#352 - 📑 Journal Club - The Complete Episode from September 14th 2025

Hello friends 👋

In this week’s Journal Club, Ben and Daphna review several recent neonatal studies with direct implications for practice.

They begin with the BORN trial from Italy, which investigated whether transfusing preterm infants with cord blood–derived red blood cells, rather than adult donor blood, could reduce severe retinopathy of prematurity (ROP). While the intention-to-treat analysis showed no difference, per-protocol findings suggest potential benefits that warrant larger trials.

Next, they review a large international cohort study of outcomes in infants born at 22–23 weeks, highlighting striking variability in survival and morbidity across networks, with Japan showing the highest survival rates.

The EBNEO segment features Dr. Gabriel Altit discussing an Indian randomized trial comparing norepinephrine vs. dopamine as first-line therapy for neonatal septic shock. Although primary outcomes were similar, norepinephrine showed some favorable metabolic and perfusion markers.

The hosts then cover a delivery room resuscitation study identifying expiratory tidal volumes of 4–5 ml/kg as key for successful lung aeration, a Canadian trial of atropine for neonatal intubation, and a retrospective study from Alabama on optimal timing and frequency of pulmonary hypertension screening in BPD.

The episode concludes with a case report on the use of continuous glucose monitoring in a neonate with congenital hyperinsulinism.

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The articles covered on today’s episode of the podcast can be found here 👇

Cord red blood cell transfusions for severe retinopathy in preterm neonates in Italy: a multicenter randomized controlled trial. Teofili L, Papacci P, Pellegrino C, Dani C, Cresi F, Remaschi G, Ansaldi G, Giannantonio C, Campagnoli MF, Vania B, Fabbri M, de Vera d' Aragona RP, Molisso A, Beccastrini E, Dragonetti A, Pasciuto T, Gabbriellini S, Baroni S, Serrao F, Purcaro V, Raffaeli G, Villa S, Prati D, Mondello I, Falcone A, Patti ML, Boggini T, Bergamaschi P, Lepore D, Franco FGS, Orazi L, Mozzetta I, Baldascino A, Valentini CG, Locatelli E, Albiani R, Besso FG, Cantone GV, Coscia A, Trimarchi A, Cavallaro G, Ghirardello S, Vento G.EClinicalMedicine. 2025 Aug 13;87:103426. doi: 10.1016/j.eclinm.2025.103426. eCollection 2025 Sep.PMID: 40838199

Outcomes of Preterm Infants Born at 22 to 23 Weeks' Gestation in 11 International Neonatal Networks. Isayama T, Norman M, Kusuda S, Reichman B, Lehtonen L, Lui K, Adams M, Vento Torres M, Filippi L, Battin M, Guinsburg R, Modi N, Håkansson S, Klinger G, de Almeida MF, Helenius K, Bassler D, Su YC, Shah PS; International Network for Evaluation of Outcomes (iNeo) Investigators.JAMA Pediatr. 2025 Aug 25:e252958. doi: 10.1001/jamapediatrics.2025.2958. Online ahead of print.

Dopamine versus epinephrine for neonatal septic shock: an open labeled, randomized controlled trial. Singh G, Bhaskar V, Batra P, Gupta P.J Perinatol. 2025 Aug 28. doi: 10.1038/s41372-025-02399-7. Online ahead of print.PMID: 40877444

EBNEO Commentary: Review of the 'Norepinephrine Versus Dopamine for Septic Shock in Neonates: A Randomised Controlled Trial'. Altit G.Acta Paediatr. 2025 Jul 23. doi: 10.1111/apa.70241. Online ahead of print.PMID: 40698742 No abstract available.

Respiratory Targets Associated With Lung Aeration During Delivery Room Resuscitation of Preterm Neonates. Rub DM, Hsu JY, Weinberg DD, Felix M, Nadkarni VM, Te Pas AB, Kuypers KLAM, Davis PG, Ratcliffe SJ, Kirpalani HM, Foglia EE.JAMA Pediatr. 2025 Aug 11:e252521. doi: 10.1001/jamapediatrics.2025.2521. Online ahead of print.

Atropine Versus Placebo for Neonatal Nonemergent Intubation: A Randomized Clinical Trial. Afifi J, El-Naggar W, Hatfield T, Sandila N, Baier J, Narvey M.J Pediatr. 2025 Jul 9;286:114719. doi: 10.1016/j.jpeds.2025.114719. Online ahead of print.PMID: 40645282

Screening for pulmonary hypertension in preterm infants with bronchopulmonary dysplasia: when, how often and does it matter? Gentle SJ, Carlo WA, Ambalavanan N.Arch Dis Child Fetal Neonatal Ed. 2025 Sep 5:fetalneonatal-2024-328405. doi: 10.1136/archdischild-2024-328405. Online ahead of print.

Continuous glucose monitoring in a neonate with hyperinsulinemic hypoglycemia and ABCC8 gene mutation. Iwańczyk P, Majewska A, Issat T, Hoffman-Zacharska D, Krajewski P, Lipska-Karpińska K.Endocrinol Diabetes Metab Case Rep. 2025 Jun 5;2025(2):e250002. doi: 10.1530/EDM-25-0002. Print 2025 Apr 1.

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Watch this week's Journal Club on YouTube 👇

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The transcript of today's episode can be found below 👇

Ben Courchia (00:01.048)

Hello, everybody. Welcome back to the Incubator podcast. We are back today for an episode of Journal Club. Daphne, good morning. Very good. It feels like our Journal Club spot has been stolen by so many other good episodes.

Daphna Yasova Barbeau, MD (00:07.597)

Good morning, how are you?

Daphna Yasova Barbeau, MD (00:17.017)

Yeah, right, we're reviewing very important recent journal articles, but it's been keeping us out of reviewing journal articles.

Ben Courchia (00:24.824)

What's interesting about this is that people think that we are sort of the nerds of the neonatology world and that we're always reading. But what's interesting is that when we have people who come on to do the review of the recent literature, whether it is the team from the Neonatal Nephrology Collaborative, whether it is the team from the Newborn Brain Society, I invite you to go listen to these episodes because it's great to have these experts review content-specific literature.

Like it doesn't mean that in the background I'm reading more and more. I, I slack off. so.

Daphna Yasova Barbeau, MD (00:54.553)

Well, it's why we started the podcast, right? Because we couldn't keep ourselves accountable.

Ben Courchia (00:59.968)

I know, but you would think that if without the podcast now, would be still, no, no. If that calendar invite is not on my outlook, then yeah.

Daphna Yasova Barbeau, MD (01:11.993)

We fall behind. I mean, we, I mean, we, we feel from the community, everybody who's having a hard time keeping up with the literature on their own, you know? But I, mean, I second what you said. You know, I was thinking this. listened to every episode, even the episodes that we record to remind myself, you know, what we talked about, what are we, what are the takeaways? What are we learning? But these year in review have been really good. I learned a lot.

I'll say just from the nephrology review, I've used already. I've sent many times to many colleagues and used in the unit those resources. So I hope people take a look at our summer offerings.

Ben Courchia (01:52.61)

That's something that really came in my opinion from our time at CHNC. I think that CHNC is a venue where you go and you interact with a lot of sub-specialists that you just maybe engage with as consultants. But the idea to see them as partners and collaborators, and that these are the type of people that also think about your babies, they think about these preemies after they leave the NICU. I think it prompted us at least to say, hey, we want to maybe share a little bit of...

Daphna Yasova Barbeau, MD (01:57.433)

Yeah.

Ben Courchia (02:21.23)

How do you think about these things? And if we know how they think after babies leave the NICU, we are better at counseling families while they are still in the NICU. And the kidney is a big deal. So many of our babies do have some degree of kidney injury because of their PDA, because of their inherent physiology. The brain, I mean, come on. We don't even begin to scratch the surface of how babies' brains are affected during the NICU stay. So it's interesting to get that perspective for sure. All right.

Daphna Yasova Barbeau, MD (02:43.875)

Yeah.

Daphna Yasova Barbeau, MD (02:48.365)

Totally.

Ben Courchia (02:49.262)

We have an EBNEO segment today. We are very happy to welcome one of the incubator team members on the podcast, Dr. Gabrielle Altitte from Montreal Children, who's going to review the impact article of the month for the EBNEO team. So stay tuned for that. And without further ado, I think we are ready to begin. I'm going to start today with an article that I found in the Lancet. It's by first author Luciana Teofil.

Daphna Yasova Barbeau, MD (03:08.569)

Let's do it.

Ben Courchia (03:18.59)

It's published this year and it's called Cord Red Blood Cell Transfusion for Severe Retinopathy in Preterm Neonates in Italy, a multi-center randomized control trial. This is the born trial. Okay, so red blood cell transfusions are a common part of neonatal care. We know that particularly when we're talking about L-GANS, also known as extremely low gestational age neonates. Now these...

Daphna Yasova Barbeau, MD (03:29.441)

a very cool study.

Ben Courchia (03:44.194)

Babies often require repeated transfusion early in life. We're trying to identify guidelines that would help us reduce the amount of blood they're exposed to. But one of the things that we talk about a lot is the idea of this rapid transition as they are born from their fetal hemoglobin to more of an adult type of hemoglobin HbA, which happens after birth, and that we are kind of accelerating with the process of transfusions.

The authors mentioned that there are several studies that have linked to lower levels of fetal hemoglobin with the development of retinopathy of prematurity or ROP and that hemoglobin F, fetal hemoglobin has properties that may actually protect preterm infants. It has a higher oxygen affinity. It has greater nitric oxide availability and better oxidative stress resilience. Now with that in mind, this study asked a critical question, which was what if we could transfuse this particular cohort of babies?

with cord blood derived red blood cells, which contain fetal hemoglobin instead of your standard sort of adult PRBCs, could this potentially reduce the incidence or severity of ROP? Yeah, it's a great question. And so this is what the born trial set out to investigate, whether transfusing babies with cord blood derived red blood cells instead of adult red blood cells would reduce the rates of ROP.

Daphna Yasova Barbeau, MD (04:51.276)

Very cool.

Love it.

Ben Courchia (05:09.838)

Now, one of the things that I want to highlight is that we're going to go through the methods, and I'm going to go over some aspects of that. So it's a prospective randomized multi-center double blind control trial conducted in eight Italian NICUs between 2021 and 2024. The eligibility criteria were basically preterm neonates born between 24 and 27 weeks and six days.

and they excluded babies that had maternal fetal immunization, high drops, congenital malformation, prior transfusion, hemorrhage, and congenital infections. were randomized, babies were randomized one-to-one. The control arm received adult donor RBCs and the intervention arm received cord blood derived RBCs. They put twins in the same arm and randomization was stratified by site and by gestational age using permuted blocks.

The intervention lasted until about 29 weeks and six days post menstrual age. blood derived RBCs were obtained from a public cord blood bank and processed within 14 hours of collection following a standardized national protocol. You can go through the section on methods and see that actually they had an intimate involvement of the blood bank, which they're always so nasty to everybody else. So the fact that the blood bank did cooperate with this particular process and was the one generating these

these pouches of RBCs was quite neat. The outcomes that they were looking at, the primary outcome was the incidence of severe ROP at discharge or at 40 weeks post-menstrual age, whichever one came first. And they defined severe ROP as stage three or higher in zone one and two and or the presence of plus disease. They had a slew of other secondary outcomes, the rate of ROP requiring treatment, the incidence of BPD, composite outcome of death, severe ROP, BPD or neck, transfusion related measures and so on.

Now, what's interesting is that initially, they designed, and I think this is why it's important, we don't often spend time on statistical analysis of the different papers because a lot of the time it's done very well. But sometimes it's so interesting about how do we go about answering a question. So I want to spend some time on the statistics of this paper because this study was initially designed as an intention to treat analysis.

Ben Courchia (07:29.698)

The study had to contend with a lot. And the intention to treat analysis means that once randomized, always analyzed. the problem with intention to treat is that if you have protocol deviation, then you still do not move babies from one arm to the other. And this is a study that, as we'll see, it's hard to get cold blood, red blood cells. And if a baby needs a transfusion, guess what?

The team is not going to just say, you're going to stay very anemic and symptomatic, and we're not going to transfuse you because we're waiting for that pack of core blood derived red blood cells. So there was a lot of protocol deviation. And so to handle this, basically what the team did is that they added two more types of analysis, the per protocol analysis, meaning only patients who received their assigned product before 30 weeks, and then an as treated analysis where they basically looked at

the groups based on what they actually received. The sample size was calculated to detect a significant reduction in severe ROP accounting for gestational age strata and a 15 % mortality rate. And so they basically landed on a power analysis that dictated a need for 146 subjects. So I think it's always interesting to read the statistical section of these papers because you will see how

Understanding this basically helps you analyze the results of the paper. So let's walk through what the investigators found. So out of 145 randomized neonates, 142 were included in the intention to treat analysis, 73 in the control group, 69 in the intervention group. Severe ROP developed in 16 patients in the control arm, 14 in the intervention arm.

So that's 28.6 % versus 25%. The risk difference was negative 3 % with a 95 % confidence interval from minus 21 % to plus 14%, and the p-value was not significant. When we're looking at ROP requiring treatment, it was observed in 13 controls and 12 in the intervention. 22 % in the control, 21 % in the intervention. Again, not significant.

Ben Courchia (09:42.486)

The composite outcome of death, severe ROP, BPD and neck was seen in 76 % of the controls, 82 % in the intervention arm, also not significantly different from one another. What's important obviously is how many protocol violations do they have? And that amounted to about 42 % of the cohort. that's a lot, 24 patients in the intervention group received adult RBCs.

contributing to the dilution of the intended intervention and complicating interpretation. what's interesting is that if you look at how the trial was designed and intention to treat analysis and you look at the numbers, no statistically significant difference between the two. But now if we start taking into account these protocol deviations and we start looking at two other ways and we look at the per protocol analysis, this is where it gets interesting. Only 17 patients in the intervention group actually received

only cord blood derived RBCs prior to 30 weeks post menstrual age. They were compared to 38 patients in the control group who only received only adult RBCs. And when they're looking at that severe ROP occurred in 34 % of the control and 0 % in the intervention group, which is obviously a very striking difference. When looking at ROP requiring treatment, it was seen in 26 % of the control and 0 % in the intervention group.

And they even saw a reduction in BPD, 63 % in the controls compared to 29 % in the cord blood derived RBC group. When we're looking at an as treated analysis, meaning we did three groups, you had 49 patients who received only adult RBCs, then you had 17 babies who received only cord blood RBCs, and then you had 15 who received both.

in this particular, with no particular cutoff in terms of when they received it. In this analysis, severe ROP occurred in 36 % of the babies who received adult RBCs, 0 % in the ones who only received cold blood, and 53 % in the mixed group. And there were similar results for ROP requiring treatment. Even after adjusting for confounders like gestational age, birth weight, sex, intra-urine growth restriction, ABGAR scores, et cetera, adult,

Ben Courchia (12:07.634)

RBC transfusions given before 30 weeks significantly predicted both severe and treatment requiring ROP. And so the conclusion of the authors was that the Bourne trial is the first in their assessment prospective randomized control trial evaluating the clinical impact of cord blood derived RBC transfusion. And the trial results suggest a significant favorable effect of cord blood RBCs in preventing and or minimizing severe forms of ROP and BPD and indicate the urgent need for larger randomized studies.

And obviously, this is where we see that the trial design is becoming a bit of an issue because in the intention to treat, they cannot really make a formal conclusion. But it's these other analyses, the per-protocol analysis, the as-treated analysis that maybe shine a light on an avenue where if we were rigorously following the intervention, is there a signal there? And I think that this was quite interesting.

Daphna Yasova Barbeau, MD (13:03.608)

Yeah, I think it's really, I mean, innovative, exciting. You know, I think when we think about those like innate stem cell potential, like it's really, it's like the door's wide open potentially on how we could use some of these. I mean, obviously to do the studies, we to see if it works, but it feels like there's like all this untapped potential. You know, very interesting. Thanks buddy.

Ben Courchia (13:26.498)

Yeah. Yeah. Very cool. Yeah.

Daphna Yasova Barbeau, MD (13:30.584)

Okay, I had this paper that I think will spark some interest. This is in JAMA Pediatrics. It's outcomes of preterm infants born at 22 to 23 weeks gestation in 11 international neonatal networks. And I will underscore that none of those international networks are in the United States. So I think we're going to get a really good picture of what's happening around the world.

And so this is from the International Network for Evaluation of Outcomes Investigators, the I-Neo investigators who are looking at exactly that for these very small, very early babies. What does it look like across countries? It'd be nice if they included us, but these countries also have better national registries, obviously. Like we have a lot of networks that collect

data, but we don't have a national registry. So I'll get into it. Their question, their objective was really to evaluate survival and major morbidities. And what does the variation look like across these national networks for infants born at 22 to 23 weeks gestation? So basically what they did, they took an anonymized

Did say that right? Anonymized patient level data on neonates born before 32 weeks gestation. So that's what the iNeo database collects. So born before 32 weeks gestation or with a birth weight less than 1,500 grams. And the NICUs were in these following neonatal networks. So Australia, New Zealand, Brazilian, Canadian, Finnish, Israeli, the neonatal network of Japan, Spanish, Swedish, Swiss.

Ben Courchia (14:54.338)

Anonymized, yeah?

Daphna Yasova Barbeau, MD (15:21.752)

Tuscany and the UK neonatal collaborative. But they were trying to highlight specifically this sub-cohort of the 22 to 23 weekers. They actually I think did a very nice job of really trying to verify gestational age. So they used the best estimate in this order. So if you had an in vitro fertilization date and early prenatal ultrasound, which they indicated that they had for greater than 90 % of neonates.

last menstrual period or the physical exam at birth and in that hierarchical order. So if they had the IVF date, then that was the date that was selected. They looked at maternal corticosteroids. Any administration of corticosteroids was considered receipt. So obviously they had different protocols. One dose would be counted as receipt of antenatal steroids, where say here in the States, we would want to see two doses.

They looked at a number of pregnancy related comorbidities and then a lot of neonatal comorbidities. But the primary outcome was survival to NICU discharge and the secondary outcomes included grade three or four IVH. They also wanted to look at PVL, ROP that was treated either by ablation or anti-VEGF injection.

They looked at BPD, defined as oxygen use at 36 weeks post-menstrual age or at the time of discharge, if earlier than 36 weeks. They looked at neck, bell, stage two or higher, survival without severe PVH or PBL, and survival without severe PVH, PBL or ROP receiving treatment. They highlighted that they didn't include neck and BPD in that composite outcome due to concerns about the kind of between network.

variability of those diagnoses. So the overall cohort included 5,019 infants. Of the 5,019 infants, 17 % were born at 22 weeks. That was 846 babies. And 4,173 or 83 % were born at 23 weeks gestation. And then they really wanted to look at the variation. So number of infants admitted for neonatal intensive care in each network was, there was a wide range.

Daphna Yasova Barbeau, MD (17:46.392)

So at 22 weeks, it was from zero infants in Switzerland to 404 infants in Japan. And then for 23 weeks, the lowest was 37 infants in the Italian cohort to 1,097 infants in Japan. And I'm realizing I didn't tell you the dates. So I wanted, they were using, sorry, the dates from...

2015 to 2021. for as far as a decade ago. Okay. And then they wanted to look at each of some of these following characteristics. So for example, for antenatal steroids, they received antenatal steroids went from 18 % all the way to 83 % in the 22-weekers, depending on the national cohort.

57 to 98 % compliance in the 23-weekers. Then they looked at C-section births, 0 to 42 % in the 22-weekers and 5 to 73 % in the 23-weekers. And then they wanted, like I told you to look at survival to discharge, there was also significant variation there. So in infants born at 22 weeks, the survival to discharge,

was between 9 % in kind of the lowest performing unit up to 64 % in the highest performing unit network. And then in the 23-weekers, 16 % to 80%. So a lot of variability there. Severe PVH or PVL, 24 % to 65 % across networks in the 22-weeker and 18 to 56 % in the 23-weeker. Survival without severe

Severe PVH or PVL, 7 % to 53 % in the 22-weeker and 9 % to 69 % in the 23-weeker. ROP receiving treatment among survivors, 32 to 57 % in the 22-weeker and 16 % to 48 % in the 23-weekers. Survival to discharge increased day by day of gestational age and substantially differed between

Daphna Yasova Barbeau, MD (20:09.481)

early and late parts of the week within the same gestational week strata. So, I mean, I think we know that we see that, that at 22 and zero tend to have worse outcomes than the 22 and five, six weeks babies. So when we tell parents that every single day matters, that really is shown here.

Then they looked at these different epochs. So survival to discharge was not significantly different between 2015 to 2017 and the 2018 to 2020 for any network except for the Swiss neonatal network, which did show a significant increase in survival at 23 weeks in the later time period. And then they have these nice graphs that really kind of show you by neonatal network, obviously looking at the

each day of life between 22 and zero and 23 and six. And for all of the networks, there's this kind of upward slope linear correlation. You can see some of the networks, you know, really were not admitting anybody in the 22 weeks. That's right for those groups. That's right. And then

Ben Courchia (21:22.664)

The graph begins a little bit later in the gestation.

Daphna Yasova Barbeau, MD (21:28.759)

I wanted to show the adjusted instances of survival major morbidities in infants born at 22 weeks. The top performer, let's say, survival to discharge is definitely the Japanese network with, it looks like about 65 % survival to discharge. They have the lowest adjusted probability of severe PVH or PVL.

about 25 % and their survival without severe PVH or PVL is the highest of all the networks. I'd say about 55 % of babies in the 22 weeks survival without severe PVH or PVL. They have low rates of neck. I mean, consistent with, I think, reports around the US about 7%.

And they do still have quite a bit of ROP requiring treatment. About 55 % of babies had ROP requiring treatment. And those trends are pretty similar in the coal cohort, 22 to 23 weeks. Go ahead.

Ben Courchia (22:37.474)

Yeah, I think it's where it gets really interesting to dissect the numbers in this particular paper because let's talk about the Japanese, for example, and I'm only using them because they probably have established themselves as one of the countries of excellence when it comes to the care of these babies. And it's important to realize that their outcomes for babies born at 22 weeks and babies born at 23 and six are not the same. They're not.

Daphna Yasova Barbeau, MD (22:47.169)

Mm-hmm.

Mm-hmm.

Ben Courchia (23:02.946)

Like there's still a big difference. when you look at this graph and you try to isolate the Japanese and it's kind of easy because they're sort of floating above everybody else. So it's kind of nice to see that trend, but a 22-week-old in Japan has a percent chance of survival of about 40%. And if you're 23 and five, 22 and zero, but if the same baby is born at 23 and five, then the odds are like 80 some plus percent. so, so there is still,

Daphna Yasova Barbeau, MD (23:16.513)

The 22 and zero, right? Yeah.

Daphna Yasova Barbeau, MD (23:24.545)

Mm-hmm. Yeah.

Ben Courchia (23:30.648)

They haven't solved this particular problem. And that trend continues to manifest itself of, yeah, the odds are going to be the lowest at the lowest gestational age, even in Japan. And 40 % survival means 60 % mortality. And that's a big deal. That's a big deal. So I think that we

Daphna Yasova Barbeau, MD (23:39.511)

Mm Yeah.

Daphna Yasova Barbeau, MD (23:49.344)

Yeah, agreed. And it's not just that they've established themselves as a country of excellence, but they've been doing it for longer than most other countries, right?

Ben Courchia (23:56.302)

the

Yeah, they've established themselves from the standpoint of their numbers are just some of the best in the world. Yeah. And because they've done it for much longer.

Daphna Yasova Barbeau, MD (24:04.619)

That's right. That's right. Yeah. Absolutely. Longer. Yeah. So I thought this was interesting as we keep seeing papers about what are our US outcomes, know, how, how, how do we, what are we doing and what are our international colleagues doing? think it's really interesting.

Ben Courchia (24:22.124)

Yeah, and I think it puts perspective on those prenatal consults. yeah, it's quite interesting, especially when we, I mean, we've been dealing with a lot of pre-viable sort of consults where we have to cancel what will we be doing at 22 weeks and so on. It's just, it puts everything in perspective for sure. Okay, maybe we're going to take a very quick break. And then when we come back, we will have...

Daphna Yasova Barbeau, MD (24:27.019)

Mm-hmm.

Daphna Yasova Barbeau, MD (24:44.855)

Absolutely.

Ben Courchia (24:51.534)

our EBNEO segment for this month. So see you in a little bit.

Ben Courchia MD (00:01.588)

So we are joined today for this EBNEO segment by one of the incubator team members and host of the French edition of the incubator podcast, Dr. Gabriel Altit. Gabriel, welcome to the podcast.

Gabriel Altit (00:12.46)

Thank you so much, Ben. It's such a pleasure to be here.

Ben Courchia MD (00:14.324)

For people who don't know you were, yeah, it's a pleasure to have you. mean, and for the people who don't know you were interviewed during the neo heart coverage of 2023. And that's where it all began. So it's cool that to have you back. And if people need to hear more of Gabriel, there's so many outlets. He is the host of the French edition of the podcast, but definitely check out his main site, neocardiolab.com.

Gabriel Altit (00:22.448)

Yeah, I think so. That's a long time ago.

Gabriel Altit (00:43.106)

Thanks, Ben. So it's a bit weird to be on this platform and actually speaking English, I'll be fully honest. I feel like we're... Yeah.

Ben Courchia MD (00:44.126)

You're welcome.

Ben Courchia MD (00:48.999)

And for the

And for the people who do not know, we literally just recorded a French podcast. So it's asking us to switch languages on the fly, but we're going to do it. So today, Gabriel, you're coming to talk to us about an article that we reviewed on the podcast that was published, I believe, in the Journal of Pediatrics called Norepinephrine versus Dopamine for Septic Shock an open label randomized controlled trial. We were able to review that study on a previous episode of the podcast. But for those of us who

Gabriel Altit (01:01.794)

Okay, per-

Ben Courchia MD (01:20.296)

may not remember exactly what they were looking at between Norepi and DOPA. Can you summarize for us what was the question, how did they study it, and what was the main findings?

Gabriel Altit (01:28.366)

Yeah, absolutely. So, um, again, this paper was published in journal of pediatrics. Uh, it was a randomized control trial. Basically they compared, uh, 80 neonates with what they called fluid refractory septic shock. Um, they either allocated norepinephrine in 41 of them or dopamine and 39 of them as the first choice for the first line therapy. And, uh,

while they have a whole algorithm in order for escalation and obviously everything was blinded. So they had to make sure concentrations were appropriate to achieve these various targets for the dosages. The primary outcome for the study was actually what they called shock reversal at 30 minutes of the initiation of the vasoactive drug. But they also looked at many other outcomes, mortality, they looked at NIRS profiles, they look at acid-based balance, lactates.

And some of the side effects potentially of the drugs like glycemia, tachycardia, and some of the other common morbidities of infant septic shock. What they call the primary outcome, which is shock reversal within 30 minutes, was partially related to some of the parameters that we commonly measure in the NICU for some of these patients.

but also a lot of it was related to actually physical exam endpoints, so like capillary refill, normal pulses and things like that. So not just about a blood pressure or lactate or other such things. What else? So that's pretty much for the methodology that they used as a brief summary, because I know you already discussed this particular article on the English edition. In terms of the outcomes of the study,

What did they find? They find that basically their primary outcome of reversal of shock was quite similar between both groups. So we talk here about 32 % and 46%. And they looked also at the need for second agent or third agent, which was quite similar between the two groups as well as well as the requirement for steroids. So there was not.

Gabriel Altit (03:43.532)

much differences in much of the primary or secondary outcomes that they were measuring for this particular study in this population. But they did have in their table three, a few of these other markers that they looked at. So one of them was, for example, the use of NIRS, which they looked for the first 24 hours after the initiation of the intervention. And they found that at 24 hours, the cerebral NIRS had higher values in the group that was exposed to norepinephrine.

And they also found that patients exposed to Norepi had slightly better markers of acidosis. So the pH at six hours was seven point, sorry, the pH is at six hours. No, so at 24 hours was a 727 in the Norepi group as an average compared to 719. And there was slightly different CO2s as well.

during that timeline. not huge differences between the two groups, but maybe some elements in their secondary outcomes that would favor the exposure to norepinephrine in this small study in terms of population. just to mention also, it was a study that was done in one single center, level three NICU in India.

And they also provide some of the profile of the organisms that they had in terms of culture whenever they had a positive culture. Because it's important to mention that they had quite a significant portion of their population, which was with negative cultures, but with what they call this positive screen with inflammatory markers.

And so if we're looking at particularly some of the organisms, we see that the majority are Klebsiella, but they had quite a significant amount of Acinetobacter. I wouldn't be able to tell this with an English accent. But they also had like some E. coli, pseudomonas, MRSA and MR cons, but like no bacteria like GBS, for example. They also had...

Gabriel Altit (06:00.526)

quite a diverse population in terms of gestational age and birth weight. So although their average is 33 weeks for both groups, we can see that they had kind of babies spanning the less than 35 weeks to the more than 35 weeks. But when you look at the birth weight, we can see 1.6 kilos the average. So not that many patients that would be kind of less than a thousand grams or less than 28 weeks or extreme preterm range based on the data that they provide.

So that's kind of the summary, big picture of the study. You know, their conclusion is that obviously we need more trials and more studies to kind of understand what's the best agent to provide during episodes of shock. But that from their preliminary or at least initial data that they obtained in this particular study, Norepi seems to be as well tolerated as dopamine.

and seems to be conferring maybe better profiles in terms of metabolic acidosis and nearest values once shock has initiated in their particular population.

Ben Courchia MD (07:12.146)

Yeah, think this was obviously a very interesting article. And I think that the population, you did a good job at sort of breaking down that type of population and obviously the incidence of sepsis. And what's interesting is that dopamine and norepinephrine are very similar in terms of their profile, in terms of some of the receptors on which they act. And they are related to one another, but they're not exactly the same. And so I am wondering a little bit in terms of what you wrote in your commentary.

about what do you think methodologically about using this comparison in this particular population? And also the team being quite astute in not just looking at blood pressure as a number and looking at other measures of blood pressure like near-infrared spectroscopy.

Gabriel Altit (08:02.274)

Mm-hmm.

Yeah, no, totally. Well, first of all, I'm going to say that, you know, in general, doing trials in this group of population that are quite sick is always commendable in the sense that, as you know, it's very difficult and challenging to recruit these patients. They may come at any day and time of the night. They're quite sick. Parents are very worried. And so just the simple fact of attempting to do a trial like this is already something quite commendable for this team. So I want to outline this.

I think to answer your question about the methodology itself in terms of using all of these other markers of perfusion, mean, it's interesting and provides great information, especially for those who are looking and designing like a follow-up to this study and maybe expanding this to a bigger population in order to understand it individually, what are these agents doing in particular subgroup? think...

one of the concern or the challenges with this study is that it has like a whole bag of different gestational ages, weights, etiologies. And so can you necessarily then generalize the conclusion to like subgroups within this population? It becomes a bit more challenging, know, especially if you're looking at extreme preterm patients who develop bacteremia and secondary sepsis and secondary shock.

this study may not necessarily represent fully that particular population, which is often one of the highest risk that we see in our NICUs. So that's one thing that comes to my mind. The other thing is that when you look at the primary outcome, you know, shock reversal within 30 minutes, you could argue that, of course, when you look at surviving, you know, surviving sepsis campaign and all of these other hallmark articles looking at trying to

Gabriel Altit (10:02.47)

improve mortality with this very severe condition. You want to reverse this shock picture as early as possible, but I think that as an outcome, it is also important to look at some of these other elements like mortality from the shock episode, which may require a much bigger sample size, in order to kind of show a difference between different types of agents. And the other difficulty that sometimes we face in the clinical grounds is that

You know, different babies may present very differently and their response to the inflammatory surge may be quite different. We may have babies or patients that will present a significant vasodilatory type of shock. Others may have a lot of cardiogenic features to their shock. so, you know, a one recipe fit all may be difficult to apply.

And so I wonder if future studies should actually look into algorithms based randomized controlled trials or adaptive randomized controlled trials where we're able to actually incorporate strategies based on much more physiological information. know, for example, if you have a patient with severe cardiac dysfunction from an equal sepsis, you know, maybe just putting norepinephrine may not be the solution.

in that particular baby, right? Because you're going to increase significantly afterload and you're going to increase a lot of the SVR. And while it will be a drug that has a lot of interest in a vasodilatory shock, it may not be the solution for some of these other babies that have very complex hemodynamics in that particular neonatal septic shock episode. So I think kudos to these authors to attempt to find an answer to what's the best strategy.

in what they call septic shock to get this outcome of shock reversal. But for me, I think I would want to see mortality outcomes that are different. I would want to understand better how these drugs are impacting the different phenotypes based on this multimodal assessment that you were mentioning.

Ben Courchia MD (12:19.976)

Yeah, I think that that's exactly right. I think that you could look at it from the standpoint of identifying the merits of each of these medications, or you could look at it from, if you do not have a sophisticated and robust hemodynamics program where, like you said, you could actually look at the hemodynamics and the effect on the myocardium in terms of what does that change being on norepinephrine versus on dopamine in this particular patient? Because again, like you said, they might need to be looked at individually. Then it's also interesting to know that

Gabriel Altit (12:47.544)

Hmm.

Ben Courchia MD (12:49.84)

It's not like one is dramatically better than the other. so it's interesting. And to me, what's always funny is that the adults know this, know that In sepsis, Norepi is quite good. So it's just confirming something that many of our colleagues also know, that we could use Norepi in septic Shock. And I think that the setting is also very important, as you mentioned. think that the fact that this was done in India, I think is also an interesting point because

Gabriel Altit (12:59.832)

Hehehe.

Ben Courchia MD (13:19.134)

for many of us even in the US, the resources are different. It's very variable, at least from one place to the next, up the street, down the street, not even necessarily from state to state. I think that's very interesting. And do you think, I mean, you're very biased, obviously, do you think that any of, you mentioned how difficult these studies are to be done, but does that mean that moving forward, if you don't have hemodynamics to assess the response, you just can't do these?

Gabriel Altit (13:22.808)

Mm-hmm.

Gabriel Altit (13:28.942)

Mm-hmm.

Gabriel Altit (13:46.414)

I mean, trials are going to stay the gold standard to better understand what are the best strategies. I just wonder if practitioners and scientific who are doing hemodynamics and those who are designing effective trials should sit down together and better understand how can we in a trial setting incorporate all of this, whether it is algorithms that you compare within a trial model with some of these

outcomes that are both hemodynamics related like blood pressure and perfusion, et cetera, and some of these important parent related outcomes. I think that's going to be where precision medicine can be better tested. So I think we just need to sit around the table and how to think this through. The problem is that these studies will probably require a lot of collaboration among sites, a lot of patient population and

Ben Courchia MD (14:29.588)

Thank

Gabriel Altit (14:40.876)

And, as we outlined earlier in the discussion, these are patients that are very difficult to recruit. You know, I'm even amazed of how they were able in this particular study to recruit these septic shock patients that were very sick from the get-go and that had quite some degree of high mortality. So, and it's actually unclear, and I do mention in the commentary, it's unclear to me how they obtained consent. Was it like a...

deferred consent, was it like a prospective consent? And so, you know, when you establish these kinds of trials, you really need to think through how you're going to be able to kind of take all of these boxes and make sure that you're consenting appropriately and forming appropriately the families when they're kind of living very challenging moments. We're currently, so two things I wanted to mention out of what you said. So we had like a PAS platform two years ago

in Toronto actually with Audrey Hepburn, Stephanie Ford, Satya and Shazia. And we decided to put together an article out of this platform. And it includes a lot of information relative to the fact that, you know, the status quo about using just a dopamine centric approach is probably something we start, we need to start to challenge as a practice and how, although we don't have as much trial data.

we do have lot of cumulative data that there are agents that are leading to different effects to our babies. And so this particular trial that we just reviewed today, I think will add on to the body of information that, as you said, an agent like Norepi is definitely usable and seems to at least be equivalent. And there may be some elements that shows a bit of improvement in some of these soft markers of perfusion, but that we need much more studies, right?

and that we need to better understand how much of these different agents can be used to tailor the treatment, but that they're all at the end toxic, right? So we have to be aware of that. We have to be aware of the polypharmacy. We have to be aware that different gestational ages may not necessarily respond the same way, the immaturity of organs. And so we have to be very cautious as we advance as a community.

Gabriel Altit (17:01.294)

using the best information that we have to tailor the treatments. And hopefully there'll be more of these trials that are like kind of spanning from this to better understand, well, is it nor epi the best agent? Maybe it's epi, maybe it's a combination, maybe it's a titration, maybe it's to, you know, include various monitoring tools to kind of tailor the therapy, get rid of it as quickly as possible when it's not necessary anymore. But I think that this first study is definitely kind of a

Ben Courchia MD (17:01.332)

Mm-hmm.

Gabriel Altit (17:31.694)

a good one to start thinking about how to design trials within our context, for example, in our NICUs in North America and Europe, and how can we apply these ideas to design trials, including hemodynamics principles, so that we can finally answer some of these questions about what's the best agent, the timing, the dose, based on the different contexts and the different gestational agent maturity level.

Ben Courchia MD (17:39.976)

Mm-hmm.

Gabriel Altit (18:01.09)

But yeah, more questions than answers, I feel.

Ben Courchia MD (18:04.102)

As always, Gabriel, we thank you for taking the time to share your commentary and we'll speak to you very soon on the Incubator.

Gabriel Altit (18:10.125)

Thanks for having me here. It's always a pleasure. And I didn't even speak French, so bonjour à tous.

Ben Courchia MD (18:16.574)

But you can wave off. You can sign off in French if you want.

Gabriel Altit (18:22.766)

Perfect, super, have a nice day everyone.

Ben Courchia MD (18:27.58)

Merci.

Ben Courchia (25:38.51)

Thank you for the EBNEO team for contributing to monthly journal clubs. I want to take us next to another article that was published in JAMA PEDS Daphna following up on your latest review. And this is a paper called Respiratory Targets Associated with Lung Aeration During Delivery Room Resuscitation of Preterm Neonates.

Daphna Yasova Barbeau, MD (25:43.831)

Okay.

Ben Courchia (26:08.173)

I this to be a very interesting article. I'm going to tell you who is the first author. It's David Rube. Senior author is Liz Foglia. Haresh Kirpalani is on that paper as well. And what's interesting is that this is a paper that addresses the transition from intrauterine to extrauterine life and the fact that it requires really rapid and effective lung aeration, particularly when we're talking about preemies whose

Lung structure, physiology, functionality, due to that immaturity makes it more complicated. So we know from resuscitation, from NRP, from L-Core that positive pressure ventilation is what's needed for these infants and that it matters tremendously how well you deliver PPV. It also is a very risky procedure because these infants are at high risk of barotrauma, value trauma, and in the delivery room, depending on what you're using,

you may be inadvertently delivering too much pressure. So it's always a fine balance. And there's been a lot of papers that have come out on how good are we at delivering what we intend to deliver in the delivery room. Now, the current guidelines, like the ones from the neonatal resuscitation program, suggest to start PPV at a peak pressure of 20 centimeters of water.

But what is not really yet known is what is the tidal volume and pressure that actually lead to successful lung aeration in the real world? And we assume that by giving 20 of pressure of PIP, then we are actually delivering the right tidal volume, but we don't know. And so this is the study that they coined the inflate study that aimed to prospectively identify respiratory parameters such as

pressure and volume that are associated with successful lung aeration using the most reliable clinical science we have, which is getting a sustained heart rate above 100 beats per minute during delivery. So the inflate trial, let me just.

Ben Courchia (28:20.43)

I cannot find the acronym for what INFLATE stands for. I have it written down somewhere. If it comes up, I'll find it. I appreciate that. So this was a prospective multicenter observational core study conducted under the umbrella of the INFLATE initiative, short for infant lung aeration during transition events. And this is a study that is coordinated at UPenn and Children's Hospital of Philadelphia.

Daphna Yasova Barbeau, MD (28:27.543)

I'll find it, I'll find it buddy.

Ben Courchia (28:46.926)

So basically the data came from two sources. They had an observational cohort of eligible preterm infants born between 2016 and 2021 at the hospital of the University of Pennsylvania. And then they had another cohort that they had from the SAIL trial, the Sustained Aeration of Infants Lung Trial, which we've reviewed in the past. It's an international randomized control trial comparing sustained inflation to standard PPV. Now,

What they are looking at is basically using what's known as RFM data, which basically helps give you lots of different measurements on respiratory parameters. The babies that they included in the study were babies born between 22 and 31 weeks of gestation, and they had to receive positive pressure ventilation for bradycardia after birth, which was a heart rate being below 100 beats per minute.

And they had to have this RFM, this respiratory function monitoring data available during the resuscitation. Babies that had major congenital anomalies, pulmonary hypoplasia, and so on were excluded. The outcomes they were looking at were the sustained increase in heart rate above 100 beats per minute, lasting for at the very least 15 seconds. And this was used as a surrogate of successful lung aeration.

Each neonate was followed from the first positive pressure ventilation inflation until either their heart rate increased to 100 beats per minute or 10 minutes had elapsed. And if neither occurred within 10 minutes, then the case was censored and classified as target not reached. So in terms of the respiratory function monitoring, this basically gives you information on your PIP, on your inspiratory tidal volume, on your expiratory tidal volume, on your leak from the mask, on the number of spontaneous breath.

and also informs you on number of masks removal. So these metrics are captured continuously, giving them basically some real time insights into what is happening during each breath. Now there's something very interesting about the statistics of this paper. I know I'm sort of geeking out on statistics this month, but they used something called a penalized spline, which is something that I was not super familiar. I was familiar with the concept. I didn't know what this was.

Ben Courchia (31:05.41)

But basically the penalized spline is basically a way to model the association between continuous respiratory measures, like for example, the expiratory tidal volume and the probability of achieving your primary outcome. So what is it? What is penalized spline? So think of it this way. If you're trying to understand how one continuous variable like your tidal volume affects an outcome, like your heart rate, you could draw a straight line through the data. But what if the relationship

isn't exactly linear, then that's where splines come in. And basically, this allows for curves. So a penalized spline is a flexible statistical model that lets you fit a curve to the data, but penalizes the model for becoming sort of too wiggly or for performing too much overfitting. So the line is allowed to bend a little, but not to go completely crazy.

And I think that this is very useful because when you suspect that there's a relationship between your variable and it's not strictly linear, what we tend to do as researchers to say, well, I'm going to establish an arbitrary cutoff. And that's when you transform a continuous variable into a categorical variable. And that has a lot of inherent issues. So in order to avoid doing that, you could use this model of penalized splines, which allow you to continue to use your variable as continuous.

but allow some curving of that relationship even when it's not completely linear.

So the primary data set included 132 infants. 113 came from the observational cohort. 19 came from the cell trial. The median gestational age at birth was 26.6 weeks. Roughly half of the babies were male. The median mass leak was about 30%, which with an interquartile range, I'm sorry, ranging from 0 to 68%. So we are still...

Ben Courchia (33:08.13)

victims of that goddamn mass leak. We still haven't, we're still not that great about that. So out of these infants, 125, 94 % achieved a sustained heart rate above 100. The median time to reach that target was about 116 seconds, just under two minutes. So what were some of the associations they noted with the heart rate increase? So in the unadjusted model, participation in the cell trial was associated with an increased likelihood of heart rate improvement, but this association disappeared when

the model was adjusted. So among all clinical covariates, birth weight was the one significant variable associated with a heart rate improvement. For every 100 gram increase in birth weight, the adjusted hazard ratio was 1.12, which is not really surprising that bigger babies will be more likely to reach a good heart rate. When we come to respiratory parameters, that's really what we were interested in. Only expiratory tidal volume.

was positively associated with an increase in heart rate with adjusted hazard ratio of 1.1, when in contrast, the PIP and the inspiratory tidal volume showed no significant association with the primary outcome. Also, and not surprising, increasing the number of mask removals was associated with a lower likelihood of heart rate improvement. So don't continuously take out that mask to do whatever. So let's look at.

Let's explore tidal volume and use the penalized splines method. So the authors found that the relationship between expiratory tidal volume and heart rate wasn't exactly linear. And there was a clear benefit at some lower expiratory tidal volumes, but it of leveled off beyond the point, which were not really surprising. And so what they found was that

Consistent expiratory tidal volumes reaching up to 4 ml per kilo was strongly associated with an increased heart rate. But beyond 4 ml per kilo, the effect plateaued. And a similar pattern held true with a 5 ml per kilo threshold. So it's interesting that we know, for example, so it seems that achieving a minimum of 4 5 ml per kilo may be enough to trigger successful lung aeration in preterm neonates, but that going beyond that volume

Ben Courchia (35:20.238)

didn't really yield at least further benefits in terms of heart rate for that particular cohort. We know that the title volume expectation is four to six. And a lot of people always ask like, how do we know that? Where do we get that number? But it seems like it's holding true with this particular data set. When they use the confirmatory data set in the second data set of 115 infants used for confirmation, this group also showed

that an expiratory tidal volume of about 4 ml per kilo was beneficial. So the conclusions are that in this particular population and confirmed in another, a minimum expiratory tidal volume was associated with successful lung aeration during preterm neonate resuscitation. Further clinical trials are needed to establish the utility of volume targeted resuscitation in preterm neonates.

I think that this is something that should start being integrated directly into our resuscitation tables, if you ask me, because it seems that that particular piece of information could really help us perform better resuscitation in the delivery room. So I thought that was very interesting.

Daphna Yasova Barbeau, MD (36:25.942)

Yeah, I agree. That kind of like in real time feedback, I think, will be very valuable for sure, for sure. Very neat. Okay. Well, go ahead.

Ben Courchia (36:30.392)

Yeah.

Ben Courchia (36:35.288)

But that it's real-time feedback, but also the fact that it's the expiratory tidal volume you're getting that matters most. so you have like how much leakage you have around your mask matters tremendously. And it is what the baby can send back that really informs you on how well you're, And it's probably a much more granular way of looking at this rather than saying, do I have symmetric chest rise, for example? Like that's a very crude way.

Daphna Yasova Barbeau, MD (36:40.904)

Yeah, right.

Daphna Yasova Barbeau, MD (36:46.806)

Sure. For sure.

Thank you.

Daphna Yasova Barbeau, MD (37:01.812)

Mm-hmm. The bare minimum. Very cool. Well, since you were highlighting bradycardia, I'll carry that vein along. We've got an article from the Journal of Pediatrics. It's Atropine versus Placebo for Neonatal Non-Emergent Intubation in Randomized Clinical Trial. Lead author, Jahir Fifi, senior author, our good friend, Michael Narvey.

Ben Courchia (37:04.919)

Yeah, comparing.

Ben Courchia (37:11.17)

Hahaha

Daphna Yasova Barbeau, MD (37:30.881)

They wanted to compare the rates of severe bradycardia, so less than 80 beats per minute for greater than 10 seconds between neonates who received the combination of basically RSI, so atropine fentanyl succinylcholine. So this was the atropine group versus placebo fentanyl succinylcholine before orotracheal intubation.

So, I mean, the background, they really talk a little bit about how rapid sequence induction is kind of the standard, but say that.

Ben Courchia (38:05.283)

information.

Rapid sequence intubation, not induction.

Daphna Yasova Barbeau, MD (38:09.108)

Yes. What did I say? Induction. Just finished talking to our L &D colleagues. Gravit sequence intubation. But they've done polls, right? And basically very few neonatologists or NICUs in general have a pre-medication protocol. Some people use it sometimes, but not all the times. And you know,

Ben Courchia (38:12.526)

you

Daphna Yasova Barbeau, MD (38:37.704)

more than 10 % of units weren't using any premedication for non-emergent intubation. So they wanted to look at that specifically. So basically it was a multi-center, double-blind, randomized clinical trial in three academic units in Canada. And eligible neonates were admitted to the NICU at these sites. They had a post-menstrual age of less than or equal to 44 weeks.

and were expected to receive a non-emergent. basically within 30 minutes from decision for intubation, maybe for surfactant or some sort of elective intubation, like for a procedure. They excluded infants with cyanotic heart disease, upper airway anomalies, anybody who needed an urgent intubation and those with any contraindications to the medications given, specifically succinylcholine.

It looks like every week they pre-prepared these masked vials of steady medication. So either, I mean all the meds, but either atropine or placebo. And then at the time of needing intubation, consent was obtained and then the babies were randomized. So then the baby either got the placebo vial or the atropine vial.

And then all the infants also got premedication with fentanyl and succinylcholine. They also got pre-oxygenation, so ensuring that they had an oxygen saturation of 90 % before intubation. All the intubations were orotracheal, they used direct laryngoscopy, and they said, quote, limited to the most experienced intubator in attendance. And then importantly, when they wanted to document intubation attempts, so any time that the laryngoscope,

Ben Courchia (40:01.837)

Mm-hmm.

Daphna Yasova Barbeau, MD (40:30.4)

Gopal blade was put in the mouth and taken out. That was an attempt whether or not somebody introduced an endotracheal tube. Intubation was interrupted if there were 30 seconds of bradycardia, less than 100 beats per minute. And they had somebody at each intubation session manually recording the time of each intubation attempt. And they also were tracking a number of...

vital signs, obviously heart rate and saturation, that's really what they were looking at. But they also looked at blood pressure, checked at two time points, 10 minutes before steady medication and 30 minutes after the completion of the intubation. The primary outcome was looking at severe bradycardia, like I told you, so a heart rate of less than 80 beats per minute lasting for greater than 10 seconds during the whole procedure.

The secondary outcomes they looked at were intubation conditions. So they wanted to look at the number and the duration of temps and the total intubation and procedure times. They wanted to look at other physiologic responses. So overall bradycardia, any heart rate of less than a hundred beats per minute for greater than 10 seconds. Episodes of hypoxemia, so stats less than 80 % for greater than 10 seconds. The duration of severe bradycardia, were they associated with hypoxemia?

were their episodes of tachycardia, so heart rate of greater than 200 beats per minute for greater than 10 seconds. The mean and lowest heart rates in SATs and the pre and post changes in heart rates and SATs and as I mentioned, the blood pressure. They also looked at safety outcomes, so profound bradycardia. So I told you they were specifically looking at less than 80 beats per minute, but profound bradycardia they defined as heart rate of less than 60 beats per minute for greater than 10 seconds.

and the receipt of advanced resuscitation, so needing chest compressions or epinephrine. So these were predefined kind of stopping rules. Okay, so now we can get into it. They screened 305 neonates who were eligible, but in total they had 60 neonates. Some neonates had more than one participation, so 76 intubation events.

Ben Courchia (42:30.701)

Mm-hmm.

Daphna Yasova Barbeau, MD (42:47.478)

who were randomized. So neonates had a mean gestational age of 29 plus or minus 4.6 weeks, a mean birth weight of 1,466 grams plus or minus about 900 grams. 31 % were less than a thousand grams at the time of intubation. There was no difference between the groups. So 33 % in the atropine group were less than thousand grams and 31 % in the placebo group were less than a thousand grams.

They had total of, I told you 76 intubation events, but some didn't have all the information necessary for the primary outcome. So they use these 73 intubation events. 49 were among those who received placebo and 24 among those who received atropine. So of those 24 intubation events using atropine were multiple attempts.

I want to make sure.

Okay, so of all the events, of 24 of the total intubation events out of the 73, so that's 33 % were multiple attempts. And this was statistically significant between the two groups. Actually, the placebo group was 26 % requiring multiple attempts. The atropine group, 46 % requiring multiple attempts.

11 events had repeated need for additional succinylcholine, 18 % in the placebo group and 8 % in the atropine group, but this was not statistically significant. Across the board, the indications for intubation were RDS, 26%, surfactant administration, 23%, procedures, 22%, unplanned or failed extubation, or an unplanned extubation, accidental extubation.

Daphna Yasova Barbeau, MD (44:45.686)

16 % and apnea is 12%. So regardless of the randomization arm, none of the procedure is complicated by that profound bradycardia less than 60 or needing advanced resuscitation procedures during the study period. Thank goodness. So for their primary outcome, looking at severe bradycardia of less than 80 beats per minute for greater than 10 seconds during the whole procedure.

is actually six times higher in the placebo group compared with the atropine group. So 25 % in the placebo group had that severe bradycardia versus 4 % in the atropine group. The placebo group also showed significantly longer duration of severe bradycardia and higher rates of severe bradycardia. 43 % in the placebo group, 12 % in the atropine group.

The median duration of overall bradycardia was also different, 10 seconds in the placebo group versus zero seconds in the atropine group. Associated hypoxemia was seen in 59 % of the placebo group versus 87 % in the atropine group, so higher in the atropine group of the associated hypoxemia, and this was statistically significant.

In addition, the median duration of the hypoxemia, 9 seconds versus 38 seconds, is also statistically significant and was higher in the atropine group. The study groups, though, were not totally equivalent when it came to the number and duration of in... Which is interesting.

So compared with the placebo group, the atropine group actually had a longer median time to successful intubation, 394 seconds in the atropine group versus 282 seconds in the placebo group. This was statistically significant with a relatively greater proportion of multiple intubation attempts and lower rates of first successful intubation. So 54 % in the atropine group versus 73%.

Daphna Yasova Barbeau, MD (47:03.616)

in the placebo group. So this was statistically significant. So to kind of reiterate that, to wrap it up, they needed more intubation attempts, longer time to intubation in the atropine group. They had longer hypoxemia episodes, but they had much lower rates and

length of time spent in the severe bradycardia. They looked at the other vital signs. There was no difference in baseline measurements between the study groups one minute before the procedure. During the procedure, the placebo group had significantly lower mean heart rate, 147 beats per minute versus 159 beats per minute. The placebo group had a median lowest heart rate, 83 beats per minute versus 136 in the atropine group.

And there was greater heart rate variability with a 20 % change from baseline in the placebo group, 84 % versus 58 % in the atropine group. There were no differences in blood pressure. There were also no differences in the primary outcome, though there were differences overall in the primary outcome, less severe bradycardia in the atropine group. There was no difference in the primary outcome between the study groups during the first intubation attempt.

There were no instances of the severe bradycardia in the atropine arm. The placebo group did experience this outcome. So 0 % in the atropine arm, 10 % in the placebo group. Placebo use led to significant lower mean heart rate, a lower median lowest heart rate, and longer median duration of overall bradycardia compared with atropine use.

but the median loess saturation was significantly higher in the placebo group compared with the atropine group. So again, to reiterate, there was a 20 % absolute reduction in the rates of severe bradycardia, so less than 80 beats per minute for greater than 10 seconds favoring the atropine arm. But compared with the placebo group, the atropine group had significantly lower rates and durations of overall and severe bradycardia.

Daphna Yasova Barbeau, MD (49:28.448)

but higher rates and durations of associated hypoxemia compared with the placebo group, which was likely related to the greater proportion of multiple attempts and longer time to successful intubation. So I guess my takeaway is it depends what the problem is in your unit. If bradycardia is really a big problem in your unit, then considering atropine, they couldn't really quite explain why

The babies needed more attempts or, you know, longer total time, which are not benign. Sure. Absolutely.

Ben Courchia (50:08.514)

Yeah, I mean, I think some intubations are harder than others just based on anatomy and other parameters. And I think that the heuristics that I'm sometimes fall prey to, is like, I'll be able to intubate very quickly. I don't need to premedicate as much. I think that's wrong. I think that it's interesting to see that.

Daphna Yasova Barbeau, MD (50:23.764)

Yeah, right before sign out.

Ben Courchia (50:37.292)

Yeah, I mean, you probably need to premedicate these babies so that you can buy yourself a little bit of flexibility, but it doesn't mean that you should take your sweet time either. I think you still need to be very fast, even when they are premedicated and that the measure of heart rate in and of itself is a good one, but it's not the only one. And I think that the overall stability of the patient is what you should look at, not just say, sats are 12, but the heart rate is okay. Like that's not how works. So I think that what

Daphna Yasova Barbeau, MD (50:46.55)

Great. Sure.

Daphna Yasova Barbeau, MD (51:01.046)

That's right.

Ben Courchia (51:06.562)

what this paper, in my opinion, highlights quite well, because then we can get into the... You've done a good job in getting into the nitty-gritty of the different outcomes and variables. But you should aim for a controlled, stable environment. then what happens after that is beyond your control, probably. But at least the things that are in your control should be controlled.

Daphna Yasova Barbeau, MD (51:19.446)

Mm-hmm. Mm-hmm.

Daphna Yasova Barbeau, MD (51:24.374)

That's true.

Daphna Yasova Barbeau, MD (51:29.354)

Yeah, no, absolutely. And again, the placebo arms still had premedication, right? They didn't even, I think Dr. Narvey doesn't even think it's ethical to do a non-medicated intubation.

Ben Courchia (51:31.106)

and

Ben Courchia (51:36.3)

That's right, that's exactly what I was going to say.

Ben Courchia (51:43.106)

Yeah. Yeah, fentanyl and succinylcholine. So who knows? And sometimes, sometimes I'm sorry to say, like, depending on how your medications are stocked, you say, we just have fennels available right now. And I've been in units where 30 minutes is not enough to get all that stuff set up and delivered. So yeah, mean, optimizing system-based practices is probably another interesting, interesting.

Daphna Yasova Barbeau, MD (51:47.091)

Yeah. Yeah.

Daphna Yasova Barbeau, MD (51:54.825)

Yeah, if this is going to take an extra, yeah, two hours, then that's really problematic. Yeah.

Ben Courchia (52:12.846)

Yeah, it's a humbling, these papers are always humbling. Yeah. Okay.

Daphna Yasova Barbeau, MD (52:16.901)

that's a good reminder. Yeah.

Because sometimes at the end of the intubation, you're just glad that it's over. And sometimes if you're the intubator, you're not even really sure what all the vital signs looked like during your intubation attempt.

Ben Courchia (52:33.326)

Yeah, mean, after the baby, especially if you're not premedicated and so on, yeah, it's a very stressful procedure for sure. OK. Do I have time for one more? All right, I'm to do a quick one. It's a paper that was published in the archives of this is in Childhood of Fetal and Neonatal Edition. First author is Sam Gentle, and its paper is called Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia. When, how often, and does it matter?

Daphna Yasova Barbeau, MD (52:42.697)

Yeah, do it.

Ben Courchia (53:00.142)

The title was very clever. really liked it. So I dived into the article.

Daphna Yasova Barbeau, MD (53:04.691)

Yeah, how could you not read the article, you know?

Ben Courchia (53:07.648)

on. And I think that we are all aware that one of the major complications of bronchopulmonary dysplasia is the feared sort of BPD-PH phenotype, which is considered to be the most severe phenotype of BPD when you have associated pulmonary hypertension. And the question is, if the baby is not doing too bad, when do I start screening for pulmonary hypertension? And there's some guidelines. mean, the American Heart Association and the American Thoracic Society recommend

a screening echo at about 36 weeks PMA. But in specific cases, and these include babies who are on positive pressure ventilation, those you can't really wean from oxygen, or those whose oxygen need is kind of disproportionate to their pulmonary disease. And so what is exactly the optimal timing and frequency? That is not really stated. Like, do we just do one? Like, do we do more than one?

And so that's really what these authors are trying to answer. What is the best time to screen and which strategy should we adopt to screen for BPD associated pulmonary hypertension? So this was a retrospective cohort study conducted at the University of Alabama between 2017 and 2023. They included babies who were born before 29 weeks of gestation and who require respiratory support at 36 weeks. And they had the usual exclusion criteria. But what's interesting and why the retrospective study actually works for this particular

context is that they had a protocol where they do an initial echo at postnatal day 28 for babies who are on respiratory support. And then they do echoes monthly until discharge or until there's like resolution of their respiratory needs. So they use that protocol to basically see what they found. The big question obviously is like, how do you define BPD-associated pulmonary hypertension? And they said they were doing this based on these particular echo.

cardiogram findings, either a bidirectional flow through a PDA or a PFO, septal flattening with an eccentricity index of 1.2 or above, or tricuspid regurgitation velocity above 2.5 meters per second. Again, is a bidirectional flow through a PFO sufficient to make a diagnosis of pH? I'm not going to get into that, but that's the criteria that they used. So they basically then took the data that they had and they did

Ben Courchia (55:29.174)

and they looked at comparative screening strategies. And because every infant was screened systematically from postnatal day 28 until discharge, they retrospectively looked and compared. And they said, what about if we have an early screening, which is an echo starting on postnatal day 28 up until 36 weeks? What if we have a singular screening? We just try to do an echo around 36 weeks. What if we do late screening, meaning we start screening after 36 weeks?

until discharge, or do we do a comprehensive screening where we look at all echoes from day 28 up until discharge? The early screening part looked at the same, but only until 36 weeks, just so that we're clear. Then they looked at true positives, meaning the first echo showing evidence of pulmonary hypertension, a true negative, where there's no evidence of pH during the entire hospitalization, or false negatives, which was

based on missed detection during the earlier echoes, but then later findings of pulmonary hypertension during the hospitalization. So in terms of the results, they looked at 394 infants. 258 had BPD. 136 developed BPD-associated pulmonary hypertension. And for these babies, they had 2,542 echoes available for evaluation. That's a lot of echoes.

In terms of patient characteristics, the babies who had BPD-associated pulmonary hypertension were not really surprisingly born earlier with an average gestational age that was 24 weeks compared to 26 weeks in the babies who only developed BPD. They had a lower birth weight as well. And they were more frequently treated with inhaled nitric oxide, more often treated with steroids, and more often had a PDA. In terms of screening strategy comparisons, which is the crux of the paper,

The comprehensive screening strategies detected all 136 cases of BPD-associated pulmonary hypertension. So looking at day 28 until 36 weeks. The early screening detected 78 of the 100 cases. And again, the singular, the early screening looked at, I'm sorry, I'm going to say this again. So looking at the results,

Ben Courchia (57:51.274)

Looking at the different screening strategies, the comprehensive screening detected obviously all 136 cases of BPA-associated pulmonary hypertension. And that means looking at all echoes that they had starting from day 28 monthly until the time of discharge. When we're looking at early screening, which is looking at day 28 until 36 weeks, then you only detect about 78 cases compared to 136. If you do just a singular screening at 36 weeks,

you get only 59 cases. And if you do screening after 36 weeks until discharge, you do the late screening, you get 121 cases out of 136. So I think that was very interesting. When we're looking specifically at the gestational ages at which BPD-associated pulmonary hypertension was first detected in the early screening, which again, for the purpose of this is defined as between day 28 of life and 36 weeks post menstrual age,

Daphna Yasova Barbeau, MD (58:33.299)

Mm-hmm.

Ben Courchia (58:47.726)

it caught pulmonary hypertension at a PMA of about 35 weeks. When you do the singular screening, it caught it later at about 37 weeks. And obviously, if you do late screening, it often finds it at around 40 weeks of gestation. So that's really, I mean, we're running out of time, but I think that's really it. The conclusion of the group is that while obviously BPD associated pulmonary hypertension is

something that is evolving with respiratory disease, they identified that late echocardiographic screening as a potential optimal screening strategy and that this screening strategy in which echocardiography are done beginning at 36 weeks and that continue monthly until hospital discharge identify a similar number of patients with BPD associated pulmonary hypertension as a screening strategy in which echocardiographic screenings begin very early, especially as early as like.

very early in the course of the hospitalization. Moreover, there's a lot of cost effective, this probably represents a cost effective approach without compromising the number of babies that you can actually identify. And there's obviously more evidence that is needed to corroborate these particular findings. So I think this was very interesting because it's something that we definitely want to know. I think that in our, no, I don't think I know in our unit, obviously we do it at 30, we start screening at about 36 weeks and.

Daphna Yasova Barbeau, MD (01:00:06.911)

Mm-hmm.

Ben Courchia (01:00:11.084)

And I found that trying to screen even earlier is often a very frustrating endeavor because you don't We sure do try. That's right. And it's rarely positive. And I think that it's important for us to know that they had some pretty loose screening criteria for pulmonary hypertension. Because technically, again, if you have a bidirectional PDA or a bidirectional PFO, it seems like you would just be considered to have some...

Daphna Yasova Barbeau, MD (01:00:14.485)

Mm-hmm. Because we sure do try.

Ben Courchia (01:00:40.458)

elevated pulmonary pressures. So I think that's interesting.

Daphna Yasova Barbeau, MD (01:00:44.693)

Very interesting. I guess the discussion point really comes like, there a group of babies that would benefit from treatment of the pulmonary hypertension before 36 weeks? I don't know the answer to that. I don't know that anybody knows the answer to that, but it feels like there is.

Ben Courchia (01:01:01.142)

I think that if you have babies that have some predisposing conditions that could lend them to become hypertensive before 36 weeks, then yeah, you will find them. But your typical baby that will develop pulmonary hypertension as a byproduct of their severe pulmonary disease, I think it's rare to find them to be having echocardiographic findings of pulmonary hypertension before that particular gestational post menstrual age mark.

because I think that the heart has an ability to compensate for a very long time. So I think that too is something that's interesting. And the non-invasive methods of looking at that, whether it's ProBNP and so on, probably are not that much better either.

Daphna Yasova Barbeau, MD (01:01:44.575)

Yeah, that makes sense. I had one more article, but we are way over time. So instead of a full research article, I just wanted to highlight this case report. It was actually an endocrinology diabetes and metabolism. It's a journal for case reports and it's entitled continuous glucose monitoring in a neonate with hyperinsulinemic hypoglycemia and ABCC8 gene mutation.

I just thought it was an interesting case for a number of reasons. Their background is, I think, pretty good, pretty easy to read about hyperinsulinemic hypoglycemia. So obviously we have some transient cases. We see that all the time with infants who are LGA. Those have perinatal asphyxia, the preterm infants. But then there are some babies who have these genetic problems that cause this prolonged

hyperinsulinemic hypoglycemia. And the big things I wanted to highlight is so they had this case report of a 37-weeker. It was a G1P0, no major concerns during the pregnancy of the Hashimoto’s thyroiditis. The baby came in 37 weeks in labor, or the mom came in 37 weeks in labor, and the baby was admitted obviously to the NICU or special care unit for

very low blood sugars, less than 25. And basically continue to have severe hypoglycemic episodes despite they set up to 30 % IV glucose infusion. So obviously they got their specialists on board. Lots of medications, octreotide, diazoxide, lots of things to try to recover this infant and was later found on whole exome sequencing to have a genetic cause for their...

severe hypoglycemia, so their congenital hyperinsulinism. But that's not really what I wanted to highlight. What I wanted to highlight was two things. They documented that in the first 10 days that this baby required 110 heel sticks to document and follow the blood sugars. And I think that's not uncommon. I think we've sometimes put babies on Q3 sugars, Q6 sugars.

Daphna Yasova Barbeau, MD (01:04:08.725)

And sometimes people forget about it even as the sugars are getting better. The nurses don't forget about it. Those people ordering it often forget about it. And then because they recognized that this was going to be a long-term problem and that the baby was getting so many kind of skin-breaking procedures, they started the baby on a continuous glucose monitor. So was the Dexcom G6. They inserted it in the right...

thigh of this infant. And I think some people will have a question. So the baby was 37 weeks, I told you that, and the baby was 4.69 kilos. So a big baby. And they decided obviously to use the thigh as kind of the biggest spot to implant the Dexcom sensor.

But then they were able to follow this baby with continuous glucose monitoring. I just think it's really exciting. I think that if you have access to it, you've got some really good endocrinology support, that this may be of consideration for some of those bigger, older babies. We know that our bedside glucose monitoring isn't even that accurate at really low levels or really high levels. So for some of those babies, I think it's exciting.

as we look to really incorporate continuous glucose monitoring into the unit. Hopefully we can do it before day 10 on babies who need like.

Ben Courchia (01:05:29.23)

Yeah, I mean, there's more and more data. I believe that one of the impact article of the year candidates for the EBNEO team was one of these papers that we had reviewed as well. the data is there. I feel like maybe the tech is lagging a little bit behind because it's not that used as prevalently as we would probably think.

Daphna Yasova Barbeau, MD (01:05:33.94)

Yeah.

Daphna Yasova Barbeau, MD (01:05:37.951)

That's right. It's coming.

Daphna Yasova Barbeau, MD (01:05:46.313)

Yeah, or maybe, I don't know, maybe we're not brave enough to be using it in cases where we could be using it given, know, case reports and not just case reports, but studies, you know, like the ones you mentioned. So, all right.

Ben Courchia (01:05:49.346)

Maybe we're not.

Ben Courchia (01:05:55.918)

for sure.

Yeah, absolutely. All right, buddy, that was great. I will see you next time for another episode of the podcast. We are working very hard for the changes coming to the 2026 edition of the podcast. We are taking the feedback that you guys provided during the end of year survey, and we will have more journal clubs. We will have more easy to access content. And so stay tuned for that.

And if you have not secured your spots for the upcoming Delphi conference in January 2026 in Fort Lauderdale, Florida, please go to the incubator website, the-incubator.org and secure your spots. Now tickets are selling fast and we have a great lineup of speakers. So we're looking forward to seeing you all there. Daphna, have a good rest of your day.

Daphna Yasova Barbeau, MD (01:06:45.973)

Thanks buddy, bye everyone.

Ben Courchia (01:06:47.842)

Bye.