The Path for CARPEDIEM In The US

OK, so I have the uh pleasure to uh present Doctor Stuart Goldstein and Doctor Claudia Roco um next. And, uh, so Doctor Stuart Goldstein is a professor of pediatrics and a nephrologist at Cincinnati Children's, uh, where he serves as the director of the Center for Acute Care Nephrology. So I will, uh, talk a little bit about, um, neonatal CRT in uh the United States, and then the path uh for carpe diem. Um, it's really important, uh, that we acknowledge it's, it's amazing we can do CRT in babies. Um, and when I was a, uh, nephrology fellow, uh, in the mid-1990s, this is not anything. that we would ever offer. And when Doctor Ronco uh published the first case series of the children in Vicenza, we started thinking about how can we do this better. And really to, um, uh, Doctor uh Bendel's previous discussion, um, you, you won't advance things if you don't try, um, but you have to do it in a thoughtful, systematic way so that we can Uh, make incremental improvements, but also radical improvements like Doctor Roco has said. Even with the best practices, this, uh, approach does expose the smallest children to added risk, and so we need to understand when we think the benefit may be, um, reasonable, and therefore subject the families and the patient to many, many months of care. So, uh, Claudio discussed, uh, the, the drawing, and here it is, he sent it to me, of course, it's on Venetian paper and signed. It is in my office for anyone who wants to come and see it. Um, my office door is always open, and this really is a legendary technology. And this was when we met in Vicenza, uh, and started to discuss, um, the first patient and also how we could move this to the United States. I should say that Um, I am a consultant for, uh, Belco and Medtronic, um, in the, and had worked with them for 7 years, um, to ultimately get FDA approval for the carp A diem, but I have no other financial interest in the machine. So, again, Claudio um talked about this book, and it is in English, and it's the first, Claudio's caused many firsts for me, and it's the first time I've ever been, uh, had a blurb on a by leaf, uh, on a fly leaf, and so you can see it. So let's talk about um how we how we've advanced um CRRT in children uh over the last 2.5 decades. Many, many single-center reports showed that um children could be, uh, uh, survive after CRT. Even smaller children could survive. Even patients who, uh, underwent bone marrow transplant and had acute kidney injury or liver transplant. But you just had to try and not um be pessimistic. Ultimately, though, we developed a registry from 2001 to 2005 called the Prospective Pediatric CRT registry or the PPCRT. And from 2001 to 2005, the PPCRT collected data from 13 US centers that treated about 15 to 20 patients annually, and the data set includes 370 patients over the five-year, um, 5-year experience. Each center followed their own institutional practices. This was a prospective observational registry, we didn't tell anyone what to do, but, um, the data, even though they're observational, have really changed. Um, the foundation and the basic practice for CRT in children, and in fact have set some standards that adult, um, physicians have followed in terms of fluid overload and um other initiation strategies. This was the largest. Um, uh, patient population study from Scott Sutherland, where we looked at the different mortality rates based on fluid overload, um, and found that patients who, um, died had significantly more fluid overload. Um, but you would say, well, maybe the patients who were more than 20% fluid overloaded, uh, were, um, sicker. Well, they didn't have a higher prevalence of multi-organ dysfunction syndrome. They didn't have a higher prevalence of sepsis, and their PRISM scores were no different. And in fact, um, by every metric, the middle group at 10 to 20% fluid overload was um sicker than the kids under 10% fluid overload, but by um no metric were the patients greater than 20% fluid overloaded, sicker than the middle group. And so fluid overload is one of the things that we can address. And in fact, when we put this into a multivariable regression model, fluid overload was still independently associated with mortality, and if a patient got to greater than 20% fluid overload, the odds ratio for mortality was 8. Higher than cancer, higher than sepsis, higher than multi-organ failure. And you and I cannot control if a patient has sepsis, cancer, or multi-organ failure, but we can demon we can determine when to start CRT and we can help with fluid overload. So, now we start thinking in, these are the KDO guidelines, kind of a, a, a bundle about when should we start thinking about renal replacement therapy, and that's really at AKI stage 2. So again, is the risk greater than the benefit though for the smaller patients, and Doctor Roco demonstrated all of the issues that pertain with continuous renal replacement therapy. Clearly, peritoneal dialysis is going to be our go to, but there are a number of patients who can't tolerate peritoneal dialysis. And David Oshkenazi from the University of Alabama looked at the outcomes of kids in the PPCRT registry and demonstrated that kids under 10 kg had significantly worse survival than kids greater than 10 kg, and there was nothing else that was different about them except for their weight. So that is what really spurred us to think that maybe a technology like the carpe diem could improve patient outcome. So, um, I am happy to tell you, as Professor Roco did, that our, uh, publication, um, of the Italian registry compared to the prospective pediatric CRT registry group was just accepted this week, um, in pediatric nephrology, so I'm able to share some of the data with you. So, in the CRP ADM registry, and these, by the way, were the same data, exact same data that were used to to submit to the FDA to achieve clinical approval. And so the PPCRT was important because we had a relatively comparable control group. The FDA did not require a randomized prospective study of the carppe diem. They wanted to understand the safety and make sure that the outcomes were at least as good, if not better, than that in the PPCRT. Ultimately, um, to the bottom left, we, um, have published or will publish, um, the kids who were less than 5 kg because there were very few, um, in the CAP ADM registry that were greater than 5 kg. And in the PPCRT registry, we ended up having 48 kids who were less than 5 kg for comparison. And what you can see here, there are some differences um between the CARP ADM registry and PPCRT. Um, for CARP ADM, um, a bit higher um prevalence of cardiac, um, uh, underlying diagnoses and Um, but no, uh, uh, cancer, uh, diagnoses, um, and, um, similar inborn error group, and, um, no, uh, hepatic, um, diagnoses. So, um, we did our comparisons for the whole cohorts and we did our comparison for the same underlying diagnoses, and I'll show you the data and they're exactly the same. So, if we look at the kids less than 5 kg, what is amazing is that all but one of those kids on CAM survived to um the uh uh discontinuation of renal replacement therapy. And that was true if the kids had acute kidney injury, or if they were receiving invasive mechanical ventilation, or if they were on a oppressor. Now, when, and so based on these data, in April of 2020, the FDA approved carpadium for marketing in the United States. Um, this is the visual abstract, um, that will be published. Um, and again, you can see that, um, significantly improved survival compared to discontinuation of, uh, renal replacement therapy. But then when you get to ICU discharge, There is not a statistical difference. However, what was really important in that, and the FDA required this of us, is we went back to the carppe diem registry and we looked at the death certificates and the time off CRT to mortality. And what we found was, of the patients who died, all of them had severe underlying diagnoses that were not renal related, and all but one survived for more than 48 hours off of carpe diem. And those data were critical for the um FDA to say there was no selection bias, and that the, the, uh, uh, investigators and clinicians in Italy were doing something to make the CAP ADM numbers look better. They were getting these data, they had no idea we would be using them for FDA approval. So, um, In uh in the US, our first patient was treated at Cincinnati Children's in November of 2020, 1 month old with end-stage kidney disease, secondary severe, um, congenital anomaly of the kidney and urinary tract, and was being treated at a very good pediatric institution. Uh, near us. This patient developed fungal peritonitis, unfortunately, and continuous renal replacement therapy was attempted with a standard platform, the same platform that we use here, um, at Cincinnati. The patient was transferred to us specifically for us to attempt CP A diem support for the patient. It was absolutely successful, um, and a miracle as it was for the first patient in Vicenza. The PD catheter was then removed, uh, fungal, and the fungal peritonitis was treated. The PD catheter was replaced after about 1 month, and the patient, um, was, uh, restarted on PD successfully after 6 weeks of support with the CAP ADM. So in follow-up, he was safely transferred. transferred back to his home institution. He's been discharged home on peritoneal dialysis with the parents a few weeks ago, and he'll likely be referred back to us because we are the transplant center um for the University of Kentucky. Um, so we'll likely see him in 18 to 24 months. And Doctor Keisling, who's the professor and chief of pediatric nephrology at the University of Kentucky, um, Also agreed that this uh machine saved Brandon's life. I'm able to use Brandon's name cause his parents have, uh, signed a waiver for us to be able to do that. What's really gratifying now is, um, we've treated 5 patients here, and now With what we've learned here, many other centers are getting, um, the CRP AM installed, um, and they're getting training. So I believe every pediatric institution who treats a baby like this, and that's most of them, um, should have this technology available. I appreciate, um, your time. Uh, I appreciate the opportunity to learn from Doctor Onco, and everything I've done has basically been, uh, to follow him, so we don't call it, uh, Cincinnati here. We call it Vicenzinnati if you're in the, uh, if you're in my center. Thank you so much. Thank you both, uh, Doctor, uh, Ronco and Doctor Goldstein, and congratulations to the both of you. Um, what a, what a wonderful achievement and what a game changer, uh, in the care of our, of our children. Um, and, uh, so thank you for the work that you've done, uh, to date on this. Um, I have, I have a question, uh, first to Doctor Goldstein. Um, so from, from what you've learned in your many years of work with the system, uh, and the efforts to bring it to the US, what barriers still exist, uh, to the broad expansion of its use in our neonatal population, and what, what do we still need to know? Yeah, thank you, Doctor Taba. I think what's really critical is we need to get a catheter. Um, that's the first technical piece. We're still using 7 French catheters, um, in the internal jugular vein. We do not have the range of catheters, um, that are, um, Uh, that are able to handle, uh, low blood flow, and, uh, you know, that's why I said it was impossible to think that a 4 French dual lumen catheter could be used for CRT is just mind-blowing to me, um, but it can, and we need to get those catheters here. I think that will greatly expand the use. We are doing a post-marketing registry, um, uh, that actually Medtronic wanted to do the, um, Uh, FDA was not requiring it, but we want to, um, really recapitulate the PPCRT experience so we can rapidly disseminate data on best practices. Um, there are some, uh, uh, concepts with anticoagulation and how we manage that, for instance, um, all of the Italian, um, centers still use heparin. Um, and so we're learning how to use citrate and other anticoagulants. Um, but I think what this, and we need to also not jump to carppe diem for every specific, um, patient or every, every general patient. But think about with the technologies that centers like all of ours have, when is the appropriate use? When is it escalation of care to carpe diem? When do we de-escalate care, and how do we learn? It's a very different technology and the way you prescribe, it's very different. So, we want it to be successful. I hope that answered your question, Doctor Dubaugh. Yes, uh, thank you very much. Um, and, and I, I know that we have, uh, some time, uh, before we start applying this, uh, to certain populations, but, um, how do you see this kind of in the future, um, Benefiting the bilateral renal hygenesis population, um, because I know that we've had quite a few problems with, uh, with hemodynamic status and trying to provide dialysis to these patients. Do you think that carpe diem will be a game changer in that patient population? I think we have to try it, right? We've been very aggressive, um, you know, we, the University of Alabama, where, uh, CAR is, um, and, and Seattle have been very, very aggressive with using other technologies that have saved babies that otherwise couldn't, but the bilateral renal agenesis group has still been difficult, um, for us, and I think it has a lot to do, um, with the adrenal issues, and so we'll be looking at Um, uh, renin and angiotensin and other ways to, uh, to, to try to help these babies. Uh, but again, I think, um, we were at the limits of what we could do, and I think the accuracy of CAP ADM will take out a lot of the fluid. shifts that are just incumbent with the lack of accuracy of other machines. And so while we've made great strides, now that we have CARP ADM I'll be very interested in our, you know, working together with you and our neonatology group to start to think about this again. Can I ask a question about um interfacing with PD catheters. So one of the struggles that we have in neonatology is we put these early PD catheters and we have to use them earlier than we want to, and we end up with leaks, and that's just a, a, a natural but uh unwanted consequence of PD catheters. Um, now, with the ability to bridge PD from the beginning with the hemodialysis catheter and carpe diem, do you have any experience or recommendations on how long Uh, or if it's even reasonable to start with putting in both your hemo PD catheter, do hemodialysis with carpe diem for X number of weeks before you transition to your PD catheter. Yeah, we actually do. That's a great point. So, even before CAppe diem, um, we, uh, took the lead, uh, took the guidance, um, from one of my, uh, former fellows, Doctor Askenazi, um, at the University of Alabama, who started using the Aqueduct device, um, to be able to provide, um, uh, hemofiltration, not in this population, but more in the cardiac population. And we had two kids that we Uh, from our fetal care center, um, that we started PED on, and they had abdominal catastrophes, and, but once David published that, we, we, um, calibrated that, and now what we do, except for the bilateral renal agenesis, now, even though we've tried it, but even patients with functional renal agenesis, bilateral MCDK, we tell the families in the, um, in the fetal center, in the prenatal consult that We will place an IG catheter, um, well, I won't, but a surgeon will, um, an IJ catheter, um, and then on day two, if, if the patient is deemed to be a pulmonary survivor, we start modified CVVH 8 hours a day. Um, and, uh, for 3 weeks. At 1 week, we put in the, have the surgeons put in the PD catheter because I believe these kids don't have the normal cellular integrity in the gut. And when you, because we put in PD catheters and do peritoneal dialysis up in the cardiac ICU and neonates every day, and we don't, they don't have colon, they don't have intestinal rupture. And so we work with our neonatologists with very high nutrition to get them to be anabolic, and then we're also managing their fluids, so they're not fluid overloaded, so when we start peritoneal dialysis, we're not having the, we do have leaks occasionally, but they're in much, much better position. And now I think with CAP A diem, we would, uh, uh, it's not that we'll treat every patient with CP A diem in this situation, but patients who are more unstable, I would start with CAP ADM and then de-escalate to other platforms, and we're gonna learn how to do that. I if I can make a quest, a, a, a little comment, uh, um, I understand that, uh, of course, at the beginning, uh, people are cautious and uh use Carpeen in extreme cases where they cannot use other more consolidated and classic treatments. However, As soon as groups will become familiar with the machine and they will see how simple this machine is to be managed and how low-risk profile has the entire treatment, uh, I think that you can even prescribe carpe diem for 1 day or 2 days after surgery. Uh, in conditions of transient fluid overload and so on, resolving cases that sometimes PD is not able to resolve because of uh low ultrafiltration rate or complication, hyperglycemia and so on. But of course, uh, I'm a little biased because I uh I have seen uh the birth of this machine, uh, and the idea was to create something so simple that even nurses that are not using everyday the technology, they can become familiar in hours or minutes and the accuracy is So, uh, uh, let's say perfect that, uh, uh, uh, it's very difficult to make mistakes of fluid balance, for example. So this I think is very important and it is lowering the risk of, uh, neonates. But of course, I am, uh, I'm not a pediatrician, so, uh, I leave to you guys. No, I think you're absolutely right, um, Claudio, and I can tell you people, once the paper was published in The Lancet, I would get a call every few days, every few weeks, when is the carpe diem coming? The big issue for us is a very simple one. It's, we need a small catheter. And once we have a smaller catheter and we're not worried about damaging, you know, a blood vessel, if you damage the blood vessel of an adult, it's not the same thing as damaging, uh, an important vein for a child. And so once we can get a smaller catheter, then this becomes absolutely the treatment of choice each and every time. So, Doctor Unco, um, you know, in Europe, they have, uh, a longer track record of, of using Carpe diem, and, uh, and so I'm curious as to, you know, what your thoughts are on any ongoing challenges or opportunities with the machine, um, and what additional advice do you have, um, for, for us in, and other US centers? Well, you know, uh, uh, it's interesting that, uh, in spite this machine is the only one authorized for use in very small babies, uh. Uh, we are even using the machine of labeling several patients that, uh, weighed something like 900 g or 1 kg, and this has been done in, uh, several different places in Europe. Uh, we, um, developed, uh, a, a series of educational days to train. People how to use Carpadine, but I think in Europe, uh we are much more used to non-standard treatments uh and uh more personalized therapy. This, as far as I know in the adults, for example, is very different compared to adult dialysis in, uh, in the United States. So experience is going on, um, in particular, for example, in our center, when we had this baby, uh, the first baby treated, uh, we asked the company to make available uh plasma filter in order to do plasma exchange with carpe diem, which is not, uh, uh, authorized and will be an off-label, uh, treatment. We even used the You know, I discovered, for example, but I could not imagine that pediatrician do blood exchange with syringe manually and uh using uh carpe diem is so easy and so simple that uh Makes this machine probably uh coming into the routine use. The only problem is to uh make people familiar with the fact that an extracorporeal therapy is not an heroic therapy, is not, not magic. It's something that can be done if you are well trained and if you know what you're doing. This reminds me very much about 40 years ago when we started teaching intensivists to do CAVH and then CVVH. Originally, they didn't want to deal with extracorporeal therapies in the ICU unless there was a dialysis nurse. Now, they are almost uh uh all using these techniques with no problem. So, my feeling is based on what is going on in Europe that very soon In the United States, uh, uh, there will be a dissemination of this therapy and the indications will be expanded probably because once you see the risk is low and the benefits are high, the indication will be expanded. Uh, in fact, in the United States, you are slower than Europe, but once you take over, then you are faster. So, in the, in the coming years, probably you will have, uh, you will see an explosion of these, uh, Uh, treatments, I suppose. Thank you very much. And, and so I, I heard that uh you mentioned uh dialyzing children as, as, as small as 900 g or 1 kg. And Dr. Goldstein, I've seen, uh, in your data that you presented, I saw that you had a category of less than 5 kg. Now, is there a lower limit to that at this point as to, as to when carpe diem is being applied? And I'm sorry if I missed that during your talk. Oh yeah, so it's indicated, so the FDA indication is 2.5 to 9.9 kg, um, but as pediatricians, you know, 85% of what we do. Um, is, is off-label. So, um, we will go on a case by case basis, but I certainly, if, again, it's a catheter issue, um, and, uh, you know, we'd have to think about UAC UVC, because you can go down to 23 mils per minute of blood flow. Um, so we'll just have to see how that works. But, no, I, I certainly would go down to 1.5 kg or even lower if, if my neonatology colleagues tell me that, um, the baby has a chance, then we'll try. But, uh, the official word is 2.5 kg. There, there, there is another issue that uh people may not have considered and it is that you can actually take a baby of 15 kg and still use carpe diem because uh with the blood flow. Between 0 and 50. And dialysis flow rate that can reach clearances in the range of 1015 mL per minute. Uh, you can have enough efficiency to dialyze uh babies a little bit, uh, uh, bigger than uh what the, the label advised. So, um, it's, it's a, it's a possibility of, it's a flexibility of the device that is very important. Although, as you know, when you focus about accuracy, you have to focus for the worst clinical case. So, the, the, the very small babies.