Good afternoon. Thank you to the Society and Dr. Oktober for the ability to present today. I'm going to talk about systemic anticoagulation during pediatric ECMO, looking at efficacy and cost effectiveness at a single institution. I don't have any disclosures pertinent to this presentation. I will discuss off-label use of medications, and I have some pictures at the end that are shown with permission. We know that ECMO typically requires systemic anticoagulation to prevent thrombosis, and non-fractionated heparin has been used traditionally for many, many years, although direct thrombin inhibitor use in pediatric ECMO has been increasing. However, the drug cost for DTIs such as bivalirudin has been reported as potentially prohibitive for some centers, so we aim to look at the efficacy and cost effectiveness of these two classes at a single institution. Two studies that I want to briefly mention beforehand that we thought were very informative for us was the BATE study by Heidi Dalton et al., which was a prospective study looking at factors associated with bleeding and thrombosis in pediatric ECMO. And the important thing, or one of the many important things, was that institutional practice variation remains very high, and that it likely contributes to the bleeding and thrombosis complications seen in ECMO. And a recent survey that was published by Carolyn Osment et al. in 2019 shows that that practice variation continues. However, while most centers are still using heparin, we've moved to anti-TIN-A in terms of monitoring for heparin, and about half the centers are still replacing with antithrombin 3. However, some centers have moved to a primary use of bivalirudin. So I'm going to briefly compare the anticoagulants. This is in no way meant to be very thorough, but just to give some brief understanding of why we're even talking about alternative anticoagulants. So infractionate heparin is an indirect thrombin inhibitor. It requires an antithrombin. It doesn't inhibit clot-bound thrombin. There can be some increase in platelet aggregation. But we've been using it for 50 years on ECMO, and it's almost exclusively used on bypass. We have a lot of experience with it, as opposed to the direct thrombin inhibitors. And I will talk specifically about bivalirudin. By the name, it's a direct thrombin inhibitor. It doesn't require cofactors. It can inhibit clot-bound fibrin. It can decrease thrombin-mediated platelet aggregation. But we haven't been using it that long. So the adult experience, mostly in PCI, was in the 1990s is when it started. And the first U.S. use in pediatrics was in 2007, and that was with leperrudin, which we don't use anymore. And really, we have been using it a lot more in the cardiac world for peds in the VAD population, and had tremendous success. I am not going over this. Bob is here, if you'd like to come up and go over it more. But my only mention is that regardless of what we're testing, which regardless of what anticoagulant we're using, we're doing a very small snapshot of the whole system. So either where we're looking at anti-10A or we're looking at the direct thrombin inhibitors. And we're not talking about the involvement and the interaction of activated platelets and endothelial cells, excuse me, or VWF and factor VIII, which is getting a lot more look at in the mechanical support world. So direct thrombin inhibitors mostly are looked at through heparinized PTT or PTT monitoring. There are other things that I won't discuss at our institution we're using heparinized PTT. So we looked at a retrospective cohort of our patients requiring pediatric ECMO from June 2020 to June 2022. And this was at the time that we initiated a specific ECMO anticoagulation consult service. And really we did that because we were trying to get away from this variability. There's so many different ways to look at things. And we don't have a ton of experience with doing it. And so we created this service. And that was meant to reduce or try to reduce this variability, hopefully to improve safety. And those recent ELSO guidelines do recommend involving providers with expertise in this area. Regarding our methods for infractured heparin, patients with recent cardiac surgery got 10 units per kilo per hour when the bleeding had slowed down. And then otherwise it was based on age. And there was a maximum based on weight. The target anticoagulation assays we used were anti-10A, although based on the consult service we could sort of change. Some patients were more on the 0.3 side. Some patients were more on the 0.7 side, which we were based on intensity goals. We did monitor ACT, but only to have that as a baseline in terms of emergencies. We did not do that to titrate medications. We monitored anti-10A every four to six hours until too therapeutic. Then every 12 to 24 we'd monitor an antithrombin once daily because we do use it. And I will go over that in a moment. And again, ACT levels just to provide baselines. Regarding the DTI specifically, I'll just mention bivalirudin because it was the one we most predominantly used. Different doses depending on your renal function or clinical concern for bleeding. Following heparinized PTT after titrations, and then again trying to get to that goal of 12 to 24 hours. And the target anticoagulation was based on an individualized nomogram through our consult service based on a baseline heparinized PTT. In terms of transfusion practices on infraction and heparin at our institution, we were repleting with antithrombin through a continuous infusion to maintain anti-3 activities based on the age of the patient. We did not administer that on DTI. And then transfusion of other blood products were based on clinical concern and not specific numbers. So functional, more functional assessments. Regarding the results, 44 patients required ECMO for 47 runs. The vast majority of those were VA ECMO. Three patients had a second remote run. 11% were eCPR. The median patient age was 3.7 years. 40% of the group were involved neonates. Median weight was 4 kilos, but we did have one patient who was as high as 131 kilos with a median BSA of 0.6. 61% of our patients had congenital heart disease. At our institution, you can have ECMO in one of three locations. So the PCICU, the PICU, or the NICU. The consult service follows patients no matter where they are. And I'll just highlight the highest percentage, which is 38% were patients that had congenital heart disease and cardiogenic shock. Some were post-op and some were medical. And then because of the era, COVID was in this cohort. So five of them, or 13%, had either MIS-C or myocarditis. In terms of the results, infractionated heparin was the primary anticoagulant in 49% of the runs. Over 40% of those patients, excuse me, were transitioned due to inadequate anticoagulation goals or development of circuit thrombosis. And the conversion to the DTI occurred on median ECMO day five. The direct thrombin inhibitors were used in 40% as a primary anticoagulant. And any use of DTI then ultimately became 64%. The most common DTI was bivalirudin with argatrabin used in three cases. Five of the patients were not anticoagulated due to persistent bleeding. And those were runs that were quite short. Regarding additional results, the median duration of ECMO was about twice in the DTI group with one patient being on for 50 days. The median mean time to therapeutic range in the DTI group was also significantly less at five hours. The vast majority of them were therapeutic by the first HEPI-TT assessment. The mean therapeutic dose, if you can see, in unfreshly heparin is actually not that high. So a lot of these thrombosis things were happening on relatively lower doses of heparin and the direct thrombin inhibitors, although it started at 0.6, the peaks ended up being 1.39. In terms of cost, which is another area we were looking at, you cannot get away from the fact that heparin is extremely cheap and it doesn't really matter what size you are. When you're on a direct thrombin inhibitor, this price does go up as you get bigger. But what becomes the cost is any additional things. Like if you're using antithrombin, of course that becomes expensive because we used it based on a continuous infusion at a very fixed rate. The cost is the same no matter how big you are. And really the biggest cost comes from the labs. So the lab assessment on monitoring your antithrombin 3 was $208 at our institution. Obviously that is not being monitored on by Valirudin. Antitin A is $248 if you're assessing it twice a day. So $124 for each time you're assessing it. And then I still put the PTT cost because even though we were monitoring antitin A, we're still following their coagulation system. So we still followed PTT. So I put $50, which is the cost of a PTT at our institution, heparinized PTT is the same cost. So if you flip over to the bivalve group, then you see that the mean daily cost, depending on how many times you are checking it, runs between 100 to 200. So overall, the total US cost is about $1,300 using heparin and then some variability based on weight for the direct hormone inhibitor group, but significantly lower. In terms of thrombosis and bleeding, on fractionated heparin as the primary anticoagulant five of six of those thrombosis occurred. All of those were therapeutic. There was one stroke. That patient ultimately was changed to bivalirudin, did not have any other circuit related clots or patient related issues. CNS bleeding occurred in three out of four patients. That fourth patient, as you can see, they were not in the bivalve group, was a patient who was post-bypass, who on fractionated heparin was used in the operating room, but no anticoagulation post-op. In terms of circuit related thrombosis for bival, there was one patient in that group, but that patient actually was not therapeutic at the time. There were no stroke or CNS bleeding. So 13% of runs requiring circuit related thromboses occurred and the vast majority of those, 83% occurred on therapeutic heparin. 11% had CNS thrombosis or bleeding and all those patients were in primary on fractionated heparin use. And they actually occurred more early in runs as opposed to the later. We often in cardiac world talk about that day 14 of ECMO, but these patients all happened very early. Additional results looking at transfusions. So platelet transfusions decreased by 58%. I wanted to look at both the addition of the consult service because that's a different thing that not everybody has and also the comparing the drug. So I split it out here, 58% with the consult service, 41% comparing the two different anticoagulants. In terms of PRBC transfusions, we are going to delve into a little bit more because there's actually a signal for an overall decrease in transfusions. So I'm not sure how much that is related to the consult service or just a general advancement in ICU care and thinking about we can potentially use lower thresholds for transfusion. The survival to ECMO decamination was 72%, 92% in the DTI and 55% in the runs with primary heparin. In terms of the limitations, this of course was a retrospective review. Although some of the data was collected, actually a lot of the data was collected in real time via RedCap by our perfusion team. We do have the consult service and now we've also instituted a monthly review of all our patients. It's hard to sort of tease out underlying conditions and some of these things, especially like CNS complications and the reproducibility is really important because there was a significant learning curve and obviously there may be different costs at different institutions. In conclusion, DTI use in pediatric ECMO was efficacious, especially for long runs. I'm sorry I didn't show you that picture that I showed on that slide was the oxygenator from 50 days, which was a single oxygenator run. Directed by our consult service, rapid time to therapeutic range and cost effectiveness. And while heparin is extremely inexpensive and I'm not saying it's not appropriate for many places, there are other considerations such as lab costs to consider. So our future directions, I won't go into this in detail, but we are looking at a number of things related to more cost and blood transfusion exposure. And we just finished looking at our CRT filter life for patients that had renal failure and the filter life is significantly longer on direct time inhibitors. So we actually use it exclusively for all renal replacement therapy in our institution now. So I'd like to thank the study team, which is many people. It's hard to get them all together for one picture. So that's why you have little tidbits here. And this is why we do it, of course, for all of our patients. So thank you so much again.

systemic anticoagulation

pediatric ECMO

direct thrombin inhibitors

bleeding complications

cost effectiveness