Thanks, Dr. Friedman and Dr. Alexander, and good afternoon, everybody. I am going to just really talk a little bit about the scientific basis for our trial design and to also use the slides that was really similar to what Dr. Sleeper just showed you. So these are my disclosures. We already said that ECMO patients undergo frequent red cell transfusions. We need hemoglobin and ECMO to carry oxygen to tissues. But oxygen delivery is a function of hemoglobin, and that's in the equation. But it's not a linear relationship, such that as hematocrit increases, it's not that oxygen delivery might not increase in a linear fashion. And that may be related to issues such as viscosity of blood as your hematocrit rises that reduce tissue oxygen delivery. The optimal hematocrit, as previously said, at which oxygen delivery is optimized has never been determined. Most sites use 30% to 40% in their ECMO circuits as a way of delivering oxygen to tissues. And most of the transfusions provided for patients in ECMO is based on this threshold. So if you get below a certain threshold number that your site has, then we would transfuse the patient. And here is the current RBC transfusion practice, and this comes from the Capcom network sites. And as you can see, the majority of ECMO centers transfuse patients between 35% and 40% hematocrit. And does it actually provide you patient benefit? And this is some really important work done by the group from Children's Hospital in Arkansas to show that the majority of patients get transfused at a time when their oxygen delivery to the tissue is already optimal. So we're really transfusing a number rather than providing patient benefit. This is the green parentheses here shows where normal tissue oxygen delivery and the number of transfusions that happen really all fall within a mixed venous saturation that's really within normal. So you're not really providing transfusion to improve oxygen delivery to tissues, but you're largely treating a number. Similarly, your hematocrit already at the time of transfusion is high. And therefore, there's just really no benefit to the majority of blood that you provide for ECMO patients. The issue with this is that the transfusion volume is associated with increased mortality. So the more blood exposure, the more likely that your ECMO patient's going to face mortality. This again is from Dr. Muszynski's study from the Capcom network. Total volume transfused in this 500 patients is about 30 mLs per kilogram. And she showed that there was a 10% increase in mortality for every 10 mLs per kilogram per day of ECMO blood transfused. So really, there's a modifiable reason as to how we might improve ECMO outcomes in our patient population. So as Dr. Sleeper said, there's a trade-off between maintaining higher hemoglobin hematocrit just because we imagine that it's in the equation and we might provide more tissue oxygen delivery, but we're really not, and then ECMO outcomes. And the question we asked was, would reducing unnecessary blood transfusion improve ECMO outcomes? And whether an indication-based approach, where you're actually providing a blood transfusion for indications such as bleeding or lactic acidosis, suggesting reduced tissue oxygen delivery, would that actually be a better way of providing transfusions to patients rather than just treating a number? So that is the question that we asked as part of the title trial. Just before we talk a little bit about justification for the endpoints, I want to just point out two things. One is that patients going on ECMO die because of poor prognosis from their primary illness that landed them on ECMO, or there's no recovery from their cardiorespiratory failure that's persistent of end-organ injury, or they acquire new injury as part of ECMO. And if you actually look at organ function across the course of ECMO, patients who tend to survive tend to recover their organs, and patients who tend to die actually have persistence of their organ dysfunction or develop new organ dysfunction. And one could use this change in organ function scope as a way of looking at how effectiveness of ECMO in our patient population, and we certainly use that as part of our trial endpoint. Another area of concern is a restrictive transfusion policy. Is that going to affect long-term outcomes such as neurodevelopment in our patient population? And this study comes from my center, where the majority of work on what hematocrit strategies should be for patients undergoing cardiac surgery were determined. And this is from the hematocrit trials. There were two of them. One compared hematocrit of 20 versus 30, and looked at one-year neurodevelopmental outcomes in that patient population. The second trial compared 25 versus 35. And what they showed was in the 20 to 30 comparison that the neurodevelopmental outcomes were poor at one year of age for patients who were maintained on cardiopulmonary bypasses, low-flow bypass. So it's an effect of dilution of blood when you go on bypass, and if your hematocrit was maintained around the 20s, then you had poor neurodevelopmental outcomes. And there was no difference between 25 and 35. And Dr. Whippy, who was a statistician, put both those trials together and determined that neurodevelopmental outcomes are poor if your hematocrit threshold is less than 23.5. That was kind of the cutoff point. And if you raise hematocrit beyond that, there's just really no benefit to neurodevelopment. So there's perhaps a threshold hemoglobin hematocrit that determines neurodevelopment as well. And so with these two things in background, we constructed our trial. And Dr. Sleeper showed you this. So we're comparing center-specific threshold, which is a hematocrit of 27 to 35 across the network sites. And then we are comparing that to an indication-based approach to transfusion, where we're going to transfuse patients for moderate to severe bleeding or reduced tissue oxygen delivery, or a lower hematocrit threshold of 25 or hemoglobin of 8. You saw this already from Dr. Sleeper's slides. So we are testing to say our hypothesis is that we would see less organ injury and better neurodevelopment in the restrictive arm compared to center-specific threshold arm. Our endpoint is the change in organ function across the course of ACMO. And we're using the pediatric SOFA score as an objective measure of organ function. And we are comparing a change in organ function across that. And this is just validation to show the change in organ functions actually discriminates mortality in ACMO patients. So that's our endpoint. And our second long-term endpoint, really, is standardized neurodevelopmental testing, which is going to be an in-person testing. We're going to study children less than six years of age supported with venoarterial ACMO. And it has to be the first ACMO doing index hospitalization. We're excluding patients who had multiple episodes of ACMO during their hospitalization. Again, you saw this. So we are randomizing ACMO patients across 20 ACMO sites. Our goal is to get to 228. And as you saw, we were actually 53 as of yesterday. So we're really grateful to our site PIs for really pushing this concept forward. It's not easy to approach a family at a time of distress to get consent to participate in a randomized trial in ACMO. So this is a real huge undertaking. And we're really grateful to our site PIs and our site research coordinators to getting us going. Every trial really requires an oversight. I'm a novice at trial. This is my first exposure to a randomized trial. And we have one of the best steering committee to help us with getting a trial going. And we're really grateful for our sites participating in that. With that, thanks very much. And we are on clinicaltrials.gov if people are interested in looking at a protocol. We're also on ACMOtrial.org, which is our website. And if you use this barcode, it'll take you to the website. And please contact us if you have questions, suggestions, and are interested. Thank you.

ECMO

blood transfusion

hematocrit thresholds

patient outcomes

neurodevelopment