Hello Friends 👋
In this episode of Journal Club, hosts Ben and Daphna dive into several impactful studies in neonatology. They begin with a series of papers on patent ductus arteriosus (PDA) management, discussing pharmacological treatments, transcatheter closure techniques, and new clinical practice guidelines. The conversation highlights the evolving landscape of PDA treatment and the need for more robust research.
The hosts also explore a study on diazoxide for neonatal hypoglycemia, examining its effects on glycemic stability and feeding outcomes. They discuss recent findings on infant mortality rates in Texas following abortion restrictions, emphasizing the impact of policy changes on neonatal health outcomes.
Additionally, the episode covers a systematic review of quality improvement interventions to prevent intraventricular hemorrhage in preterm infants, highlighting the complexity of implementing effective "neurobundles".
The hosts conclude with a study on vasopressin as an adjunctive therapy for pulmonary hypertension in term newborns, noting its potential benefits in improving oxygenation and hemodynamic status.
Throughout the episode, Ben and Daphna provide insightful commentary on the clinical implications of these studies, making complex research accessible to listeners while emphasizing the need for continued investigation in key areas of neonatal care.
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Register for the upcoming Delphi Conference here:
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The articles covered on today’s episode of the podcast can be found here 👇
Jensen EA, DeMauro SB, Rysavy MA, Patel RM, Laughon MM, Eichenwald EC, Do BT, Das A, Wright CJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.Pediatrics. 2024 Jul 16:e2023065056. doi: 10.1542/peds.2023-065056. Online ahead of print.PMID: 39011550
Mitra S, Bischoff AR, Sathanandam S, Lakshminrusimha S, McNamara PJ.J Perinatol. 2024 Jul 12. doi: 10.1038/s41372-024-02052-9. Online ahead of print.PMID: 38997403 Review.
Leahy BF, Edwards EM, Ehret DEY, Soll RF, Yeager SB, Flyer JN.Pediatrics. 2024 Jul 15:e2024065905. doi: 10.1542/peds.2024-065905. Online ahead of print.PMID: 39005106
Peng Y, Cheng Z, Zhang Y, Yi Q.Pediatr Res. 2024 Jun 14. doi: 10.1038/s41390-024-03317-x. Online ahead of print.PMID: 38877281
Jordan KA, Rao P, Byerley JS.JAMA. 2024 Jul 3. doi: 10.1001/jama.2024.8485. Online ahead of print.PMID: 38958947
Cooper WO, Hickson GB, Dmochowski RR, Domenico HJ, Barr FE, Emory CL, Gilbert J, Hartman GE, Lozon MM, Martinez W, Noland J, Webber SA.JAMA Netw Open. 2024 Jun 3;7(6):e2415331. doi: 10.1001/jamanetworkopen.2024.15331.PMID: 38842804 Free PMC article.
Gemmill A, Margerison CE, Stuart EA, Bell SO.JAMA Pediatr. 2024 Jun 24:e240885. doi: 10.1001/jamapediatrics.2024.0885. Online ahead of print.PMID: 38913344
Laing D, Walsh EPG, Alsweiler JM, Hanning SM, Meyer MP, Ardern J, Cutfield WS, Rogers J, Gamble GD, Chase JG, Harding JE, McKinlay CJD.JAMA Netw Open. 2024 Jun 3;7(6):e2415764. doi: 10.1001/jamanetworkopen.2024.15764.PMID: 38869900 Free PMC article. Clinical Trial.
Edwards EM, Ehret DEY, Cohen H, Zayack D, Soll RF, Horbar JD.Pediatrics. 2024 Jul 10:e2023064431. doi: 10.1542/peds.2023-064431. Online ahead of print.PMID: 38982935
Santelices F, Masoli D, Kattan J, Toso A, Luco M.J Perinatol. 2024 Jul 4. doi: 10.1038/s41372-024-02015-0. Online ahead of print.PMID: 38965377
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The transcript of today's episode can be found below 👇
Ben Courchia MD (00:00.647)
Hello everybody, welcome back to the Incubator Podcast. It's Sunday, we're here with an episode of Journal Club. Daphne, how are
Daphna Barbeau (00:11.692)
Okay. How are you buddy? That was a little, a little, low key for even for
Ben Courchia MD (00:13.691)
I'm tired.
Ben Courchia MD (00:19.131)
Yeah, mean, it's we have a lot of stuff going on. It's nothing that we can complain about, but.
Daphna Barbeau (00:26.42)
No, this is all exciting stuff that we get to do. And it's a lot of work.
Ben Courchia MD (00:31.803)
Yeah, but you see, it's a lot of work, but that's what I wanted to say. Now that I wanted to whine about the fact that we have a lot of work, it's kind of where Journal Club becomes such a valuable asset because to be fair, if we didn't have to record Journal Club, I would not have read any of the papers that I read for this episode because of course, no, there's some great papers. What I'm saying is that that's the plight of the neonatologist. We get busy like right now. I'm busy
Daphna Barbeau (00:36.942)
and
Daphna Barbeau (00:48.59)
and there's some great papers.
Ben Courchia MD (00:58.013)
clinical stuff, busy with family stuff, busy, we're busy planning Delphi, which is going to be quite, quite amazing. I think, I mean, this is, this is, I mean, I just still can't believe that we're able to put together this lineup. We're so grateful of the people who are, yeah, giving their time to come and speak at Delphi. To be honest, we have this vision for this conference and, and it's kind of a utopian vision of where we're going to
leaders in the field of neonatology, people from other specialties, a TEDx event and all these things. And it just happens. It's kind of insane that we're able to put this together.
Daphna Barbeau (01:39.436)
Yeah, because the best part of the conference, the meat of the conference, my family's vegan though now, so let's say the peas and carrots of the conference are really that these amazing speakers and people said yes right away, people made their travel arrangements. Some of the work that's been so complicated are logistical things, but the goods are there.
Ben Courchia MD (02:05.967)
Yeah, which by the way, as neonatologists, we're definitely not trained for. So, no, but I mean, I'm saying like we have some pretty big names. Ryan McAdams is going to be there. Pia Wintermark from Canada who did this phenomenal study on sildenafil and HIE is going to talk to us about her work. Terry Ender is coming. We have Dr. Guillermo Santana from Canada as well. I'm just browsing the agenda. have Henry Lee from California, James Berry from Colorado.
We have a lot of very interesting TEDx speakers. mean, the TEDx sessions are going to be phenomenal.
Daphna Barbeau (02:39.266)
Very cool,
Yeah, and actually I think some people wonder about this TEDx thing. And I got to tell you, I got to hand it to you. I didn't buy into the TEDx. I didn't see the value, but it was people's like, maybe favorite part of the conference. And we had outstanding speakers last year, but our goal of the TEDx and the conference in general is just to like open people's minds, right? Like let's think about things in a different way than we usually do.
And so I'm sold on the TEDx and we've got some really cool talks for the
Ben Courchia MD (03:09.807)
All the while, you can bring it back to your day -to -day life and day -to -day practice. So we have some physicians. We have Dr. Annie Janvier, who's going to come talk to us. All the work that she's done to work with families is so interesting. Dr. Rachel Fleischman, who's going to talk to us about writing. We have Dr. Bruce Becker, who's going to come from California. He's an OBGY and he's going to talk to us about climate and the impact climate has had on our practice of medicine, has had impact on pregnancy.
Daphna Barbeau (03:15.286)
Absolutely.
Ben Courchia MD (03:40.158)
We have and then we have the people who are going to talk to us. mean, I can I can start teasing this because people who are listening, we're going to have someone named Alec Posta, who if people know him from YouTube, maybe you know him, but he's basically a Lego master builder and he builds these amazing things out of Lego. And I think it's interesting from his perspective to talk to us about how do you remain creative and innovative?
all the while dealing with constraints, right? So he constantly deals with constraints of whatever the Lego bricks are, but yet he finds these ways to overcome that. So he's going to give us some pretty powerful lessons when it comes to that. I mean, these are some of the people that are going to come talk to us. It provides such a great break halfway through the conference because like I always say, sometimes I go to big conferences and I attend and I listen to the talks, but at some point you're like, I'm saturated. Like I just, I just can no longer.
Daphna Barbeau (04:36.536)
Mm -hmm.
Ben Courchia MD (04:38.205)
Process information even good information even amazing information because I'm just my brain is fried I think this provides a little bit of a yeah, so this is very exciting and then we're going to have a special episode We're going to have some more social media coverage for Delphi as we plan We'll show you a little bit some of the behind the scenes But we're very excited about some things that we've been hard working hard at. I mean Maryam Bakhtiari from the far see a podcast is helping us plan the conference
Daphna Barbeau (04:45.751)
a reset.
Ben Courchia MD (05:07.271)
we're going to be able to offer virtual attendance this year. So we finally got confirmation that the data rate or whatever the broadband within the venue is enough to do virtual.
Daphna Barbeau (05:17.4)
I mean, we're learning a lot to doing this stuff. Now we know, and where to go.
Ben Courchia MD (05:21.159)
But it's, so we're going to roll out the registration for virtual attendance. We're very excited about that. And then again, like I said, I mean, I haven't gone through the whole agenda, but Satyan will be there. Dr. Suresh Gautham is going to be there. Susan Hintz is coming. Dr. Agarwal from the University of Miami will be there. So there's a lot of, I mean, there's a lot of phenomenal speakers. This is going to be a cool event, but that's why we're busy. That's why I was not so a beat.
right off the mark. Okay, that said, we have a big journal club. I ended up going down the rabbit hole this week with a bunch of papers on the PDA. So I
Daphna Barbeau (06:06.658)
those for you. I thought you were going to like them. The cohort of papers.
Ben Courchia MD (06:09.595)
Yeah. So many, so many. So yeah, mean, whatever. mean, I guess I told me to begin. I guess I could begin. I'm to try to go in order, try to make to use papers that make sense. So the first paper that I'm going to begin with is published in pediatrics. It's from Eric Jensen and colleagues, and it's called the Acetaminophen
Daphna Barbeau (06:19.298)
Go for
Ben Courchia MD (06:36.349)
PDA and risk of mortality and pulmonary morbidity. The background is extremely interesting. I would recommend reading it, especially since we're in July still and that you're first year fellows. These are the things you must read to get a sense of what's happening. So they mentioned that how in recent years, obviously, acetaminophen has gained prominence and a tremendous place as an alternative pharmacologic treatment for PDA. And that surveys do indicate
that it is being used by more than 80 % of NICUs in many countries. And for almost 50%, it's the first line agent in certain regions. Now, despite the fact that it's very commonly used, the risk and benefits of acetaminophen in extremely preterm infants is quite still uncertain. There are very few infants that are born before 28 weeks of gestation that have been enrolled in the few trials that have looked at this modality.
And accumulating evidence does indicate that the lungs of preterm infants may be more susceptible to the toxic effect of acetaminophen. And that was something that was puzzling to me, because it's like, really, I didn't remember that. But they do mention how acetaminophen -induced cell damage results from the conversion of acetaminophen to a toxic metabolite called N -acetyl -B...
and acetylp -benzoquinone imine, so NAPQI basically. And this is done by the xenobiotic enzyme cytochrome P450 family 2 subfamily E member 1, so CYP2E1. Fine. You don't have to remember that. But murine data does show that this cytochrome P450 2E1 is highly expressed in the lung and specifically in the mesenchymal myofibroblast.
during the secular stage of respiratory development and that it far exceeds the typical adult lung levels. So we usually assume that babies have less of stuff than adults, but this is one of these rare cases where we actually express this more in that stage of development. And what's fascinating is that the hepatic version of the CYP2E1 is low during fetal development and only increases
Ben Courchia MD (08:59.985)
to adult level after term gestation. And so what's interesting is that we always think of acetaminophen as this drug that has liver disease, damaged liver toxicity. But what they're saying is because there's this expression of this CYP2E1 in the lungs as a fetus more than in the liver, in infants born preterm, the lungs rather than the liver may be the greatest risk of injury from the use of acetaminophen. So I thought that's...
set the stages so well for this conversation. And the question they're asking is basically, does treatment with acetaminophen versus Cox inhibitors alone for PDA increase the risk of inhospitable mortality or respiratory morbidity among extremely preterm infants? This was basically done using the NICHD Neonatal Research Network generic database. And this was a retrospective review. This data, as you all know, is collected prospectively.
And it includes babies that are born between the gestational ages of 22 and 28 and six weeks or birth weights 401 gram to a thousand grams. The babies they decided to include in the study were born between 2016 and 2020. They survived 12 postnatal hours, received the acetaminophen, ibuprofen and or indomethacin for PDA. They excluded babies that were born outside neonatal research network centers that had some severe congenital or genetic.
so congenital malformation or genetic syndromes, or that they were enrolled in other trials that would interfere with the analysis. The intervention of interest obviously is the pharmacological treatment of PDA with acetaminophen, and they compare that with the treatment with other pharmacologic agents, indomethacin and or ibuprofen. Now, it's a retrospective review. The decision to treat the PDA really was left to the discretion of the clinician and the information on the dose, the route, the timing.
and the exposure to the evaluated medication that was not recorded in the database. The primary outcome was the composite outcome of death or grade two to three BPD using the Jensen criteria. And the secondary outcome involved the individual components of the primary outcome, death before discharge, death or home oxygen therapy, home oxygen therapy among survivors and so on and so forth. So the results.
Ben Courchia MD (11:15.165)
showed that about 2000 infants who received acetaminophen, ibuprofen, and or indomethacin were included in the study. Among the evaluated infants, 33 % received acetaminophen and 67 % received only ibuprofen and or indomethacin. So still in the minority, the infants treated with acetaminophen were on average more likely to be born at a lower gestational age. They were more likely to receive invasive respiratory support during the first days after birth.
And they were more likely to have major complications of prematurity, including severe IVH, sepsis, surgical neck, and intestinal perforation. In total, 180 infants, which is 28 .7 % of infants who received a acetaminophen also ended up receiving ibuprofen. And 6 -17 % received the indomethacin.
Interestingly enough, as they were looking over the timeline of the study, the use of acetaminophen increased steadily throughout the study period. So the news are relatively positive. Primary outcome is that neither the unadjusted nor the multivariable risk adjusted models, remember, because there were some baseline differences, none of these revealed an association between the use of acetaminophen, the exposure to acetaminophen,
the primary study outcome, was death or grade two to three BPD. When they looked at secondary outcomes after they adjusted for center and differences in perinatal and early postnatal characteristic, which was their third model, acetaminophen was associated with an increased risk of death before hospital discharge, death or home use of respiratory medication and surgical or catheterized PDA closure.
In expiratory models that adjusted for later post -natal covariate, acetaminophen remained associated with surgical catheterized PDE closure, but not the other study outcomes. I think this is where you start seeing a little bit the limitations of the study where it could be quite concerning to see these association on adjusted analysis. But again, as you keep tweaking the variables, you lose some of that significance. And the authors are very upfront about this and about the limitation of doing this study.
Ben Courchia MD (13:36.517)
The conclusions are mostly focused on the primary outcome, where they say that they did not find any evidence that pharmacologic treatment for PDA that includes acetaminophen versus those that use cyclooxygenase inhibitor alone affected the risk for the evaluated in -hospital respiratory morbidities. They mentioned that the use of acetaminophen to treat PDA was not a clear independent risk factor for BPD or other evaluated in -hospital measures of pulmonary morbidity. However, there's a possible increase.
see how careful they are in the choice of where they're in risk of pre -discharge mortality associated with acetaminophen exposure. This finding was strongest when the cohort was restricted to infants who received single drug therapy for PDA. The results of this observational study supports a cautious approach towards the use of acetaminophen in extremely preterm infants until robust safety and efficacy data from a large randomized trial are available. I think that is the most important conclusion of the paper that
We adopt things without robust studies, and maybe that's why we should always be careful. I highly recommend people listen to the interview we did with Barbara Schmidt, who really talks about this eloquently when she mentions the caffeine situation where at the time that she crafted the CAB trial, people were using caffeine, but it was about doing this in a robust manner to understand the ins and outs of this treatment. But yeah, an interesting paper.
Daphna Barbeau (15:05.71)
Absolutely. Yeah, I think that's what happens in medicine. I think it's part of why we get some distrust in medicine. We roll out things and they're like, well, we didn't see that. Now we got to bring it back. I think people are trying to balance this PDA discussion as much as possible and it is a complicated
Ben Courchia MD (15:28.809)
I think it's worse than that, to be honest, because I think we use a medication or an intervention because that's all we have. So we say, hey, I don't have anything else. And then it starts getting used. And then you sort of lose the opportunity to do these nice trials because now people have no interest in doing a trial. Hey, I'm using it. don't want... And then you've murked the water because all you're left with are these retrospective studies that can't do the test you want them to do, because it doesn't look at the data the right way. And
Daphna Barbeau (15:36.29)
Mm -hmm.
Daphna Barbeau (15:46.808)
That's true.
Ben Courchia MD (15:57.969)
I think that's why everybody commands Dr. Schmidt for what she did because it's extremely difficult to do these types of trials as a medication gets a grassroots sort of adoption within the community. So if it's okay with you, do you mind if I continue?
Daphna Barbeau (16:09.006)
Mm -hmm.
Daphna Barbeau (16:14.806)
Yeah, it makes sense. think you've got this whole collection of papers. Do it, do it.
Ben Courchia MD (16:18.365)
Okay, so there's another paper published in pediatrics by Brianna Lehigh. I think I'm pronouncing this correctly. And now this looks at the other aspect of PDA management, which is transcatheter and surgical closure of the PDA. And they looked at the paper is called Transcatheter and Surgical Ductus Arteriosus Closure in Very Low Birth Weight Infants, 2018 to 2022. I think this transitions nicely to this discussion about, if
if pharmacologic treatment is so controversial, how about these new modalities? So the background is that the study is investigated very low birth weight PDA management utilizing a large databases. But the purpose of this particular paper was to look at VLBW infants who underwent transcatheter closure or surgical PDA closure in the US between 2018 and 2022, and really look at survival
and short -term clinical outcomes for both populations. They used a very popular database. they looked at, they did a secondary analysis of the data collected by the Vermont Oxford Network. The eligible population were very low birth weight infants that were defined as having a birth weight between 401 and 1500 gram or a gestational age from 22 to 29 weeks and who were inborn
at a reporting hospital in the US within 28 days from birth. They included babies who had a report of PDA treatment. The PDA treatment was categorized either as pharmacological, where it was acetaminophen, ibuprofen, or indomethacin, or invasive, transcatheter, or surgical closure.
They excluded babies who did not survive to NICU admission, had additional congenital heart disease, or incomplete or no PDA treatment information. The outcomes looked at survival, length of stay, change in weight Z -scores for survivor, and a selected complications of prematurity and the level of support at discharge. What is a selected complications of prematurity? So what is this selection? They include BPD, late onset infection, ROP, neck, focal perforation, and IVH.
Ben Courchia MD (18:36.285)
So they had data from 726 US Vermont Oxford Network member hospitals. And the review of the data population yielded an eligible study cohort of 41 ,976 infants, so 42 ,000 kids. The majority of infants treated for PDA received pharmacologic treatment as part of their management. That's 96 .3%. That should not surprise anyone. I rarely see kids go straight to surgical closure.
Of those, most required no additional treatment. They got pharmacologic and 88 % were done. 6 .4 % went to transcatheter closure, 5 .6 went to surgery, and 0 .06 % of them needed both. Somehow, I've had a case like this, maybe a few more throughout my career, and man.
This is so frustrating. Oh my God. Of the treated infants who did not receive pharmacologic intervention, 51 .8 % received transcatheter closure compared to 47 .2 % who received surgical intervention. So pretty much a split there. What's interesting to see is really how transcatheter PDA closure is gaining in popularity. And so what they document is
Daphna Barbeau (19:36.302)
It's a bummer. Yeah.
Ben Courchia MD (20:03.485)
From 2018 to 2022, transcatheter PDA closure went up from 29 .8 % to almost 72%. So a dramatic increase. The infants selected for transcatheter device closure usually had higher birth weight, were less likely to be SGA, and had lower markers of respiratory severity. And I think that even that is going to change, because I think that in the beginning, we were reserving this for the bigger kids, but
There's a level of expertise and we'll talk about that in a second where we get more and more comfortable doing it on smaller and more fragile infants. The method of delivery, antenatal steroid use, resuscitation parameters were similar. Now, over the study period, the transcatheter increased and that's something that the use of transcatheter increased by 40 % for kids who were less than 750 grams, by 47 % for kids that were 750 to 1250, and then by
to 11 % for babies that were above 1 ,250 grams. The adjusted incomes comparison showed that infants who underwent transcatheter closure were more likely to survive than those who underwent surgical closure. And after adjusting for gestational age, small for gestational age status, maternal hypertension, inborn or outborn status, and clustering of infants within hospitals.
There was also no difference in length of stay, selected complications of prematurity between treatment groups, or the level of support at discharge. And so in conclusion, what they're showing is that there's an increasing use of transcatheter closure compared to surgical closure in the US between 2018 and 2022, even though the number of closures per year remain relatively constant. So it's clearly a transition to this new modality.
low birth weight, short -term outcomes after transcatheter closure, including survival, neonatal complication, and length of stay may have been slightly, they say that they could have been slightly more favorable, obviously, because of this adjusted analysis result in the transcatheter closure group. They do mention in the conclusion that, as we were just saying, a retrospective observational study does not include many other important clinical factors.
Ben Courchia MD (22:25.221)
and statistical observation should be interpreted cautiously and in the appropriate neonatal clinical context. They say that, to further understand VLBW -PDA clinical management, additional research on patient selection criteria, complications associated with transcatheter device use, et cetera, may be beneficial. So a very interesting situation where we're still
The Jensen paper really shows us that we are still evaluating our pharmacologic treatment. All the while, our surgical methods of closure is changing. And so the next paper that I wanted to mention was a paper that was published in pediatric research. And it's coming out of China. It's called Long -Term Follow -Up of Patients with PDA After Trans -Catheter Closure. This is by Dr. Peng and colleagues.
and so what they did is that they wanted to analyze independent risk factors for adverse events and to assess the trends of adverse events during a five year follow -up of babies who wonder went, transcatheter closure. So they retrospectively analyze all their PDA patients who wonder when transcatheter closure in China from not in China. I'm going to correct that. is from this particular hospital, the Chongqing medical university hospital in China.
So it's not a national study. want to make sure that this is clear. From 2012 to 2017, they had to have documentation of PDA diagnosis on echo. They excluded those who went through transcatheter closure as a secondary revision or as a secondary treatment. Like, for example, if they had a residual shunt, people who had congenital heart disease,
or other severe diseases that could be affecting the cardiac function. Okay, so they went through the EMR, they collected sociodemographic variables, including sex age, time of transcatheter PDA closure, they extracted preocclusion radiological variables, pulmonary artery pressure, the shape of the PDA, the aortic end diameter, the pulmonary end diameter, and using the outpatient EMR, they collected all their echographic characteristics during the follow -up period, including residual shunt, aortic stenosis, pulmonary
Ben Courchia MD (24:52.221)
and occluder migration. And their follow -up time points were quite interesting. I think it's rare that we have that long of a follow -up. It included a 24 -hour, a one -month, three -month, six -month, one -year, and five -year follow -up. In terms of the results, they were able to include 1 ,045 consecutive patients who wonder when transcatheter closure at their institution. The shape of the PDA was actually reported, and they say that it was mainly conical in shape 89 % of the time.
followed by a tubular ductus in 10 % of the time. And the median diameter of the pulmonary and aortic end of the PDA were 1 .9 millimeter and 6 .7 millimeter respectively. The multivariable logistic regression analysis indicated that the age of the infant, sex, so in that case, female, and pulmonary end diameter were independently associated with adverse event within 24 hours of closure. And so a young female with high pulmonary end diameter
were independent risk factors for adverse events in that time span of 24 hours. A total of 86 patients had adverse events within 24 hour of closure. 78 patients returned to normal at subsequent follow -up, and eight cases still remained with abnormal results. At five years after transcatheter PDA closure, five patients had persistent residual shunt.
two patients had aortic stenosis and one patient with left pulmonary stenosis. The aortic and pulmonary stenosis was considered as a result of the occluder excessively protruding into the aorta or the left PA, all of which were very mild considering and that did not require subsequent follow -up. They were continued to be observed and they did not need a further intervention as well. For the patients who did not have adverse events within 24 hours of the closure,
the abnormal rates at follow -up really did not change significantly. And so I have this figure saved because it's quite interesting. You can see that they had these two bar graphs. And by the way, if you're downloading the paper, the paper comes out in black and white and the graph is awful to see. You need to go on the website and get it in color. But what you see is that for the babies who do have complications within 24 hours, these tend to, the portion of the bar graph that represents these complications shrinks.
Ben Courchia MD (27:18.525)
notably over time at one month, three months, and five years. But for the babies who did not really have adverse events, then they basically don't have adverse event throughout. So I thought this was very interesting that this 24 hour period after the transcatheter closure really is a critical window into what's going to happen in the future. Their conclusion is that this stratified follow -up study of transcatheter PDE closure with a median age of 22 months at follow
found that age, sex, and pulmonary end diameter were independently associated with adverse events within 24 hours of closure, and that most adverse events, such as residual shunt, hemolysis, thrombocytopenia, I skipped on that because they didn't find anything significant, returned to normal at long -term follow -up. What they also mentioned is that, moreover, patients who had no adverse events within 24 hours of closure did not show any abnormality in five years of follow -up.
Based on the results, the value of long -term follow -up may be limited for patients who had no adverse events within 24 hours of closure, saying maybe we should even need to follow them that long, and for those who had adverse events within 24 hours of closure but returned to normal during five -year follow -up. They say that this work still needs to be validated in different populations and different scenarios, and that if validation is successful for this subset of patients, consideration should be given to canceling or reducing time.
of follow -up to save economic cost and medical resources, something that in not just communist countries, I guess, but also social countries is always a concern as in terms of the burden of these follow -up appointments on the medical system. So I thought that was interesting, again, trying to bring a different perspective.
Ben Courchia MD (29:06.859)
So the last paper that I wanted to talk about is we're left a little bit with this confusion of, well, so what should I do then? We're seeing, that's right. But you're seeing that, hey, more and more people are using this transcatheter closures. It doesn't seem to be terrible. By the way, this, I have saved a few of these.
Daphna Barbeau (29:16.706)
this ongoing confusion.
Ben Courchia MD (29:33.509)
a few of these tables from this paper from China. I'm just going to pull them up very quickly because you look at the outcomes and they're really not that bad. Let me just see.
Ben Courchia MD (29:48.211)
This is the paper. But if
Ben Courchia MD (29:53.757)
If you look at some of the results, mean, you look at residual shunt, even when we say that things get better, like it's 78 % within 24 hours and it goes down to 29, 9%, 7%, 5%. The rates of aortic stenosis less than 5%, pulmonary stenosis less than 2%, occluder migration mostly 0%. Hemolysis, can see, and thrombocytopenia, they can see like 30 % in the first 24 hours, but even within one month, it's like less than 5%. So it's very minimal.
And the question is, who do we recommend for these closures? And so there's a beautiful article published in the Journal of Perinatology by our good friend, our good friend, Souvik Mitra, who's the first author of the paper. He is accompanied by a guest, star -studded guest list of authors. Adrian Bischoff is one of them. Yeah.
Daphna Barbeau (30:49.186)
Yeah, it's a must read paper, obviously.
Ben Courchia MD (30:52.645)
Satyan is also on this paper. Patrick McNamara is the senior author. Shyam Satanadham is also on this paper. So they're publishing a clinical practice guideline for the procedural closure of the patent doctor's arteriosus in preterm infants. So I was shocked to see that this was published, obviously, because I was not expecting... I guess we've never had anything definitive about the PDA. clinical practice guidelines don't come about very frequently when it comes to the PDA.
They have a very interesting background section talking about the potential complications associated with pharmacologic treatment of the PDA. The procedural closure of the PDA are brought up that there's an increasing use of less invasive techniques for PDA closure using transcatheter approach. They mentioned how, since there are several national and international guidelines on pharmacotherapy management of the PDA in preterm infants, which I don't know
This is such a, I mean, I think these guidelines are not as well established as we would like them to be. They said maybe there's a need to establish procedural guidelines for transcatheter closure. And so they basically had a group of four neonatologists with expertise in neonatal hemodynamics, and they had one pediatric cardiologist. And they wanted to establish these guidelines with primary health outcomes of death and severe BPD in mind. They also had safety outcomes in mind.
And they also, and so this is how they of crafted these questions and these recommendations. So they basically sent this survey that included four background questions that included two intervention questions in order to develop provisional guideline recommendations. I think they sent the survey to 71 experts and ended up getting maybe 45 definite responses. 13 were from, they say,
general neonatologist and 32 were formed from what they call self -identified neonatologist with hemodynamics expertise. So what are some of these clinical practice guidelines showing? So in terms of background question, the first question that is being asked is what is the gestational age? Is there a gestational age cut off below which definitive PDA shunt elimination should be considered? And so what the panel is recommending
Ben Courchia MD (33:19.453)
is that definitive pediatrician elimination should be considered only in infants that are at high risk of death or severe BPD, regardless of the shunt characteristics. They say that usually this is patients who are below 28 weeks of gestation. They're classifying this as a strong recommendation with 82 .2 % agreement among respondents.
The second question they asked is what is the timing of shunt elimination? Is there a postnatal age or a duration of ventilation above which definitive PDA shunt should be considered? And the panel recommends that definitive PDA shunt elimination should be considered beyond 10 days of age or after 10 to 11 days of mechanical ventilation. This is a conditional recommendation with only 75 .5 % agreement among respondents. This is based on data showing that shunt exposure beyond eight to 10 days
is associated with worse clinical outcomes. In terms of clinical characteristics, the next question asks, should clinical signs of the infants be considered in addition to echo characteristics in determining the need for definitive pediatrician elimination? And the panel recommends that continued mechanical ventilation beyond 10 days of postnatal age may be considered as a clinical characteristic to decide on definitive pediatrician elimination. In addition,
to echo findings. This is a conditional recommendation with 80 % agreement. They mentioned that the TrioCAPI RCT of early ibuprofen therapy showed that infants with moderate to large hemodynamically significant PDA that persist beyond 14 days are only at risk for developing BPD if they also receive prolonged tracheal ventilation for 10 days or more. And so these are some of the data points that they are using to make this recommendation that beyond 10 days,
postnatally and based on echo findings, there may be a need for definitive closure. And then the follow -up question, which makes sense is what are the echo characteristics we're talking about? Which ones should be considered to characterize a significant shunt volume that may benefit from PDA shunt elimination? And so the panel agreed that the best available evidence of benefit from procedural PDA closure was infants demonstrating signs of large persistent transductor shunt
Ben Courchia MD (35:41.789)
meaning that the PDA size is superior to 2 and 1 millimeters, in addition to one of either left ventricular output that is superior to 300 ml per kilo per minute, and hollow diastolic flow reversal in the descending aorta. This is a conditional recommendation with 73 % agreement. So these were the background questions. And then we have two intervention questions. And this is where things get a little
A little bit tricky. The first question they said is, before we recommend definitive closure with transcatheter closure, should repeat pharmacotherapy versus procedural closure be used for the treatment of persistently hemodynamically significant PDA? The panel suggests that we should be attempting a second course of pharmacotherapy with ibuprofen or indomethacin, and maybe a third course of pharmacotherapy with acetaminophen over
procedural PDA closure for a persistent high volume PDA shunt following failure of primary pharmacotherapy. This is a conditional recommendation with 82 % agreement. However, it doesn't stop here. The panel also suggests that procedural PDA closure may be considered earlier in some instances, even after one or two courses in centers where there's a high success and low adverse event rates with procedural closure, or if there are contraindications to pharmacotherapy.
fine. But they are starting to introduce that concept of like if your team is super comfortable doing these closures, you may very well go for it earlier on and that's a conditional recommendation. They also say there's an absence of high certainty direct evidence comparing repeat pharmacotherapy versus procedural PDA closure. And so for this question, the balance of desirable and undesirable outcomes probably favors repeat pharmacotherapy primarily
due to the perceived risk of major adverse events. But like I was thinking when I was reading the paper, as more papers come out and show that there's not so much adverse event, maybe that's going to change. So the final question is, should surgical PDA closure versus transcatheter closure be used? So do you go with an open approach, or do you go with the transcatheter closure? So they're saying that given the lack of high -certainty evidence, the panel refrained from recommending a procedure of choice. However, the panel did note
Ben Courchia MD (38:07.759)
evidence from single center experience as well as registry based report from the US and France that demonstrated favorable outcomes with the transcatheter closure for the PDA in progressively younger infants. The panel speculates that enhanced outcomes over time are likely to relate to increasing experience and refinement of interventional technique. Therefore, the panel highlighted that if sufficient institutional expertise is available and patient characteristics are suitable, transcatheter closure may be considered as the preferred approach.
over PDE allegation, a conditional recommendation, however, with 96 .6 % agreement. The panel felt that both approaches were acceptable and choice should be made depending on institutional expertise and adverse effect profile associated with the procedure. Typical in Souvik -Mitra fashion. Further, given the lack of established benefit with respect to patient -important outcomes such as death and severe BPD, the potential harms associated with either approach, the panel emphasized
the need for shared decision making with the families to evaluate their values, their preferences with respect to the best local estimates of benefits and harm. And so in conclusion, I think it is very interesting. They're saying that if sufficient institutional expertise is available and patient characteristics are suitable, transcatheter closure may be considered over a surgical PDA closure for definitive PDA treatment in extremely preterm infants requiring continued mechanical ventilation beyond
10 days postnatal age and confirmed to have a large PDA on echo. The other important thing is that it has to happen at centers with high local rates of death and BPD, since this is the outcome of choice. And since you're trying to make a dent in that particular outcome, you need to have high rates of death or BPD in order to justify this intervention. They do highlight the need for future high quality RCTs comparing transcatheter PDA closure with surgical ligation or medical therapy.
or just conservative management and exploring meaningful short and long -term clinical outcomes that will be required for a stronger recommendation either for or against the routine adoption of this practice as the standard of care for definitive PDA closure in preterm infants. And I think that this sort of concludes our overview of these PDA papers.
Daphna Barbeau (40:28.926)
Holy smokes, that was a whirlwind. Thank you for that. I think you put them in a nice kind of order pathway for us. Yeah, I highly recommend people take a look at those papers. That was a heavy, heavy journal club. Lots of things to think about. I have some...
Ben Courchia MD (40:42.404)
Ha!
Ben Courchia MD (40:47.921)
I'm gearing myself for Neo Hearts because we're going to be surrounded by all these cardiac aficionados over there and I want to be able to hold my own.
Daphna Barbeau (40:55.47)
We got to learn to speak their language, you know? I have kind of some lighter papers to discuss. Do you have things you want to talk about after my light papers or are you, we're getting to the 41 minute mark here. You have.
Ben Courchia MD (41:11.438)
You know me, I always have one more that is not related to the PDA. There was this very interesting article on diazoxide, so I can review it quickly if you want afterwards, but we'll see.
Daphna Barbeau (41:16.088)
That's right. Yeah.
Well, because I have some articles, but I wanted to review this kind of like in the news stuff that I think we should give people a little break here. I did want to highlight, just saying, I did want to highlight clinics and perinatology. I love when they put out these issues. And this one is on quote unquote, prematurity. So you name it, they talk about things surrounding.
Ben Courchia MD (41:26.471)
Go for
Daphna Barbeau (41:46.062)
Prematurity, the thoughts behind causes and prematurity, the data, socioeconomic data. I think it's a really good look. So I recommend people take a look there. Something that has been a hot topic this week is that the AAMC put out the state of women in academic medicine, the 2023 to 2024 progressing towards equity update.
let's say, and people are talking about it. I thought people might be interested to know that it is out. The key findings included the following significant progress in representation, increases in some leadership roles. There remains a challenges, some, but not all leadership roles. And there still remains significant challenges in pay equity and high rates of gender
Ben Courchia MD (42:31.481)
Some, some. my God.
Daphna Barbeau (42:46.094)
So I'm not going to go through all the details, but definitely things for people to go look at. And the AAMC is actually hosting a webinar to talk about the results of the report. If this is something that interests you, you're trying to make some change at your institution on Wednesday, July 24th at 12 Eastern. And you can register at aamc .org. There was another paper that we wanted to highlight.
this was a viewpoint in JAMA. It is entitled, Where are all the pediatricians? Yeah. And so, the goal of the paper lead author, Catherine Jordan from UNC, was really to talk about what are we going to do in the future? The match
Ben Courchia MD (43:23.991)
huh. I'm happy you're highlighting
Daphna Barbeau (43:40.206)
into pediatrics. So pediatric residency has been super stable, right, for a very long time at about 98%. So 98 % of all the available spots in pediatrics fill typically. But this year, only 91 .8 % of positions filled. And that's even after, what are they calling it now? The soap, the scramble, like the thing that happens after the initial match.
And in addition, family docs who care for Peds patients is decreasing and they highlight that only 5 % of APPs are in pediatrics. So this is a huge kind of constellation of problems. And finally, many pediatricians are leaving pediatrics or like we're hearing kind of across specialties going part time. So what are the reasons for this? Obviously there's less reimbursement. That's true for everybody in medicine, but specifically in pediatrics.
There's less time to spend per patient visit. There's an increase in complexity of patients. So we see this in the NICU. We are sending more medically complex children out to our pediatric colleagues. There are more mental health concerns, especially since the COVID pandemic, that they're having to deal with in office because there's less availability of mental health professionals. There are new laws that are limiting the autonomy of pediatricians to discuss certain topics with their patients.
So they believe all of these things are leading to this decrease in people going into pediatrics. So what do they say we can do about it? think some of us, those of you that are interested in advocacy and the lobby work, obviously lobbying for funding for equitable reimbursement in particular for Medicaid patients. So Medicaid patients do not get the same reimbursement that Medicare patients get and certainly not private insurance.
Commensurate pay for our colleagues who care for adults. Possible loan reimbursement for lower paid specialties, including pediatrics. And then improving. Yeah, huge, huge.
Ben Courchia MD (45:41.595)
I mean, that's so important. I mean, I'm so sorry to harpoon on that because, and we're going to, I'm going to try to bring it up at a few talks that we're going to give in the future. it's not that pediatricians want more money, but it's like the students graduating or finishing training are coming out, or no, but it's financially very frightening to come out of training with an insane amount of debt. Insane,
Daphna Barbeau (45:55.746)
Yeah, they went the same amount of money as our adult colleagues.
Ben Courchia MD (46:08.893)
cost of going to school has continued to increase. These interest rates are six, seven, 8 % sometimes. And life costs more than it ever has. Especially down here. I and I don't know what these politicians are talking about saying that the cost of living is better. It's like, it's extremely expensive to live in the United States right now. And so I understand the real concern young graduates have about, I'm sure people like
Daphna Barbeau (46:19.245)
especially down
Ben Courchia MD (46:37.949)
pediatrics, the love for pediatrics has not gone away. But at some point you have to ask like, how am going to make ends meet when I have crazy monthly repayments for my loans and where getting a home, putting kids in school and doing all that is going to not be sufficient based on my salary. When you have the competency of being another type of doctor that would make twice as much, three times as much. It's critical. And at the end of the day, the patient suffer because there's a shortage and,
This has started to happen in France already like several years back and we're seeing this in the US. So when Satyan mentions that we're not taking care of smaller adults so that we could get smaller payments, he's absolutely right. He's absolutely right.
Daphna Barbeau (47:22.114)
Yeah, and absolutely, this group of papers that has come out that really just shows even for every specialty, the pediatrician version of that specialty makes less money than the adult version of that specialty. I'm on this Facebook group, Physician Side Gigs, as if we don't have enough things going on, just to know what people are doing out in the community.
Ben Courchia MD (47:37.806)
Nuts. Nuts.
Daphna Barbeau (47:47.982)
And they collect annually like data from people in the group. And it's a pretty large group. I'll tell you it's, I'll tell you right now, too slow. 113 ,000 members. Okay. Fine. And, um, I mean, they have just this bar graph of, uh, doc, what doctors make by specialty. mean, pediatrics is the lowest of all, all of these other adults specific.
Ben Courchia MD (47:58.951)
Wow.
Daphna Barbeau (48:17.966)
even the subspecialties. Painfully so. The last point they wanted to say is advocating for one of the major causes of burnout we know is using the EMR. We don't even really have great pediatric -specific EMRs, even less so neonatal -specific EMRs. Those are the things they say we can do to make change. But I think your point about is, it financially feasible to go into pediatrics? Yeah.
Ben Courchia MD (48:45.637)
Life is expensive. Life is life is very expensive. I'm sorry to say it's very expensive. And Satyan has written beautiful op -eds about this. So you should read it
Daphna Barbeau (48:55.102)
Yeah, and the cost to get to be a general, say a general pediatrician or a specialist is the same potentially as becoming an adult subspecialist.
Ben Courchia MD (49:02.181)
It's the same. Yeah. If you mentioned that you want to be a pediatrician, you still pay the same tuition than medical school. So it's not really fair. Have you seen this paper in, I think it was JAMA something, JAMA Network Open, about the physician specialties who are most likely to be reported for bad behaviors? You saw that? And that they... yeah, yeah. And so they talked about like, they looked at safety events.
Daphna Barbeau (49:08.867)
That's right.
Daphna Barbeau (49:19.427)
Mmm. Yeah, you told me about it. I to go look it up. But
Ben Courchia MD (49:30.013)
to see which specialties would be most likely to be reported. And I think they looked at something like 35 ,000 physicians. And they said that surgeons were the most likely to receive a coworker report and that the least likely were pediatricians. And so that
Daphna Barbeau (49:48.888)
We're out here being nice, okay? And not getting paid for.
Ben Courchia MD (49:53.149)
Are we the useful idiots? mean, come on. But what was interesting, and so what was interesting afterwards though, was that when you looked at the actual data in terms of the different subspecialties, so like, fine, so surgeons, sure, they were working in very stressful environment, but I think it was pediatric surgeon of these surgeons who were the most likely to be cited, which I was kind of surprised by
Daphna Barbeau (50:22.21)
That was strange.
Ben Courchia MD (50:23.447)
Yeah. Anyway, so I that was funny.
Daphna Barbeau (50:26.702)
Okay, perfect. I wanted to move on to a serious paper, but again, not so data heavy. So there was a paper, hold on, now I lost all my papers here. I got distracted chuckling with you. In JAMA Pediatrics, that looked at the title of the papers, infant deaths after the Texas 2021 ban on abortion in early pregnancy.
Ben Courchia MD (50:41.99)
Ha
Daphna Barbeau (50:54.126)
So I think this is something our community should be up to date about. Basically, they looked at this cohort study of 94 ,000 recorded infant tests in Texas, and they used 28 comparison states. I mean, the gist, go ahead.
Ben Courchia MD (51:13.132)
Can you tell us what's the deal with, no, no, with text, what did they do in that you're measuring? sorry, sorry, sorry, sorry, sorry.
Daphna Barbeau (51:16.526)
Yeah, I'm getting there. I'm getting there. I know, I'm going to tell you. But I'm going to tell you the punchline first. What they found is that the Texas abortion ban was associated with unexpected increases in both infant and neonatal mortality in 2022. So they're talking about Senate Bill 8. This was introduced in September 2021.
Ben Courchia MD (51:28.378)
okay.
Daphna Barbeau (51:41.942)
and Senate bill eight banned abortions after embryonic cardiac activity. So this can occur as early as five to six weeks gestation. So it's the most, one of the most rigorous conservative bans that we have in the country. And it did not allow really for any exemptions, including congenital anomalies. So they wanted to look at what happened to deaths.
in infants and neonates and how did this compare to the rest of the country? Where, by the way, lots of different bans are happening across the country, but again, this is the most stringent, I guess I would say. So they excluded states and the District of Columbia that had fewer than 10 infant deaths in any month for the years 2018 to 2022. So basically they used an inclusion of 28 comparison states, plus again, Texas in their infant
Ben Courchia MD (52:25.204)
huh.
Daphna Barbeau (52:39.762)
in their analysis of infant mortality. But I think people would be interested to know what states they're comparing to. So Alaska, Arizona, Arkansas, California, Colorado, Florida, Georgia, Illinois, Indiana, Kansas, Louisiana, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Texas, Tennessee, Virginia, Washington, and Wisconsin. So a range
Types of bands, political leanings in those states. They also use 19 comparison states then for analysis of specifically neonatal mortality. I'm not going to go through them. They're equally diverse, I would say. And between 2021 and 2022, there was a 255 death increase in infant mortality in Texas, increasing from 1 ,985 to 2 ,240 deaths.
This change represents a 12 .9 % increase in infant mortality in Texas. This exceeds the 1 .8 % increase observed in all other US states in Washington, DC. So that was the infant mortality, but then they wanted to look at the rate. So again, between that same time period, the infant mortality rate also increased by 8 .3 % for Texas, whereas the rate increased by 2 .2 % in the rest of the United States.
go ahead.
Ben Courchia MD (54:06.529)
Whatever, finish.
Daphna Barbeau (54:08.078)
Okay, then they wanted to look, that was infant mortality, okay? So infant mortality as a reminder is the death between day one and one year of age. Then they wanted to look at specifically neonatal deaths. So that's before 28 days. Estimates for neonatal deaths showed a similar pattern. So it increased from the usual 1 .6 % increase to 10 .4%. And the rate then,
The rate increased in Texas by 5 .8%, but it actually decreased in the rest of the United States. Then they wanted to look at expected deaths. So for the entire kind of exposure period, they estimated an expected 1 ,697 infant deaths based on kind of this synthetic model of Texas. But, so 1697.
There were actually 1 ,913 observed deaths, so in excess of 216 infant deaths. At the monthly level, they observed statistically significant greater than expected counts for four months during that time period. And the analysis of the neonatal deaths found the same pattern, a greater number of observed deaths in the post -policy period than expected deaths. This number was 1233 versus the expected of 10.
88 or 145 excess deaths. They also looked specifically at like what were the deaths. So among the top 10 causes of infant death, they observed a 22 .9 % increase in congenital anomalies in Texas compared with a 3 .1 decrease in the rest of the US, especially for our community, right?
Ben Courchia MD (55:50.769)
That's the kicker, in my opinion. I mean, that is impressive. I'm going to say something. I'm always a little bit like with every paper we review, this is a year over year comparison. So it's 2021 versus 2022. I'm saddened that we may get more data points to analyze. However,
Daphna Barbeau (55:59.438)
You
Daphna Barbeau (56:04.568)
That's right.
Daphna Barbeau (56:12.206)
Well, and I mean, I should say, sorry, table one, so change from prior year. The change was either constant or a decreased change from prior year, right? Because theoretically we're getting better at taking care of babies, but this was a dramatic change. So they have infant deaths here really listed from 2018 to 2022. And again, the change was nominal since 2018 until this change
Ben Courchia MD (56:35.037)
And so, unfortunately, we will get data for 2023 and 2024, but this diametrically opposed direction where congenital malformation, deformations and chromosomal abnormalities goes up by 23 % in one state while it is going down by 3 % in the rest of the country. I mean, that should give people pause for
Daphna Barbeau (56:58.638)
Yeah, absolutely. They also mention, okay, other infant deaths, unintentional injuries, 20 .7 % versus 1 .1 % increase in the rest of the US. And interesting, necrotizing enterocolitis of the newborn, 73 .3 % versus 6 .4 % increase in the rest of the US.
Ben Courchia MD (57:14.343)
Do see that? This is crazy. I mean, it's not, these are small. Yeah.
Ben Courchia MD (57:22.602)
So no probiotics. so let's see how, I mean, this is just
Daphna Barbeau (57:28.462)
So anyways, to our Texas colleagues, I mean, you've really been dealing with a lot, but I mean, I think we will all be seeing this in increase in congenital anomalies, more deaths in the NICU. And this number about this necrotizing enterocolitis rate was, I was surprised to see
Ben Courchia MD (57:47.547)
Yeah, mean, it's been something that's been difficult for me because I've always had this issue with, what's the point of, like, we're going to go to the senator and what does that mean? know, like, we're going to advocate and so on and so forth. But this paper really shows you how political decisions can have a dramatic impact on the ground level in a fairly immediate manner. And what's even more depressing is that, especially in the US, this issue of abortion has become such a polarized
that politicians try to make a stand just to, to, gain some, some coverage or some media coverage and say, I'm, I'm, I'm the most restrictive and no, I'm the most restrictive. But in the end, when you see that it increases such, such disparities, it's just, it's just sad. It's just unfortunate.
Daphna Barbeau (58:37.358)
Well, and I think to your point, I think what's the most frustrating is when you see them discussing these topics, right? People can have a variety of reasons. Okay, religious, political, social, fine, fine. But like, they don't know what it means when they say these things and what the medical decisions that accompany these legal restrictions. I think that's the most frustrating and I think that's where we can be the most useful.
is providing education about like, what does it look like in our day -to -day
Ben Courchia MD (59:09.799)
Yeah. Yeah. And the simplification of the problem of are you pro -life or pro -choice? It is such a reductive. Yeah, but I'm saying it's a way to make this problem easy to discuss, but it's just shortchanging everybody involved in the process. Ugh, all right, bring it, This is awful.
Daphna Barbeau (59:16.653)
Yeah, it's so cool.
Daphna Barbeau (59:29.386)
Yeah. I will mention there's an associated editorial in the same issue that was interesting. Read, abortion bans harm not just pregnant people, they harm newborns and infants too. So, okay. Do you want it to do one paper? And then I have, I want to do at least one more. Okay.
Ben Courchia MD (59:42.039)
Mm -hmm. Ugh.
Ben Courchia MD (59:49.309)
Sure, Okay, so I saw this paper in JAMA Network Open from New Zealand called Diazoxide for Severe or Recurrent Neonatal Hypoglycemia, a Randomized Clinical Trial. We're going back into good old clinical research here, Dr. Lang and colleagues. And again, great background section saying that up to 30 % of newborn have at least one risk factor for hypoglycemia, including preterm birth, maternal diabetes, fetal growth issues.
And about half of these babies experience hypoglycemia. Now for the new trainees, why do we care so much about hypoglycemia? It's because the developing brain is uniquely sensitive to neuroglycopenia, which can cause selective neuronal necrosis, impaired maturation, leading to cognitive deficits and learning difficulties in later childhood.
And so this is especially true for those exposed to severe hypoglycemia with a blood sugar concentration of less than 36 or recurrent episodes of hypoglycemia. So neonatal hypoglycemia remains one of the most important and potentially preventable cause of impaired development in newborn. And just to go through some physiology in pancreatic beta cells, insulin exocytosis is controlled by this ATP sensitive potassium channel, which close as
glucose -generated ATP increases, triggering cell membrane depolarization. Diazoxide actually works by binding to these potassium ATP sulfonylurea receptor, causing hyperpolarization and attenuation of glucose -stimulated insulin secretion, in turn leading to less insulin production. Diazoxide therapy by modulating beta -cell responsiveness to glucose could improve glycemic stability, allowing earlier weaning from heavy fluids and establishment of enteral feeding.
So another great background section, especially if you are a trainee, I will highly recommend this. We've used diazoxide usually in the context of support from our endocrinologists. yeah, so I think, yeah, I mean, I've rarely used it as a first line, but it usually is something that we've used when it comes to, yeah.
Ben Courchia MD (01:02:13.117)
when it comes to refractory hypoglycemia. So this trial is called the Neoglucotrial, the neonatal glucose care optimization trial, and it investigates the use of low -dose oral diazoxide in the early management of severe or recurrent hypoglycemia in late preterm through full -term newborns. It's a double -blind to arm parallel randomized trial. It took place in New Zealand from 2020 to 2023.
Eligible infants were born at 35 weeks or more admitted to the NICU in the first week of life with severe hypoglycemia. What is severe hypoglycemia? ask. Blood glucose concentration less than 22. A concentration less than 36 after two doses of dextrose gel and feeding in a single episode. So either really low, like either 22 or 36 after. Or it could also be considered hypoglycemia if you have three or more consecutive episodes of blood glucose concentration.
less than 47 in a 48 -hour period. They excluded patients with congenital anomalies and other usual exclusion factors. And the intervention was really to randomize these babies one -to -one to either a placebo or diazoxide. The diazoxide dose included a loading dose of 5 mc per kilo orally, followed by maintenance of 1 .5 mc per kilo every 12 hours. The interventions were titrated at the bedside using an algorithm.
commencing before the third maintenance dose to a target blood glucose concentration of 47 to 98. That's where they wanted to land, representing the 10th to 90th percentile. Now what's interesting is that they couldn't, for the placebo, I think that's a very important point that we need to bring up, is that they couldn't just use like saline or whatever because the diazoxide is quite thick. And so they ended up needing to add cornstarch.
4 grams per 50 ml to the placebo so that it could visibly look like that as oxide. What is the effect of cornstarch as a placebo in a case of hypoglycemia? That remains to be determined. The primary outcome of the study was resolution of hypoglycemia. You're shaking your head.
Daphna Barbeau (01:04:17.582)
I used to know, but
Ben Courchia MD (01:04:20.805)
It sounds like it could help with hypoglycemia, no, cornstarch?
Daphna Barbeau (01:04:23.276)
mean, don't we use cornstarch in some of those metabolic disorders? So it's not quite a placebo potentially. Okay.
Ben Courchia MD (01:04:26.651)
Yeah, yeah.
That's exactly right. That's why I'm bringing it up. The primary outcome was resolution of hypoglycemia. So that was defined as the point at which all of the following things occurred for at least 24 hours. You were receiving enteral bolus feeds. You had normal blood sugar level between 47 and 98, and you had no IV fluids. They had some secondary outcomes, which included the time to achieve normal glycemia, feeding at discharge, use of IV fluids.
duration of IV fluids and so on and so forth. They had some secondary safety outcomes as well. I will let you go through them since it's already pretty late into the episode. So 133 patients met eligibility. They were only able to approach 112 and they only got consent for 75. So they randomized those 37 in the diazoxide group, 38 in the placebo group. The diazoxide group had a mean gestational age of 37, nine weeks and 72 % male in that group.
So quite of a predominance of male patients. The placebo similar stuff, 37 .4 weeks and 71 % male. The gist of it is that there was no significant difference in the time to resolution of the hypoglycemia between the intervention and the placebo group. I forget which figure it is, but they have a very nice graph showing that lack of significance. However, they do mention that the diazoxide group compared with the placebo group had reduced time
to reach bolus feeds, had reduced duration of IV fluids. It had reduced the number of episodes of hypoglycemia, the duration of the hypoglycemia, and the number of blood glucose tests that needed to be done. In terms of the length of stay or the duration of the admission, there was no difference. And so a few more interesting results is that they mentioned that despite these effects, the time
Ben Courchia MD (01:06:23.101)
to achievement of normal glycemia, which is a glucose between 47 and 98 milligrams per deciliter for at least 24 hours, appeared to be longer in the dioxide group. And they're saying that the reason for that is because they had more episodes of elevated blood glucose levels. So it sort of corrects it almost too fast, right? So the time, I'm going to say this again, because that could be missed. So you hear that
the time to achieve normal glycemia was potentially longer in the diazoxides. You'll be like, oh, that's not good. But it's because you're over -correcting so fast and you have more episodes of elevated blood glucose levels rather than low ones. The rates of hyperglycemia, sugars above 125, also occurred in both groups but was infrequent. There was no evidence that diazoxides was associated with increased use of oxygen or respiratory support or with congestive heart failure.
There was one newborn that had a seizure two days after the randomization, but the blood glucose concentration was normal and the brain imaging demonstrated a neuronal migration disorder. So that was not associated with the intervention it looks like. And then no newborn developed to GI bleeds, feeding intolerance or neck and all newborns survived to hospital discharge and had a newborn, normal newborn metabolic screening results. They're saying that in this trial of late preterm to full term infants with severe or recurrent hypoglycemia early or low dose.
Early low dose oral diazoxide did not reduce the time to resolution of hypoglycemia, but did reduce the time to establish enteral bolus feeding and weaning from IV fluids and reduce the duration of hypoglycemia and frequency of heel pricks for blood glucose compared to placebo. They're recommending further investigation for newborns whose condition is refractory to initial management of transitional hypoglycemia with dextrose gel or end breastfeeding.
get to my paper. That's impressive.
Daphna Barbeau (01:08:19.086)
Okay, buddy, I have two more, but I mean, we're really over time here.
Ben Courchia MD (01:08:23.407)
Nah, go for
Because now we're splicing the episode so people can listen to them at their own pace. then, yeah, and then if they want to listen to the one hour and 20 minute long version, then more power to
Daphna Barbeau (01:08:27.232)
Okay, that's true. That's true.
as they
Daphna Barbeau (01:08:40.79)
Okay, I have this paper in pediatrics, quality improvement interventions to prevent intraventricular hemorrhage, a systematic review lead author, Erica Edwards, senior author of Jeffrey Hobart, but it does include Dr. Roger Saul. So this study included single center or multi -center quality improvement intervention studies with a primary focus or objective to reduce the incidence or severity of IVH and preterm infants. includes the
They ended up including 18 studies, 11 from the US, two in Germany, two in Brazil, two in Canada, and one in the Netherlands. In total, it included 5 ,906 infants. There are about 2 ,500 in the pre -intervention groups and 3 ,300 in the intervention groups. Nearly all of the QIIs, so again, quality improvement interventions, included clinical interventions in antenatal care, in the delivery room, and in the NICU.
Most of the articles, I'll get more into more details, but had these variety of interventions. There was an exception of two papers that focused solely on umbilical cord management in the delivery room. But of note, mean, the papers are pretty different. In general, it's hard for us to review reviews in this podcast format. So I definitely encourage everyone to take a look at the paper themselves. That's true for every paper review, but especially these. I know that's what you want to
Ben Courchia MD (01:10:03.389)
But what is the one intervention that reduced the rates of IVH by 60 %? The one intervention.
Daphna Barbeau (01:10:08.226)
That's what you want to know. That's what you want to know. But the problem with this paper was that they really weren't able to tell us that. That's what we want to know. I wanted to highlight a few things. I think when people are providing kind of neuroprotective care, there's a difference in what is our weight cutoff, what is our gestational age cutoff, and different papers use different things.
I'd say the most restrictive was this Kramer et al paper using less than a thousand grams in less than 28 weeks. So for sure, babies of that size and gestational age are included at almost all kind of neuro bundles. Then I want everybody to go look at table two, which lists all of the interventions that were included in these 18 papers. I'm only going to tell you the three page table. I'm just going to tell you the categories because I think that's useful.
Ben Courchia MD (01:10:55.901)
three page table.
Daphna Barbeau (01:11:03.886)
The categories included antenatal, they included delivery room, parental engagement, staffing, environment, positioning, minimizing, handling pain, stress, meds, hemodynamic and electrolyte management, respiratory care, protocols and procedures. And the most interesting thing I think to know is the gist of the paper is that many studies, most studies used multiple interventions. How many interventions?
So aside from the ones that were just looking at umbilical cord management, they ranged from five interventions as part of their neuro bundle to 42 interventions as part of their neuro bundle. Um, I'm going to end also, I wanted to mention, okay. So four of the 10, um, reporting data on IVH and nine of the 14 reporting data on severe IVH.
saw improvements, not everybody, but those papers saw improvement. And they didn't even calculate a forest plot or draw other conclusions because of the heterogeneity of these interventions in these different studies, the types of methods used to calculate the results, as well as the uncertainty in the estimates. So I'll get to that. But I think if you're trying to create a neuro bundle for your hospital, for your unit,
I think there are some interventions that were more commonly used across studies. So I'm going to just tell you a little bit about that. Six of the studies looked at antenatal care. All of those included antenatal betamethasone. So steroid prenatal betamethasone, yes. 15 looked at delivery room management and 10 of 15 specified avoiding hypothermia. So people felt strongly about that. 12 looked at modifying environment and all 12 instructed to minimize noise. Nine out of 12 to minimize light.
15 looked at positioning and all 15 maintained a midline head position. Despite the fact that there's still relatively few studies that have proved which position is the correct one. 15 looked to minimize pain and handling, 10 out of 15 of those reduced weighing and measuring across kind of those time periods. So they also wanted to look at the quality of content of the interventions. So they use this QIMQCS score.
Daphna Barbeau (01:13:26.222)
with higher scores indicating higher quality. The median QIMQCS score was 11 of 16. Again, higher scores, higher quality. 11 received scores of more than 10. Six received scores of seven to 10. And then one received a score of lower than seven, low quality. So basically, I'm going to just read this. I thought this was the most valuable kind of nugget.
Most of the QIIs included a wide range of clinical interventions. For most, was not possible to ascertain which produced the results. It is possible that some of the changes observed were due just in part to the QI methodology. Systematically applying the four key habits for improvement, the habit for change, the habit for evidence -based practice, the habit for systems thinking, and the habit for collaborative learning and working together as a team on a shared goal can help promote measurable improvements.
It didn't tell me what I was hoping for or even which interventions in general, but there are certainly some interventions that are seen recurrent across neurobundles. Yeah.
Ben Courchia MD (01:14:28.406)
it says.
Ben Courchia MD (01:14:36.573)
It says a lot though. It says a lot, number one, as to the multi -pronged approach. You're not going to solve IVH by just looking at the first 24 hours of life. You're going to need to look at this prenatally in the delivery room, in other aspects of care, including respiratory management and so on. I think that's very valuable. And then gives another, the confusion, maybe an opportunity for young trainees that, hey, this is something that needs to be looked at.
opportunity for someone to investigate.
Daphna Barbeau (01:15:06.166)
Mm -hmm, more opportunities for sure. I also think if you've got a good neuro bundle, but your rates are not where you want, maybe come take a look at the list and see what else you can add to your neuro bundle or evaluate, are you following your neuro bundle? Are people educated on your neuro bundle? You know, are you all speaking the same language? Even though you have one, is everybody using it? I think those are some key takeaways. And the last paper that I wanted to present today, actually it's not true. I had one more, but this is it for me today.
Ben Courchia MD (01:15:15.675)
Yeah, that's true.
Ben Courchia MD (01:15:30.299)
The last paper.
Daphna Barbeau (01:15:35.512)
This one's from Journal of Perinatology. It's vasopressin as an adjunctive therapy and pulmonary hypertension associated with refractory systemic hypotension in term newborns. So this is a very specific group of babies. Lead author Felipe Santalises, this is coming from Chile, notably this unit, Pontificia Universidad Católica de Chile is a national referral center for PPHN.
Just like you've indicated in many of your papers today, I thought this was an excellent overview of vasopressin in their background material. What does it do? Where does it act? Why are they even using it for this purpose? Because in particular, it does not increase pulmonary vascular resistance until you have very high levels in the blood. It does occur at doses higher than two milliunits per kilogram per minute. But in this paper, they're using doses lower.
This is a retrospective cohort study conducted in a referral level three level, I'm sorry, in a referral level four NICU. So basically they took all the medical records of all neonates admitted to the NICU during this 49 month period between 2019 and 2023 who required vasopressin due to A, refractory PPHN, this was diagnosed by echocardiographic signs of pulmonary hypertension, B, persistent hypoxemia defined as an OI greater than 20,
NC, systemic hypotension, defined as systolic or diastolic blood pressure less than the third percentile. They excluded infants with congenital heart disease, lethal malformations, or any patient that received vasopressin for less than six hours. Now, I want to start by saying when you're looking for kind of a protocol in a study, they had a study because they have implemented this phased management approach for hypotension in PPHN.
So they've been doing this since 2019 and this is what they do. Epinephrine is started as the first line drug up to a dose of 0 .07. Hydrocortisone is the second line and then vasopressin is suggested as the third line drug. And then they have a starting dose. They use 0 .3 million units per kilogram per minute and they titrate up every 15 to 16 minutes in increments of 0 .2 to 0 .3 to achieve targeted arterial pressure.
Daphna Barbeau (01:18:00.652)
however, defined by the attending physician. So in addition, that's right. You can do with that what you want. You can do with that what you want. But my point is all of these babies were on the same protocol. So in a retrospective cohort study, I think that's really valuable information. In addition, targeted echo standard of care. So they want to evaluate the association of therapy with echocardiographic parameters.
Ben Courchia MD (01:18:04.335)
I've been
Daphna Barbeau (01:18:29.902)
and they did echocardiography within six hours prior to the start of vasopressin, that was time zero, and another performed between three and 24 hours from the start of the drug. That's time one. They looked at for comparisons. No patients were excluded because of this because every single one had echocardiography performed. results, they had 79 neonates with a diagnosis of PPHN who received vasopressin who were identified during this period. 11 patients were excluded.
because they received vasopressin for less than six hours. Of these patients, four died, unfortunately, as they were critical at the moment of starting the drug, and seven were connected to ECMO within the six -hour window of exclusion. And in all these patients, vasopressin was started after deciding on ECMO. So total, they had 68 patients included. The median gestational age, 38 .4 weeks, the median birth weight, 3 ,065 grams.
The cause of PPHN, congenital diaphragmatic hernia in 57 patients, that's 84%. Meconium aspiration syndrome in seven patients. pneumonia in two patients. Pulmonary interstitial glycogenosis and interstitial pulmonary disease, one patient for each. The median age at initiating vasopressin was two days with a range of zero to 13 days. All patients were on mechanical ventilation. Most of them, 87 % nearly on high frequency ventilation.
and all of them were receiving nitric oxide at a starting dose of 20 parts per million. And according to their phase management approach, all the patients were on epinephrine and hydrocortisone when vasopressin was started. The average duration of vasopressin therapy was 80 .5 hours with a range between 48 and 165. And they were looking at a number of parameters in the first 48 hours. Now I'll tell you, they have these
beautiful graphs for a handful of parameters that basically show these changes over time. And you can see that the change is pretty immediate in the first four to 12 hours. There's this linear improvement on a number of these parameters. And I'll tell you about them specifically. And then they kind of stabilize out with kind of a more modest improvement. The diastolic, systolic, and mean blood pressures increased
Daphna Barbeau (01:20:49.912)
four hours after the start of vasopressin. This was statistically significant. Again, the cohort are babies with PPH and hypotension. Concomitantly, they observed a drop in the requirements of vasoactive drugs. So they used the vasoactive inotropic score to quantify vasoactive drug support, and the equation is there. But basically, they saw a decrease in the requirements of vasoactive drug reflected in this
decrease in the vasoactive score after eight hours of initiation, also statistically significant. They declined from a median of 26, that's a score, to a nadir of 10 at 36 hours. Urine output, lactate, pH, all improved from four hours after starting the treatment. In addition, base deficit and heart rate also decreased during the study period. This was also statistically significant.
They looked at respiratory parameters, the mean airway pressure and oxygen requirements significantly decreased their medians after four hours of treatment, an oxygen requirement of 100 % to 85 % and mean airway pressure is 15 to 14, resulting in turn in a decrease in the OI that remains significantly low during the entire evaluation period.
Then they looked at the echocardiography. I told you time zero was before initiation and time one was in the first 24 hours, four to 24 hours in all of the 68 patients. And after the drug was initiated, supra -systemic pulmonary hypertension characterized by an exclusive right to left ductal flow was found in all patients at study time zero, so before initiation. At time one, 48 % of the evaluated patients had an exclusive left to right ductal shunt.
This was statistically significant. And the 52 % remaining head now bidirectional or some with right to left jump. Now regarding ventricular output assessment, left ventricular output increased from 124 mLs per kilo per minute to 154 mLs per kilo per minute. This was statistically significant. And the right ventricular output also increased, 126 to 172, also statistically significant.
Daphna Barbeau (01:23:08.538)
so I thought this was very interesting. I thought the charts were very helpful. The graphs about seeing the impact and then obviously these kind of clinically significant, markers are there. This is sick group of patients. Obviously they're already on a lot of support. but they're basically an extremist, right? And so, I mean, you could see how, how the initiation of the protocol.
helped improve this group of babies. So, thoughts?
Ben Courchia MD (01:23:45.469)
I think it's interesting because we recently interviewed on the French podcast Dr. Audrey Hebert. I'm not going to try to pretend to Americanize her name. But Audrey is a neonatologist in Quebec and she is now Twitter famous for her PAS talk titled Death to Dopamine. And she had spoken to us about the use of vasopressin, right? How this was gaining popularity.
Daphna Barbeau (01:24:04.824)
Mm -hmm.
That's right.
Ben Courchia MD (01:24:14.941)
especially when we're talking about refractory acute pulmonary hypertension. And so she did similarly a retrospective single centered study where she did show improvement in oxygenation and hemodynamic status. And so I think that what's interesting is that vasopressin is gaining in popularity and we're getting some of that early retrospective data. And I think we may be inclined to, I think,
Daphna Barbeau (01:24:29.166)
Mm -hmm.
Ben Courchia MD (01:24:45.017)
we are trained not to take retrospective studies with a grain of salt, but in this case where there's really not a lot of evidence, that is all we have. And to see retrospective studies echoing one another is always a reassuring sign, I think. So I'm excited about the use of vasopressin. I must say that in our unit, we've used vasopressin in the past and it's worked quite well.
Daphna Barbeau (01:25:02.03)
Mm -hmm. Mm -hmm.
Daphna Barbeau (01:25:11.214)
Mm
Ben Courchia MD (01:25:13.711)
So I'm a little bit biased, but I'm looking forward.
Daphna Barbeau (01:25:16.92)
So you're looking for the multi -pronged RCT here.
Ben Courchia MD (01:25:20.025)
Well, actually, yeah, my excitement is definitely growing for that RCT. But no, this is good. I'm always happy to see that we're able to feature work from outside the US. So love to see our Chilean colleague represented. Yeah. You sure you don't have one more? No problem. No problem. That was good. That was a good journal club.
Daphna Barbeau (01:25:33.038)
Mm -hmm.
Daphna Barbeau (01:25:39.126)
Mm -hmm. Okay, I'm done.
No, I do, I, I was going to have to wait till next
Daphna Barbeau (01:25:50.22)
Yeah, thanks for all your hard
Ben Courchia MD (01:25:51.599)
All right, and feedback coming. Like we said last time, we closed the survey giveaway thing so people should have heard from us. If you haven't won the prize, there was a lot of prizes to win. We decided that instead of having one big, big, prize, we were going to have... What did we end up doing in the end? 25 prizes? Something like that. Yeah, at least. have been more. Anyway, we're very happy and thankful for everybody who participated to continue sharing feedback with
Daphna Barbeau (01:27:27.146)
At least it may have been more.
Ben Courchia MD (01:27:35.249)
so that we can keep improving the platform. Definitely it's been fun. Have a good rest of your Sunday. Bye.
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