Welcome, everybody, to another exciting SCII-sponsored webinar on a congenital heart disease topic, PDA occlusions in the very low birth weight infants. My name is Frank Ng. I'm from UC Davis. I'll be your moderator. Dr. Hawaida El-Sayed from UC San Diego will be my co-moderator, and she'll be monitoring the chat and question box. So please type in your questions and chats, and we'll try to work on this as often as possible during the lectures. Alongside of me are three other distinguished speakers and panelists, Dr. Satyen Lakshmi Reshima, who's chief of pediatrics at UC Davis, and a neonatologist extraordinaire, Dr. Guru Hiramath from University of Minnesota, and Dr. Shyam Santanandam from Le Bonheur Children's Hospital in Memphis. Today's webinar will consist of a brief introduction by Dr. Satyen. He will give a neonatologist perspective on this topic. Unlike other congenital heart disease interventions, the premature infant belongs in the NICU, and the neonatologists are the gatekeepers of the PDA. They decide when to close the ductus and when not to close. So it's really important for us to have this collaboration with the neonatologists and to get their perspectives on this particular topic. We will follow with four lectures, and I will introduce lectures as we move on, but suffice to say that the first three lectures will be more technical, working, introducing new devices and some of the tips and tricks on how to do the procedure, and the last lecture, which is last but not least, in fact, we're saving the best for last, which is going to be on the long-term outcome data that Dr. Shayam will be presenting. So let me go on to the next slide. So the learning objectives, as I mentioned, would be to describe the various devices available for PDA occlusion in a very low birth weight infant, to discuss the tips and tricks of PDA occlusion with the very low birth weight infants, examine the latest outcome data on PDA occlusion in this group of patients. It's interesting that today we actually have two major groups that registered for the webinar. One is actually the pediatric interventionists. The other group are the neonatologists who are interested in this topic. So I actually think that we're going to have some very interesting discussions and questions as we go through with this. So let me hear the disclosures of the faculty. So here's the disclosures. Several of us are consultants, and then finally, this is the link to the original registration that you can go back to to provide an evaluation and obtain MOC or CME credits. The MOC will be done through the American Board of Pediatrics. The deadline is June 26. You have until then to fill this out. So with that, I'm going to open up, introduce the next speaker. Satya, maybe you can share your slide. He will, Dr. Satya is actually my boss. He is a neonatologist who's got a special interest in pulmonary hypertension and chronic lung disease of prematurity. He has an animal lab and does a lot of studies on creating models of pulmonary hypertension to try to better understand the processes leading to bad lungs. So Satya, why don't you take over? Thanks, Frank. Thank you for the kind introduction. And at the outset, let me congratulate you on being the master's award, receiving the master's award last year. It's great to have you here as a colleague. On behalf of the neonatologists who have joined this webinar, I want to briefly talk about some of the concerns and concerns that neonatologists have with respect to device closure in PDA. Let me start off with a brief case. This is actually a patient that we have in the NICU right now, a 27-week gestation, 963-gram female infant, had respiratory distress syndrome, got one dose of surfactant, successfully extubated, around 28% O2 on NIPPV, and has a large PDA on echo on day six. Got three doses of indocin, the PDA did not close, and on day nine, we have a 3.5-millimeter PDA with a left-to-right shunt, with a dilated left atrium with a LA aortic ratio of 2.73, with a high BNP. So this is what we face on a day-to-day basis, and we are wondering as to what we should do with these infants who have not responded to one course of standard medical therapy, and should we invite you all to help us with a percutaneous closure in this case. As many of you know, there are several side effects of having a PDA open, and physiologically, we have all seen the effects of not only over-circulation, but also ductal steel that can in turn lead to problems with conditions such as necrotizing enterocolitis in babies. So the over-circulation of the lung is a real important entity from a physiological perspective, and we know that the presence of a large left-to-right shunt flooding the lungs with more blood, especially in the setting of RDS with evolving BPD, is a major concern. This in turn can lead to pulmonary edema, protein leaks, surfactant dysfunction, and eventually, as the BPD gets worse, put the baby at higher risk for pulmonary vascular muscle hypertrophy and pulmonary vascular remodeling, leading to pulmonary hypertension. This, in fact, is an angiograph that I borrowed from Dr. Ng, showing different phases of pulmonary vasculature on angiography. Here is a nice, normal-looking pulmonary arterial tree with a nice blush. On the other hand, here, with advancing pulmonary hypertension, you see this vascular pruning, where you don't see this normal vasculature at all. And a big concern we have as neonatologists is as to what is happening if the PDA remains open and keeps on pouring blood into a lung that is prone for BPD. Are we putting these babies at higher risk for pulmonary hypertension? And that's a major concern for us. Moving along, one area where some distrust has developed is that extremely preterm infants that we all take care of are not small babies, and they are unique beings, and in fact, I think they're aliens. They don't respond to typical physiologic parameters, and this has been reflected one study after another in neonatology. For example, there was a study comparing oxygen for resuscitation, and it was very evident that unlike term babies, preterm babies did not do well when they were resuscitated with 21% O2, and in fact, they had higher death rates. Similarly, the neoprom trials with over 5,000 babies showed that when you use slightly lower targets, there was increased death in these babies. This was totally unexpected when the trials were being planned. More recently, the SAIL trial, where sustained inflation, which is supposed to open up the lungs and help out babies, did not help at all, and in fact, there was early death among babies who received sustained inflation. In addition, the Australian placental transfusion trial, which thought that giving more blood through delayed cord clamping would help, this particular study showed that there was no difference in death or major morbidity by 36 weeks postmenstrual age. Anup Katheria recently showed that milking the umbilical cord, which is thought to be something that provides additional blood to the fetus or the baby, actually led to increased incidence of interventricular hemorrhage, and we are all aware of various trials of inhaled nitric oxide in preterm infants with hypoxemic respiratory failure, where physiologically it should make perfect sense and it does work very well in term babies, but in extremely preterm infants, we really do not see a clear benefit. All this shows that we really need randomized control trials with a placebo arm when evaluating a device closure in PDA in extremely preterm infants to get major buy-in from all parties concerned. So this is where we are right now. We're trying to debate between an evidence-based neonatal approach and a physiological benefit-based approach, and physician decision-making, especially among neonatologists, is a complex phenomenon that's influenced by several factors. So what are the factors that favor the use of a device closure in PDA? Definitely there is physiological benefit with short-term improvement. I mean, Frank shows me X-rays before and after PDA closure and they look so dramatically different. It's like night and day, the amount of change in pulmonary vasculature. It appears safe. Many of you have done many PDA occlusions and most of these babies have done quite well with very few complications. Moreover, it's an FDA-approved device, at least for babies above 700 grams per weight, and you do not need a theracotomy compared to surgery. We don't see a very high incidence of post-ligation syndrome, although this is slightly controversial. It clearly reduces pulmonary flooding and ductal steel, and it's very effective, anywhere from 98 to 100 percent effective in closing the ductus. And there's possibility of an imminent randomized controlled trial, and many of the colleagues here from interventional cardiology are seeking funding for an NIH-sponsored clinical trial in this area. So what are the factors that influence a decision-making against device closure among neonatologists? So we do not have really evidence-based guidelines approved by AAP or by AHA or ATS in this area. There is some concern about cost, although the cost of surgical ligation is equal if not more than what happens with the device closure. Expertise is only available in limited areas, and that's a concern, especially in babies that are born in smaller NICUs. Transport of the baby to the center where PDA occlusion is available, transport from the NICU down to the cath lab, requirement of intubation and anesthesia are all concerns. Long-term benefits are not known in a randomized controlled trial, although I'm looking for Dr. Sadanand's talk referring to some of the short-term and long-term benefits and effects of PDA closure. So it all matters as to how we choose the right baby for PDA closure, and using the most appropriate inclusion criteria will be really important for us. With that, let me introduce you to the next speaker, Dr. Guru Hiramet. Both of us come from University of Mysore in India. I'm a few decades older than him. That's a different story. He is a phenomenal interventional cardiologist at University of Minnesota, and he will be giving the next talk, comparing MVP versus picular devices. Guru, your turn. Thank you for the kind introduction, Dr. Sadanand. Thank you, Dr. El-Sayed, Dr. Eng, and ACI for inviting me to present at today's webinar. It's a real distinct pleasure to be here today, and I have been tasked today to review the Medtronic microvascular plug and the Abbott picular occluder, two devices that have really revolutionized transcatheter closure of PDAs in very low birth rate infants. These are my relevant disclosures today. PDA closure in preemies is proof of the pediatric interventional cardiology spirit to adapt, to innovate, and continually strive to improve our techniques and abilities. In that regard, we always have wish lists for all kinds of devices, and if we were to have a wish list for what an ideal preemie PDA device should look like, I think we will all come to a list that would look similar to my wish list here. We all want a device that is deliverable through a low-profile delivery system. Microcatheter compatibility would be ideal. We want the delivery system to be flexible so that it doesn't distort the anatomy. Anatomy distortion could result in blood pressure drop, low cardiac output. Anatomy distortion or a stiff delivery system could result in tricuspid valve injury and may impair our accuracy of device placement. We want a device that is resheetable and has reliable detachment properties. We want it to be retrievable and ideally through the same delivery system that we are putting it through. And of course, we want the device to be visible easily on x-ray and echocardiography. Short device lengths are ideal, obviously, so that we can deploy them intraductal so that nothing sticks into the PA and to the aorta. So with that, let's start with the first device that I'm going to talk about today, the Medtronic microvascular plug. MVP is a device which has really led the way for us with regard to preemie PDA closure. It's a first-of-its-kind microcatheter deliverable plug. It was originally developed by Reverse Medical and later acquired by Medtronic. The device itself is an ethanol-based device. It's a hexagonal frame, and it's covered with PTFE all around except in the distal 3 millimeter, as shown in the diagram here. It has a screw-type control delivery system, which is attached at the tip of a 0.018-inch nitinol pusher cable. It's fully resheetable, retractable, and it was originally approved by the FDA in August of 2013 through the 510K pathway for peripheral vascular embolization. And just like everything else, we pediatric interventional cardiologists started using it originally in collateral closure and ultimately in preemie PDA closure. The device itself comes in four sizes, but the size most relevant to preemie PDAs is MVP5Q. If there is one MVP size that would close most of the preemie PDAs, it would be this one. It's designed to close a vessel with a target vessel diameter of 3 to 5 millimeters. It's deliverable through a 0.027-inch microcatheter. Unconstrained, it's actually 6.5 millimeters in diameter and 12 millimeter long. Constrained, however, the device elongates further by 3 to 4 millimeters, which we should be cognizant about. Shyam Sathandam, who is here with us, has really led us all from the forefront with the preemie PDA closure, and he continues to do so. He shared with us his initial experience with preemie PDA closure using the MVP device back in 2016 with 15 patients with great success and no complications. John Brynolt at the same time shared with us eight patients where he had one device embolization nine days later that was successfully retrieved. Since then, we all, you know, all over the country and around the world, we have adapted our own techniques and started doing the same. We here at University of Minnesota started our preemie PDA program in 2017, and I believe the typical preemie PDA case is similar across many institutions. We don't do arterial access anymore. We cross the PDA from the venous side. We size them based on echocardiography and sometimes lateral angiography, and we place the device with echo and fluoro guidance. We here at the University of Minnesota tend to use more echo with very limited fluoro in between, and here is a montage of echocardiographic pictures showing us the catheter being pulled back into place into the ductus with echo guidance and the device being deployed with echo guidance, which ultimately we should all get used to if we were to take it to bedside. We make sure the LP and the aorta is good and there is no residual shunt and the device is released. So if everything goes well, it's a pretty straightforward procedure. So what are the strengths of the MVP? In my mind, the greatest strength of the MVP is its flexible delivery system, which does not distort the anatomy too much and providing us a stable patient with and aids us with accurate device placement. The other advantage, of course, is we can deliver the device through the same catheter that we used to cross the PDA, so it avoids a sheath exchange. And until recently, I believed firmly that the distal uncovered part and the lack of discs prevents aortic obstruction, even if it protrudes a little bit into the aorta. You know, that may not be completely true. I will show you why in the next few slides. Although not a big advantage, MVP can in theory be delivered through a three French venous access system, and I have done several of those after our initial few patients. We just park a GR catheter through a three French venous sheath in the right atrium, cross the ductus, and then exchange it for a micro catheter and do everything through a micro catheter. So that could be an advantage. What are the disadvantages of the MVP? I think for this particular indication, the greatest disadvantage for the MVP, I think, is how challenging it is to visualize both an echo and on fluoroscopy. As seen in the images here, the distal markers are easy to see, but if you want to really see the body of the device, it's really hard to see on fluoroscopy. The length may be too long for some ductuses. In my mind, any ductus that is longer than 5 or 6 millimeter is amenable to MVP closure. And as Dr. Ring showed at the ACI abstract session, it takes time to fully form and take shape, so we've got to remember that. The other disadvantage is the PTFE is delicate, and it may be damaged by multiple resheathing, and one of sham series, one of the residual shunts was attributed to that. In my own experience, if after a couple of resheathing, I would just take the device out and put a new device in, because I've had the same experience with PTFE. One disadvantage, as we talked about, is poor echo visibility. We here at the University of Minnesota published our experience in trying to use harmonic imaging to make it more echo visible. If anybody is more interested, I'm happy to refer them to this publication, or you can ping me, and I can provide you with details. While published data on MVP and pre-MEPD is limited to series like this, you know, the largest of which is from sham here, which showed great outcomes with no significant complications. Dr. Shahnawaz at Cincinnati is collecting pooled retrospective data from several centers around the country, and we hope to have really robust data on the retrospective, which will shed more light on some of these outcomes pretty soon. I already showed you John Brinehold's data. The French group put together their experience a couple of years ago that included 10 patients amongst the 100 with MVP, but I just wanted to point out one late aortic coarctation seen in one of their series with a 7q MVP that failed balloon dilation and needed surgery. I want to spend a slide on looking at Ryan Alex's case report. I think it's worth mentioning because it tests our notion that the uncovered portion sticking into the aorta is forgiving, and that's what I firmly believed in. In Ryan's case report, they noticed late coarctation four months after closure in a 1,200 gram baby who was closed with 5q MVP, and what's interesting is, you know, this patient failed balloon dilation, underwent an end-to-end anastomosis surgically, and if you look at the explanted pathological specimen here, the part of the MVP that is sticking out into the aorta, which we thought is uncovered, is actually completely covered now with neoentema and endothelialization. So I believe that we've got to be careful as to how much of the device is sticking out into the aorta even though it is uncovered. MVP has, of course, been associated with some LPO obstruction. I've known of several cases around the country through personal communication. Most of them, as we know, improve with time, but I want to share with you this patient of mine who developed LPS stenosis six months after closure with the 7q MVP, although this was not a typical preemie. This was an older child, much larger PDA, longer PDA, but I just want to make a point that this particular patient, the LPS stenosis, responded really beautifully with high pressure balloon dilation, something that my pediatric interventional cardiology colleagues may be interested in if they have a case like this. I'm not sure whether the piccolo would respond the same way to balloon dilation, but the MVP did in my case. Let me quickly transition over to the Abbott-Samplatzer piccolo occluder, which has really taken over the preemie PDA market since 2019. This is a self-expanding nitinol mesh device. It's got a central waste with two retention disks with radiopic markers at both ends. It is delivered to a four French torque tube delivery system and it got approved in the United States back in January of 2019 for preemie PDA device closure in anybody who weighs more than 700 grams and is at least three days old. And the PDA has to be at least three millimeter long and the largest minimal diameter has to be less than four millimeters. And that approval was based on a U.S. pivotal trial that included 50 patients. And we know that as part of the continued access, there are 150 more patients that were enrolled in that study. And hopefully Sham can share some of that data later this evening. It comes in nine total sizes, which includes three waste sizes, three, four, and five millimeters, and three waste lengths, two, four, and six millimeters. The waste length does not include the thickness of the disks. The disks add a total of 1.45 millimeter on each side. And we should remember that that is unconstrained length. Constrained, the device could be even a couple of millimeters longer. A typical PDA case looks like this. For us at the University of Minnesota, we prefer to use a high-torque floppy wire through a coaxial system of microcatheter and glide catheter. We cross the ductus. We put the microcatheter and the glide catheter. We take a small site angiogram. And there is published data in the IFU telling us what size device to use. It's based on the length as well as the diameter. I will not go through the details. But suffice to say, in the US pivotal trial, the majority were closed with just three sizes, 4, 2, 5, 2, 3, 4, 4. So what are the strengths of the Piccolo device? The major strength is its excellent radio opacity. It's very easy to see on echo. It's got shorter lengths for shorter PDA. So there's hardly a PDA that we cannot close with Piccolo based on the length. The operator familiarity with Amplizer devices becomes very handy. It's very easy to use. Retrieval is easy. And for a lot of us, including neonatologists, families, and interventional cardiologists, the on-label indication just makes it so much more easy to convince families and everybody else. What about the not-so-strengths of the Piccolo? I think the major disadvantage of Piccolo is the relatively stiff delivery catheter and cable in relation to how soft the baby's heart is. As shown in the montage of picture down here, the PDA angle and anatomy may be distorted by the stiffer delivery system and may result in a drop in blood pressure and drop in cardiac output by resulting tricuspid valve insufficiency. Sham has taught us to use calcium bolus prior to passing the stiff delivery system around, so that may help. And the stiffer delivery system may have something to do with the tricuspid valve injury that has been reported in some of the case series, which I will go over in the next slide. There are reports of tricuspid valve injury with the Piccolo device, and the incidence ranges from zero to 10%. But the good news is most of them are mild and none of them have needed intervention so far. In the US Piccolo trial, in the sub-2kg group, five out of the 100 patients developed some degree of tricuspid valve insufficiency. In the French survey, 4.1% of the patients sub-2kg developed some degree of tricuspid valve insufficiency. There were 0% incidence in the Marville paper from 2017. And even in the hands of extraordinary, exemplary interventional cardiologists like Dr. Eng, he published his data, he presented his data at ACI last month, three out of the 28 patients in the Piccolo had some degree of tricuspid valve insufficiency post-procedure compared to 0% in the MVP group. So something that we have to keep in mind, is it the stiffer delivery system or is it the technique with the wire catheter mismatch is still debatable. If we just look at those five patients from the Piccolo trial, two were associated with device retrievals and one was withdrawn from the study. One patient died, so we did not have long-term follow-up. The death was unrelated to the procedure. And so in the three who had six-month follow-up, two of the tricuspid valve insufficiencies remain moderate and one was mild. But the good news is none of them needed intervention. LP and aortic arch obstruction have also been reported with Piccolo, just like I mentioned with MVP. Some even have been stented from carotid artery access. The other disadvantage of the Piccolo is that the largest minimal diameter, at least for the IFU, that you can use the Piccolo for is four millimeters, whereas for the MVP, you can even close bigger devices, bigger PDAs. I was fascinated by Dr. Ng's talk last month at ACI, where he showed that the Piccolo may be associated with some extra fluoro time compared to MVP because of that one extra step of sheath exchange. And I tried to look at Sham's fluoro time. Sham, of course, is the master. If you just look at his MVP series, the fluoro time is very short at four minutes. But if you look at the fluoro time in the whole group in the Piccolo trial, it was 10 minutes. So maybe Piccolo is associated with slightly higher fluoro times. But when I compared my own first 15 patients that I did with MVP and the next 15 patients that I did with Piccolo, there was not a whole lot of difference. So let's go back to the wishlist that we started with. I think both MVP and Piccolo are excellent devices with different strengths and limitations. They both do very well on our wishlist. LP and aortic obstruction can happen with both devices, but the TR with Piccolo is something we got to learn, we got to think about as we grow on this learning curve. While we are lucky to have these two devices available to us, the onus really is on all intervention cardiologists here to make this procedure as easy and as safe as we reasonably can. Because that's the only way to improve its acceptance by our neonatology colleagues, compete with our surgical colleagues, and make sure that more and more babies can benefit from this innovation. With that, that is the end of my talk here. And I would like to introduce the next speaker, Dr. Haveda El-Sayed. Dr. El-Sayed is an exemplary interventional cardiologist. She's the professor of pediatric cardiology and the director of the cardiac cath lab at Rady Children's Hospital in San Diego. She's also the current chair of the Congenital Heart Disease Council at ACI. Dr. El-Sayed is gonna share with us her experience and introduce us a new device, the CURT Amplads plug for use in preemie PDS. Dr. El-Sayed, all yours. Thanks, Guru, for this really nice introduction. I'm going to share my screen. Can you guys see my screen just to confirm before I start? Guru, can you see my screen? Yes, we can. Okay, super. Okay, so, oh, sorry. Sorry, I actually had the wrong title, unfortunately, because Frank told me to change something on it. So I'm gonna talk about basically the preemie PDA closure using the CURT Amplads microvascular plug. I'm going to just show, I'm going to show here how we modify it. But first I want to show you how we put it in. So we're putting the angle glide through the venous route. Then we're putting a micro catheter, usually a Renegade, through the angle glide with a wire that's usually a BMW wire. This transition is very smooth. Over that, we are able to pass our angled glide. We take the micro catheter out and I'm sorry about that, hold on. So we take the micro catheter out and then we're able to inject in the PDA. So I'm just gonna see this again, going across pretty easily. It finds its way into the PDA. And then we are able to inject here. We can make the measurements for the PDA. And then the nice, oh my goodness, I'm sorry. The nice thing about this is that it can be delivered directly through the angle glide. So you don't have to upsize the sheath. You basically deliver it directly through the angled glide. Now, the other thing that you can see here, Gura was talking about how the Piccolo device can be stiff and straighten the PDA, make it a little bit more horizontal. You can see that when this device is placed, it actually, it's pretty soft and it takes the curvature of the PDA. And because there's no sheath, it's just the angled glide, the babies are extremely stable during this. We haven't had to give additional calcium or anything else. It's detached, not like the Piccolo really. And then you can see that it's, it hasn't, it does, it's pretty short and I'm gonna show you all of those lengths. Once you detach it, you're able to take that out. Then you're gonna be able to take your angiogram from the pulmonary side to confirm that it's where you want it. And of course, like you normally would, check by echo for the aortic end. And the only thing that we have published our first few cases, they were eight cases. We, the only thing is you actually have to modify it a little bit to make it work. So here, I'm going to show you how we modify it. Play that. So this is a regular vascular plug. So in order for you to use it, you have to modify the delivery micro catheter a little bit. So usually we use the angle glide catheter, put it on the table. I mark it on the table for the length of the angled glide and I have the connector on there. And then I just kind of estimate about five centimeters after that. This is the micro catheter that comes with the system. It's pretty long. If you use that, you will, you won't be able to inject on the pulmonary side, which I find is important. So all you have to do is just shorten the micro catheter. Once you've shortened the micro catheter, then basically this micro catheter, you can pull the micro catheter off the cable and still inject. So here we are loading the plug, which is already attached to its cable through this modified micro catheter. And this is not the micro catheter we use to cross with. We cross with the Renegade or the Prograde catheter. Here, we're pulling this micro catheter into its micro catheter itself. It's similar to the Piccolo, but it's a lot softer and it's only two millimeters long. Here, when you're putting it in, so you're going to put it through your hemostatic valve with its micro catheter. And then here, I'm just kind of showing at the end. Here, you have your angle glide in place. So you haven't had to put a long sheath, and then you're going to be delivering this very short, very soft catheter. You're going to peel your micro catheter off the cable because when the micro catheter is inside the glide, there's not enough space in the lumen to inject contrast. So basically, I pull it just to keep it on the back there, and then that allows you to inject. If you don't like it, you push the micro catheter back on to pull it back into the glide. You probably could pull it back into the glide, but it works much better with its own micro catheter. So here, you can inject on the PA side, and this is the combo that you would be using here, which is basically the angle glide and the... Let's get that again. So it's basically that angle glide combination with the micro catheter that it comes with. And that's basically your delivery system that you have. So right there, so you can see the angle glide. This is that micro catheter. This is the cable, and this is your KA medical, or now they call it the micro plug. So we, again, here have published our first few patients, and in those patients, you can see here, they were varying weights, varying degrees of respiratory support prior to coming to the cath lab. The important things that we had is we had pretty much no LPA obstruction at all because it's very short, no obstruction of the aorta, and we had absolutely no tricuspid valve injury. So the device is very visible, as you can see here. It takes the angle of the PDA, and you can see that there's really no turbulence in the LPA or in the aorta. And this is kind of what's happened to us over time. So going back to when we started in January, 2018, we started with the MVP, and you can see we use the MVP. I just have these divided in six-month increments. And then here, when the piccolo was approved, we started using the piccolo, and then we very quickly shifted away from the piccolo and went back to the MVP, and then we've used the KA medical, as you can see here, pretty exclusively. So just to kind of give you an idea, when we looked at our groups, and we're in the process of hopefully getting this out, is we used 25 MVPs, 25 microplugs and eight piccolo devices. And then here, we're kind of showing what ended up happening with the devices. So all the microplugs or the KA medicals stayed in place. The piccolo devices, we had issues with them. We had a couple, two tricuspid valve injuries, and we had one device embolized, and then we took it out and ended up putting an MVP. And then we had two others that just didn't sit very well and distorted the anatomy, and we actually took them out and put MVPs. In the MVP group, we've also had some problems with those. We've had two embolized and ended up having to go to surgery. One was sticking out in the aorta, and we actually took it out, but that PDA actually spontaneously closed just from catheter manipulation. And we had one that we started with an MVP, and it looked too long, and then we converted it to a KA medical. So with that, just to kind of compare the three. So this is similar to what Guru showed, but includes all three of them. Echo visibility, the piccolo and the KA medical are very visible. The MVP is hard to see on the Echo. X-ray visibility, the piccolo is the most visible. The KA medical is second in that. Trackability, the MVP and the KA medical, because they go through a microcatheter, seem to be more trackable. The lengths are variable. The MVP is pretty long, 12 to 16. The KA is pretty short, 2.5. And when we use the piccolo, we pretty much stuck in the two range. We didn't really feel the need to use the longer ones. And they come in various diameters that are pretty similar. The piccolo device is more expensive than the MVP and the KA, but that's not necessarily why we use the KA medical. So with that, I just wanna thank our cath lab team and thank our hospital for actually allowing us to use this device, even though it is off-label use of the device. And that's it. So the next speaker is gonna be Dr. Ng. You all know Dr. Ng. He is the director of the cath lab at UC Davis, and he's a very active member at SCI. And with that, I would like to give it to Dr. Ng. Well, thanks a lot, Hawaida. So let me just share my screen. Hang on for a second. Here you go. And I'll play. Okay, so I'm gonna talk a little bit more technical here and just go on for some of the tips and tricks on PDA occlusion in this group of patients. Here's my disclosure. Now, I know some of you are fairly experienced in this, but some of you are just starting out. So I wanna just start with that first. Definitely, this is one of the few interventional procedures where I truly think it's a team approach and where communication is key. And that involves interventionists, the anesthesiologist, the neonatologist, the bedside nurse, cath lab staff, as well as the respiratory therapist. Homeostasis for the very low birth weight infant for transportation in the cath lab is a key thing. We know that these micropremies can lose their temperature core temp pretty quickly. And there are a lot of things that can go awry in the transportation and in the cath lab. A lot of things that we take for granted for the full-term baby or the older patients. So early in your experience, I would suggest that perhaps you could ask one of your neonatal staff member to actually join you in the cath lab. Number one, just see the procedure and have another eye on looking at the ventilators and the preemie babies. This could be a neonatal nurse fellow or an attending. I strongly suggest that when you start out, start with a regular pre-cath huddles where you discuss the specific needs of a premature infant. As people have alluded to, this is a very special group of patient that are very fragile. At the end of the procedure, we've always just had a group meeting discussion just to go over any potential adverse events or areas for improvement for the entire process. And I think that by doing that, you can actually develop a nice QI checklist to help your procedures. Now, we know that for some of the places that are new to this, all it takes is one bad outcome and you will never get another referral. So it's really important to make sure that you have good outcomes at the beginning, even at the end. So I actually created this checklist over probably the first 30 patients we've done. And again, I'm happy to share the checklist with people. Just email me, text me, and I'll send it to you. Basically, things that we take for granted, like for example, make sure that your isolate that you use to transport has full battery power. Early on, somebody forgot to plug it in during the cath. So by the time we're done, that battery was dead. That's not good, right? But these are the things that you can go over at the beginning and check off, say, this is what we're gonna do. You make sure that the isolate actually has a warming feature. Not every isolate has that. So just make sure whatever you use has that feature. Chemical warmers. These are the kinds that are used for heel sticks. Have them just in case you need to warm the baby up for anything that might have caused hypothermia that you didn't account for. Heating lamps is a must in the cath, especially when the baby is fully exposed and you're sterilizing the body. Forced air warmers. So make sure that you use the infant size ones. The adult size are just too big and baby can still get cold. It's easy to increase the ambient temperature in the cath lab. So if I know I have a case coming up, I tell the techs to raise the temperature to 75, 76 ahead of time. It makes you hot and sweaty, but it's better for the patient. Plastic wraps. I learned this from the anesthesiologist. You can use these sort of like saran wraps to wrap over the body and the head to not only maintain temperature, but also to decrease insensible losses. Now we do trans-thoracic echo with the procedure. And of course you need gel for that. And one of the things we tend to forget is that you leave the gel in place and of course the babies get cold as the gel evaporates. So wipe it off after each of the interrogations. Temperature probes. We like to use the esophageal temp probes. You wanna ask for the history of any hypo or hyperglycemia for that particular patient and monitor your glucose carefully. As far as your airway, not every baby need to be intubated at the time of transport. But if I know this, we will actually have them intubated in the NICU. I truly believe that for the micropremius, the neonatologist is the best at doing this, not the anesthesiologist. You learn the history of airway from the bedside nurse. For example, the nurse may tell you this baby needs frequent suctioning. You better know that in the catheter or there's a specific position where the head turned in a certain way might cause the ET to be pulled too far back. So understand that from the bedside nurse. They know that better than anybody else. And if you understand that, you will be able to manage your patient much better when you do the case. Have your portable end-tidal CO2 monitoring. Make sure you have extended tubing because those babies are so small that you have to move the cath lab table along the distances and the tubing may not be long enough. So make sure you have those for the lab. Have your O2 blenders for transport as well as your transcutaneous CO2 monitoring in the cath lab. Those babies that are oscillators, I used to be worried about babies on oscillators for the procedure, but I've learned that you can actually do this quite safely. We have a TXP system for transportation that has a high frequency ventilator that you can exchange from the oscillator for the transport and then put them back on the oscillator once you're in the cath lab. So I'll show you examples of this. As far as fluid's concerned, understand what is needed for that particular baby. Again, as I said, monitor your glucose carefully. For cath lab fluids, we use heparinized saline. We don't give a bolus of heparin as we do for all the other procedures in older patients. So therefore it's really important to make sure that you keep your flushes so that the bloods don't clot within the catheters. And I'll show you examples of why that's important. We have our IV fluid warming units. The Hotline is one of the brands we have, but there are many other brands to purchase to keep your IV fluid warm for use. As far as sodium, D10, half or normal saline can be used, or sometimes we'll use an albumin. We've also used NEARS to maintain a constant monitoring in both the cerebral and renal. We want to discuss the particular needs of that particular patient, such as any example of brain hemorrhage, IDM baby, vascular access issue. If we know this in advance, we can prepare. Make sure you know the hemoglobin going in. Many of these kids will be referred within the first two months of life, and of course they can be very anemic. So I tend to transfuse them before the procedure. Check your creatinine, obviously you're given contrast. I've learned that if you dilute the contrast, two-thirds contrast to one-third saline, it actually works just as well as full amount of contrast. So therefore you can minimize the amount of contrast. I'll show you an example of that later. Know where the PICC lines are. If it's going through one leg, you don't want to stick the same leg. So you want to use the other leg. Just be aware, if you do have a PICC line, when you withdraw the sheath, I've had this happen where the PICC line gets wrapped around the sheath and it can get pulled to the other side. So be very careful when you pull the sheath, if there's a PICC line on the contralateral leg. Put your blood pressure cuff and stat monitor on the opposite side where you gain access. If the anesthesiologist needs IV access, sometimes they ask for two, try to get it done in the NICU so that you minimize your time in the cath lab. Here's an example of the hotline fluid warmer we use to maintain some warmth in the IV fluids. This is low-tech warmers. This is the chemical warmers we use for heel stick. We have them during the transportation just in case. This is definitely a low-tech warmer where if you're gonna give saline and flushes, my tech will know to hold that in their hands just to warm it up when we use it. This is the plastic wrap. I learned this from the anesthesiologist. Great way to minimize heat loss and insensible losses. Here's a heat lamp there that we use during the sterilization process. The cerebral and renal nerve monitoring, we put that on as well as part of the anesthesia monitoring. As far as the cath lab space, every space is gonna be unique. So you know that for these babies, there will be a lot more machinery. So make sure you understand where things are gonna go. It includes the separate NICU ventilator, the echo machine, the T-com monitor, the fluid warmers. There are a lot more equipment around the baby. So make sure that you understand ahead of time. Once you have this down, it's easy, but you gotta do that and understand it ahead of time. What we do is that we tend to move our lateral panel down to the foot of the table, put the baby on and then move the lateral back up. When we first started, sometimes we've forgotten and we have to move the baby back out and then settle down on the lateral panel. So these are little things that we often take for granted for the older kids. You wanna minimize stimulation, minimize that transportation time and minimize the time in the lab. Prepare in advance, have your blood products ready. I know if you need supplies. And then there are some specialized drapes that I learned from Cheyenne. This is an example I got from him. It's a CVL drape line where there's a lot of, you can see through the body in case there are any issues. And the area of the groin side is actually well suited for this procedure. This is our TXP transport system with a high frequency ventilator on that. So for the babies, when the oscillators, we use that to transport from the NICU to the catheter and back, and it works really well. Anesthesia monitoring, here's our T-com, our transcutaneous CO2 monitoring that is used for the procedure. As far as sheath is concerned, there are many forefront sheaths, but there's a paper from Divakar Abhay that basically look at the outer diameter. And it turns out that the radial sheath, this particular one has the lowest outer diameter, which I think that for small babies is very useful. We've done a study looking at the ultrasound of the veins afterwards, and we have had zero venous occlusion. And we'll be publishing that soon. Here's an example of right upper lobe adalectosis after the procedure. You can see the device here. And after we learned this, this early in our experience, the nurse said, I had to suction this kid every half hour. Well, had we known that at the beginning, we would have been very careful to do that during the procedure. And it was only after that, that we started making sure that the bedside nurse had their input as for every kid that we work on. We actually will have the transthoracic echo done under the drapes at the beginning, just so that the techs can get familiar with their position, with the position of the probe, and seeing the things they wanna see before we even put the sheath in, just as to help us get prepared in advance. You see that sometimes we'll have the chemical warmers on the head, even during the procedure. So here's an example of using 1 3rd contrast with 2 3rd saline. You can see it's very hard to see the ductus. Well, if you just make it 2 3rd contrast and 1 3rd saline, actually you can see it much better. And this is just a still frame of the best image of those two. And you can see that on the 2 3rd contrast, it's enough to use for measurement. So therefore you can minimize the contrast use, especially if you have a baby with high creatinine. We talked about the stiffness of the delivery system for the piccolo. And I wanna just show this as a thing to watch for. When you disengage the ductus from the delivery catheter, I mean, the device, you notice that the catheter jumps up a little bit. So you gotta be really careful not to put too much pressure because you can imagine that can perforate the outflow tract. Now, the same patient, we take a picture, and actually this is early in the experience where I look at this and say, hey, it looks really good. But watch what happens when I freeze it to one frame. Well, if you push this a little harder, you can imagine this will perforate the MPA. So you gotta be really careful that these stiff systems can straighten up a little bit once you release. And in fact, you might not even want to leave it in that position. Might as well take it out. Here's a 755 grammer on an oscillator. You can tell from looking at the chest, the vibrations of the oscillator with a large PDA. I want, I bring this up because it's really important to be aware of thrombus. As I said, we don't give a bolus of heparin here. So here's a patient with the big ductus. The picture is taken, large PDA. We put the device in, and I don't remember this to be a very long procedure, but I do remember that after we finished this, you tend to want to draw back before I take my picture. And I remember it was kind of hard to draw back on this patient. Well, at that point in time, I said, okay, I'll just give my contrast. I take this picture. So you might actually notice something wrong with his angiogram. And here it is. You notice that there's a thrombus in the RPA. In fact, if I slow it down, freeze frame this, here's that thrombus. And I'm sure I shot that out of the catheter when I did the injection. So the trick here is to make sure that if you cannot draw back blood on the sheath, either the tip is against the wall or there's something in there preventing blood from getting in. It's gonna be a thrombus. And so in fact, on the echo, this is the echo of the RPA before the device implant. This is after. And obviously this corresponds to that radial lucency in the angiogram. And of course we put them on heparin, and fortunately the thrombus resolved. So since then, I have stopped to, I always wanna check that withdrawal before I take a picture. But here's another thing. So after that, I figured that might be a one-off. I started looking at flushing the clots out just to see what it looks like after the procedure. And this was another example where I had a hard time withdrawing, but I learned my lesson from the last case. So I did not, I just pulled the sheath out and I withdrew that from the catheter. In fact, I just flushed out some more and here's another clot sitting within there. Had I not paid attention to that and gave the angiogram, you can imagine that will go into the PAs, right? So again, pay attention to making sure that it doesn't draw us back. And so the question that I beg is that, do we really need to get a post-release MPA angiogram? I talked to Shyam about it, and this is his quote, and I actually find that to be quite funny, but true. He said, echo is my angiogram. Now that tells me how old I am because I was at the time where my mentor, Chuck Mullins, would say echo schmeckle, meaning that he didn't trust echoes. But here we've gone full circle where now our echo can be just as good as our angiogram. So in fact, I have stopped doing this because I think that if the echo shows a good flow with no compression in the branch pulmonary, I don't necessarily need to take a picture there. I think that would actually be helpful to minimize fluoroscopy and contrast and any of these risks. So here's a rare complication of tricuspid regurgitation. I think that Guru mentioned that on my series, that this is all on the Piccolo device. This is before the procedure, here's afterwards. And of course, when I see this, I mean, I'm pretty sad and concerned. Now, luckily over time, this just improved. I did not have to do anything else. In fact, I had other clips showing the improvement over time but I didn't have time to add this. But when I've thought about why I got a TR with the Piccolo device and no TR with the MVP, it has to do, I think, with the flexibility of those catheters. So here's the MVP using a four French angle catheter. It's three cases in general. Look at the curvature of this. Now, contrast this to the four French delivery system from the Piccolo, you notice that the curvature is a lot more stiff, more straight. You can imagine that could put some undue stress on the chordal tissues, on the chordae of the tricuspid valve. Again, this is just my own limited experience, but when I compare the curvature of these two delivery systems, certainly the Piccolo delivery system is a lot stiffer. And you can imagine that because that system requires an extra exchange, there's higher risk for damaging tricuspid valve. So here's an example of a baby that is 110 kilos who had some TR to begin with. This is the echo beforehand. I started worrying if I have a mild TR to begin it with, could I potentially create more TR? And so with that, I came up with a new idea. And this is, I think I've done this a few times now, but here's an example of what I did here. I actually took this picture with this catheter. I don't know if you recognize that particular catheter, but it actually is a forefront snare catheter. It's what you use for the 10 millimeter gooseneck snare. So when I put this in, you notice the curvature is quite much similar to the angle glide catheter. And with that, I can actually run a 5-2 Piccolo device through the snare catheter. It's a little tighter than the Piccolo delivery system, but it works really well. So I'm running this 5-2 Piccolo device through the snare catheter and I've delivered this. Now you can see that I'm putting into position and this took a little while. I was being very careful because I wasn't sure how flexible it was for the catheter, would it buckle on me or anything? So this was done. I take a picture and you see that it's pretty deep in there. Well, during this time, the echo shows that there is a co-octation caused by the device. Well, I didn't like that, right? So we actually were able to withdraw the device through the same catheter. So this forefront snare can deliver the catheter device as well as to retrieve the device. And then we can reposition it using the same catheter without having to exchange for the bigger system that is stiffer. And then of course, this is the final position and here's the PDA and here's the picture afterwards just to show that this works really well. You notice that this doesn't have the same stiffness as the delivery sheath. So just another little thing that I've learned. This is the echo afterwards, the same amount of TR, no change, no different. And here's the echo of the arch after device is put in. It was, there was no turbulence there and no gradient. So here's just comparing a regular forefront sheath from the piccolo system to the forefront snare catheter. You clearly see that the snare catheter has a lot more curvature to it. And I think that accommodates the orientation of the tricuspid valve to the outflow tract. So here are the two catheters. We typically use the forefront glide catheter for angiogram, the forefront piccolo. This is the forefront snare catheter and they're all the same size on the outer diameter. But if you look on the inside, I don't, I'm not a photographer so I can't get really clear images. But if you see this, that the inner diameter is bigger between the snare catheter and the piccolo catheter and you can see that the glide catheter is smaller. So again, another, it's shown the internal diameter of the snare catheter quite comparable to the piccolo catheter. Device embolizations. Now, one of the biggest fears that I've heard from people is that what happens if the device embolizes? Am I gonna get into trouble? So here's an example of a case where the device actually dropped into the LPA at release. And you can see that this obstructs the LPA here. And of course, I'm not happy with that, but you can see it clearly, you can get a gooseneck snare in there and pull that out. And that's it. So therefore you can retrieve these devices even if they embolize. Here's the summary. PDA occlusion in the very low birth weight infant is safe and effective, but requires a team approach and detailed planning for homeostasis of the fragile patient. Techniques are available to minimize risks and complications. Beware of thrombus formation within the catheter. A device reposition can be performed to optimize position, minimize the risk of flow obstruction to both the LPA and the aorta. And embolizes, the devices can be retrieved safely even in very small patients. Here's just some of the babies that I've worked on. And it's the best thing to when you see them in clinic running around, having grown and this just makes my heart smile. Thank you for your attention. I'm gonna introduce the next speaker. And I actually think of him as being the star of the day. And so therefore it's Shyam Santhanandam. I think he has the most experience in PDA occlusions in the preemies, probably in the world. So we're all excited to hear your lecture, Shyam. Why don't you take it over? Thank you, Dr. Ying. Thanks for the kind introduction. I hope everybody's kind of building me up. It makes me worry. Can you all see my screen? Yes, we can. Okay. So I was tasked, by the way, thank you for this kind invitation from Sky and putting this together. Dr. Ying, Dr. Al-Saeed for putting this together and all the attendees staying late to listen to these talks. So I was tasked to talk about the latest outcome data of PDA occlusion in the very low birth weight infants. This is my disclosure. So I don't know where to start data. I thought I'd start the data from the PICLO clinical trial. And as you all heard so far, it's been approved for children greater than 700 grams. Got approval in January, 2019. The paper was published in May, 2020. During the clinical trial with the IDE and the clinical, so and the continued access protocol, we had 200 patients. These are the gestation ages of these patients at birth. Interestingly, 78% of the patients were less than or equal to 26 weeks. A gestation age, even two patients who were 22-weekers or 10 patients were 23-weekers. All of these premature babies were supported with mechanical ventilation, all 100% of them. There were other comorbidities as well. When you look at the clinical outcome divided based on the procedure weight, which is less than two kilograms or greater than two kilograms, those who are less than two kilograms, the procedure outcome was 99% success rate. There was some less success actually with the bigger and older patients. Complications, there were two embolizations in the less than two kilogram, the three embolizations in the greater than two kilogram. And overall survival, even up to April, 2020, was pretty good considering many of these patients were less than 26 weeks gestation age. When we looked at only those who had the procedure who are less than one kilogram at the time of the implant, so these are extremely low birth weight patients and their implant weight was less than a kilogram. There's 33 of them during the clinical trial. The success rate was 100% with no vascular embolization or vascular access complication, which is very reassuring that the smaller the patient, the complication rates are not higher and the success rate is very good. And we looked at the growth velocity of these 33 patients who were less than a kilogram at the time of the implant. So all their birth weights were less than a kilogram. The implant weight was also about a kilogram and this is kind of their growth after the implant. So anyway, based on the IDE as well as the Continuous Access Protocol data, the overall implant success rate of 95%. The piccolo occluder was approved by the FDA as a non-surgical option for transcatheter PDA closure. As my personal experience, now we've done almost 300 babies now weighing less than three kilograms. Over 200 of them weighing less than two kilograms. Over 100 who weighed less than a kilogram at the time of the procedure, the smallest baby around 560 grams. So obviously their heart is much smaller and you had to be careful maneuvering catheters. This is, again, personal experience of patient number one to patient number 241. These are born at gestation age 22 to 27 weeks only. While 28 weeks are older, I don't think the PDA is that big a deal. The morbidity is not as much, but if you're 27 weeks or less, this is pretty much 26 weeks or less at the time of the birth, they have higher complication. And our personal experience based on the procedure rate, we've done over a hundred babies less than a thousand grams. Just like Dr. Ng showed, these are some of the babies that we've treated, very, very small infants. And it's very gratifying to see them get better and grow and walk and run around as being normal. And as again, Dr. Ng suggested, this is an X-ray of a 23-weeker who was two weeks old at the time of the procedure. The weight was 600 grams. This is the X-ray just before the PDA was closed. And this is right after. And you can see the X-ray getting dramatically improved after the PDA is closed. Here's a recent publication of a hundred consecutive percutaneous PDA closure in infants less than a thousand grams. This is just a single center experience from us. And our procedure success rate was 100% with a 3% major adverse event rate and 3% minor adverse event rate. Our mean weight at the time of procedure was 821 grams. And the mean age at the time of procedure was 24 days with a range between nine days and 50 days. So definitely, I think there's no doubt that it is feasible to perform transcatheter PDA closure. And obviously we've learned a lot doing 300 closures. So I don't want to go over what we've learned from a procedure standpoint, but I want to introduce some topics which are more, what should I say, important for neonatologists, especially while referring these patients. First thing I want to state by saying that transcatheter PDA closure is feasible and carries very low risk of complications. So, but the big questions remain, the big questions include whether to treat the PDA or not. If the PDA needs to be closed in the first place, what is the ideal time to close the PDA? And what is the best therapy for the PDA? I think these are de-lingering questions for neonatologists. And as cardiologists, we think most PDAs should be just closed. However, we need to take a step back and really wonder what is the best therapy or when it should be treated and how it should be treated. So I want to start the how to treat question first. Then we'll go to when to treat. And then finally, finish off with whether the PDA has to be treated at all. When I said how to treat, I'm not going to talk about the conservative management, which is fluid restriction, diuretics, positive pressure ventilation. Because to me, there's nothing conservative about this. This is all pretty invasive. Positive pressure ventilation and diuretics are invasive therapy. But leave that aside for a minute. We'll talk about medical treatment, which is using prostaglandin inhibitors versus surgical ligation and transcapsiclosure. Surgical ligation is definitely invasive, whereas transcapsiclosure, I think, is minimally invasive. The good thing about surgical ligation and transcapsiclosure is we can guarantee immediate closure. Whereas medical treatment takes days to weeks and may not be 100% effective, surgical ligation and transcapsiclosure, if done properly, should be 100% effective. The complication rates for surgery, depending upon the literature you read, is between 10% and 25%. For transcapsiclosure, I quote about a 3% complication to the families when I counsel them. But it's about 3% to 5% based on at least our experience. Medical therapy don't have complications, but they do have side effects. And the side effect profile could be between 5% and 20%. The syndrome called the post-ligation syndrome, it's a topic by itself. It's a whole talk. I don't want to go into it. But it seems to be unique only for surgical ligation. We have not seen post-ligation syndrome with transcapsiclosure. We classified a few of them as post-ligation syndrome initially during our experience. But eventually, we learned this is not really post-ligation syndrome. I don't want to go into the talk because it's a whole talk by itself. And the good thing about transcatheter closure is if you want to assess hemodynamics, we can actually assess hemodynamics. So we know whether the PDA is hemodynamically significant or not just by transcapsiclosure. So how should the PDA be closed? This is a study that we published. This is actually a while ago now. I think it was published in 2017. We compared surgical ligations. We compared 40 patients who underwent surgical ligation with 80 patients who underwent transcatheter PDA closure, which is TCPC. These were propensity score-matched patients. So there were no difference in gestational age, procedure age, birth weight, procedure weight between surgical ligation and transcatheter closure. But when we looked at the outcomes, one of the outcomes we are interested in was a score called the respiratory severity score, or RSS, which is basically a product of the mean airway pressure and the fractional inspired oxygen. So the bigger the score, the more support the patient is needing. So smaller score is best. And we found that if you have surgical ligation, they had an increase in their score post-procedure. And it took longer for them to come down to the pre-procedure score. Time to extubation was longer. And the time to take taken for the score to come to less than 1 or less than or equal to 1 was also longer with surgical ligation, which are all statistically significant. What we did not publish in this series was the incidence of post-ligation syndrome, which we went back and looked at. Incidence was 4% in transcatheter versus 42% with surgical ligation. Even this 4%, I'm not sure whether we can call that post-ligation. Again, we will not go into it. So this is really what the post-ligation syndrome is. This is a patient with a surgical clip on the left side and a device closure on the right-hand side. After surgical clip, you can see this transient pulmonary edema that you see on x-ray, whereas transcatheter closure, we don't see the post-ligation pulmonary edema after device closure. We're going to shift gears to timing of PDA closure. When is the best to close the PDA? So this is a recent publication that we had in, what, a year now, July 2020, when we published this paper, which was titled Hemodynamic and Clinical Consequence of Early versus Delayed PDA Closure. We only looked at extremely low birth weight infants. So these are babies born less than a kilogram. We divided them into three groups based on the timing of PDA closure. It's a retrospective study. All these infants are born less than or equal to 27 weeks gestation and the weight less than or equal to one kilogram at birth. So group one had 34 patients. All these patients had PDA closure less than or equal to four weeks of life. Group two, between four and eight weeks. And group three were patients who had their PDA closure done greater than eight weeks of life. And these are all transcatheter PDA closures. Obviously, when you compare their demographics, the procedure age was later for group three. And the procedure weight was also bigger because they closed their PDA later for group three. Otherwise, everything else was fairly similar for all three groups. But this is what the difference was. For those who are not interventional cardiologists, we looked at three hemodynamic parameters. The first one is called the QP is to QS ratio, which is basically a ratio of pulmonary to systemic blood flow. And if you see that, all three groups had increased QP-QS ratio. That means they had, for example, group one had two and a half times more pulmonary blood flow than systemic blood flow. And even group three, there's 1.8 times more pulmonary blood flow, but that is not statistically significant. So all were hemodynamically significant PDA based on the shunt volume. Whereas when you look at the last one, which is called the pulmonary vascular resistance, which is basically how much resistance there is to the blood flow coming into the lung, the higher the resistance, the more the pulmonary vascular bed is resisting blood flow and probably have pulmonary hypertension. And interestingly, those in group three, their pulmonary vascular resistance was about twice as much as those in group one, suggesting that if you wait later to close the PDA, the resistance in the vascular bed increases with time. And we also looked at the respiratory severity score after PDA closure. So in this Kaplan-Meier curve, the x-axis is the time since PDA closure in days, and the y-axis contains the respiratory severity score. And we looked at how many patients had a score greater than or equal to two based on timing of PDA closure. Those with the blue dots are the ones that had early closure, and those with the red squares are the ones who had delayed closure. And clearly, there's a demarcation or separation between the blue dots and the red squares. So group one patients who had the early PDA closure had better or lower respiratory scores sooner compared to group three patients. Even though they're older, they required a longer time for ventilator support. We also looked at the predictors for prolonged, which is greater than 30 days, elevation of a score greater than two, and found that only two parameters were significant. One was if the PDA was closed more than eight weeks of age, so later closure, and if the pulmonary vascular resistance was greater than 3.5, then they had worse respiratory outcomes or needing more respiratory support. We also made a comparison of those who had pulmonary hypertension or no pulmonary hypertension. And those who had pulmonary hypertension, they had their PDA closure done later. And everything else was also worse. So the baseline respiratory scores were higher. The time for the respiratory score to come to less than two was longer. Time to extubation was longer. So if you're already developing some resistance to pulmonary blood flow, then your respiratory outcome seems to be worse. So in short, I think based on this study, maybe early closure benefits these patients. Also in the study, we looked at growth velocity. And this is how we concluded it. So between the ages of four weeks and eight weeks of life. Again, remember, these are all patients born less than 27 weeks. When they are between four and eight weeks of life, the weight gain in patients in group one was around an average of 25 grams a day. Whereas group three, between four and eight weeks, remember, their PDA was still open. Their weight gain was 16.2 plus or minus 6.4 grams a day. So in the crucial second month of life, there seems to be a difference in weight gain if the PDA is open or PDA is closed. Again, supports the notion that maybe early PDA closure may be beneficial, especially for extremely low birth weight infants. And this is kind of a growth curve velocity. Anyways, this is a big question. Should the PDA be closed at all? Because there's a lot of controversy. We sent out the survey about three, four years ago now to 100 prominent neonatologists in big academic centers and 100 prominent cardiologists in big academic centers and asked them a simple question. Does closing a hemodynamic significant PDA make a difference in mortality and morbidity in children born less than 28 weeks gestation? The cardiologists all think so. About 90% of the cardiologists think closing a PDA will make a difference in mortality and morbidity, whereas the neonatology community is still very split. So why is that a big difference? Why do cardiologists think closing PDA is good for the patient, whereas neonatologists are not convinced? A lot of it is to do with the trials that neonatologists have been involved in. This is a meta-analysis of 60 randomized trials by Dr. Bennett. And what it shows is that ductal patency rate was pretty low. That means they were good in closing the PDA, whereas when you look at outcomes such as death, BPD, need for oxygen, NEC, IVH, there's no difference whether the PDA is closed or not. The outcome seems to be all the same. In fact, if you look at many randomized trials for pulmonary effects, in 35 randomized trials, 22 trials showed no difference in the need for mechanical ventilation or oxygen use whether PDA is closed or not. Three trials showed no difference in blood gas. Seven trials actually reported higher oxygen requirement, more surfactant use, and more use of mechanical ventilation than surgical ligation. Ligation is associated with prolonged mechanical ventilation. Endomethasin was associated with increased oxygen requirement. So basically, it looks like the therapy is worse than the disease. So why treat the PDA? And based on all these trials, you can see this is a secular trend of all PDA treatments. There's 61,000 infants born between 23 weeks and 30 weeks gestation. And they're split based on the gestation age. That's a big series in 61,000 infants. So red are the ones born 23, 24 weeks. But you can look at all these graphs. The use of COX inhibitors has been slowly trending down. PDA surgical ligation is really like half of what it used to be 10 years ago between 2006 and 2015. Whereas mortality has not really gone up that much. BPD has gone up slightly in those born 23, 24 weeks, but maybe because they are living longer. So yeah, even though the treatment for PDA is coming down, the mortality of BPD rates don't seem to have changed. Though we know that PDA is associated with all these bad outcomes, like prolonged ventilation, IVH, and NEC, and whatnot. This is from Dr. Bill Bennett from Stanford, who's been a big, what should I say, voice for not posing PDA. He himself agrees that PDA patency in the premature is associated with a variety of bad outcomes. This is from his slide deck, and I have his permission to do this. But his critical question is whether medical or surgical closure for the PDA reduces any risk for bad outcomes. This is where I have a problem with Dr. Bennett, and I've debated him multiple times. The problem is all these studies are based on medical or surgical closure, and not really the definitive therapy, which I think is transcatheter closure, because it's not based on surgical closure, and it is definitive. Number two is all these trials never looked at whether the PDA was hemodynamically significant. Most of these are based on clinical parameters, not really even an echo was done to see whether PDAs were large or small, or what the size of the PDA was. Because if you group small PDAs with large PDAs, then the outcomes may not be crucial. And these are all shortcomings. And pharmacotherapy is only effective in 50% of extremely low birth weight patients. And surgical ligations have all these complications. So perhaps we need to do these trials with transcatheter closure. I'm going to end with this one study from Jeff Fineman's group. This is not a human study, but this is an animal model where they used a sheep model and created an iota pulmonary shunt. They didn't actually keep a PDA open, but they put a shunt between the iota and the pulmonary artery, and they did MRI of the pulmonary lymphatics. So panel A is the normal pulmonary lymphatics when you do not have a left to right shunt, whereas panel B is the pulmonary lymphatics when you have a left to right shunt. So you can see the pulmonary lymphatics are all engorged and distended. This is what you see on the X-ray as pulmonary interstitial edema because of the PDA. And this is a slide from Yoav Dori, which Yoav Dori, for people who know him, he's who I call a lymphatic nut. We trained together, so I'm very good friends with him because we were both in the same class of training. And what he does is he's injecting dye to a thoracic duct. And this is a baby who's stuck on a ventilator with a large PDA. The thoracic duct is supposed to drain into the innominate vein, whereas it does not drain into the innominate vein, and it just leaks into the extracellular spaces in the head and neck. And many of these babies in the NICU, they have this large head and neck with a lot of edema and body wall edema. This is because of the thoracic duct unable to drain properly. So in this patient, they closed the PDA and they held the ventilator for a second and just watched this white arrow. Soon as the PDA is closed and the ventilator is off, the dye is back into the innominate vein. So again, tells you that there are a lot of things that our eyes don't see, and especially we don't know what the damage to the pulmonary interstitial lymphatic system is happening. And even the thoracic duct seems to be occluded in these patients with PDAs. And to close it, it seems to be doing better. So for the future, I really think we need to have a randomized trial. So for the first step, we have set up something called the US PDA Registry, which I'm hoping to get most of the PDAs closed where transcatheter route in premature babies into this registry. And that'll be helpful to have some long-term outcome data. There is this trial, which is kind of spearheaded by Nationwide Children's Hospital. Carl Backus is really working hard to get this pivotal trial, which is basically percutaneous intervention in one arm and observational therapy in the other arm, and just waiting on some NIH funding for it. And hopefully we'll get going the next year or so for a randomized trial with percutaneous closure versus observational therapy. So in summary, I think transcatheter PDA closure is feasible even in extremely low birth weight babies. Transcatheter PDA closure is definitive, unlike pharmacotherapy, which may not be effective all the time. It is definitely just like surgical ligation, but does not involve cutting or stitching of babies with transcatheter closure. What we have learned so far, personally, I feel it is best to close the PDAs early. The first four weeks is probably the ideal time window. Beyond four weeks, I think the benefit is not as great. Personally, the earlier, the better. And if we can do it, I don't think the first week is enough, but maybe the second week we should consider closing them. I think early PDA closure affords faster weaning off the ventilator and oxygen support and allows for better weight gain. But currently all evidence of whether PDA should be closed or not is not based on definitive therapy. Therefore, we do need new evidence for this. I'm going to end with this one slide. This is a very classic slide from Sembrova, which was published in 2017. This is a consequence of non-intervention. So all these patients, these are from Ireland and the Czech Republic. They are divided based on the gestational age. So red being those less than 26 weeks and the number of postnatal days. And they've just kind of looked at the natural history. If you don't do any intervention, what have, how many PDAs spontaneously closed? And you can see if you're born less than 26 weeks, more than 50% are still open at two months of age. So this is a lot of consequence to this PDAs. So I'm going to say my personal opinion to this. So I'm going to put a line at the 30-day mark or kind of the four-week mark. And I'm going to put a line at the 50% mark and put a line at the 10-day mark. I think the best time or the best patients to target are these patients in the green square, which are 26, 27-weekers or less than that. Between 10 days and 30 days, I think these patients definitely will benefit from PDA closure because the rate of spontaneous closure beyond day 10 is less. So they're not going to spontaneously close and perhaps we need to close these PDAs. I'm going to put a blue square here. I think these are patients who do not have spontaneous closure. They still have PDAs open at 30 days. And maybe we need to consider closing their PDAs as well. But in the first 10 days, maybe we need to wait. We've actually done one study which shows that intervention the first 10 days, or even, I'll put it this way, the corrected gestational age is a better indicator. The corrected gestational age is 25 weeks or less. So that means if it's a 23-week and the first two weeks apply, they're at higher risk from a procedural complication. So maybe we don't have to intervene the first 10 days of life. But what we don't want is beyond 30 days, we don't want all these PDAs to be kept open because these are the patients who have the long-term pulmonary hypertension, like Satyen's early slides. We don't want these patients to go on to develop pulmonary hypertension. So we don't want any of these in the yellow box to be kept open. That's kind of my personal take on this. And I do have to thank a lot of people in my team. These are just a little drop of people that I need to thank, but thanks everybody for making this program successful here in Memphis. And hopefully it's translatable throughout the country and the world. Thank you very much. So, you know, we have a, I know we're running late. There are a couple of questions. Hawa, do you want to just bring those up and we'll just have two minutes for some quick discussion and we'll end it at that point. And thank you for staying with us, even though we're late. So we tried to answer some of the questions on the chat. The ones that were interesting is the, why do we think that the MVP causes late LPA narrowing? So Gaurav, if you can quickly answer that. So I answered that in the chat. I strongly believe it is the inherent tendency of the MVP device to the 19-old devices to get bigger with time. And I have a feeling that whenever I've seen them, it's a slightly oversized device. As we get more and more comfortable with these devices, we have to be cautious not to oversize the device too much. Also, I have noticed that if there's a baseline gradient, which we sometimes see in some of these patients, that may be also a risk factor. But once for the MVP device, maybe Shabana's data can shed more light on this. So another question for Sham is, do you think that there is, anybody has looked at the neurodevelopmental outcomes for patients who've had device closure versus not? Yeah, thank you for that question. We are actually looking into that. And actually my nurse practitioner is sitting right next to me. So she is truly driving this. We have a clinic, as I said, we have 300 patients now, who have PDA closure with transcapsular closures. And we have some historic surgical patients and those who are non-interventional patients. So she's developed kind of a neurodevelopmental assessment system. So she sees them all in clinic. We have the PDA clinic and does the neurodevelopmental assessment. Currently we are doing it up to three years, but now that the babies are getting older, we are going to five years and with aims to even go even longer because ultimately we do want them to be good in math and good in science. And that's our ultimate goal. I don't know what the preliminary data shows. She may be able to say, but time will tell, but that's our ultimate goal. Let's look at neurodevelopmental outcomes. What about intraventricular hemorrhage? Do you think it's better, worse, the same? Great question. So IVH is a complication that happens early. So the IVH risk is highest in the first week of life. Anecdotally, we haven't had any IVH post-PDA closure, but we don't do them in the first week of life. So we don't know for sure. I wish our neonatologist now with all this experience would allow us to do some early closure to see if there's IVH risk goes down. IVH and pulmonary hemorrhage, those two are very bad complications, which I think the PDA has some role for it. Unfortunately, we need to the only way to prove it is do it in the first week of life. So with that, I think we're going to end. Again, thank you very much for joining us, everybody.

PDA occlusions

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devices used for PDA occlusion

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transcatheter PDA closure

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early closure