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#186 - 📑 Journal Club - The latest research in Neonatology (Feb 25 2024)





Hello Friends 👋

We have a great episode of Journal Club for you this week, where we review the latest papers published in peer-reviewed journals. This week we also have the pleasure of welcoming back to the show the EBNEO team who shares with us their commentary on the two-year outcomes of the OPTIMIST trial.

As mentioned in the beginning of the show, Ben & Daphna will be visiting Columbus, Philadelphia and Toronto in the coming weeks - so if you are in those areas feel free to come hang out with us.

Enjoy this episode.

Happy Sunday!

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


Esophageal versus Rectal Temperature Monitoring during Whole-body Therapeutic Hypothermia for Hypoxic-ischemic Encephalopathy: Association with Short and Long-term Outcomes. Wu TW, Schmicker R, Wood TR, Mietzsch U, Comstock B, Heagerty PJ, Rao R, Gonzalez F, Juul S, Wu YW.J Pediatr. 2024 Feb 1:113933. doi: 10.1016/j.jpeds.2024.113933. Online ahead of print.PMID: 38309524 Free article.


Norman M, Magnus MC, Söderling J, Juliusson PB, Navér L, Örtqvist AK, Håberg S, Stephansson O.JAMA. 2024 Feb 6;331(5):396-407. doi: 10.1001/jama.2023.26945.PMID: 38319332

 

Tanne JH.BMJ. 2024 Feb 15;384:q416. doi: 10.1136/bmj.q416.PMID: 38359912 No abstract available.

 

Kim SH, El-Shibiny H, Inder T, El-Dib M.J Perinatol. 2024 Jan 16. doi: 10.1038/s41372-024-01874-x. Online ahead of print.PMID: 38228763

 

Tracy MB, Hinder M, Morakeas S, Lowe K, Priyadarshi A, Crott M, Boustred M, Culcer M.Arch Dis Child Fetal Neonatal Ed. 2024 Feb 9:fetalneonatal-2023-326256. doi: 10.1136/archdischild-2023-326256. Online ahead of print.PMID: 38336472

 

Wei X, Franke N, Alsweiler JM, Brown GTL, Gamble GD, McNeill A, Rogers J, Thompson B, Turuwhenua J, Wouldes TA, Harding JE, McKinlay CJD; pre-hPOD Early School-age Outcomes Study Group.Arch Dis Child Fetal Neonatal Ed. 2024 Feb 12:fetalneonatal-2023-326452. doi: 10.1136/archdischild-2023-326452. Online ahead of print.PMID: 38307710

 

Effect of human milk-based fortification in extremely preterm infants fed exclusively with breast milk: a randomised controlled trial. Jensen, G. B., Domellöf, M., Ahlsson, F., Elfvin, A., Navér, L., & Abrahamsson, T. eClinicalMedicine (2023).

 

Colaizy TT, Poindexter BB, McDonald SA, et al. JAMA. 2024;331(7):582–591. doi:10.1001/jama.2023.27693

 

EBNEO Commentary: De-MIST-ifying the 2-year outcomes of non-invasive surfactant therapy. Loft L, Ferguson KN, Tingay DG.Acta Paediatr. 2024 Jan 25. doi: 10.1111/apa.17116. Online ahead of print.


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


Ben Courchia (00:00.984)

Hello everybody. Welcome back to the incubator podcast. It is Sunday. We're doing journal club and, um, we have a lot of exciting articles to go over with you guys, definitely. How are you?

 

Daphna Barbeau (00:11.69)

I'm doing really, really well, buddy. How are you? Yeah.

 

Ben Courchia (00:15.072)

I'm doing good. I'm doing good. Lots of exciting articles to present today. There's lots of things happening. Yeah, no, things are busy for us on every front, which is good. We're gonna make some announcements, I guess, but I guess we can say that the incubator is gonna be like a little bit going on a tour. We're gonna be going around the country a little bit. So if you are in these areas and you wanna come say hi, then please.

 

Daphna Barbeau (00:24.412)

Hmm.

 

Daphna Barbeau (00:35.598)

Mm-hmm.

 

Ben Courchia (00:44.76)

feel free, I think we'll be at Nationwide Children's for Grand Rounds on March 27th. And then after that, we will head to CHOP to the Children's Hospital of Philadelphia. And I think that is in April. And if I'm not mistaken, this is right before PAS, right? So hold on. So I'm pulling up my calendar here.

 

Daphna Barbeau (00:50.274)

Hmm?

 

Daphna Barbeau (01:09.09)

That's correct.

 

Daphna Barbeau (01:14.654)

It's actually May 2nd. We'll be at shop.

 

Ben Courchia (01:17.696)

It is, that's exactly right. May 2nd at, uh, at CHOP. And then we'll follow that with our presence at PAS. Um, and then after that, there may be some other things, but for now, I think the next, and then after that we'll be in, uh, in Chicago in September for the district six conference and, um, and after that Delphi in Fort Lauderdale. So, uh, lots of exciting things. Um, I must say that every time I'm not, I don't feel like we are.

 

celebrities that people need to come and take pictures with us. However, I must say that every time we meet with people, there's an exchange of ideas that help move the incubator forward. And that's what I'm excited about. So, um, I think many people have ideas, but there's a little bit of a, of a, an activation energy that where they don't just, they don't just send us the email and they just think about it. And then they see us and they're like, Hey, have you thought about doing this? And I must say that every time we've met with people in person, whether it was at CHNC at the next symposium, other places,

 

Daphna Barbeau (01:53.474)

That's right.

 

Daphna Barbeau (02:09.289)

Mm-hmm.

 

Ben Courchia (02:15.436)

great stuff has come out of our conversations. So yeah, just, let's chat. That's, uh, that's exactly right. That's exactly right. All right. So this week we, um, we have journal club, we have an EB neo segment as well. And, um, yeah, let's get started. I wanted to change things up for journal club a little bit. I wanted to maybe talk a little bit about like the, the brief mentions in the beginning, cause I feel like sometimes they get buried inside the episode and, um, there's

 

Daphna Barbeau (02:21.43)

Come find us. That's right.

 

Ben Courchia (02:44.824)

two articles that I really thought people might be interested to look at. The first one is the one published in the Journal of Perinatology, and I was curious to get your thoughts on that because it says the title is Therapeutic Hypothermia for Preterm Infants, 34 to 35 Weeks of Gestation with Neonatal Encephalopathy. I must say that the author list is sort of what prompted me to read this. Yeah, so first author is Sehun Kim.

 

Daphna Barbeau (03:08.394)

Yeah, the who's who.

 

Ben Courchia (03:12.708)

who I am not familiar with, but obviously also on this paper is Terry Ender and Mohammed El-Deeb, both very accomplished physicians in this space. And what they were trying to look at is, what about therapeutic hypothermia for babies who are born at 34, 35 weeks of gestation? And now automatically I'm thinking like, oh my God, that's it, the needle keeps moving backwards and we're gonna try. And I was surprised to hear that at their center, they do...

 

offer cooling for babies in this gestational age range, because I initially looked at the methodology and it's retrospective. So I'm like, wait, one second. So they were doing it. And it's like, yeah, they were doing that. And some of them of the babies were also having mild encephalopathy. So really what they wanted to do was, what are the short-term outcomes and safety of cooling in babies that are 34 and 35 weeks? They're not really looking at long-term outcomes and they just wanna know, is it safe?

 

There were previous studies that had shown that as you try to cool smaller babies or more immature babies, it could become unsafe. And this was a matched retrospective court study of 20 preterm infants that and that were matched to 40 infants born at 36 weeks or more between 2015 and 2021 and what they found was those babies at 34, 35 weeks who received therapeutic hypothermia

 

their short-term outcomes were comparable to the ones that were more full-term regarding seizures, IVH, blood transfusion, subcutaneous fat necrosis, brain injury on the magnetic resonance imaging, and mortality. And that these findings were consistent when short-term outcomes were adjusted for birth weight. And so the conclusion is that it's feasible and safe, which obviously begs the question, are we going to start calling now 34 weeks? To their credit, they're not making the case.

 

that because of what they're publishing here, they're saying, ooh, there's a benefit. We should do it. They're just saying it's not unsafe. So maybe the next step would be, should we look at this in a more rigorous manner in terms of looking at outcomes on the larger sample, long-term outcomes, and so on and so forth? So I don't want to say that the authors are being careless with their recommendations. However, it does look like the therapeutic creep is definitely happening. And so I'm just curious what you think about that.

 

Daphna Barbeau (05:39.822)

Well, I mean, that's been a major point of discussion, right? Like, why 35 weeks, you know? And can we go lower? Can we go younger? And also, you know, there's this group of babies who are mature but small, right? Or immature but big, you know? So what happens to those babies when they fall on either side of the line? So...

 

Ben Courchia (06:03.784)

Which is a question I had, which was how did they determine the gestational age? But I didn't really, when I read the paper the first time around, I didn't ask myself this question. When I went back to look at it, I couldn't find if this was mentioned or not. But obviously, it becomes a question. How do you assess the maturity of the baby?

 

Daphna Barbeau (06:07.391)

Mm-hmm.

 

Daphna Barbeau (06:18.878)

Yeah. And then you wonder in a decade, like, how low, how low do we go? Right? We'll just have to see. Maybe not a decade, given how long it takes us to translate science right now, but what that will look like in the future. Very interesting.

 

Ben Courchia (06:34.72)

Yeah, absolutely. Another interesting paper I found was something that actually made the rounds on Twitter. It was in the archives of disease in childhood. And it's called the randomized study of a new inline respiratory function monitor, the Juno, to improve mask seal and delivered ventilation with neonatal mannequins. First author is Mark Brian Tracy that's coming out of Australia. So,

 

It's a cool tech, actually. I don't think there's much for us to even take home, but basically it's like a little adapter, and it looks like a rectangular LCD screen that you attach to your Neopuff, and it's a device that I can have some specification. It weighs 85 grams. It's running on battery, and it gives feedback to the provider giving ventilation in various ways. But it's, and it's

 

It's not very technical, actually, because the way they're doing it is by showing you ranges. So the device will tell you if you have a mask leak, and it will basically do it in the traffic light format. So if you have a leak between 0% and 30%, then it will sort of flash orange. No, sorry, if you have 0% to 20%, it will flash green. If you have between 30% and 60%, it will flash orange. And if you have 60% or more of leak, then it will flash red. So you're like, oh, you have to try to aim to get back into the green.

 

Then it will also give you some feedback about tidal volume with some baby icons, whether you're giving between 2 and 1 to 10 mLs, 10 to 25, 25 to 50. And it gives you all these feedback. And you're able to theoretically provide much more effective ventilation. So they did this study. The device, I don't think, is available. I think they said pre-market. So I think it's just a prototype. However,

 

So they did this on mannequins. So they didn't test it on babies. And what they showed was that when they gave this to 49 experienced neonatal staff, they made them do some ventilation. And then what they did is that they did sort of blinding with the same group. So the providers were initially giving ventilations and the LCD screen was covered. And then they uncovered and saw how was the difference. So same providers, same setting.

 

Ben Courchia (08:57.452)

just whether they had access to this screen. And what they found was obviously they mentioned the number of ventilation that was inflations that were given like 15,000 something. And they said that there were significant reductions in all groups in the number of inflations out of target range. So when they were using the self-inflating bag or the TP3 recitator, so with the self-inflating bag, the...

 

Inflations out of range went down from 22% to 6%. For the TPs, it went down from 7% to 4%. That was in the preterm mannequin. And in the term mannequin, with the self-inflating bag, it went down from 55% to 37%. And with the TPs, from 67% to 63%. The percentage of mask leak inflation above 60% was also reduced from 20% to 7% in the self-inflating bag, 23% to 7% in the TPs. And in the term mannequin,

 

8% to 3% in the term mannequin and 23% to 6% in the TP3 necessitator. So I would say, check it out. We'll link the article. I must say the tech looks cool. And I have a feeling that this idea of having something that can give you some feedback as you're giving ventilation has been tested and we know helps deliver more accurate. So I feel like something is coming. But this might be it. It's small. If it's cheap enough.

 

Daphna Barbeau (10:10.722)

Mm-hmm.

 

Ben Courchia (10:19.968)

This is something that might have some.

 

Daphna Barbeau (10:21.618)

I mean, I think this is hugely important, right? Like those, you know, whether you have a Neo in-house or whether you have a Neo just around the corner, a few minutes, those first few breaths can set the whole, I mean, this is with a mannequin, right? But I mean, theoretically, if this can, if we can get this into delivery rooms or something like this into delivery rooms, those first few breaths are basically the difference between like a downward spiral or a.

 

Ben Courchia (10:24.536)

Mm-hmm.

 

Daphna Barbeau (10:48.91)

recovery of a baby, you know, and if you didn't say what level the professionals were who were in the study. Yeah. And even the experienced clinicians had a significant improvement. So I mean, this is, I think this is amazing. I think it's gonna be super valuable for training. I think it's gonna be super valuable when the first responder is not a neonatologist or maybe even a pediatrician. Or in these communities where, you know,

 

Ben Courchia (10:50.155)

Yeah.

 

Ben Courchia (10:56.8)

They were quite experienced. So.

 

Daphna Barbeau (11:17.93)

Helping babies breathe where all they have is PPV, right? I mean, it will potentially be life-saving in some of those communities.

 

Ben Courchia (11:21.866)

Mm-hmm.

 

Ben Courchia (11:25.056)

Yeah, it's very humbling. I want to give a shout out to a physician I worked with Deepak Jain. I may have mentioned this on the podcast where he did something. He did, he was conducting a similar study where we had some, uh, title volume feedback and we practice in our pulmonary lab and fellowship and you think you're pretty good, especially as a failure. Like, Oh, I, I do, I give good. And then you look at the feedback you're getting and you're like, Oh man, this is terrible. Uh, it's a very humbling experience. Very humbling.

 

Daphna Barbeau (11:31.253)

Yeah.

 

Daphna Barbeau (11:43.51)

there.

 

Daphna Barbeau (11:52.45)

But I think this is cool. I think that this is where the innovation is, right? Small changes. This is a simple system, you know? No, no shade. This is, I didn't think of it, but you know, but could drastically improve outcomes, I

 

Ben Courchia (12:05.76)

Yeah, and I think the idea, I think where it's smart is that number one LCD screens today are cheap. People, these are made routinely. But the idea of saying, hey, we're going to give you a range really removes the pressure from the company to give you an exact number. You know what I'm saying? And say, oh, your number is actually within a 10 percent. It doesn't matter. You're getting like if you're within that big fat range, you'll know. But at least you want to be so far off. So, yeah.

 

Daphna Barbeau (12:11.42)

Mm-hmm.

 

Daphna Barbeau (12:20.347)

Mm-hmm.

 

Daphna Barbeau (12:30.37)

So far off. Yeah. No, yeah. And I mean, it's, uh, in terms of ease of use, red light, green light, yellow light. Love it. Uh, okay. My turn. You know, you're not sure.

 

Ben Courchia (12:36.544)

Yeah, that's exactly right. All right.

 

Sure, go ahead. No, no, these were my short articles. And then I have some I've looked into more depth. But I've spoken for now, 12 minutes, so you go.

 

Daphna Barbeau (12:57.23)

Okay. Well, since you started off with a, with an HIE cooling paper, I will do the same. This was esophageal versus rectal temperature monitoring during whole body therapeutic hypothermia for hypoxic ischemic encephalopathy. Association was short and long-term outcomes. The lead author Tai Wei Wu, and this is in the Journal of Pediatrics. So it's basically from the heel.

 

trial group. They conducted a secondary analysis of, again, the multicenter high dose erythropoietin for asphyxia and encephalopathy, or HEAL trial. Of course, all infants in that study had moderate or severe HAE and were treated with whole body therapeutic hypothermia. As a reminder, this was studying the impact of high dose erythropoietin as an adjunct. So getting cooling might be a good example.

 

Ben Courchia (13:25.284)

Mm-hmm.

 

Daphna Barbeau (13:53.102)

erythropoietin improve outcomes. And unfortunately, what it found was that the incidence of death or neurodevelopmental impairment didn't differ significantly between the groups. However, there were more serious adverse events in the erythropoietin group, just as a reminder. The occlusion criteria for this sub analysis were pretty much the same as for the HEAL trial and most other cooling trials.

 

Ben Courchia (14:11.847)

Mm-hmm.

 

Daphna Barbeau (14:20.662)

gestational age greater than 36 weeks, presence of perinatal depression, confirmation of moderate to severe encephalopathy, and the exclusion criteria, like most other studies, less than 1800 grams, head circumference that was too small, genetic or congenital anomalies, and this imminent mortality. So the primary outcome, much like the HEAL trial, was death or neurodevelopmental impairment at the 22 to 36 months of age. They call that the two years.

 

And then they did secondary outcomes, seizures, MRI brain injury using both an additive global injury score and MR spectroscopy markers of injury. But they also looked at complications to the hypothermia because they were studying the temperature probes. All children surviving until 22 to 26 months followup were assessed by the GMFCS, the Modified Gross Mortar Function Classification System.

 

to look at the motor impairment, they look at CP status, and they define neurodevelopmental impairment as any of the following cerebral palsy diagnosed by a neurologic exam, a modified GMFCS level of one or greater, one or equal to, greater or equal to one, indicating the inability to take 10 steps independently or a cognitive score of less than 90 on the Bailey.

 

They also did a four level outcome scale in decreasing order of severity. I won't belabor their points, I think I'll just get into the results. So of the 500 infants enrolled in the HEAL trial, 59% were cooled with esophageal temperature monitoring, that's the E group, and 206 or 41% were cooled via rectal temperature monitoring. You know, it's interesting, as for the type of the cooling devices, they, there was...

 

Ben Courchia (15:54.472)

Okay.

 

Daphna Barbeau (16:14.562)

a whole plethora of devices used. The blank control was the predominant used, 82%. The tico theorem, 24%. Critical, 24%. And the Arctic Sun, 12% at the study sites, respectively. But while most study sites use blank control, six study sites even used more than one device at the same site. And so this is interesting just to talk about. Yeah. Because in.

 

Ben Courchia (16:16.396)

Mm-hmm.

 

Ben Courchia (16:37.468)

Yeah, that's a problem. That's a problem, sounds to me.

 

Daphna Barbeau (16:43.722)

We haven't had a lot of, there have been some head-to-head trials of the cooling devices, but in my, I'll just say my experience, they don't all cool the same way. And they don't, they have a, they have different ranges in how close they can keep to target temperature. Okay. Yeah.

 

Ben Courchia (16:54.157)

Oh.

 

Ben Courchia (17:01.996)

For companies who want to seek Daphna's endorsement of their product, please reach out to me. I'm her manager.

 

Daphna Barbeau (17:09.978)

Anyways, overall, there were no significant differences in the maternal and neonatal characteristics before the cooling, right? So proportion of subjects who received chest compressions, no difference. Proportion of subjects who received epinephrine during initial recitation, there was no significant differences in the severity of encephalopathy. Oh my gosh, I'm really slurring my words this morning. The severity of encephalopathy, there's no difference.

 

in how much erythropoietin was received between the groups or time to target temperature between the two groups. However, between the two groups, as a baseline characteristic, there was a higher incidence of intubation during resuscitation in the esophageal monitoring group, 75.5% versus the rectal monitoring group, 61.2%.

 

Ben Courchia (18:00.32)

Say that again, more intubation at what point?

 

Daphna Barbeau (18:03.442)

I mean, during resuscitation in the babies who ended up getting esophageal monitoring. Because those are the two groups, right? Okay. So the results, the frequency of the primary outcome of death or neurodevelopmental impairment was similar in the two groups, 49% versus 54% with an odds ratio of 1.05, and the risk of death or neurodevelopmental impairment remains similar in the two groups after adjusting for potential confounders.

 

Ben Courchia (18:08.504)

Fine, fine, okay, okay. Yeah, yeah, makes sense.

 

Daphna Barbeau (18:29.898)

an adjusted odd ratio of 1.26 for the rectal group compared with the reference esophageal group. In addition, secondary outcomes such as clinical or electrographic seizures, the mean MRI injury score, and the MR spectroscopy measures also did not differ significantly between the two groups. However, infants in the rectal group had a lower rate of over-cooling.

 

than those in the esophageal group, 44% versus 58% and adjusted odds ratio of 0.52. And the group difference in overall cooling rates, interestingly, was only present during the first day of therapeutic hypothermia. But I actually think that's an important point. There was also, there was a lower rate of hypotension requiring intervention in the rectal group compared with the esophageal group, but this is not statistically significant.

 

And on multivariate analysis, the rectal group, the rectal monitoring group had significant lower odds of hypotension requiring intervention and adjusted odds ratio of 0.57 and any cardiovascular complication and adjusted odds ratio of 0.63. There were no significant group differences in the other adverse events such as inotropic agent use, cardiac function compromise, duration of mechanical ventilation support, the use of nitric, incidence of coagulopathy,

 

or fat necrosis. So these are other complications, obviously, of over-cooling. So I mean, I thought this was interesting. No earth-shattering findings, but as we're discussing the importance of fine-tuning our cooling protocols and the way we do it is keeping temperature in better therapeutic range.

 

more, how important is it? I think this is interesting. So it looked like, again, the rectal monitoring group had lower rates of overcooling than those in the esophageal group. I think this makes sense, but it's interesting to see it. No major changes in the quote unquote long-term outcomes.

 

Ben Courchia (20:25.926)

Mm-hmm.

 

Ben Courchia (20:45.78)

Yeah. Do you think that's going to spark a change in what people favor for cooling?

 

Daphna Barbeau (20:53.039)

I think it might. I think it might. I also...

 

Ben Courchia (20:54.18)

Mmm.

 

Everybody's always reluctant to shove the probe down the baby's butt. And yeah, I mean, I'm sorry to say, we do esophageal stuff all the time. We put in OG, NG. We're much more comfortable with that. It's just as invasive. But yeah.

 

Daphna Barbeau (21:03.872)

I think some of them have.

 

Daphna Barbeau (21:09.034)

all the time. Yeah.

 

Daphna Barbeau (21:16.242)

Yeah. I also think it will depend on what the nurses in your unit prefer, because I think that's a huge, a huge barrier to overcome, I think.

 

Ben Courchia (21:22.648)

That's true.

 

Ben Courchia (21:28.576)

I mean, that's a great point you're making, just because we tend to forget, like as you said, there are multiple devices. And the most important thing is that your team is comfortable with whatever devices you, because that's the worst case scenario where you have a device and you don't use it properly and God forbid you're just, oh, the baby didn't get cooled appropriately or something along those lines. So I agree with you. Whatever people are comfortable with is what is going to matter most.

 

Daphna Barbeau (21:37.496)

Mm-hmm.

 

Daphna Barbeau (21:40.924)

Mm-hmm. I see.

 

Daphna Barbeau (21:50.773)

Yeah.

 

Ben Courchia (21:58.048)

Mm-hmm. All right. All right, I have time for one more. This is before we take a quick break and bring in the EB-Neo team. So there is this paper in JAMA called Neurodevelopmental Outcome of Extremely Preterm Infant Fed Donor Milk or Preterm Infant Formula. It's a big trial. It's the milk trial done by the NICHD.

 

Daphna Barbeau (21:59.168)

Alright.

 

Ben Courchia (22:28.328)

So it really something that was worth reviewing. And we'll see how interesting it is that it's a, it's probably a testament to how our field has changed also over the years. So the question they were asking was, does nutrient fortified pasteurized donor milk improve neurodevelopmental outcome at 22 to 26 months corrected age compared to preterm infant formula in extremely

 

preterm infants receiving minimal maternal milk. So we'll go into the, like me, you'll have a lot of questions and we'll answer those in the methodology. It's a double-blind randomized clinical trial that's done at the 15 centers within the NICHD Neonatal Research Network. And they enrolled babies since 2012 until 2019. And we'll talk about why this took this long to do.

 

The follow-up visits were done at 22 to 26 months. And the eligibility criteria were that you had to be less than 29 weeks or have a birth weight less than 1,000 grams. You had to be less than seven days of age. And then you had to follow and you have to meet some of these eligibility criteria. Number one, the infants' birthing parents never initiated lactation. Because obviously, you don't want to prevent a mother from using their own milk for this study.

 

Lactation was initiated. However, the mother seized to express milk prior to 21 days. And then during that time, they were able to enroll if the mother had stopped producing and said, I'm done. Or last point, that the milk supply was really minimal and that they were going to have to need to be supplemented anyway from day 7 to day 21. The exclusion criteria are.

 

chromosomal anomaly, all sorts of stuff, prior neck, and so on. I don't need to go into that. These are very straightforward. So what was the intervention? So you had infants that were in the no maternal milk group that were receiving a study diet for all feeding from randomization to hospital discharge, death, or 120 days.

 

Ben Courchia (24:43.936)

And then we had babies that were in the minimal maternal milk group, which received any minimal amount of maternal milk that was available, and the study diet, which was the preterm formula, until the same endpoints. The primary outcomes were the cognitive score on the belly at 22 to 26 months.

 

The study was designed to be pragmatic. So that's very important. What did they do? They only controlled the base diet. So they only said, all right, this baby's gonna get preterm formula or donor milk. Okay? When was the feeding initiated? How did you fortify the feeding? How did you advance the feed? All that stuff was left to the clinician. Okay? So that was not regulated, which is a very critical point. And that's the kind of stuff that you may skim over during the...

 

the methods, but it will have a huge implications when it comes to the results. The donor milk recipes were required to provide 2.8 to 3 grams of protein, and they assumed that the donor milk would provide about 0.8 to 0.9 grams per deciliter of protein, but it did not measure the content of the donor milk. They had a bunch of secondary outcome. They looked at the individual scores on the belly. They looked at moderate or severe cerebral palsy.

 

they had a category for moderate to severe or severe nother mental impairment. So what were the results looking like? So they had 483 infants were randomized, 239 in the donor milk group, 244 in the preterm formula group. The median gestational age was 26 weeks, the median birth weight 840 grams.

 

88% of the survivors were assessed at the follow-up at 22 to 26 months. And in that cohort of 483, 114 babies never received maternal milk, and 370 received minimal maternal milk. Now, what's interesting is that the enrollment had to be stopped for this trial due to declining enrollment, loss of equipoise among participating centers, and the increasing use of donor milk in the neonatal research network over time. So it's so sad that...

 

Daphna Barbeau (26:57.651)

Wow, very interesting.

 

Ben Courchia (26:59.384)

I know, right? That as they were doing this trial, like the field shifted and people are like, well, we don't really want to do this anymore. So it's interesting to see that's to me is a testament to these researchers who do this work and who are putting themselves out there when it comes to subjecting their question to the test of time and the test of trends and changes and new evidence coming out. So what was interesting?

 

two, three outcomes that I want to go over, the growth, the weight gain was slower in the donor milk group compared to the preterm formula group. At the end of the study, the mean weight in the donor milk group was 143 grams lower than the preterm formula group. Length gain and head circumference growth did not differ between the groups during the study. So growth did tend to favor the preterm formula group. However, remember what we said, like.

 

Fortification, all that stuff was not controlled. So you could talk about this in their discussion. Could this be that all these other practices did have an influence? It's very possible. The primary outcome, 369 infants went through follow-up and the adjusted Bayley score was 80.7 in the donor-mail group, 81.1 in the preterm formula group. No significant difference. I mean, they're pretty much the same. The Bayley motor and language scores did not significantly differ between the groups as well.

 

and among the infants with barely cognitive score of less than 70. So if you only look at the ones that are really, some people would say a barely score of less than 70 is really what would be considered impairment. They did this for both less than 70 and less than 80. Still, when you compare these babies who have these scores, there's no difference between the groups. The prevalence and severity of neurodemental impairment did not significantly differ between the groups. And then when they said this, maybe it's the maternal milk that they received. So they actually isolated

 

the 114 infants that never got maternal milk. So let's take these kids out because in prior studies, there's always the maternal milk that could potentially confound the issue where you say, oh, they got some maternal milk. Maybe that's why their cognitive outcomes are better. Well, the cognitive score for these babies that never got milk was 80.2 in the donor milk group and 80.9 in the preterm formula group. So identical. So what does that mean? Well, the thing that's not surprising, which probably explains why the...

 

Ben Courchia (29:24.552)

the trial lost some momentum is that the mortality and in hospital morbidity outcomes are what we have known now for some time is that the outcome of death prior to hospital discharge occurred 10% of the donor male group versus 7.4% in the preterm formula group. That was not statistically significant. The outcome of death prior to follow up was 13% versus 11%, not significantly different. However, necrotizing enterocolitis, 4.2% in the donor male group compared to 9%.

 

in the preterm formula group. So as we have already known, this is not new information. They do acknowledge that in the results. They said, we also, we now know that the main benefit of donor milk in this preterm population is reduction in incidence of neck. So yeah, so given the conclusion is that given the observed benefit of maternal milk, this randomized clinical trial tested the hypothesis that the use of donor milk compared with formula in extra preterm infants who received no or minimal maternal milk during hospitalization would result in a better outcome and they found no.

 

significant difference.

 

Daphna Barbeau (30:26.798)

I mean, not getting neck is a big deal, right? I mean, we can't just say like, no, it's the same. It's still not the same. Now, the big deal is, is it the same as mother's own milk? No, it's not. None of that thing is the same as mother's own milk.

 

Ben Courchia (30:32.404)

It's huge. They, and they do it.

 

Ben Courchia (30:39.372)

It's not the same.

 

Ben Courchia (30:48.2)

So to their credit, their primary outcome, what they were originally looking for was the long-term outcomes. They then included neck to show that it is consistent with other evidence that donor milk should be preferred specifically for this outcome. I mean, if you're a parent, who cares if your baby is a bit tinier, but is neck free. They do mention all that in the discussion. So it's a huge result. And even though they were not really powered or looking for neck specifically, because it is consistent with the rest of the evidence.

 

Daphna Barbeau (30:56.418)

Yeah.

 

Ben Courchia (31:15.736)

sort of seems to reinforce the need and the use for donor breast milk.

 

Daphna Barbeau (31:19.39)

Yeah. And it's interesting. There's no difference in mortality, but babies who have neck are more likely to die than babies who don't have neck. Right. So I, I mean, the big, the big deal is we have to change our whole, our whole society so that birthing parents, breast milk providing parents can have the opportunity to provide breast milk. That's how we really will change outcomes. But.

 

Ben Courchia (31:27.409)

I'll talk about that in a little bit then.

 

Daphna Barbeau (31:47.462)

Not having neck, I think, is still a big deal. Still a big deal.

 

Ben Courchia (31:49.22)

It's huge, huge. And especially when you look at, it's not like 2%, it's like double, double the incidence of neck.

 

Daphna Barbeau (31:54.622)

Yeah. You know, I think it's good that we're studying it, right? We're investing a lot in trying to push donor milk, but I wouldn't say it's for not. I mean, again, I think it's what we have.

 

Ben Courchia (32:05.08)

So yeah, we're going to take a quick break. We're going to let the eBneo team come and talk to us about their article of the month. And then I'll come back and I'll answer some of the questions people are having about this particular period because I found another article in the Lancet that sort of talks about what we're aiming at. And I think it'll be interesting to follow up with that. So yeah, stay right here and we'll be right back.

 

Okay, I'm going to take a quick break. We come back, we do the eBneo segment, and then we come back. So if it's okay with you, I'll come back and I'll do this fortification article.

 

 

Ben Courchia MD (00:00.952)

Okay, so today we are joined by the EB-Neo team with, we're with Dr. Kristin Ferguson, Dr. David Tingay and Dr. Lucy Loft from Australia. Thank you guys for making it on the show today.

 

David Tingay (00:18.451)

Thanks, Ben.

 

Ben Courchia MD (00:20.996)

We wanted to start with Lucy because we're talking about the two-year outcomes of the Optimist A trial. But I think for many of us, it's like, well, the Optimist A trial, what was that again? Maybe someone can jog our memory and tell us what the Optimist A trial was and what it was aiming to show and what did it show. Lucy, do you want to take this?

 

Lucy Loft (00:44.191)

Sure, thanks very much, Ben. So the Optimist trial was an internationally blinded and randomized controlled trial that was run between December 2011 and March 2020, which involved 33 tertiary NICUs over 11 countries. And they were comparing minimally invasive surfactant therapy or mist to a sham treatment, which consisted of a transient repositioning of the infant, but with no.

 

instrumentation of the airway. And they looked at 485 preterm infants with a gestational age between 25 and 0 and 28 and six weeks on CPAP that were needing 30% oxygen or greater within six hours of birth. And they randomised in that 241 babies to the mist group and 244 to the sham treatment group. And they looked at their...

 

composite outcome of death or physiological BPD at 36 weeks post-menstrual age in that. And their primary outcome showed that it was not statistically significant between the MIST and the sham treatment for the composite outcome there. But they did have some secondary outcomes which were statistically significant from that trial. In particular, with the MIST treatment they showed decreased BPD or bronchopulmonary dysplasia in the survivors.

 

as well as a decreased rate of intubation within 72 hours of birth is the main outcomes there and that's led on to then the follow-up trial for this.

 

Ben Courchia MD (02:25.504)

Yeah, yeah, some impressive results, obviously, about 44% of the cohort in the missed group that developed the primary outcome of death or BPD versus 49.6% in the control treatment. Obviously, that was not statistically significant. And when they looked at the individual components of that primary outcome, meaning death prior to 36 weeks, that too was not really statistically significant, but they did find

 

that for their definition of BPD, there might have been a bit more BPD in the group that was in the control arm, 45% versus 37%. And that was positive, a significant P value. And then there's all these other secondary outcomes as well as you mentioned. And so today, this was published a couple of years ago. I might not forget now, maybe 2022. I don't remember. However,

 

But today we're reviewing the two year outcomes of that cohort. So maybe Kristen, do you want to tell us a little bit what that paper showed that was published in JAMA? And we'll obviously link all that in the show notes. But yeah, tell us a little bit what those outcomes look like.

 

Kristin Ferguson (03:39.538)

Yeah, for sure, Ben. So the paper that we've done the commentary on is essentially looking at the two-year outcomes of the OPTIMUS trial. So obviously, as Lucy summarized the trial, the main outcome for this paper was the composite outcome assessed at two years corrected age of death or moderate to severe neurodevelopmental disability. And I guess the important thing there is how they've defined moderate to severe neurodevelopmental disability, which was...

 

either moderate to severe cognitive or language impairment, cerebral palsy, which had an equivalent GMFCS rating of two or greater, visual impairment or hearing impairment. And the outcome for that was that there was no statistically significant difference in death or moderate severe neurodevelopmental disability at two years with 36% in the missed group versus 36 in the sham group. So the same.

 

I think what's interesting is some of their secondary analysis, where they looked at the composite components. So death and moderate to severe neurodevelopmental disability, and neither of the components had any statistically significant differences. Where I find the interesting thing is the two-year respiratory health.

 

outcome, which is sort of somewhat of a novel thing that I think in the neonatal trials, we don't often see it. So they looked at a number of markers of respiratory health. So they included overnight hospitalizations for any illnesses or respiratory illnesses specifically, and then a number of parent report respiratory outcomes. So parent report of wheeze or difficulty breathing, use of any bronchodilator therapy.

 

Ben Courchia MD (05:07.812)

Mm-hmm.

 

Kristin Ferguson (05:29.098)

a parent report of physician diagnosis of asthma, which I think is an interesting one that we can talk about later. So ultimately, they did find some statistically significant differences in these secondary respiratory outcomes, particularly in hospitalizations for any illnesses, but also for respiratory illnesses. And I think interestingly,

 

The rates of parent reported wheeze or difficulty breathing at two years was actually higher than the BPD diagnosis in the original trial. So in the missed group, 40, essentially 41% were reported to have wheeze or difficulty breathing versus 54% in the sham or control group.

 

Ben Courchia MD (06:14.34)

I think one of the interesting things that we need to clarify, obviously, is because as Lucy mentioned, the initial trial looked at two groups that one received surfactant, the other one received a sham treatment. And I think you may quickly leap to say, well, obviously, if you're looking at a group that didn't receive surfactant, they're going to do worse from a respiratory standpoint. But there was a time point where that was being looked at when it came to the OPTIMIST-A trial.

 

even in the control group, these babies had also received some surfactant down the road. So it's not like we withheld surfactant from the control group. And I think that could sometimes be lost because of the way the groups were randomized. So I think it's important to know that if you go back to the original trial, you'll see that the average dose of surfactant each group received was one. So they all did eventually get surfactant, except the intervention group got surfactant in that specific manner this early on. I think the, what was the time again of?

 

how early these kids got certified. I have like two, three hours if I'm not mistaken. Yeah, yeah. Okay, so David, we're gonna bring you into the discussion and maybe you can share with us what are your collective thoughts on this paper and what some of the things that you guys are bringing up in your EBNEO commentary this month.

 

Kristin Ferguson (07:12.198)

Yeah, the average was two to three hours.

 

David Tingay (07:34.243)

Yeah, thanks, Ben. I think first, just to reiterate the point you made, that this isn't a trial of exclusivity of surfactant therapy. It's a trial of early, less invasive surfactant therapy. I prefer the term less invasive rather than minimally invasive because the baby still had a laryngoscope placed in the mouth and a small plastic device for the vocal cords. But that's my own personal issues. Yeah.

 

Ben Courchia MD (07:58.94)

I don't think that's your own personal. There was this paper in JAMAPEDES that came out recently that we reviewed where they looked at oropharyngeal administration of surfactant precisely to address this issue where they say, even if you're doing minimally invasive, you're still doing laryngoscopy. So technically how little, how less invasive truly is it? So you're not, you're not alone.

 

David Tingay (08:06.995)

Mm.

 

Daphna Yasova Barbeau, MD (she/her) (08:07.02)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (she/her) (08:16.65)

Mm-hmm.

 

David Tingay (08:18.031)

No, I agree. Yeah. I think this is another issue to talk about on another day in detail. But the terminology, I think, in the Mellinkature is important, because we now have trials recruiting of laryngeal masks. In fact, and I would argue that's not minimally invasive either, but I think less is a better term. But coming back to the follow up of the Optimist A trial, which I think is really quite important, because it's unusual for us to see

 

Ben Courchia MD (08:22.576)

Yeah.

 

Daphna Yasova Barbeau, MD (she/her) (08:34.338)

Mm-hmm.

 

David Tingay (08:45.455)

follow-up trials or follow-up data being reported of early respiratory interventions in the endotology and importantly that those interventions cover the breadth of the organs you'd expect to be involved rather than focusing purely on neurodevelopmental outcomes. The primary outcome of death or neurodevelopmental disability at two years I think was it was could be argued to be a negative outcome because there was no difference but I think we could turn that the other way.

 

and actually say it provides some reassurance on the safety of an intervention, which does involve some engagement with the baby as opposed to not giving surfactant using the traditional methods. And historically, remembering the time Optimus Day was being conducted, minimally invasive surfactant was still novel. And we were coming from the era of coin, where there was either intubation and surfactant or non-invasive ventilation and surfactant. And that

 

That is a really important point to remember because the preterm baby faces two challenges when they're born. One is they're surfactant deficient. And the other is they need to avoid being intubated because of the risk of lung injury. And those two challenges blunt against each other. So minimally invasive surfactant tries to address those two core issues which we face clinically as a challenge, which for...

 

the younger neonatologist wasn't a challenge, but for those of us who've been around a bit longer, it has been something we've struggled with for a long time. Probably more importantly though, is the secondary outcomes of respiratory health. And I think it's, we feel that is important because, and also not surprising, that there is a rationale to say, well, we wouldn't expect there to be a neurodevelopmental disability difference in a group of babies that have one brief intervention.

 

a few hours after they're born. But that intervention is designed to deliver a drug, which is, we know will change the way the lung behaves, not just at a mechanical level, but at a molecular level too. So there's a very strong biological plausibility that if you blunt the inflammatory events that are occurring in the preterm lung shortly after it's born by using surfactant, you will expect there'll be a propagation of that.

 

David Tingay (11:05.191)

benefit occurring on a breath by breath, week by week, day by day basis. So I think it's really important that we saw a respiratory difference in this group of babies because it provides some reassurance that these early therapies we're giving to babies may actually have a long-term benefit. And we really haven't focused well on that in neonatology when it comes to respiratory interventions. We've stuck it out to BPD and then magically the babies go home.

 

and we kind of hope that the intervention may or may not have an influence on them later. We're now more aware that respiratory outcomes later in life are probably more important than the diagnosis of BPD itself. So in a bigger setting, this provides us some time to consider how we think about measuring the respiratory outcomes of babies.

 

Ben Courchia MD (11:47.553)

Mm-hmm.

 

David Tingay (11:59.647)

after they've been in the NICU and that was one of the things we discussed a little bit in our commentary and I think we could probably discuss this a bit more in detail as a group. The other issue we really focused on in the commentary was the concept of how they followed up this group of babies and that requires some time to discuss as well because the follow-up process here was quite complicated, it was multi-layered and the follow-up rates were high.

 

And the challenges we've often faced in these trials is how do we get high follow-up rates to make the outcomes of the trials meaningful, but also how do you ensure that the follow-up is valid and scientifically sound when you review that data. So they were the main issues we focused on in the commentary. And I don't know Ben and Daphne, if you want to talk a bit more detail about them.

 

Ben Courchia MD (12:49.72)

Well, yeah, I think that the point you're bringing up is an important one. I think of the 488 patients that were randomized, the two-year follow-up outcome includes 485 of them, which is staggering. Yeah. So yeah, I think these are things that we definitely want to talk about. My big question based on the things you've currently said and Chris and Lucy, please feel free to take this as well if you would like, but do you think that what we found...

 

Daphna Yasova Barbeau, MD (she/her) (13:02.046)

Incredible. That's incredible.

 

David Tingay (13:03.376)

Yeah.

 

Ben Courchia MD (13:18.444)

in the secondary outcomes of this trial are sufficient enough to maybe change the way we're doing things around the time of delivery, or is it just going to be enlightening us a little bit about the importance of early proper respiratory physiology?

 

David Tingay (13:38.119)

I think this trial in itself can't answer your first question, but it provides the vanguard for us to start considering how we can develop better functional measures for respiratory health that can be used to better understand these early life interventions. We have a black hole at the moment. So a baby leaves hospital.

 

And then we don't have good ways of measuring respiratory function in these children until they get to an age where they're compliant with standardized tests like pulmonary function tests. And that's six, seven, eight years, which is far too long for families. It's far too long for babies. It's far too long for clinicians. And it's far too long for funding agencies for grants, which creates the problem. Here we see, I think, a really quite ingenious way to try to address that gap.

 

because families care less about the diagnosis of BPD than they do about what their child can do and what their family's life will be like. And here we've used a series of measures which you can easily criticize because they're quite subjective. Things like have you been to hospital and so forth. But they are measures that a family can understand and I think a family can relate to. So I think this trial allows us

 

challenges us to question how we should be defining follow-up respiratory health in these children and is BPD alone the fit that we all need?

 

Ben Courchia MD (15:13.508)

Yeah, I mean, you're bringing up such an important point. How many times do we talk to parents about the diagnosis of BPD? And their first question is like, well, but practically what does that mean? Like, is my kid just gonna have like asthma? And it's true, BPD, defining BPD is a pointless endeavor. And for parents, it's even more pointless if it doesn't tell me exactly what is that gonna mean? Is my baby gonna go home on oxygen or is my baby gonna be able to run around at school? I think these are the outcomes that matter most. Definitely, go ahead.

 

Daphna Yasova Barbeau, MD (she/her) (15:20.783)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (she/her) (15:40.234)

Yeah, no, I totally agree. I love that they included this kind of parent report of respiratory outcomes. I think it just gives us such a fuller picture, not only for a research perspective, but just for our own understanding of what life is like for these families when they go home. I also wonder, what do you think is the right way for us to pick the parent-reported measures? You know, this is still something we...

 

the team chose, right, to ask the parents, and how do we better define what's important to families.

 

David Tingay (16:17.059)

I can talk on this, but I'm gonna let Kristen or Lucy go first, because I've had the last two talks. See? Blocks.

 

Ben Courchia MD (16:25.628)

Go ahead to see.

 

Lucy Loft (16:27.043)

I would say that's a really good question. I think obviously I would say that the main way to go about it would be to talk to the parents, both the parents that are going through the process of having a premature baby and what they think now of what will be important later, but obviously to go back and look at the babies who have been born premature and talk to the parents later in life and see what has impacted their quality of life and what did they find important in the first you know, two, four, six, eight years of.

 

Daphna Yasova Barbeau, MD (she/her) (16:51.234)

first two, four, six, eight years of their child's life, and then develop a set of questions around that. And that might be a very wide capture, I think you could do that across a huge spectrum of parents, and really get down to the nitty gritty and find some really good questions that are most important to parents. And as David said, that would probably look more at.

 

Lucy Loft (16:54.935)

their child's life and then develop a set of questions around that. And that might be a very wide capture. I think you could do that across a huge spectrum of parents and really get down to the nitty gritty and to find some really good questions that are most important to parents. And as David said, that would probably look more at things that the parents really care more about rather than the definition of BPD and what we use at the moment.

 

Ben Courchia MD (17:22.416)

Thank you. Kristen?

 

David Tingay (17:23.779)

and just Christian you go and I'll comment.

 

I was gonna just follow up. Yeah, yeah. I was just gonna follow up. I think what Lucy's saying is really important. We have to be engaging with, I hate the term, but it's the term that's been used, consumers and co-designing our research. And this is a really hot topic across all of clinical research at the moment. There are a number of partnership.

 

Ben Courchia MD (17:29.088)

Uh, Christian is, is passing, is passing on the question. That's fine. Go ahead, David.

 

David Tingay (17:54.343)

priority setting partnerships that are being undertaken right now because I'm involved in few of them and I know that we're about to be reporting one on the top 10 research questions for babies born less than 25 weeks. So there is a large body of work happening internationally looking at priority setting and it's critical we do this. We have to have research outcomes that are meaningful to people to make for better science too. I think what you're getting to Daphne though is

 

are these the right questions? I think we don't know for sure but what we do know is that these are reasonable questions. They are also questions with a biological plausibility because they reflect a change in respiratory health and

 

Daphna Yasova Barbeau, MD (she/her) (18:26.882)

Mm-hmm.

 

David Tingay (18:38.031)

when you leave the NICU with BPD, you don't stop having BPD, you don't stop having a preterm lung, that preterm lung is going to be growing and changing for decades to come. So, and that lung will still be exposed or at risk to other inflammatory and injury-based events. So, if you're having repeated hospital admissions for RSV, you're likely to have a worse outcome. That second hit hypothesis, I think, holds true in the preterm lung. And then, but ultimately,

 

we will need functional measures that are validatable, or at least can be used to validate these consumer-led methods. And that's where a gap lies. There's different ways we can look at this and we're involved, or we're leading a big project here looking at trying to develop functional methods at one year of respiratory health using lung imaging. And I know there are other groups looking at this as well.

 

Daphna Yasova Barbeau, MD (she/her) (19:32.974)

I love that. I think that would give us a much better perspective about what is important to families. I did have one question that relates to so much of what you guys have been talking about, about how even the control group receives their fact. And I wonder if you feel like the outcomes really are more dependent on the less invasive

 

Daphna Yasova Barbeau, MD (she/her) (20:02.54)

surfactants.

 

Kristin Ferguson (20:07.146)

I think this is really hard to pick apart in this trial. Ben and I were actually discussing this before we started recording. And is the initial OPTIMUS trial really a trial of minimally invasive surfactant therapy? Or is it that earlier administration of surfactant at a lower threshold of FIO2 in comparison to the other trials that had been done previously?

 

And I actually found it really tricky to pick that apart. And I think my sense is that it's probably more the earlier administration of surfactant as opposed to the mechanism of delivery, particularly given that surfactant was also received in the control group.

 

Kristin Ferguson (20:51.27)

Not sure if you have anything to add, David.

 

David Tingay (20:51.872)

I agree.

 

Daphna Yasova Barbeau, MD (she/her) (20:52.558)

thoughts, David. And then, you know, my last question is really, so where do we go next? What are the things we still have to learn about surfactant and the way we give it?

 

David Tingay (21:07.347)

I'll let the other two comment first.

 

David Tingay (21:12.299)

they're both practicing fellows so they should be telling us what to know.

 

Kristin Ferguson (21:16.302)

I actually think one of the things that I think is really interesting is something that's come up clinically very recently, is that actually the interfaces for which we are delivering non-invasive ventilation have changed since the MIST, since the OPTIMUS trial. So if you look at the videos of MIST online, it is with the Hudson prongs, which are a much lower profile.

 

And I know that a lot of my colleagues, particularly as juniors, we don't get a lot of intubation practice. We don't get to do a lot of direct laryngoscopy and we now have, definitely in Australia, a midline interface, which makes this a lot more difficult. And I think clinically we're finding that we are delivering missed, but potentially at times not with the continuation of non-invasive respiratory support.

 

because of the difficulties of those interfaces. So I actually think there's been an evolution in practice since the trial that we need to face and something from my practice that I think needs to be addressed.

 

David Tingay (22:22.515)

Lucy, did you want to comment?

 

Lucy Loft (22:30.143)

Mike issues. Hi, so the other thing I think is obviously that the initial optimist trial only looked at 25 plus zero weeks and up. And I think now the population in neonatology is changing and becoming more premature, I guess, and MISTA is getting extrapolated into this population in some environments as well. So I think it would be interesting to.

 

Daphna Yasova Barbeau, MD (she/her) (22:31.634)

issues.

 

So the other thing I think is obviously that the initial optimist trial only looked at 25 plus zero weeks and up. And I think now the population in the endotology is changing and becoming more premature I guess. And MISTA is getting extrapolated into this population in some environments as well. So I think it would be interesting to see this minimally invasive surfactant

 

Lucy Loft (22:58.347)

see this minimally invasive surfactant and how things have changed in the even more extreme pre-term population and seeing if those kinds of results extrapolate into the same population because even when you went into these papers and you stratified it by various gestations we saw that the benefit it missed was at the older gestation not at the younger ones. It'd be interesting to look at that side of things.

 

Daphna Yasova Barbeau, MD (she/her) (23:06.053)

and seeing if those kinds of results extrapolated to the same population. Because even when you went into these papers and you stratified it by various gestations, the benefit it missed was at the older gestation, not at the younger ones. It would be interesting to look at that. I'm getting a tiny bit controversial. Please.

 

David Tingay (23:23.223)

I'm gonna, can I be controversial and say a few things? Because I, this will not surprise Kristen and Lucy. I'm gonna say, I'm gonna suggest some things which are not controversial and some that are, but I think really Lucy's pointed out a very important concept there that all of the, surfactants not a new drug, it's not a new agent. How we deliver surfactant is not a new concept. We're trying to refine it or discuss it and we have been doing so ever since I was in the Enable Trainee.

 

Ben Courchia MD (23:27.272)

I'm sorry.

 

Daphna Yasova Barbeau, MD (she/her) (23:28.63)

you than us.

 

David Tingay (23:53.167)

But we have to remember that those trials were in babies who were not born at the extremes of our prematurity. And that's really important. Most of the evidence we have does not relate to those extremely pre-term babies. We need to almost go back to the drawing board and start again, I think, with that group so we understand the evidence is correct. I don't think that's the controversial thing. I think some of the things we need to think about, I'm less interested in the way the device we give it.

 

They're all less invasive. And I think to a certain extent, unless I can be convinced that one piece of plastic to deliver surfactant is different than another one, then in terms of how it delivers the surfactant safely and effectively into the lungs, then I think the solution to how we do it is actually gonna depend on the operators and the system you work in.

 

Daphna Yasova Barbeau, MD (she/her) (24:43.038)

Mm-hmm.

 

David Tingay (24:44.435)

there's clearly going to be environments where people are going to be better at using laryngoscopy and there'll be environments where people are probably better at using LMAs. And they should be factors that we think about. I don't think we consider that when we look at evidence around the implementation. I'm also old enough to know that there are, there was back in the day, there was discussions around different types of surfactant. I think we still haven't yet worked out. We're using biological agents.

 

Daphna Yasova Barbeau, MD (she/her) (24:57.912)

Hmm.

 

David Tingay (25:12.859)

that the discussion around non-biological surfactants sort of artific constructed surfactants is still ongoing. I think it's sort of not going far, but it's still ongoing. The other thing that comes to my mind, and this is my second controversial potential point, is we've spent a lot of time talking about when we give surfactant. Maybe we should be talking about who we give surfactant to and refining, and maybe the answer is not to dichotomize babies into large groups for this drug.

 

but to say we now have different times we can give surfactant, we have different concepts around why we're giving it, whether it's prophylactic or rescue, and we have different ways that we could give it. I think acknowledging that less invasive surfactant is clearly the way to go compared to invasive, but we need to think about...

 

which baby is going to fit for the different permutations of those options. So it comes down to understanding the phenotype of the baby we're giving surfactant to. And the last thing, which Lucy didn't mention, because it's something I know she's been thinking about, is are there other ways we can make the delivery of surfactant more efficient? We're talking about how we get it into the lung, but we also need to start thinking about where it goes when it gets into the lung.

 

Daphna Yasova Barbeau, MD (she/her) (26:34.69)

Hmm

 

David Tingay (26:35.455)

So we've talked about the delivery device, we've not talked about whether how the lung is behaving at that time. So would it be beneficial to have the lung recruited, de-recruited, use a higher PEEP, a lower PEEP? We've seen the Inric Shore paper that was published a few years ago that raises that question as well. So I think there's still quite a lot to know.

 

Daphna Yasova Barbeau, MD (she/her) (26:55.846)

I really love that what I hear you saying is that why we would like a protocol that fits every single baby, that that's not going to be the case, that different babies need different things. And I love that you have actually given us a lot to think about. More questions for the community to work on. We've really appreciated your expertise. Kristin, Lucy, David, thank you so much for joining us today.

 

David Tingay (27:24.627)

Thank you.

 

Kristin Ferguson (27:26.802)

Thanks for having us.

 

Ben:

Okay. Okay, we are back. And this was very pleasant to have the eBneo team. It was kind of a hard eBneo segment to schedule with our team all the way across the world, but we make it happen and we're always so excited to have. That's exactly right.

 

Daphna Barbeau (32:41.462)

Mm-hmm.

 

Daphna Barbeau (32:57.63)

And it was worth it, it was totally worth it.

 

Ben Courchia (33:00.896)

So before the break, we talked about this article from the NICHD that compared donor breast milk with preterm formula. And I think one of the big questions that came out of this paper were obviously all the outcomes could be put on trial because of the fact that fortification was not really looked at. It was only the base diet. And you could say, well, what about the incidence of neck and the fact that it had doubled? Could it have been due to the fact that they were fortifying differently?

 

That's a question I had, that's a question I've seen people asking. And so it's interesting that in the Lancet, there's a paper that might help us answer this question. And it's called Effect of Human Milk-Based Fortification in Extremely Preterm Infants Fed Exclusively with Breast Milk, a Randomized Control Trial. First author is Gorg Bock Jensen. And it's a study that's coming to us out of Sweden. Now they conducted.

 

the Nordic study on human milk fortification in extremely preterm infants, which basically aimed to look at the effect of human milk nutrient fortifiers on neck sepsis and mortality as a composite measure of severe outcome in extremely preterm infants that were fed exclusively with breast milk in a setting where individualized target fortification was used. This is the

 

Ben Courchia (34:25.513)

a randomized controlled superiority trial. The infants were enrolled from seven level three NICUs in Sweden and the eligibility criteria were that you had to be 22 to 27 in six weeks of gestation. You had to have survived the first three days. The home clinic of the infant had the logistic of maintaining the study intervention. In Europe, we do call hospitals slash medical centers clinic. So they were not in an outpatient clinic, but this was an inpatient center, obviously. They had to be able to continue the intervention until 34 weeks.

 

And they wanted, because it was fortification, they included babies once they had reached about 100 mL per kilo per day of feeds. They excluded babies for all sorts of reasons, GI malformation, chromosomal anomalies, and an interesting one, which was feeding intolerance. And I was like, what the heck do they mean by feeding intolerance? I feel like every baby has feeding intolerance at some point. So how do you not exclude everybody? That's right. But...

 

Daphna Barbeau (35:14.158)

Does it feel like it's getting worse, not better? Feeding intolerance? We'll come back to that.

 

Ben Courchia (35:20.712)

I looked back and basically what they meant by that was that they were looking at how long it took them to reach full feeds. So if they were really lagging behind and they ended up not being an issue where babies tend to, were more likely to reach, what is it called, full feeds within 10 days of starting enteral feeds. So they were assigned one-to-one to receive either human milk.

 

They were either one-to-one human milk fortifier or bovine milk-based fortifier once the feeds had reached 100 ml per kilo per day. Now, what they did is that they did analyze the breast milk using the Myris analyzer. And so the macronutrients analysis of the mothers on milk were performed weekly.

 

And the breast milk analysis of the donor milk as well was performed for each batch that they received. So the primary outcome was a composite of neck, stage 2 to 3, culture proven sepsis and mortality during the study period from the inclusion to discharge no longer than 44 weeks corrected. And I was like, that's a peculiar outcome. I've never really seen measures of outcome of mortality. I've seen neck. But.

 

next sepsis or mortality felt a little bit bizarre. I think if you're reading the literature, you always have to ask yourself, what is the outcome and why did they pick this outcome? Because then it's more difficult to then tease it apart. If you say, no, I'm just gonna look at their rates of neck, then you can look at that, but it's not what they were powered for. That's not what they intended to study. So they powered their study for this sort of triple outcome. And interestingly enough,

 

in the discussion. So I'm jumping a little bit here, but they did mention why they picked this. So they said, we chose a composite of neck culture proven sepsis and death as the primary endpoint. The rational being that neck and sepsis share many pathogenic mechanism, and that the diagnosis of neck and sepsis is often a continuum. And that with previous results indicating a positive effect from the human milk based fortifier on both neck and sepsis, they thought they could put all these things together. Something you mentioned when we were talking earlier about the outcome of neck, that neck.

 

Ben Courchia (37:37.728)

all these things are related. And then they said, obviously, mortality constitutes an intrinsic censoring effect in infants at high risk of developing severe sepsis or neck. Now, their trial did not have the power to study neck as a separate outcome. So you cannot take, technically, the data from this trial and go counsel families on what is the effect on neck specifically. And the reason for that is because, as we'll see, the incidence of neck is quite low. Their neck incidence rate of about 7%

 

They said that if they wanted to show a reduction of 50% in neck rate with 80% power, they would have needed a sample size of about 1,200 infants, which is obviously huge. And they didn't have that. So they couldn't power for neck specifically. So I thought this was sort of like the methodology pause or tidbit of the week. So 228 infants were included in this intention to treat analysis trial. No significant difference between.

 

the babies and the mothers at baseline. What about the primary outcomes? So the composite of neck sepsis and mortality did not significantly differ between the two treatment groups. Of the 115 infants assigned to human milk-based fortifier, 35% fulfilled the criteria for either neck 2-3, culture-proven sepsis, or death, compared to 34.5% in the infants that were assigned the bovine milk fortifier.

 

Th