Hello friends 👋
This special edition of The Incubator podcast features a neonatal cardiology journal club discussion hosted by Dr. Nim Goldshtrom and Dr. Adrienne Bischoff. The episode covers several recent studies in neonatal hemodynamics and congenital heart disease, providing insights for clinicians and researchers in the field.
Key topics include:
The impact of early hemodynamic screening on outcomes in extremely preterm infants
Updated guidelines for targeted neonatal echocardiography
The relationship between patent ductus arteriosus and bronchopulmonary dysplasia-associated pulmonary hypertension
Use of vasopressin in newborns with refractory acute pulmonary hypertension
Response to inhaled nitric oxide in extremely premature infants
Placental pathology's contribution to brain development in neonates with congenital heart disease
Perioperative brain injury and early neurodevelopment in children with severe congenital heart disease
The hosts discuss the clinical implications of these studies and their potential impact on neonatal care. They also highlight the upcoming NeoHeart Conference, encouraging listeners to attend and engage with experts in the field.
This episode provides a comprehensive overview of current research in neonatal cardiology, making it valuable for professionals seeking to stay updated on the latest developments in this specialized area.
----
Learn more about NeoHeart here: https://neoheartsociety.org/#intro
----
The articles covered on today’s episode of the podcast can be found here 👇
Giesinger RE, Hobson AA, Bischoff AR, Klein JM, McNamara PJ.Semin Perinatol. 2023 Mar;47(2):151721. doi: 10.1016/j.semperi.2023.151721. Epub 2023 Mar 5.PMID: 36882362
Ouellet S, Drolet C, Morissette G, Pellerin A, Hébert A.Pediatr Res. 2024 May;95(6):1572-1577. doi: 10.1038/s41390-023-02995-3. Epub 2024 Jan 11.PMID: 38212386
Zhu F, Ibarra Rios D, Joye S, Baczynski M, Rios D, Giesinger RE, McNamara PJ, Jain A.J Perinatol. 2023 Oct;43(10):1288-1294. doi: 10.1038/s41372-023-01742-0. Epub 2023 Aug 7.PMID: 37550529
Villamor E, van Westering-Kroon E, Gonzalez-Luis GE, Bartoš F, Abman SH, Huizing MJ.JAMA Netw Open. 2023 Nov 1;6(11):e2345299. doi: 10.1001/jamanetworkopen.2023.45299.PMID: 38015504 Free PMC article.
Boly TJ, Dagle JM, Klein JM, Rios DR, McNamara PJ, Giesinger RE.J Perinatol. 2023 Mar;43(3):324-331. doi: 10.1038/s41372-022-01582-4. Epub 2022 Dec 12.PMID: 36509816 Free PMC article.
Nijman M, van der Meeren LE, Nikkels PGJ, Stegeman R, Breur JMPJ, Jansen NJG, Ter Heide H, Steenhuis TJ, de Heus R, Bekker MN, Claessens NHP, Benders MJNL; CHD LifeSpan Study Group ‡.J Am Heart Assoc. 2024 Mar 5;13(5):e033189. doi: 10.1161/JAHA.123.033189. Epub 2024 Feb 29.PMID: 38420785 Free PMC article.
Neukomm A, Claessens NHP, Bonthrone AF, Stegeman R, Feldmann M, Nijman M, Jansen NJG, Nijman J, Groenendaal F, de Vries LS, Benders MJNL, Breur JMPJ, Haas F, Bekker MN, Logeswaran T, Reich B, Kottke R, Dave H, Simpson J, Pushparajah K, Kelly CJ, Arulkumaran S, Rutherford MA, Counsell SJ, Chew A, Knirsch W, Sprong MCA, van Schooneveld MM, Hagmann C, Latal B; European Association Brain in Congenital Heart Disease (EU-ABC) consortium.J Pediatr. 2024 Mar;266:113838. doi: 10.1016/j.jpeds.2023.113838. Epub 2023 Nov 22.PMID: 37995930 Free article.
----
The transcript of today's episode can be found below 👇
Nim Goldshtrom (00:03.202)
Hello everyone, my name is Dr. Nim Goldshtrom. This is another special edition of the incubator hosted by the Neonatal Heart Society.
Again, I want to say thank you to Daphna and Ben and the entire incubator community for giving us an opportunity to let you hear about NeoHeart and what neonatologists who care for babies on the spectrum of cardiovascular and hemodynamic diseases do. I have the great pleasure today of being joined by Dr. Adrianne Bischoff from Iowa. I was so close to getting that right Adrianne, sorry about that. How are you today?
Adrianne Rahde Bischoff (00:37.49)
I'm good. Thanks. Thanks for inviting me to be here. It's a pleasure. I think we're going to have a nice Poo-Poo-Ree today of some of the key articles that we thought were interesting. It's very hard to choose a couple, but hopefully we have a good mix of things to talk about in terms of neonatal hemodynamics and a little bit of congenital heart disease today.
Nim Goldshtrom (00:57.758)
Yeah, absolutely. It's like the Oscars. We almost couldn't go wrong, but there's just so many good things to choose from. And you're right, it is a potpourri. This is going to be like a journal club edition of...
of this podcast. And yeah, we're hoping to highlight the things that we read and the things that make us interested in our work and how we're trying to advance the cares from the domains of myself, cardiac intensive care, Dr. Bischoff's hemodynamics program. And yeah, we're going to cover a little bit of prematurity related pulmonary hypertension, TNE guidelines, and a little bit of imaging and fetal pathologies in congenital heart disease.
And so we're going to get started with a couple of articles that you guys will be able to see afterwards on the incubator site, and we'll have references and site links to all these papers, as well as for those who really want to get invested in this and know more and get mentorship, the NeoHeart Conference coming up this summer from the end of July to August 2nd, which we will all be there and hope to see many of you there as well. And so why don't we take away? I think Adrian, you're going to start us off with some interesting hemodynamics papers.
Adrianne Rahde Bischoff (02:03.676)
Yeah, I want to start off with a paper that is very close to my heart. I probably shouldn't be doing a journal club on a paper that I'm a collaborator, but I will do it anyways. So the first article that we're going to...
Nim Goldshtrom (02:16.527)
It just means you know the paper so well. You're going to give an insightful critique of and analysis of the paper.
Adrianne Rahde Bischoff (02:23.993)
So the first one we're going to talk about is the impact of early hemodynamics screening on extremely preterm outcomes in a high performance center. This study was published at the American Journal of Respiratory and Critical Care Medicine in August of 2023. The first author was my dear friend, mentor, Dr. Reagan Geisinger. The senior author is Patrick McNamara, and the collaborators are self-included and my colleagues here at the University of Iowa.
I think this was a really key sentinel paper that I think it's good for opening the session. This was a retrospective cohort study of neonates that were born less than 27 weeks. They had to be either inborn or transferred in the first 24 hours of life. And basically what we did is we compared two epochs in.
a high-performance center who was already known for exceedingly good outcomes in extreme preterm infants even before the addition of a neonatal hemodynamics team and a screening protocol for all the preterm infants right after birth. So the two epochs were the hemodynamics screening epoch, which started in October of 2018, and then the other one was a historical control subjects from 2010 to 2017. And there was extensive data collection from my colleagues.
to account for a wide variety of adverse neonatal outcomes and factors that were associated with them, including maternal, pregnancy variables, delivery, perinatal variables, demographics from the babies, and indices of disease severity after admission, as well as characteristics of the early cardiorespiratory care. Specifically for the hemodynamic screening epoch, that was the implementation of a standardized, comprehensive targeted neonatal echo.
being performed for all of these babies at 12 to 18 hours of life. And the big shift was a physiology-guided therapy approach. These echoes, just because everyone has a little bit of fear of manipulating these tiny babies, were done in a maximum of 20 minutes by a group of advanced practitioners. Our protocol is actually very comprehensive, has 80 to 100 clips, and has full appraisal of systemic pulmonary hemodynamics, cardiac function, shunts.
Adrianne Rahde Bischoff (04:35.236)
and all the mandatory essential images to screen for major congenital heart disease and assessment of central line placement. So if you open this article, you can see on Figure 1, there's a summary of the standard approach according to the findings on this initial assessment. In summary, moderate to high volume pediatricians initially treated with Tylenol and then followed by indomethacin, acute pulmonary hypertension treated with nitric, and cardiac dysfunction treated primarily with dobutamine.
and or epinephrine if needed to escalate. And importantly to highlight for standard of care for both epochs includes active obstetric management, antenatal steroids, all the good things that we do nowadays. This has been standard of care even from the first epoch, high frequency jet ventilation, a lot of surfactant use, caffeine for everyone, all the good things that are supposed to improve neonatal outcomes. So the primary outcome of this study was a composite of death.
before NICU discharge and severe IVH, so grade 3 or higher, but then also looked at some secondary outcomes. So we included 423 babies, so it's pretty large. 191 were in the modern hemodynamic screen epoch, and then the other ones from the previous epoch. And the mean gestational age was not different between those two groups, but there was a higher proportion of 22, 23-weekers in the most modern era.
And the other thing that was different is that in the hemodynamics screening era, the most common TN-ECO screening finding was a hemodynamically significant PDA in more than 70% of the babies. There were some things that got better over time. So we had higher rates of complete antenatal steroids, latency antibiotics, magnesium sulfate, delayed cord clamping, but there were also worse maternal risk factors which could compact those outcomes.
So what we found was that looking at the primary outcome, the composite was reduced by approximately half in the hemodynamic screening area. So from almost 30% to about 15%. And the individual components of the composite were also lower, including a survival free of severe morbidity, necrotizing enterocolitis, which was already pretty low here at around 6% and went to actually 1%, grade 3 BPD, and isolated severe IVH. And we like...
Adrianne Rahde Bischoff (06:58.048)
figure three a lot because it's very clear the significant shift in the primary outcome after the hemodynamic screening was implemented and, you know, how much the composite outcome dropped quite dramatically after that. Some other things that changed was that the modern era we had a higher use of medical therapy for PDA, but that decreased the need for cath or for surgery for definitive closure. And I think...
just kind of to summarize this paper because we have a lot more to go through. There are obviously a lot of limitations to this type of non-randomized retrospective study. We try to use a lot of strategies to account for changes in practice over time, but there's probably a ton of other factors that most likely have also contributed to the improvement in outcomes in this cohort.
And also another important aspect is hemodynamic screening program is a complete package, right? It doesn't mean that doing an echo early on and changing the approach to one clinical problem is what made things better, but rather the insertion of a holistic change in diagnostic and therapeutic strategies, which are very hard to quantify or specify in a study like this. So that's kind of one of the big highlights. I wanted to hear your thoughts, Nim, on what you thought or what you have to say about this.
Nim Goldshtrom (08:15.723)
Well.
You know, first of all, congratulations for your whole program for that paper. Describing it as a seminal paper is being too kind. Anyone who hasn't read this work really should to just understand the power of, of exactly what you said. It's a package, right? This isn't probe on baby, learn something, figure it out. You guys have a regimen. A guideline about what physiologic component you are trying to fix, right?
Nim Goldshtrom (08:46.232)
visual shunts, right, pH. It's not like, well, you could decide to do this. I mean, it's a whole algorithm that you guys have worked tirelessly to implement. The fact that you're getting complete imaging in under 20 minutes in babies who are under 1,000 grams is another testament to the skill training that you guys develop. It's truly incredible. And you're right, you know, it's hard to say when you implement so many things and time moves forward, and we get better in a lot of ways
natal practices are better and we learn about better and safer respiratory management and you guys have clearly have a strategy of surfactant and caffeine and handling and what you're doing to the most premature babies, how can you really tease out what's going on? But if you look at figure three and you see this kind of like this slide that just kind of like shoots down, it's hard to say, you know, that just instituting this package in this way isn't beneficial. Which one is it specifically?
I'm sure we can sit around and debate, you know, but the side effects of epinephrine in kids versus using of dopamine, right? Do you have to do caffeine? I come from a center that does caffeine as needed, right? Doesn't do immediate caffeine doses and does surfactant when baby's requiring. And what we learned from each other, I think, is that there's clearly many ways to cut the pie.
but hemodynamics opens up an opportunity that we have not had before. The things I would have even loved to see more, and I think we'll touch on it in some of the articles we'll talk about in a second, is I wish I would have liked to see blood pressure parameters too in some of these things, to see what is actually happening to the systemic measures that we use that we know are not perfect, but are happening when you get these kids under dobutamine and epinephrine, and the fact that you've cut down your surgical PDA treatment is pretty incredible.
Just a testament to how to move the needle. You've entered a world of diagnostic and therapeutic opportunities that didn't exist before, and it's really an incredible feat. You guys should be really commended for all the work you guys have done.
Adrianne Rahde Bischoff (10:55.012)
Yeah, we got a lot of questions after publication. We still get a lot of questions. What do you think were the major changes? What is the big bulk? What are if we have to implement one thing, what would it be? The most obvious ones, I think, is we do have a more early and targeted approach to PDA medical therapy in the transitional period, which we believe is probably making a big impact, at least in terms of severe IVH early on.
But then the other one that I can probably pinpoint that was quite different between the two epochs is a change from a primary vasopressor or fluid approach to a more inotrope driven approach in the modern epoch. Because we recognize that perhaps those lactic acidosis or those hypotensive babies actually had heart dysfunction problems that should be treated in a more thoughtful manner, not just by trying to treat the symptoms by increasing the blood pressure with the use of, for example, dopamine or whatever.
Nim Goldshtrom (11:51.87)
And I mean, I cannot tell you how much mechanistically that makes sense, right? You using a blood pressure, using a physical exam, and I'm a big proponent of New Year's, but they're not a perfect tool to really get at cardiac output, refractory hypotension, low preload, low flow SPC states. You need something more. And I mean, I could sit here and we could talk about this forever, but I think you're right, you know, when...
I equate this analogy and we'll move on to the other articles, but there used to be horses and carriages, right? And then the combustion engine and an automobile came in. And this would be asking Henry Ford, what do you think about the new automobile? Which one of the components? It's like, no, it's everything.
It's, there's a combustion, it's a completely different package. Which can, I guess, feel onerous for some institutions to think, well, how am I going to do this? And like, it doesn't happen overnight. You send people to get training at places like you, or places around the country that are doing this. You build a program, you have test babies, you build an algorithm, and like, it's possible, right? I think being regimented and more thoughtful and using.
new ways to make diagnoses is helpful, but it has to be in this kind of concerted, complete way. It's not like, I have an ultrasound I can put in lies now. Great. This is a much different animal, but clearly the benefits are, seem really, really promising. Congratulations to you guys on all the success. And from that success, you guys were able to help.
implement what it takes, right, as sonographers to put in some guidelines, which I think is the next paper to talk about, right?
Adrianne Rahde Bischoff (13:30.588)
Yep. We're going to talk about the guidelines and recommendations for targeted neonatal echocardiography and cardiac point of care ultrasound in the NICU, which is an update from the American Society of Echo. This was published on JACE in February of this year. First author is my boss here, Dr. McNamara. Senior author is Dr. Wyman Lai. And many of the co-authors have been in the previous iteration of the guidelines, which had last been published in 2011. So since this previous edition, which was 13 years ago,
Practice of hemodynamics has expanded. TN-ECO is becoming popular. Everyone wants to do it. And there's been a lot of publications, just like the one we just talked about, showing enhanced patient outcomes in hemodynamics care. But there's still a lot of variability in the practice, particularly regarding standardization of imaging methods, analysis, the inconsistency in the understanding and the integration of disease-specific hemodynamic information into clinical decision-making. So what the guidelines start.
by doing is provide a rationale for the use of TN-ECO in the NICU, what are the indications of TN-ECO, and what's the importance, and highlight the importance of understanding cardiovascular physiology in those that are performing hemodynamic consults. So this is a very long paper, we're not going to go through all of it, but it's less of a journal club because there's not a lot of methodology, it's a guideline, but we thought it was important to bring it up because this is a really big milestone for our community. But if you open on table one.
You can see that there is a lot of, they describe the typical pathologies and associated symptoms that may prompt a hemodynamic evaluation with the use of targeted neonatal echo, assessment of PDA, low systemic blood flow states, shock, acute and chronic pulmonary hypertension, perinatal asphyxia, diaphragmatic hernia, and so on and so forth. Then there's a very important section that I don't want to miss talking about, which is discussing the scope of cardiac focus, because that's also something that's been talked a lot.
about these days and a lot of people kind of confuse the boundaries between those two modalities and they are not the same, right? Table two then they do specify that cardiac POCUS has its use specifically for central catheter tip placement, identification of effusions, a brief assessment of suspected hypovolemia and under perfused states. But a big highlight is that unlike in older children and adults where cardiac POCUS is much more common tool,
Adrianne Rahde Bischoff (15:53.448)
In neonates, there's a much higher risk of encountering undiagnosed critical congenital heart disease, or most commonly, complex cardiopulmonary hemodynamic physiologic states, which may warrant a more detailed and comprehensive imaging by experienced operators who can not only image the whole heart and figure out these things, but also interpret the physiologic impact of all of the findings kind of together. Then the gynecologists kind of move on towards the practical
aspects and elements that are recommended as part of a T&E evaluation. And there's a very thorough description of images and measurements that should be performed. They're all on table three, lots of good pictures. I don't know who put them there, but good job on getting nice images to include on the guideline. But looking at LV systolic and diastolic function, left atrial loading, estimates of systemic blood flow, what are the markers that are standard and recommended for assessment of
going away from the subjectively the RV looks well, markers to assess pulmonary hemodynamics and estimation pulmonary artery pressure, pulmonary vascular resistance, the presence and directionality of shunts, of course. And finally, a little bit more, which I think is an enhancement from the previous guideline, talking about central lines and exclusion of other things that we cannot miss, like pericardial effusion and other complications like thromboses or vegetations, because that is part of our assessment. And if we find it.
we have to notify the team so that the appropriate measurements can be done. So there's a lot of explanations as to why these measurements were chosen, why are they recommended, and like I said, some helpful figures as reference for the readers. There's a little bit about advanced imaging tools and some brief recommendations about how to use that and how not to use that. And then it kind of moves on to the application of the imaging and the description of how
What are the main uses of TNE in disease-based screening, which are all what you can see in table five, but then also what are the clinical scenario-based screenings such as neonatal hypotension, hypoxemia, non-cardiac congenital anomalies, central lines, and even the use that is becoming more common, even we are learning here at the University of Iowa, which is how they use this on ECMO, how they use an adjunctive tool.
Adrianne Rahde Bischoff (18:16.32)
to decide not only the cannula placement, but also decisions about when to decannulate and so on and so forth. And then the article kind of wraps up by discussing the training and accreditation standards for TNE, specifically with a competency model of consultation, and then has recommendations regarding quality assurance, the establishment of new programs, and considerations about the relationship between neonatal hemodynamic programs and pediatric cardiology. And before I give it up.
Over to you, Nim, the one thing that I again wanted to highlight that the guidelines do talk about is the importance about the first echo, which is a big difference from the previous iteration of the guideline. The previous iteration of the guideline was pretty strict about the first echo needing to be performed by pediatric cardiology, which kind of limited a lot of what we do because sometimes you don't have that ability in the middle of the night. The current guidelines are a little bit more open to the fact that these examinations
can be successfully and safely performed as long as they are being done by, with a standardized protocol, with all of the necessary sweeps that are necessary to rule out congenital heart disease, as long as they are being done for patients that have a low index of suspicion of congenital heart disease, and that the study is also being reviewed by a pediatric cardiologist within a timely fashion. So that opens a little bit more of flexibility for the programs that are being.
implemented that if you have a fresh newborn baby that is acutely unwell and you need to do an assessment, you can do it as long as you fulfill some of those security measurements to make sure that we're not missing anything that is critical.
Nim Goldshtrom (19:57.93)
No, I mean, just jump right into what you just said. I'm so glad to see the sort of liberalization a little bit of who should do it in that first echo. Because if you think about what do pediatric cardiology fellows go through in their program, right? You're a first year fellow, you've maybe had some basic training in echocardiography, it's two in the morning, you're getting called to the cardiac ICU for who knows what, a four month AV canal, your seven year old TET redo,
clearly critical to general health disease, but you're expected to go and if there needs to be a function check or a Plural effusion check for this post-op you as a first-year cardiology fellow expected to go there and use your attending and have them view That is absolutely no different than another train semi-trained in training or professionally trained TNE person whatever their background is
potentially doing a first sweep as long as they have backup, timely review, somebody else to look at their images. And sometimes like, yep, you got most of it, but like we couldn't see the arch, we couldn't see the head and neck vessels, right? We didn't get great four chamber views, so somebody else will come clean it up. But that just gives you so much opportunity, right? The fact that as a society, you were able to give guidelines to allow individuals to have greater autonomy and usefulness in the moment, right?
And you may just go, oh wow, look at that arch, it's really getting smaller. I think this might be a co-arct, I'm going to call somebody, but you're getting information when you need it, you're not sitting there saying, well, but I shouldn't because it's a first echo. It's great to see that, but.
Again, going back to, again, the paper that you guys wrote with Regan, you know, this is the roadmap, right? This is part of the roadmap of people who are going to move into this space, of what it takes, right? What are the standards? What are the standards to make sure that it's done safely, done with high degree of quality, reproducibility, and has targets that can be achievable for people implementing this in their program? So it's great to see them both exist and evolve.
Nim Goldshtrom (21:52.778)
And again, it just speaks to, again, there's a little bit of my bias. I wonder if we as neonatologists as a group have.
maybe been a little behind as maybe some of other critically oriented folks in like additional training, right? Just as a collective, right? It just seems like almost matter of fact that pediatric critical care and cardiology like do levels of other training at the years and it's not that neonatologists don't, but I don't think it's stamped into us, right? That like, hey, why don't you go do a year of pulmonology or do neuro-nicu as it is now. And I think it is happening a lot more now.
Adrianne Rahde Bischoff (22:23.34)
I'm going to go.
Nim Goldshtrom (22:26.678)
I think the skills-based training like you have and the targeted neonatal echo provides is even so much more tangible and fruitful and it's clearly paying dividends to our patients.
And I'm hoping that this great work that you guys are producing just continues to show that it is, it's very natural that even beyond just your first fellowship, it does take a little bit more sometimes to do that slightly more interesting things and to bring back extra utility. And, and it would be great to be able to get TNE within a three-year fellowship. So as a tangent, do you guys train your fellows in their three years to be targeting you and them folks? Like can they get it all done in a three-year program? I'm just curious.
Adrianne Rahde Bischoff (23:05.224)
No, no, they cannot. They do get a lot of more physiology-based training because they are so exposed to the culture of our unit. But there is no way we can incorporate all the hands-on training that requires to be proficient at being a hemodynamics consultant within the standards of what is expected for the trainees during neon So.
Nim Goldshtrom (23:06.794)
No, they cannot, right? Sure.
Nim Goldshtrom (23:15.062)
Yeah.
Nim Goldshtrom (23:23.542)
Yep.
Adrianne Rahde Bischoff (23:34.28)
It does require to do this properly. It does require an additional year of training, which I know is hard. I've done it myself, but it's worth it if that's a career pathway that people want to pursue.
Nim Goldshtrom (23:38.698)
Yeah.
Nim Goldshtrom (23:45.57)
And if I take everything you just said, and instead of talking about TNE, I talk about cardiac ICU, right? And cardiac intensive care of the neonate and the preterm infant with non-critical and critical congenital heart disease, the answer is exactly the same. We have a program, we have a dedicated neocardiac unit that is run in the NICU by us and other dual-train neonatologists in cardiac intensive care, and our fellows get tons of exposure. They are overtrained for neonatal-based cardiac ICU if they go anywhere else in the country
what is expected and usually provided from neonatologist. And again, some of that is historically limited and the way the state of the field is changing, but the idea to get them to that level, it will always be a little harder. Even with our fellows who get a lot of exposure.
there still wouldn't be able to walk into a CEICU and do everything, even just for neonates and infants. And we have our fourth year program now for cardiac intensive care for neonatologists. And I echo exactly what you said. If this is something that is a patient population in a skill set that you're passionate about, it does take a little bit more extra training. It does sometimes feel strange that you have to spend a little bit more time. But again, anytime somebody answers me, would I do my cardiac ICU training again? And 100 out of 100 times, absolutely. I mean, I probably at this point would,
and I probably went to this a million times at this point through various other podcasts, but I probably would have just done the two year cardiology fellowship, honestly, to round myself out and give myself more credentialing and licensing opportunities than just a fourth year. But I do love what I do. It's work and it's hard, but it doesn't feel like work. And I hear from you that is the same kind of passion and thing that you love to do. And it just takes a little bit more.
Adrianne Rahde Bischoff (25:21.192)
Yeah, 100%. You guys have such a unique program. It's so awesome. And obviously, I'm good friends with someone who just did it recently. And there's no doubt that it was worth it. And it serves the population in a much more thoughtful manner to have people who have dedicated themselves to learn as best as they could how to take care of these babies.
Nim Goldshtrom (25:30.659)
Yeah.
Nim Goldshtrom (25:44.334)
Yeah, and for those who this sparks an interest and motivation to do that, come to NeoHeart this year, next year, join our organization, come here and talk to us. We can help usher you in to how to get this extra level of training and support to further your careers and to put you into landscapes and opportunities that you may not thought were even possible for this. I'm sure we can talk about this for all day long and I'm sure there's going to be.
some session we're going to be on at NeoHeart that is going to cover this to some degree, but we should cover our other articles. So that was great. We're going to dive into kind of like pathologies now and human genetic pathologies that we thought were interesting, and I'm going to take over for the next article. And so we have a smattering of physiologies and we're going to pick a combo one, right? BPD, pulmonary hypertension, PDA, right? It's like the holy trinity of premature badness. This recent article...
from JAMA Open Network, patent ductus arteriosus and bronchopulmonary dysplasia associated pulmonary hypertension, a Bayesian meta-analysis. Kudos for this group for making this.
hypothesis and study possible. It's a lot of acronyms and Bayesian analysis is not very simple. The first author is Dr. Eduardo Villamor. And this is from the Mosa Kids Children's Hospital in the Netherlands. Last author is Maurice, I'm sorry if I'm butchering this name, Huizing, I hope I'm saying that right. And another legendary author on this paper is also Steve Adman.
well done for them to try to find this novel physiology and association, which I think they did a pretty good job about. So as we maybe all of you are aware of BPD is associated with secondary pulmonary hypertension in about 25% of infants who especially who have moderate and severe bronchopulmonary dysplasia. Risk factors in general in this cohort include things like smaller gestational age and lower gestational age, excuse me, and SGA hypertensive disorders
Nim Goldshtrom (27:45.206)
You know, PDA is suggestive that it's impacting BPD-associated pulmonary hypertension, but there really hasn't been a meta-analysis using those three disease states up until now. BPD and PDA certainly have some interesting results. And so here they aim to perform Bayesian meta-analysis, different from just your systemic review meta-analysis, for the question of whether a PDA is associated in time of exposure with a PDA,
with BPD and secondary high pulmonary hypertension. Not to take off too much of a tangent, and this is way out of my comfort zone of Bayesian statistics, but the idea of Bayesian statistics is really referring to a different concept of what your...
trying to get as an analysis. So most of the general statistics we do is called frequentists. We have fixed effects that we're looking at. Bayesian statistics really take a probabilistic approach. And...
assume that a lot of the factors you have are random effects and they're trying to make sense of more noise than let's say assuming that everything you have is very fixed and stuck in certain matrices. That as far as I'll explain it because that may be a C plus explanation of Bayesian statistics. So this study was done using things like the Prisma guidelines and the Moose reporting guidelines. I did not know what the Moose acronym was. Apparently it's meta-analysis of observational
Nim Goldshtrom (29:16.72)
The population exposure comparison and outcome questions were stated in this way. So do very and extremely preterm infants or population exposed to a PDA have a higher risk of developing BPD-associated pulmonary hypertension? Then do preterm infants who have had no history of exposure to patent ductus arteriosus, their comparison group. They included all preterm infants less than 32 weeks gestational age or less than 1500
and reported primary data that could be used to measure the association of the PDA to the development BPD and PH. The outcome considered in the meta-analysis again was BPD and PH defined by echographic arteria as long as the evaluation was performed at a postnatal age greater than four weeks of corrected age.
The exposure of PDA ended up being divided in a handful of ways, which I'll quickly mention because it is important to the analysis parts of this. One was first of all, any PDA, any Dr. Shunting noted on any echocardiography, hemodynamically significant PDA, which will be defined when you read the studies that they quoted there, medically treated PDA, surgically ligated or catheter-occluded PDA, and then another separate category for medical or surgical interventional PDA closure.
Nim Goldshtrom (30:47.612)
They also ended up using PDA as a continuous variable, the longest how many days of continuous exposure to a PDA that they had.
Nim Goldshtrom (31:00.786)
into the results, they were able to find 186 studies and ultimately we did down to 32 studies based on the inclusion criteria and 8,513 infants. They did an extensive risk of bias assessment which showed a low risk of all the included studies. Echo criteria is noted in the supplement and I'll just review some of the highlights there.
Wonderful to hear from Adrienne in a little bit about whether some of that criteria is meaningful, maybe too wide or too narrow, but basically all that criteria as described by the 32 studies used some version of tricuspid regurgitation, either measuring it of a gradient across the valve of 25 to 40 millimeters of mercury or greater than 2.5 to 3 meters per second in the absence of pulmonary stenosis. Am I describing that correctly as parameters? Yes? Great.
Adrianne Rahde Bischoff (31:48.54)
Yes, you are. Yeah.
Nim Goldshtrom (31:50.858)
I wanted to make sure I understood the three meters per second as like the jet flow, because I'm not used to that value of a number to look at. The other criteria they used is some flattening or bowing of the intervascular septum into the left ventricle, IV, RV hypertrophy. And then there were a handful of nuanced diagnoses, which you can read in the paper if you're interested. So.
What did they find? 10 studies ended up reporting on any PDA presence and BPD and showed that the evidence was favoring the alternative hypothesis, but that this was weak or inconclusive. So the presence of any PDA is weakly associated with the outcome of BPD and pulmonary hypertension.
moving into hemodynamically significant patent ductus. There was three studies there, and the association showed moderate evidence to favor that there was an association between having a hemodynamically significant PDA and BPD-associated pH.
So moving into treatments now, PDAs that were treated, regarding PDA treatment, they were able to show that there was extreme evidence in favor of the association between BPDPH and the surgically ligated or catheter occluded group. And just to... So, I'm going to show you a little bit of a
Pause this back, when you do Bayesian analysis, you get into these probability zones that they categorize into five sections, weak or inconclusive, moderate, strong, very strong, and extremely strong. And so this was basically the strongest association, was between the surgically or catheter ligated group on 16 out of the 32 study. This is in contrast to a weak or inconclusive association in favoring of the null, so no association for the medically treated group. So it looks like a medical treated group
Nim Goldshtrom (33:34.256)
strong connection between BPD and PDA versus the surgically-inliable group. And infants who were exposed to PDA for a... Sorry. So the other results were that in BPD and PAH, the ones who were exposed to a PDA had exposure of a mean of an extra 10 days, plus minus 2.7, longer than the infants who did not end up having BPD and PAH.
They also showed that there was strong evidence when you had prolonged exposure to PDA, both analyzed as a dichotomous variable, right? So having more than four weeks or 36 weeks corrected age, and an extreme association when it was as a continuous variable of how many days of extra exposure. And there's two other reports there that actually show you effect size. And so this is...
fascinating take on a complex interaction of physiologies, right? The length of time, how did all these studies report on intervening or not intervening, watching these ducts close, and suggesting, you know, in not a very shy way about it, that the self-selected group, kids who ended up having surgically closed ducts,
are at really high risk of developing BPD and pH and whether that the selection process is well they were sick anyways and it's their illness overall that does it or the PDA truly was the answer I think we'll need a few more studies to tease out but I this doesn't make physiological
It doesn't seem like nonsense to me. I know with, you know, made analysis, you have to take some great assault out of the 32 studies. Each association was based on like a fraction, more or less of studies that they had here. And again, a lot of the authors also note that, first of all, spontaneous closure for a lot of these kids happened in about 20 to 50% of the infants in the control groups in a lot of recent RCTs. So I'm curious to hear your take on someone who sees probably hundreds of PDAs a week.
Nim Goldshtrom (35:35.676)
To me, this seems interesting and makes sense. I don't know if it argues any more strongly or not for doing anything about it, but it does make sense.
Adrianne Rahde Bischoff (35:45.384)
I obviously have some biases, but first of all, this is a very complex type of study to do, and I am impressed at how they even try to account for so many of these variables. There's obviously some of the key problems that come to my mind is obviously the ongoing discussions that we all have in the neonatal community about how do you diagnose BPD, what is BPD, what is...
Nim Goldshtrom (35:58.518)
Yeah.
Adrianne Rahde Bischoff (36:11.984)
You know, there's so many heterogeneous ways of defining it. And then the second one is they did a pretty good job at trying to define PDA and duration and burden in different ways. But it's not just about having the duct present. It's about how you treat it. How long is it present for and how significant is for that amount of time? So I think that this is a good kind of study to start thinking about this.
in a more thoughtful manner, not just like having a PDA that got treated or didn't get treated or got closed, didn't get closed, but how significant and how prolonged was that burden of the shunt. We are trying here locally to move our studies a little bit more towards that because we have repeated assessments and we have kind of like a PDA score, which has its own problems as well, but at least gives us some way of quantifying how...
pathological the shunt was and for how long and how that might impact outcomes. But I agree with you that it makes physiological sense. You have something that is over-circulating into a very vulnerable pulmonary vasculature. You can have remodeling of the vessels that may be associated with all the inflammation and all the things that come with BPD, but also with chronic pulmonary hypertension. And we do have evidence from other studies.
that are indirect because they're all observational, but that do suggest kind of the same type of link. In centers where there's a little bit more of an aggressive, not aggressive, but more proactive maybe, approach towards the PDA, there may be less incidence of chronic pulmonary hypertension in those babies rather than in other centers that have moved toward, let's just ignore, leave the duct alone, never touch it, and they do have higher incidence of chronic pulmonary hypertension.
So I think that just kind of adds to the story and should make us think about it even more in a more thoughtful way.
Nim Goldshtrom (38:06.35)
couldn't have said it better myself. I mean, it seems like both extremes maybe aren't the answer. Close every duct, just leave them all alone because as your program is clearly learning, there's individualization, right? One person's 1.7 millimeter duct is not another baby's 1.5 and they're huffing and puffing and they've got diastolic runoff and you're like, this is clearly much worse and they've got the LV dysfunction. What's fascinating about this is,
This is exactly the same problems and exactly the same conversations we have.
When you have, for example, let's say a hypoplastic left heart baby at 30 weeks, right? Who's going to weigh 1.5 kilos. And you don't want to go in and touch him, let alone do a Norwood. Or talk about like, when is the right time to do bands? Because you're literally exposing them to the same physiology. And we have the same conversations. And we get echoes on them every week, partly because of surveillance on a single ventricle. But we're looking at the same problems. How is the TR? Are we losing RV function because of myocardium beginning strain?
loading that we're doing on the heart, right, from all that return and the high QP/QS state, when are you going to take that runoff? And when the lesion is, well, you have complex congenital heart disease with a huge left to right chunk because of unprotected pulmonary blood flow. Take even truncus, for example, right? There's no duct. It's just going to have runoff as the PDR just drops over and you're going to have the same like biventricular volume overload or left LV volume overload. When is the right time? And then at that time, are you just going to ban them to protect them from their flow? Are you going to do the full repair?
And yeah, it makes complete physiological sense. And I think you're right. Like it's not going to be every kid, but it's definitely not no kids. We just haven't found the right answer, right? If like, what is the perfect algorithm? Yep.
Adrianne Rahde Bischoff (39:52.612)
And we may not, right? It's, I think we, everyone wants a simple answer, right? We do the trials and we're like, well, the trial said that we shouldn't treat, but you can't generalize to every single baby. The modern neonatology has to be towards precision individualized care. And there are limitations to the studies. We can try to tease out subpopulations in which things may be beneficial or not, but we're not, almost never going to have a...
clear-cut approach about should we close, should we not close, is this going to cause chronic pulmonary hypertension, is it not? Because there's too many factors. But I think this gives us a good clue that if you do have prolonged severe shunts, you may be increasing the risk of these babies having other type of morbidities. And then you kind of have to put it on the scale, which one's worse, the risks of treating it, the risks of medical therapy, the risks of a procedure, or the risks of long-term.
Nim Goldshtrom (40:32.003)
Yeah.
Nim Goldshtrom (40:48.308)
Absolutely.
Adrianne Rahde Bischoff (40:51.853)
BPD and chronic pulmonary hypertension, which will require perhaps lifelong medications and therapies, right?
Nim Goldshtrom (40:57.784)
Yeah.
And it offers an opportunity also that, you know, we're a much more connected world, right? I think there are centers that then have to look at what are my tools, right? And how good are they? You know, we can't all be, let's say Tennessee who is doing bedside, calf occlusion devices of preemie babies. So kudos to them. Um, but you can't pick up a phone or a zoom, um, and call these centers and saying, I have this case, here are my resources. Um, and that's the other thing I hope that, you know, um, conversations, podcasts, articles like this could say, it's like, there is an expert, literally
a phone call, a Zoom call, oh yeah, I know this person who's there, to get advice for people who do this more often, right? And how to maybe even more tailored, and maybe that's a part of the future too, right? Better connectedness through technology. Wonderful paper.
Adrianne Rahde Bischoff (41:41.384)
Yeah, well, we're going to keep going on pulmonary hypertension and we'll move on to the next article that we're going to talk about cardiopulmonary physiological effects of diuretic therapy in preterm infants with chronic pulmonary hypertension. This was a study published at the Journal of Perinatology in October of last year. First author is my dear friend Faith Zhu, senior author is Amish Jain and their collaborators, mostly at Mount Sinai Hospital in Toronto.
Nim Goldshtrom (41:46.414)
Let's do it.
Adrianne Rahde Bischoff (42:09.692)
And the reason we chose to go through the study as a good segue of chronic pulmonary hypertension is that although it's relatively small, we wanted to present something that was a bit more echo-based in a very important topic. There's a lot of clinical studies on diverse therapies for chronic pulmonary hypertension, but not many that will go into the granular detail with echo parameters and assessment of pulmonary hemodynamics. As we all know, chronic pH associated with BPD.
has variable incidence depending on the severity of BPD and survival of these babies can be significantly decreased when this complication happens. So this was a single center retrospective study before and after diuretic therapy for preterm infants that were born less than 32 weeks who had chronic pulmonary hypertension diagnosed on TNE after also four weeks of postnatal age. The definition for chronic pulmonary hypertension was very similar to this previous study.
So either septal-flattening in endsystole, an RVSP that was equal or more than 40 was actually the cutoff that they used, and or the presence of a bidirectional or right to left PDA shunt, which I would assume was pretty unusual at that age in that center. And all of these babies were treated with furosemide, either one milligram per kilo per dose IV or two milligrams per kilo per dose PO twice daily for three days and then followed by aldactazide. And their standard approach was to do a TNE, of course, before therapy, which would indicate the need for therapy, which was the baseline echo, and then a follow-up assessment, which should have been analyzed at a maximum of two weeks after starting diuretics. And what they looked at was the indices of pulmonary hemodynamics, right and left ventricular function, and diastolic and global function.
What they chose as a primary outcome for this study was the pulmonary artery acceleration time comparing from the post-treatment TNE with the pretreatment TNE. And secondary outcomes were other indices in the echo as well as some of the clinical indices of cardiorespiratory stability and ventilatory needs. Like I said, it was a relatively small study. There were 27 babies with a medium gestational age of 27 weeks.
Adrianne Rahde Bischoff (44:23.132)
And if you look at their baseline table, the distribution of respiratory support at the time that they were diagnosed with chronic pulmonary hypertension was a mix of patients mostly on different modes of noninvasive ventilation, including NIPPV, CPAP, and high flow oxygen. If you look at table two, they described the pre- and the post-TNE variables, and there was significant improvement after diuretics in the primary outcome of the PAAT.
but also there was a reduction in the PVR index and a decrease in the frequency of right to left PFO shots. And when they looked at these babies clinically, the immediate clinical course was characterized by not surprisingly a decrease in weight gain when they compare to the week before diuretics. Many of their babies, 15 out of 27, had a reduction in the respiratory support parameters after a week of therapy. Longer term.
There were only three babies out of the 27 that had to continued worsening of chronic pulmonary hypertension and eventually required additional sildenafil treatment during their NICU stay. But the majority of them, 60% of them, had stable pulmonary vascular disease and continued on diuretics upon discharge from the hospital. So in summary, this was a physiological pre-post-treatment TNE study for preterm infants with BPD-associated chronic pulmonary hypertension.
treated with diuretics, which resulted in a significant improvement in echo markers of PVR. And they also talked about a little bit of RV function and LV global performance within two weeks of therapy. So it basically suggests that first line therapy with diuretics seems to be very reasonable and may prevent the need for other more aggressive or more long-term pulmonary vasodilator therapies in this population. I think for me, one of the highlights of the study is that
These are not severe BPD babies. You can see that there's a low incidence of babies that were mechanically ventilated at the time of diagnosis. And even when you look at their baseline table, the pre-treatment features of chronic pulmonary hypertension were not necessarily in the moderate or severe range. Because even if you look at the end systolic eccentricity index, which is a measure of septal flattening, it was just over 1.3. So that's probably kind of mild septal flattening in the majority of the babies.
Nim Goldshtrom (46:17.066)
Yeah.
Adrianne Rahde Bischoff (46:41.948)
And the other thing I wanted to highlight is that it's not surprising, but there's not a lot of, even though they said that the diagnosis was based on an RVSP of 40 or more, that's actually not reported. And they probably had a lot of missing data because most of these preemies have actually incomplete TR jets. But again, it suggests that this population consisted mostly of probably mild to not much more than moderate pulmonary hypertension cases in general.
So I think there's an applicability and it's important and perhaps we should be treating, and this is a good first line therapy for the more mild cases and hoping to prevent them from becoming more moderate or severe, but it doesn't necessarily answer a lot of questions about what to do with those worst type of cases.
Nim Goldshtrom (47:24.99)
Yeah, no, I mean, it definitely seems like an adjunct. I know the discussions about the growing preemie stuck on oxygen and one at risk for BPD and pH is a different case of what we're discussing here. I really like the discussion where they talked about the mechanistic hydrostatic pressures and capillary leaks and the risk of pulmonary edema and the...
mechanistic biological plausibility that diuretics, in this case, right, as maybe an adjunct to pulmonary vascular disease would be, would be potentially beneficial. And again, I think it helps, right, as a combo of therapies. It's clearly a lot of more work to do. I can't remember, they didn't, I mean, I'm presuming here that they, again, doing full echoes, they probably ruled out, we have to assume, all left-sided disease, right, as another source of pulmonary hypertension, right? Because it's...
Adrianne Rahde Bischoff (48:12.992)
Yeah, they don't go into a lot of detail about LV diastolic dysfunction or even the more, what we're learning more and more, which is the systemic hypertension, heart failure with preserved dejection fracture type of population. But it seems from their baseline table that these are not, at least not extremely hypertensive babies. So hopefully there's not a lot of them in that group.
Nim Goldshtrom (48:17.764)
Mm-hmm.
Nim Goldshtrom (48:23.254)
Yep.
Nim Goldshtrom (48:27.524)
Yeah.
Nim Goldshtrom (48:37.506)
Yeah, again, in risk of trade offs, it's, you know, we have a lot of experience with diuretics. Again, it doesn't, the jury's not out, right? It seems like it's going to be helpful for some babies. And again, to continue the theme, right? Individualized personalized medicine, like you said, right, that's the answer, right? It works for the baby, great. Keep it on and see how it helps them wean respiratory support, improve echo markers. And if it doesn't, you can always stop them.
This is fantastic. Going back from a chronic to acute hypertension, where we're just swinging the pendulum back and forth with our neck and neck article. I'm so glad that you sent me this article on vasopressin use. I'm a huge fan. Again, that's mostly because I do a lot of critical congenital heart disease and like, you know, vasopressin is thrown around in my unit like epinephrine and norepinephrine and no unknown.
So this was wonderful to see another application with, again, a lot of biological plausibility and seeing the, I'll call it success, right? Seeing a small cohort of a convenience sample show some utility in the use of vasopressin for a disease that you wouldn't think would be the primary disease state. And so this article for pediatric research, vasopressin in newborns with refractory acute pulmonary hypertension.
I hope I'm saying this right. O-let, I'm going to butcher this name. I'm sorry. I think they're all Canadian and I apologize. Out of the get-go. It's O-U-E-L-L-E-T. There's a lot of vowels there that I'm sure I need to better.
Adrianne Rahde Bischoff (50:00.652)
I'm going to go ahead and close the video.
Nim Goldshtrom (50:08.114)
So my apologies in advance. The last author, Audrey Hubbard, we do know well, this group from Corbett-Bec, has done a wonderful review of cases where vasopressin was used in a QPH. And again, the QPH occurs as a consequence of sometimes failed transitional physiology. About 40% of newborns do not respond to initial therapy, such as with inhaled nitric oxide. Vasopressin, to kind of generally review, naturally occurring neuropeptide,
and is a vasoconstrictor through the B1 receptors. And it's believed to have some pulmonary vasodilatation effects as well. The vasoconstrictor effects are really great because they're preserved even through shock, hypoxia, and acidotic state, which is why it can sometimes be an adjunct agent in refractory shock treatment guidelines. The literature in using vaso in shock and preemies is limited, it's much more extensive in term and older children in shock algorithms than it even is in
any kind of refractory pulmonary hypertension state. And so this group, wonderfully so, did a retrospective single center study in their unit from 2016 to 2022, looking at both term and preterm infants within the first 30 days of life who had an exposure of at least one hour of vasopressin.
for the use of an acute pulmonary hypertensive crisis. They excluded lethal congenital disease, any cases where there was redirection of care, or any kids without arterial line to do sufficient sampling, particularly for PAO2 values.
Acute pH was defined by echo criteria, bidirectional or right to left shunting at the PDA or the atrial level. Isosystemic or supersystemic PDA pressures as measured by a TR jet and or flattening or bowing of the intraventricular septum. Refractory acute pulmonary hypertension was defined as non-improvement or worsening pH on echocardiography indicated by things like the estimated systolic pulmonary pressure or TR jet deteriorating ventricular septal movement.
Nim Goldshtrom (52:11.516)
insistently and or a change in direction of flow to a right to left chunk from a baseline either bidirectional or left to right. Other things that they look for were a persistent pre and post ductile saturation differential of more than 10 percent, lack of improvement in oxygenation status as indicated by an increasing FiO2 or lack of reduction in FiO2 requirement while on at least 20 parts per million of nitric and optimized ventilatory support. Other criteria that they was hyponatremia as a balancing measure of less than 130 millimole per liter, and thrombocytopenia of less than 150 k. The primary outcome here was going to be a change in the oxygenation index, which is your mean airway pressure times your FI02 times 100 over your peripheral arterial oxygen level, ideally from a material sample, from 12 to 24 hours after vasopressor was started. Secondary outcomes also then included the change in your PaO2, FI2 blood pressure, urine outputs, and lactate.
Moreover, echo parameters of pulmonary hypertension, direction of the shunt, septal bowing, PA pressures were examined during the vasopressor infusion as well. And so for FAFE outcomes, they evaluated the currents of not only hyponatremia and thrombocytopenia, but also renal function, hepatic function as well, through biomarkers and thrombosis and ischemic events too. This was an extensive clinical variable review as well as echocardiographic measurements from a manual and short review. So table one gives us a nice
overview of who this patient population was, which we'll get to in a second. The phasor doses that this center used to start with were 0.3 micro units. So I'm just going to go to the unit structure that I like to do which is 0.0003, right? Units per kilo per minute, that's our micro units, with a max dose of one micro units per kilo per minute.
Nim Goldshtrom (54:11.542)
Dose escalation was based on clinical and equilibrium assessments suggested by the hemodynamic team at that time to go up by increments of 0.3 microunits every 30 to 60 minutes as needed.
They used multiple comparisons and all sense did about for any adjustment as well and used generalized estimating equations for linear regression, which is great for repeated measures, which is what the study is. Again, the structure here was using a minimum quasi likelihood methodology with an independence model. I, we don't have time to discuss it, please feel free to call your local neighborhood statistician to get more information about repeated measures analysis and random effects. So they were initially able to get 30 subjects.
in this six-year period from pharmacy 25 ended up meeting conclusion 14 were term and 11 were pre-term five less than 32 weaker specifically.
23 of the 25 had an QPH after birth, so in the transitional period, two of them had it after one week of life. And again, a small sample size of 25 patients. So the median gestational age here was around 37 1⁄2 weeks with a median birth weight of about 2,790 grams, slightly tended to a more female population. And the initiation of ed suppression was on a median of about two days with not a big difference at the weight of administration.
Nim Goldshtrom (55:31.82)
to be a person with 72 hours with an interquartile range of 42 to 122. So they're using this for like three plus minus days for a lot of these kids, which is, which is, again, in my opinion, fun. I just thought it would be much more a short term, but I was, you know, both surprised and, um, and kind of applaud them for being able to keep it on and seeing the utility without as many of the side effects that they're going to report here.
And so the major outcome, and again, all these kids were already in 20 parts per million of nitric. So the 100% of the population was exposed to nitric prior to vasopressin initiation. 80% had been receiving hydrocortisone already. 64% had received or were on epinephrine. 32% on milrinone, 24% on dopamine, and a handful of sildenafil and dobutamine. And the initiation dose was 0.3 micro units per kilo per minute. And so the results. So on the vasopressin in this group,
The oxygenation index improved in this cohort by 50%, went from 28.4 to 14.4 after 12 hours, and further went down to 12.25 at 24 hours. And these were both statistically significant from initiation values. The FiO2 also decreased from 91% to 50% in the first 12 hours, statistically significant. And they did see also an increase in the PaO2 and the mean arterial pressure from 41 to 51.
was from mean of 42 up to 48, also statistically significant. Also diastolic and systolic increases were significant as well. Interestingly the urine output which also increased and the lactate which also decreased slightly, these were not statistically significant.
Moving over to echo parameters, right? So after vasopressin, they were able to have 17 of the 25 patients with follow-up echoes. The pulmonary artery pressure by TR-GET went from 74 to 56.5 millimeters of mercury. This was not statistically significant, only in eight of the 25 patients. Ventricular septal bowing reduced from 52 to 40% out of 17 of the 17 echoes that they had, not statistically significant. And right to left shunting at the PFO went from 20 to 12%.
Nim Goldshtrom (57:41.48)
significant but trending in the right direction. And so out of these 25 patients, 17 or 68% did have at least one episode of hyponatremia and table three gives us those safety comparisons. And so the lowest level on average is 128, right? So just below their cutoff. The cellular levels prior to treatment and at the end of treatment were actually within the low normal range of 135
Nim Goldshtrom (58:11.36)
the ALT, urea and creatinine were all basically not so difficult to change. There were no cases of hepatic necrosis or peripheral ischemia reported. There was one case of spontaneous intestinal perforation and three cases of necks in the seven days following the initiation of vasopressin. No patient went at ECMO. And in this cohort, what is fascinating, which I would like to hear your take on this too, is that nine to 36% of these patients ended up dying from conditions that were really not related to the initial illness in six patients and
were redirections of care for more complex medical decisions. You know, there are animal studies, right, particularly rats, that show improved hemodynamic parameters and cardiac function, also following vasopressin diffusion, in contrast to the effects that you observe when you use like Dora Happy and phenylephrine for pH. And so I understand the draw of vasopressin, and we use it a lot in refractory shock. I thought this was...
a great piece of data to put out there in the world. It's not perspective, it's not randomized, it's not controlled. Those are all things I would love to see in the next study. To do this kind of novel hemodynamic approach, right? Look at a physiology and think, what can I do to change the circuitry in some way with the variety of tools that I have? And so kudos to them to first doing this as a clinical practice, right, among their group, and then to give us the insight of what they're learning as a novel way of trying to push
back against high right-sided pressures and an LV that may be unhappy to provide a little bit more of left-sided preload by increasing your systemic mean pressure.
Adrianne Rahde Bischoff (59:50.88)
Now, I kudos to them. We use it all the time. This aligns very well with our practices here. A couple of things that I wanted to highlight that were interesting to me is that I was a little bit surprised that their dosages for vasopressin were a lot slower than what I'm used to using it. One is kind of like my middle ground. I frequently go all the way up to two.
Nim Goldshtrom (01:00:09.886)
Yeah.
Adrianne Rahde Bischoff (01:00:13.74)
So we even used only 0.3. But it's not surprising because you see that a lot of their babies were already on epinephrine. So 64% of them were already on epinephrine. And when you look at that table with the blood pressures, their median blood pressures to begin with were not that low. So I think from a hypotension standpoint, these babies were kind of somewhat already treated. They were not the super sick, super hypotensive at the start of therapy. So that was something that was interesting for me.
Nim Goldshtrom (01:00:20.235)
Mm-hmm. Yep.
Adrianne Rahde Bischoff (01:00:41.544)
The other one, you did mention it briefly, but the increase in urinary output, although it's not statistically significant, which is probably related to their numbers, I think it's a good highlight to the audience because there's a lot of fear for those centers that are not using vasopressin, that the babies are going to stop peeing, and that's why they're going to have low sodium. In fact, what we see is that when you restore cardiac output, when you improve the basic physiology, the kidneys get perfused better, and the babies actually improve their urinary output.
Nim Goldshtrom (01:00:58.455)
Yep.
Nim Goldshtrom (01:01:06.222)
exactly.
Adrianne Rahde Bischoff (01:01:11.444)
And the hyponatremia most often is actually from a natriuretic effect. And you actually have to give just more salt. It's not a matter of necessarily having to restrict total fluid intake. And one of the things that
Nim Goldshtrom (01:01:11.554)
Yep.
Nim Goldshtrom (01:01:22.738)
And if they do drop off the point, you do restrict, right? Like you just pull back your TFL, right? It's all possible in a sense of care.
Adrianne Rahde Bischoff (01:01:28.652)
Yeah, it is all possible and you just have to look baby by baby. But it's not that all of them are just going to stop peeing because you gave them a vaso. And then the last point that I wanted to make that I didn't quite see, and maybe I didn't read in enough detail for this discussion, but they didn't talk much about the PDA. I get a lot of questions from other people if the vasopressin only works if your PDA is open, because you're going to change the direction of the shunt. It doesn't seem to be the case because they don't even talk about the PDA. So I'm assuming that a lot of their babies actually.
Nim Goldshtrom (01:01:56.455)
Exactly.
Adrianne Rahde Bischoff (01:01:58.368)
didn't even have a PDA that was open. And that seems to be my clinical experience as well, that a vaso works really well in pulmonary hypertension, irrespective of having a PDA open or not. But that would be a very interesting study that I would be interested if someone did or was able to do it. I don't know how they could do it, but I would like to know if there is a difference having or not having a duct open.
Nim Goldshtrom (01:02:21.718)
Yeah.
because it really does beg the question and the discussion is wonderful here, right? Is it vasos pulmonary dilatory effect? Is it your increasing afterload to have the LV fight back against the RV, right? A little bit, right? And create a little bit more LV end systolic and end diastolic pressures, right? That are going to increase maybe your left atrial pressure. Like, is that what the physiology is? Are you just allowing the left side to have more resistance but not compromise systemic cardiac blood flow
Adrianne Rahde Bischoff (01:02:43.084)
Mm-hmm.
Nim Goldshtrom (01:02:52.536)
delivery to just push back against these right-sided pressures, right? Even irrespective of Japan, I'd be fascinated to hear about those studies. I think that's possible.
Adrianne Rahde Bischoff (01:03:01.12)
Yeah, or is it an effect on the aortic root pressure and having improved coronary perfusion, which might improve secondary RV dysfunction that a lot of these babies have? So yeah, I think it's multifaceted as always.
Nim Goldshtrom (01:03:05.994)
Yeah. Exactly. Yeah.
Nim Goldshtrom (01:03:13.598)
The other thing I would love to see, especially because they had a preterm population here, is I would have wanted to hear about head imaging, right? The fear driving up these blood pressures, right?
quote unquote, so high in a preemie, right? If you're moving up to the 50s in an X, you know, 30 weaker is maybe sometimes scary for people like, like we, I'm sure in your institution, you're like, you're aiming for some number that's not 15, right, in the 21 weaker. But also it's like, it's a bit of a handling or we can have brain bleeds. Again, a lot of these cases, as they reported, were not transitional physiology, right? Not necessarily in the first couple of days of life and they kept up from day three. So, so this risk of, you know,
and intraventricular sensitivity is probably not there. But I would have loved to see it because as, so my personal research is a lot of auto regulation. This makes sense from an auto regulatory capacity to you. When you have unstable, poor cardiac output, poor delivery, pulmonary hypertension, regardless of what your blood pressure may be, your auto-regulate capacity is probably under strain as well. And so sometimes you help just improve another element of it by targeting numbers that you can't really see without different monitoring tools
or ultrasound for male cerebral artery. But I'd be fascinated about the long-term neurologic outcomes about fixing this physiology and targeting heart blood pressures as well. So a lot of interesting future work to do in this standpoint. So wonderful for them. Where do we go to next, Adrian?
Adrianne Rahde Bischoff (01:04:41.832)
I'll take the link of you talking about preemies and pulmonary hypertension and go for the next one, which is response categorization and outcomes in extremely premature infants born at 22 to 26 weeks that received inhaled nitric oxide for hypoxic respiratory failure. As the day that we are recording, this is exactly one year, so it's still within the past year. So, Journal of Perinatology, March of 2023. This is the first author is my dear colleague here, Dr. TJ Bolli and senior author again,
Nim Goldshtrom (01:04:47.153)
Nice.
Adrianne Rahde Bischoff (01:05:11.284)
my mentor, Dr. Giesinger. And the reason why we thought that this article would be interesting for today is that there's still a lot of debate in the use of inhaled nitric oxide for preemies, especially because of the lack of endorsement by some of the big bodies out there and questions about the mechanism of action of nitric in this type of population. And based on previous studies, as everyone knows, including RCTs, the use of nitric oxide in preemies
has been very inconsistent and often contradictory. And the main problem about all of these studies is the lack of precise assessment and description of the true incidence of acute pulmonary hypertension in these babies. So what this study aimed at was assessing the response to nitric and clinical outcomes in preterm infants born less than 26 weeks who presented with hypoxemic respiratory failure. This was another retrospective cohort study, and they included babies, hypoxemic respiratory failure was defined as
an FIO2 more than 50% or an OI more than 10. And the babies had to have received nitric for at least 12 hours. Bunch of variety of clinical parameters that were collected. And then what they did is that they divided the patients based on their response to nitric after two hours of therapy through a consensus of three neonatologists that were blinded to the clinical outcomes. So positive responders as one would expect would be an improvement in an FIO2 or OI by at least 20%.
And then they actually defined negative responders, so babies that actually get worse on nitric oxide. So there's an increase in FAO2 or OI by at least 20%. And then everyone else that didn't fit into either of these categories were considered non-responders. They tried to collect some data about the etiology of the hypoxemic respiratory failure if it was available and clear. And what was one added benefit was the collection of TNE data if it was...
if it had been done within 24 hours of nitric administration to try to characterize what the underlying physiology around the timing of medication was. Diagnosis of pulmonary hypertension on echo was very similar to the others. Elevated RVSP, PDA shunt with at least bidirectional right to left shunt, septal or paradoxical, flat or paradoxical septal motion.
Adrianne Rahde Bischoff (01:07:34.544)
And the primary outcome was a composite of death or grade 3 BPD. So after a bunch of exclusions, they had 107 babies. 63% were positive responders, which is very similar to the rate of term babies with hypoxemic respiratory failure that respond to nitric. 27% were non-responders, and there were 12% who were negative responders.
The demographic and antenatal characteristics were not different between the groups. So if you only looked at their baseline stuff, you could not tease out which ones would be more likely to respond or not, except that the positive responders tended to be a little bit younger at the time that they received nitric, so mostly in the transitional period. But again, other markers of clinical illness severity or hypoxemia that did not help differentiate between the groups, which again highlights how much.
using only clinical parameters to decide a therapy yes or no is not going to be enough because it's so heterogeneous, even more in preemies than in term babies. When they looked at the ECHOs, they were able to assign most of the underlying physiology in about 90% of the babies. And what they found is that positive responders had acute pulmonary hypertension diagnosis, which was 67% of them. Sepsis, sears was the next one, 9%, and lung disease was in 24%.
Whereas the negative responders, 33% had a diagnosis of actually a hemodynamically significant PDA around the time of nitric receipt, and 42% had sepsis, 25% had lung disease. And when they looked at the non-responders, it was kind of a potpourri of things. So 15% had acute pH, 26% had a hemodynamically significant duct, some of them had sepsis, and 25% had severe lung disease. The primary outcome was lower in the positive.
responder group when compared to the others. And the ones who had a negative response had an increased incidence of several morbidities, including BPD, ROP, and duration of noninvasive mechanical ventilation after nitric was already stopped. Then they did a post-hoc analysis in those who were less than four days of life, so only the transitional period babies. And they showed that there was a significantly higher incidence of the primary outcome, again, in the non-responders and in the negative responders.
Adrianne Rahde Bischoff (01:09:52.244)
The conclusions of the study are that oxygenation improvement in 22 to 26-week-curses is at a rate that is comparable to term infants, specifically if it happens during the transitional period and when acute pulmonary hypertension is the main physiology. And one of the main highlights compared to the previous study is the characterization of the underlying physiology at the time that the medication was started. So I think one of the key messages is that hypoxemic respiratory failure can be because of many different problems.
some of which nitric can be either harmful or at the very least not helpful, but with improved characterization of the physiology, specifically looking at the presence of echo features of acute pulmonary hypertension and the exclusion of pathologies in which nitric would be harmful, such as a PDA, can help the clinicians decide more precisely which population can benefit and in which ones the administration of this therapy could be.
Nim Goldshtrom (01:10:46.974)
Yeah, I mean, I don't know what else to say about having images and pictures of what's going on and, and finding the right physiology. And again, we were definitely being hard on standard vital signs in this talk, but it's the reality of the current state of the field right like.
a SAT trend or change, a heart rate up and down, your respiratory rates, blood pressure numbers, they're not good enough in this day and age, right? You need more, again, to someone who's done auto-regulation research, I don't know what to do with the blood pressure other than protect it from like the fifth or 10th percentile of hypertension because I don't know what's good for the brain. You need a Nears probe, you need to do correlation studies. You look at all the sepsis prediction algorithms coming out of UVA and all the other places,
complex features. If you can't look more intensively, more discreetly and find the etiology is exactly like you're saying, how do you know what you're treating? It's just unbelievable in that tab. Is it table one or two from the big? Zero hemodynamically significant TDAs in the responders. And then it all goes to the non-responders in group two. And it's like, it's a different physio. Of course you're going to flood the lungs if you put nitric on during that safe life, but that's absolutely not the right time.
So just a great testament to having pictures and skills and tools to be able to meta monger.
Yeah, it's, and the other things I found interesting about that is no worse IVH, right?
Nim Goldshtrom (01:12:19.422)
no worse neck, all these other untoward effects that we worry about with nitrate, like you don't see them even in these like late responders, non-responders, like they died from different things. It was a different pathology that you treat at the time. And so you don't have to be definitely afraid of these other like human dynamic swings that you think you're going to have. Again, they can still happen. You have to know to parents about them, right? There are side effects to every medication. So to say that's not going to happen, but it's just great to see that they're, you know, in a controlled setting of one group's experience, they're not seeing these balancing measures of adverse effects kind of uneven.
equally distributed in some groups versus other groups of these between the responder, non-responder, and negative responder.
Adrianne Rahde Bischoff (01:12:55.772)
Yeah. Take us to the cardiac ICU, Nim.
Nim Goldshtrom (01:12:58.87)
All right, from hemodynamics of the preterm infant with severe disease, we go to the fetal environment, my hometown, which is absolutely not true. But yeah, we're going to shift gears a little bit to congenital heart, right, from the hemodynamics of prematurity, the hemodynamics of congenital heart disease. And I thought, you know, we've talked a lot about great tools and techniques for, because with heart, with, you know, structure of the normal heart, it's prematurity, severe disease is in terms of the lungs, the heart, the best.
There's plenty that we could be talking about in the CI-C world. I thought what's interesting is to also touch upon the realities of what is fixable and what might not be fixable and how to look at the...
aspect of what is a child coming out into the world with congenital heart disease living with and I thought these two recent articles about the risks of intrauterine life on brain injury and then early MRIs would be like a nice way to end the program about like what can we do, what are these kids actually coming out into the world with that we can either have better guidance, think about more protectively.
And so this first paper out of the Netherlands, titled, Placental Pathology Contributes to Impaired Volumetric Brain Development in Neonates with Congenital Heart Disease. So first off here is Maaik Nijman, again, apologizing if I'm mispronouncing it. This is from the CHD Lifespan Study Group. The program was out of the Netherlands here. And the background in regards to this article is that,
neurodevelopmental outcomes are still not perfect in neonates with congenital heart disease. And much research in the last decade is really showing us that in utero brain development is also a now underappreciated, well, it's less now, but has been an underappreciated environment where maybe a lot of already poor...
Nim Goldshtrom (01:14:49.878)
pathophysiology is taking place and already setting these kids up to start from behind. There's already been studies out there showing that a term baby with complex or critical congenital heart disease born at 40 weeks has the brain volume size of a preterm infant with a structurally normal heart born at 35 weeks. So their brain volume size is almost a month behind already.
It is known that there's already continued altered brain development because of this and associated with poor developmental outcomes. We also know that CHG is linked to other abnormalities like abnormal placentation, higher risk of preeclampsia, lower placental weight, and various pathologies like thermosis and infarctions and delayed vellus maturation. So this group here set out to look at how fetal brain growth and placental pathology were associated to the postnatal brain development and injury in kids with congenital heart disease.
Center Prospective-Alberts Rational Study from the Wilhelma Children's Hospital in Nevelett from 2016 to 2021. They were able to recruit 96 term singleton pregnancies with a severe fetal CHD. In the article they reference the 2002 Hoffman article that differentiates severe to milder forms of congenital heart disease. These include a majority of the ones that you think about that would need early intervention, transpositions, TEP with pulmonary
ones of single ventricle like double inlet left, truncus, TAP, PVR, and some of the acyanotic ones which may need early infant, not necessarily neonatal interventions, AV canal, large VSDs, PDAs, critically asked, things like that.
They did not include premature infants here. Kids with identified genetics or major extracardiac malformations. Placenta pathologies were reviewed by two blinded placenta pathologists who were just aware of the presence of a congenital heart disease and the gestational age. All the subjects had postnatal, but pre-surgical MRI with a 3T machine. They used the human connectome project for structural processing of images to get volumetric measurements
Nim Goldshtrom (01:16:55.12)
to then identify a variety of pathologies, thromboses, hemorrhages in a variety compartment of the brain. This study ultimately because of the heterogeneity of congenital heart disease, which is a problem in doing many studies when you're trying to do CHD type of work, is how do you group kids? So ultimately what they ended up having to do because of the various heterogeneity is limited to subdivisions of transposition, single ventricles with aortic obstruction, and biventricular defects with aortic obstruction,
category. So initially they were able to enroll 123 infants but they were excluded some due to the variety of excluded criteria that was mentioned. In the 96 patient there was a mean gestational age of around 38 weeks with a mean birth weight of 3200 grams which was about a Z-score of minus 0.3 as a mean.
Between our three groupings, 31% had D-transposition of the great vessels, 24% were single ventricle with aortic obstruction, and 23% were biventricular with aortic obstruction, and the remaining 20-ish percent were these other defects. So what did they find out in the results? The placental weight in this cohort was less than 10% in 28% of the cases.
there was abnormal umbilical cord insertion in 15% and microscopic placental pathology in 90% of the cases. These included as the most common of placental pathology, maternal vascular malperfusion in almost half of all placentals, nucleated RBCs, which represented chronic hypoxic condition in 37%, chronic parenchymal inflammation in 35%, and corangiosis in 22% of placentals.
There's also delayed maturation of the placenta in 30%. There was a median placental path severity score of about 10, which is on the moderate side. There's a scoring system that they use that's been validated in preterm babies, so that's a little bit of a limitation. The maternal vascular malperfusion in the placenta was associated with maternal pregnancy complications. This was statistically significant. And chronic parenchymal inflammation.
Nim Goldshtrom (01:19:03.894)
with pre-existent maternal comorbidities, also significantly significant. In regards to the placenta characteristics and these congenital heart subtypes, there was no difference in the rates of the placenta lesions between the different subtypes, except for fetal vascular malperfusion, which occurred in about 10 neonates, about 10% of them. And fetal thrombosis was also slightly more noted in single ventricles with aortic obstruction.
And so tons of pathology in basically almost the entire cohort. And so now we move on to pre-surgical postnatal MRIs. Out of the 96, they got 68 neonates, so 71%. We're able to get a postnatal MRI at a median age of about four, median postnatal age of about four days, which is a corrected post-menstrual age about 39 and a half weeks.
65 out of the 68 had sufficient MRI quality for volume metric analysis and 54 for quantification of the gyration index. So in linear regression analyses, it indicated that the placenta pathology score significantly accounted for a proportion of variance in the cerebellum volume, which was statistically significant, the cortical gray matter volume, and total brain value when covariating for things like post-menstrual age at MRI.
This association, it wasn't seen between the placenta pathology score and brainstem or deep matter. And in the 59 infants who had brain injury analysis, 29% exhibited ischemic injury, 53% exhibited hemorrhagic injury and MRI. So that's almost 80% of the cohort improvement that term. And the predominant limousines comprised subdural hemorrhages in about a third, interventricular hemorrhages in about 24%, and white matter injury in 20%.
And so what we're coming out of this paper is placenta pathology, there may have a role here in how it is associated at least with impaired brain growth in children with CHD, especially the things like findings of nucleated RBC integrating, indicating some prolonged fetal hypoxia. And you got to imagine even with all the fetal shunts that exist, there's clearly still some kind of deficit occurring either from blood getting delivered into the head and neck vessels. If it's not able to make it out of the aorta or simply
Nim Goldshtrom (01:21:17.668)
of obstruction and a lack of good diffusion at a pathologically diseased placenta. The level of placenta pathology was not associated with pre-op hemorrhage or a ischemic brain injury. This implies that the lesions primarily affect the fetal growth rather than leading directly to post-natal brain injury. And again, comparing to a pre-me brain, which has a more arrest of maturation pathology, it doesn't always pan out to poor nor developed outcomes. And so while this association is
that these MRI findings, unless they're like hard, grade three or four bleeds, severe strokes, knowing that these things exist, it doesn't implicate our population to necessarily say, oh, this is bad, I don't have anything I can do for them. It does set them up from behind, but we definitely know from preterm literature, right? Mild MRI findings do not equate to long-term, definite neurodevelopmental outcomes. They may be a longer road and a bridge to recovery.
But it is really fascinating to just continue to see more of this work show us how Maybe unwell is too strong of a word, but How really during the fetal environment where these kids are already starting from behind from their brain development, and it's really Fascinating and I don't know what to do for this. It's not I can't treat the baby. I want to help but It's an interesting reality
Adrianne Rahde Bischoff (01:22:36.236)
Thanks for watching!
Adrianne Rahde Bischoff (01:22:43.316)
Yeah, this was really interesting for me. I'm not as familiar with this literature, and it highlighted for me that even outside of the congenital heart disease world, perhaps I should be paying more attention to the placental pathology to figure out the risk profile of what my preemie babies are set up for, and just highlighting that to implementing therapies early on and all the things that we know that are good for their brain development post.
postnatally and it was very good educationally for me because I did not realize naively that there was so much placental pathology in this type of population. I thought they had normal placentas and it's just that their hearts were messed up, but apparently that's not the case. So that was good knowledge for me to figure it out.
Nim Goldshtrom (01:23:27.071)
Yeah.
Nim Goldshtrom (01:23:30.41)
Now, I was aware there was a link. I mean, again, this is one center's experience and there are many other papers to show you the many placenta pathologies that exist with CHDH. It's just fascinating how, I mean, 90% is pretty extensive. Again, the caveats here are, we're a center, for example, that we just don't brain MRI our CHDHs anymore because we know we're going to find these things. And yet, unless it's a severe deficit, and usually severe deficits will have a clinical manifestation, right? You're going to have some kind of
deficit if you're upper lower bilateral extremities, you're going to have stroke features. It's hard to counsel a parent and tell them, well, you have a mild findings of hypoxic ischemic injury or mild watershed infarct or a small subdural. And that I can tell you that that's going to pan out into a significant delay. Like it may, but for many kids it won't, right? Like these small minor deficits don't pan out. And there are other studies looking at this to try to find pre and post differences, which we do see, right? Going on bypass, cooling a baby.
is not a low risk proposition and then having low cardiac output state and you know shock physiology afterwards is not helpful. But yeah.
the injury cascade is starting really early. We thought it was, you come out of transitional physiology, you have a runoff lesion, you're on PGE, you're waiting for surgery, but no, it starts in utero. That hopefully doesn't make parents more or less concerned and stressed. It does give us an opportunity now that we see it to think about what could we be doing different? Are there drugs, are there therapies? You think about a lot of the thrombotic issues, is there anti-coagulation in pregnancy, something to think about?
outside my wheelhouse, but it is really fascinating to see the degree of the burden. And so then the question comes out. So these kids comes out and they have bred.
Nim Goldshtrom (01:25:22.018)
MRI findings that you're going to see. What does this really mean? Does any of this pan out? And so this is a paper that kind of speaks to this next paper, kind of just speaks to that literature in general about things we already sort of know about congenital heart population in terms of what does early imaging, right, when you find it, when you find these lesions, associate itself to longer term developmental outcomes. And so this is just one of many great historical papers on neurodevelopmental outcomes.
from the Journal of Pediatrics titled, Perioperative Brain Injury in relation to early neurodevelopment among children with severe congenital heart disease. This results from a European collaboration with first author, Dr. Astrik Nuukom. Again, hopefully I'm pronouncing that right. Last author of Beatrice Lattel. This is a large, large collaboration, the European Association Brain in Congenital Heart Disease Consortium, EUABC. What a wonderful acronym from Switzerland. This was a three center study.
looking at pre and post operative brain MRIs.
to associate them with neurodevelopmental outcomes at 12 or 30 months after a neonatal congenital heart disease repair. And again, the background which we sort of cover pre-op white matter injury is not uncommon, as you guys just heard, as well as associations to placental pathology. Hemorrhagic injury strokes are up to 40% in complex CHD, about 56%. In the post-operative period, can have new post-operative white matter findings. The novelty here is that this was a three-center collaborative with a very standardized brain injury description protocol
of MRIs. And the null hypothesis was that these higher brain injury scores that they used based on prior studies in slightly different populations would be associated with worse neurodevelopment at two years of age. The three centers included the Netherlands, London, Switzerland, and this was a prospective observational study. They generally included two subtypes of CHD, so transposition of the great arteries, and a lot of the single ventricle cohort,
Nim Goldshtrom (01:27:26.4)
LV with outflow-tract and without outflow-tract obstruction and coarctations as well. They excluded genetics and preterm infants. Their MRI was again a 3T MRI imaging. Scans for each cohort were assessed using a very uniform description of brain imaging that was described in previous reports from their consortium. However, as a caveat, the brain injury score was developed based on a combination of different brain injury severity grading used in preterm babies. So I think that's probably one of the limitations that we'll get to when looking
at the analysis here. The score and the scoring system is shown in figure one that when you come out the paper, you'll get a sense of how they use it and classify it into this zero to nine total score based on zero to three sub-domain scores for worst hemorrhage, worst white matter injury, and worst stroke categories. It's how they bucket it into three domain. They did the standard Bayley at 12 or 30 months. And again, the range of why it was 12 to 30 months was a little bit of center specific guidelines of when some centers did it slightly earlier
centers that did a little bit later to kind of get the more language components of the Bayley score. In statistical analysis, they used linear and logistical model. They both dichotomized the brain injury score as either having none or Maya versus a moderate or severe diagnosis and also compared it to values greater than or less than Bayley domain scores of 85 and a total score of 85.
Ultimately, there were 202 eligible children for the study, 12 who died, five were removed for genetic conditions, and 185 subjects, 166 of them who were able to complete the cognitive testing. So 90% follow-up rate, kudos to you guys. I can barely get that in my current study, so I got to figure out how to get any kids to come back to the clinic. We have different problems in a region that serves a multi-state.
System, I digress. Moving on to the results. The median age of cognitive testing was 23 months with an IQR of about 13 to 29 months. And for the motor testing was closer to 19 months. A cognitive composite score below 85 was only seen in 11 children, which is 6%.
Nim Goldshtrom (01:29:37.842)
And in one child, which is less than 1%, the cognitive score was less than 70. So two standard deviations below, so moderate developmental delays. 23 of the subjects, which is 13%, had a motor composite score below 85 for standard deviation, and two of them, 1%, had a motor composite below 70.
36, which is 21%, had a gross motor scaled score below seven, ah, which is model impairment, and five, which is 3%, had a fine motor score below seven as well. Only two children, 1%, had CP at the time of follow-up, one with hemiparesis due to pre-op middle cerebral artery stroke, and another due to severe global hypoxic ischemic injury.
So some of the other results that we find here, and table one again gives you a description stratified by the centers and how many patients participated in each one. One of the things that we note there is that there wasn't exactly equal distribution between each of the varying centers. The interesting phenomenon also you kind of like see right away, which we don't have p-values for, it's just kind of like a global assessment is, how different the average Bailey scores are per center, sometimes being 10 points different between different centers.
And this you can kind of like look up and down and see how like the socioeconomic status doesn't really change that much. The number of cardiac surgeries doesn't seem to change that much. But it is striking how just right off the bat, the mean Bailey scores, particularly the motor scores, are really different between the two centers, let alone the cognitive scores as well, which the authors will touch about a bit in the discussion.
Length of stay was associated with motor outcomes, so longer length of stay, poor motor outcomes when controlling for things like the BIS, the brain injury score, CHD lesion, socioeconomic status, age and follow. And so this overall brain injury score, this composite number from the MRI imaging system and scoring system that they created and all the sub scores, including the preop and postop imaging, did not correlate.
Nim Goldshtrom (01:31:37.398)
with either cognitive or motor outcomes. When the overall brain injury score was then dichotomized, non-mild versus moderate to severe, still no association to the score and these outcomes. Only eight subjects ended up classifying out of the, we said 186, only eight of these subjects classified into the severe, moderate to severe group.
And of the total sample, 127 patients, about 75% had undergone only one cardiac surgery up until the time of follow-up. Most of them were the TGA groups. There was no significant relationship between the overall brain injury score and all other brain injury sub scores with the Bailey outcomes. That data was not shown here in the paper. The number of preoperative white matter lesions, however, was associated with motor outcome.
And this remained significant after they did multiple testing as well. So number of pre-op white matter injuries were associated with gross motor outcome, but they were not associated with fine motor outcome. It seems like an interesting discretion. Neither the number nor volume of post-op white matter injuries or the volume of pre-operative white matter injuries correlated with motor or cognitive outcomes. In fact, the only thing that's correlated with a cognitive outcome score.
was socioeconomic status. And there was no interaction between socioeconomic status and brain injury scores or subscore as well. And white matter, again, was grossly associated with motor function and this brain injury scoring system was just not able to be associated with NDL. And so I find this both describing really the state of our field.
And with all the best intentions of these authors, I think the scoring system they have, it's not that it isn't good enough. I just don't know if it's the right system for this patient population, because it's not finding the associations, and yet the things that we do know, right? White matter injury, white matter injury count, and a high resolution analysis.
Nim Goldshtrom (01:33:44.886)
of white matter injury is more associated with things that we expect, right? Motor, especially when we're only testing them at two years of age, motor components. And not surprising, socioeconomic status as whatever kind of surrogate you want to use it as, as a bridge. Again, this is in no way about like, it implies that there's something about the family or the situation or where they are, but this like, what is it really telling us about the child's state of support? Maybe? I don't know the right answer, but it's not.
surprising that it's correlated with cognitive outcomes, but I think it also speaks to us as an opportunity to better unpack what that variable is, better understand its components and how to get help. It seems like something we should be able to easily do for families when they leave our purview, right? Is give them better support and understand what is happening in their community, what is happening in their system, what is happening in their own orbit, because that should be a fixable problem.
Adrianne Rahde Bischoff (01:34:40.82)
Yeah. And I hope that in a place like this, where they have such a good follow-up data, that they can keep bringing even longer-term data. Because I, it's good to know what happens to them at two years, but I want to know what happens to them when they go to school, what happens to the other minor neurodevelopment, considered minor neurodevelopmental impairments and behavioral stuff and autism. So, I think this is really good.
Nim Goldshtrom (01:34:56.33)
Yep.
Nim Goldshtrom (01:35:00.97)
Yeah. Exactly.
Adrianne Rahde Bischoff (01:35:07.832)
starting work and I am excited to hear a little bit more about this and hopefully someone can figure out other ways of modifying this, right? Because that's what we all care about. We want to know what happens to them but I want to know how do I prevent this from happening. So I think this was really good work and great applaud for the authors on this paper.
Nim Goldshtrom (01:35:19.267)
Yeah.
Nim Goldshtrom (01:35:29.738)
Yeah. It sometimes both kind of like surprises me, but then doesn't when to see that like it's you know, it's 2024 and yet we're still seeing all this white matter injury like surgical cardiac ICU services have advanced all over the world, particularly at major centers like these in Europe. And yet, you know.
Adrianne Rahde Bischoff (01:35:36.844)
Thanks for watching!
Nim Goldshtrom (01:35:52.078)
30, 40, 50% are coming out with my brain injury that may or may not have long-term complications, but it clearly is still happening. Part of the work again that I do with auto-regulation is like, are we just targeting the wrong numbers? If we figure out what the brain wants for auto-regulated capacity, can it make it better? Sure, maybe, but then seeing these consistent signals in the article, that it's the stuff that is related to the family, the environment, the circumstance, the community, I really want to start to see and be reading more papers.
on, you know, the ICU is an environment that's controlled and handed off to these parents and they're probably needing more support. They're probably needing more than what we're able to give them. And is this an experiment that we need to do, right? Extended care beyond just our hospitalization to try to make better gains for these kids.
Adrianne Rahde Bischoff (01:36:40.945)
for all of our populations that we take care of. Yeah, definitely.
Nim Goldshtrom (01:36:42.814)
Yeah, absolutely. This has been great. I had a lot of fun doing this. I hope you did too. Yeah, I learned incredible, Matt. I love vasopressin even more than I did before, and I already loved it a whole lot.
Adrianne Rahde Bischoff (01:36:50.869)
I learned a lot. Oh my God.
Adrianne Rahde Bischoff (01:36:57.041)
Hahaha
Nim Goldshtrom (01:37:00.146)
And I now just have so many more places to use it, and not just in like sepsis choc and refractory cardiac output. But this is fantastic. Thank you for joining me, Adrian, on this wonderful journey. Thank you, audience, for listening. We hope if this has, again, sparked your interest, the Neonatal Heart Conference is just a couple months away in New York City, where it's going to be bigger and better than ever.
Come on by, you'll get to meet us and like-minded folks and take yourself on your hemodynamic congenital heart disease and cardiovascular journey, because we'd love to see you there. Our website is open, registration is open, abstract submissions for poster sessions and awards is open right now, and we'd love to see you there. Thank you to the incubator. Again, Adrian, thank you so much. Hope to do this again in the nearest future sometime, but it's been great.
Adrianne Rahde Bischoff (01:37:48.34)
Yeah, this was fantastic. Thank you so much.
Nim Goldshtrom (01:37:51.39)
Absolutely. Thank you everyone for listening and we'll see you guys next time.
God bless Dr. Riaria for his marvelous work in my life, I was diagnosed of HERPES since 2016 and I was taking my medications, I wasn't satisfied i needed to get the HERPES out of my system, I searched about some possible cure for HERPES, i saw a comment about Dr. Riaria, how he cured HERPES with his herbal medicine, I contacted him and he guided me, I asked for solutions, he started the remedy for my health, he sent me the medicine, I took the medicine as prescribed by him and 14 days later I was cured from HERPES, you can reach him through his Email: drriaria@gmail.com or WhatsApp him on: +234 701-062-7760
You can visit his website for…