this possible. So thank you.

ECMO

pediatric clinical studies

respiratory failure

ARDS

ELSO registry