Hello friends 👋
In this episode of Journal Club, Ben and Daphna review several recent studies that hold meaningful implications for neonatal care.
They begin by discussing a comprehensive meta-analysis on postnatal corticosteroids, exploring their impact on bronchopulmonary dysplasia (BPD) and cerebral palsy outcomes. The conversation highlights the nuanced findings, including the benefits for high-risk infants and the risks for those at lower risk, and considers how these insights could guide clinical decisions.
Next, they analyze a large observational study investigating thrombocytopenia and its relationship to major bleeds in preterm infants. The discussion focuses on whether low platelet counts directly contribute to bleeding or are merely a marker of other conditions, with potential implications for transfusion thresholds.
The episode also features an EBNeo segment with guest experts, who provide an in-depth discussion of a pivotal trial comparing video and direct laryngoscopy for neonatal intubation. They evaluate the study’s design, its impact on procedural success, and its role in enhancing trainee education.
This episode of Journal Club offers evidence-based insights and actionable takeaways for neonatal clinicians, with a focus on advancing care and improving outcomes for vulnerable newborns.
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The articles covered on today’s episode of the podcast can be found here 👇
Systemic Postnatal Corticosteroids, Bronchopulmonary Dysplasia, and Survival Free of Cerebral Palsy.
Doyle LW, Mainzer R, Cheong JLY.JAMA Pediatr. 2024 Nov 18:e244575. doi: 10.1001/jamapediatrics.2024.4575. Online ahead of print.PMID: 39556404
Jensen EA.JAMA Pediatr. 2024 Nov 18. doi: 10.1001/jamapediatrics.2024.4572. Online ahead of print.PMID: 39556388 No abstract available.
van der Staaij H, Hooiveld NMA, Caram-Deelder C, Fustolo-Gunnink SF, Fijnvandraat K, Steggerda SJ, de Vries LS, van der Bom JG, Lopriore E.Arch Dis Child Fetal Neonatal Ed. 2024 Jul 15:fetalneonatal-2024-326959. doi: 10.1136/archdischild-2024-326959. Online ahead of print.PMID: 39009429
Cornet MC, Gonzalez FF, Glass HC, Wu TW, Wisnowski JL, Li Y, Heagerty P, Juul SE, Wu YW.J Pediatr. 2024 Nov 20:114415. doi: 10.1016/j.jpeds.2024.114415. Online ahead of print.PMID: 39577760 Free article.
Stalter EJ, Verhofste SL, Dagle JM, Steinbach EJ, Ten Eyck P, Wendt L, Segar JL, Harshman LA.J Perinatol. 2024 Oct 17. doi: 10.1038/s41372-024-02141-9. Online ahead of print.PMID: 39420073
Geraghty LE, Dunne EA, Ní Chathasaigh CM, Vellinga A, Adams NC, O'Currain EM, McCarthy LK, O'Donnell CPF.N Engl J Med. 2024 May 30;390(20):1885-1894. doi: 10.1056/NEJMoa2402785. Epub 2024 May 5.PMID: 38709215 Clinical Trial.
Manley BJ, Kamlin COF, Donath SM, Francis KL, Cheong JLY, Dargaville PA, Dawson JA, Jacobs SE, Birch P, Resnick SM, Schmölzer GM, Law B, Bhatia R, Bach KP, de Waal K, Travadi JN, Koorts PJ, Berry MJ, Lui K, Rajadurai VS, Chandran S, Kluckow M, Cloete E, Broom MM, Stark MJ, Gordon A, Kodur V, Doyle LW, Davis PG, McKinlay CJD; PLUSS Trial Investigators.JAMA. 2024 Nov 11:e2417380. doi: 10.1001/jama.2024.17380. Online ahead of print.PMID: 39527075
Steflik HJ, Pearlman SA, Gallagher PG, Lakshminrusimha S.J Perinatol. 2024 Nov 20. doi: 10.1038/s41372-024-02174-0. Online ahead of print.PMID: 39567649 No abstract available.
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The transcript of today's episode can be found below 👇
Ben Courchia MD (00:01)
Hello everybody, welcome back to the Incubator Podcast. It is Sunday, it's time for Journal Club. Daphna, how are you?
The Incubator (00:08)
I think we've got some neat papers and some, yeah.
Ben Courchia MD (00:11)
It's a heavy journal club. There's some to me, these are the exciting, these exciting journal clubs where there's like some big papers, lots of implications, both, yeah.
The Incubator (00:22)
And no, I was just going to say, I didn't mean to interrupt you, but like, think that's why we started the journal club. So like when a paper comes out that you need to know about, that you know about it. So this has been a neat opportunity for us.
Ben Courchia MD (00:36)
For sure, for sure. What's new with you?
The Incubator (00:40)
But you know, gearing up for the holidays are can be an overwhelming time for people in medicine. I mean for everybody, but when you're trying to like figure out your shifts and your child care, your family doesn't understand why you're still working weekends and nights and 24s and you're like, this is another holiday. Yeah, it's for the long haul this job. And then, you know, finding ways to center yourself around all of
Ben Courchia MD (00:59)
Another weekend, another Friday night?
The Incubator (01:10)
chaos. But, but yeah, good. How about you, buddy?
Ben Courchia MD (01:10)
Yeah. Yeah.
It's busy season for us. We're going to be at Hot Topics. People have probably listened to the episode that we did recently with the organizers. So it's going to be exciting. If you're there, just come say hi. On a personal note, I'm very excited that I recently got accepted in the Hemodynamics Fellowship Program at McGill. So...
The Incubator (01:26)
Yeah.
That's right. Very exciting. Congratulations, buddy. That is a big deal. And you're going to give us the inside peek of doing a second fellowship,
Ben Courchia MD (01:49)
Yeah, I mean, actually it's a good opportunity to discuss this then. very much, I'm not going to take off fully from my clinical duties. So I'm going to do this while continuing to work. And so I was thinking, I was brainstorming the idea of maybe trying to document a little bit some of what that looks like, maybe in the form of like,
The Incubator (02:00)
Right.
Ben Courchia MD (02:18)
short YouTube videos. What does that look like to do maybe the travel back and forth, the stuff that we're learning? If there's any interest in doing that and in seeing a little bit of the behind the scenes of what doing a second fellowship while keeping a primary job, let me know. Let me know. It might be helpful. I think we all have different circumstances. I'm going to.
The Incubator (02:33)
sure.
Ben Courchia MD (02:45)
I mean, but we could talk about this during this series. So for example, like I really geared my life towards being able to do this, not taking on too much financial sort of strain. So that's a big deal for us. And also like I picked the program in Montreal because being French, it's kind of nice to be going in a place where they like, yeah, they really...
The Incubator (03:04)
I'm sorry.
Well, we have some good buddies there, that helps.
Ben Courchia MD (03:10)
Yeah, we have good buddies, but what was interesting too is that to me, when I went to give grand rounds at McGill not too long ago, and then it dawned on me that the government of Quebec really puts an emphasis on trying to promote having physicians there that are bilingual. And I realized that it's very hard to find... Yeah, I asked the people, I'm like, is he... I'm like, it's impossible to find neonatologists who are bilingual in French and English. And I was like...
The Incubator (03:29)
I wonder what that's like, you know?
Ben Courchia MD (03:40)
here I am. So anyway, but yeah. So if you are interested in maybe a little blog or a little vlog about what does that look like and what are the things that you're being taught in Hemodynamics Fellowship, just send us a comment, send us an email, and we'll prepare for it. I I'm not beginning until I think July of next year, but the plan is to have this.
The Incubator (03:40)
Well, here I am.
Ben Courchia MD (04:07)
really potentially prepare. if we want to do this, then I'll try to start working on that earlier on.
The Incubator (04:14)
I think it sounds great.
Ben Courchia MD (04:15)
Yeah. All right. Anything else that we need to talk about?
The Incubator (04:18)
No, I think those are the biggies.
Ben Courchia MD (04:21)
All right, very cool. All right. I guess I begin. I'm not going to even start. If people are joining us Journal Club for the first time, I always begin and I always ask if I should begin and you tell me I should always begin.
The Incubator (04:30)
Always.
Ben Courchia MD (04:35)
So the first paper I wanted to talk about is a paper that has been one of my favorite papers since starting fellowship. It's a paper out of Australia. Its first author is Lex Doyle.
Which, by the way, I am very excited. We can actually make that announcement now, but it is very exciting for us to say that Lex Doyle is going to join us on the podcast this month. So if you want to write that down in your calendar, December 15th, our special interview will be with Professor Lex Doyle from Australia. So he's publishing an article in JAMAPEDES.
called Systemic Postnatal Corticosteroids Bronchopulmonary Dysplasia and Survival Free of Cerebral Palsy. There is a great editorial in JAMAPEDES from Eric Jensen about this study. And it's an update on the previous paper that this group had published in the past. So for those of you who are familiar, they published a meta-regression and a meta-analysis
in 2005, looking at randomized trial of corticosteroids and trying to look at neurodevelopmental outcome in childhood. then they revisited that paper in 2014. And you may be familiar with the figure that came out of this mid analysis, which is basically this graph where you see that the effects of steroids are really mitigated by the baseline risk of BPD. And that for babies where the baseline risk is elevated, the steroids are beneficial.
But for the babies where the risk is very low, they are actually harmful. And so this is a third edition to this study. it's probably my favorite paper because it taps into Bayesian statistics and it deals with BPD and steroids, are the things I enjoy looking at. So it was very exciting to see this paper come out. The aim of this particular study was, again,
to study infants born preterm who were enrolled in randomized controlled trial of systemic postnatal corticosteroids. And I emphasize systemic because we're going to talk about other forms of steroids in a little bit. And to describe the association between the difference in rates of survival free of cerebral palsy attributed to corticosteroids and the risk of BPD, both overall and by the type of corticosteroids and by the time of starting treatment among those who are receiving dexamethasone. So.
In terms of the study design, there's not much to say. This is basically, like we said, it's an update. It's a mid analysis. They looked for RCTs on postnatal steroids that were published between 1966 and 2020. All the RCTs of postnatal systemic corticosteroid treatment versus no treatment for the prevention and treatment or treatment of BPD in 10 countries reporting all of mortality, BPD and long-term outcome, including cerebral palsy, were eligible.
If you want to find out more about the different criteria that they used, it's kind of similar to what they had done before. But obviously the results is really what we want to go into and see what things look like now. So compared to the Cochrane review that was published in 2021, there's one new eligible RCT, including it's the one of the use of hydrocortisone started in the first week of life. And that's the one that was done by Christie Waterberg that was published in the New England. We reviewed this at length on the podcast. If you want to, you can go back.
and listen to this episode. There's some new follow-up data that had been published from two other RCTs on hydrocortisone, one that was started in the first week of life and one that was started after the first week of life. There's also additional data that they were able to include on cerebral palsy that were available from one study on hydrocortisone and on BPD for two studies of dexamethasone.
In the end, basically for the current mid-analysis, they were able to include 26 RCTs that included 3,700 infants who were eligible. Now, of the 26 RCTs included in this current analysis, 18 of these trials, which is about 70 % of that group, used dexamethasone, and 31 % used hydrocortisone. One of the hypothesis is that dexamethasone works better
for that purpose than hydrocortisone. So we'll see what the results show. In 46%, the treatment was started in the first week of life. And what was very interesting is looking at the median rates of BPD. in the control group, the median rates of BPD in the control group was 50%, but it varies widely, ranging from 9 % to 89%. And the overall rates of survival free of cerebral palsy were 68 % in both the corticosteroids and control groups.
Which is something interesting. We were going to review the PLOS trial today. We're going to talk to Brett Manley about this and sort of this, this perception of what the incidence of BPD is within our unit is very difficult to pinpoint because as usual, neonatology is a, a, is a constantly changing landscape. And so we are resuscitating more 22-weekers. And so what we thought was the, the rates of BPD for babies that were just less than 32 weeks, maybe now different if we include 22-weekers and more of these immature groups. So.
I thought that was very interesting. In terms of follow-up rates, they were mostly high for all the studies, and only four studies had less than 80 % follow-up. So in terms of the actual results that matter, what they found was very interesting. And I'll try to point to a few of these results. They said that there was some evidence for a positive association between the treatment effect of systemic corticosteroids on survival free of CP
and the risk of BPD in the control group. And that's figure one. And what that shows basically is that for every 10 percentage point in the increase in the rate of BPD in the control group, the risk difference for survival free of cerebral palsy is about 1.6%. That is not statistically significant. The confidence interval is...
is minus 0.5 to 3.7. We're going to talk to Brett also about this idea of looking at relative risk and risk difference. That's also something that is becoming a little bit more useful in today's analysis of studies. Now, there was a strong evidence that the association between the treatment effect and the risk of BPD differed between dexamethasone and hydrocortisone. And so that was very interesting that really these two steroids are not equivalent by no means.
There's evidence that there's a positive association between the treatment effect of systemic dexamethasone on survival free of CP and the baseline risk of BPD. And so for every 10 percentage point increase in the rate of BPD in the control group, the risk difference for survival free of CP is 3.74%. And that was statistically significant.
Based on where the 95 % confidence interval crossed zero, the evidence of benefit from DEXA increased above a risk of 70 % of BPD. And in contrast, the evidence of harm of dexamethasone is when the risk for BPD is less than 30%. So if you have a baby that has a risk of BPD that is like 89%, then you should go right ahead and use dexamethasone because the benefit is really there. If you have a kid where the risk of BPD is about like 20 %?
You might be doing more harm than good based on this figure. Now, interestingly enough, looking at the other steroid, there was some evidence of a negative association between hydrocortisone and survival. So for every 10 percentage point in the increase, every percentage point increase in the rate of BPD in the control group, the risk difference for survival free of CP was negative 1.62%.
Interestingly enough, was a suggestion of benefit from hydrocortisone at a low risk of BPD. But if you look at these graphs, which I have here, yeah. But when you look at them and you look, there's a figure two that you're looking at, survival free of cerebral palsy between dexa and hydrocortisone, you can see that the slope of the curve is very, very different. Very different. And the slope for hydrocortisone is much, much flatter.
than the one for dexamethasone. And the dots on this graph represent individual studies.
So that's what they mentioned as well in the paper saying that the slope of the treatment effect versus the rate of BPD for dexamethasone for 14 studies with follow-up rates greater than 80 % was 0.37 compared with the slope for all 18 study. So I think it's a very interesting meta-analysis. It's a very interesting update on this meta-analysis because you see these papers that are very, very helpful. And then
more studies come out and you wonder like, does that affect these old mid-do I throw the mid analysis out in the garbage? Cause now there's more data. So the fact that now you have these updated studies is tremendously helpful. And the authors conclude that since systemic postnatal DEXA is associated with better rates of survival free from cerebral palsy in infants born preterm with a high risk of BPD, it remains an evidence based treatment option. Now they're saying equally,
DEXA should be avoided in infants at low risk of BPD. The weak evidence suggesting a benefit with hydrocortisone in infants that are at low risk of BPD requires to be studied further. I know a lot of people that I've spoken to that would advocate for that. But the problem remains to determine which infants are at high enough of a risk of BPD to decide which one will benefit from systemic dexamethasone or low enough of a risk to avoid dexamethasone. Now there's several algorithms to predict the risk of BPD well before the infant reaches
36 weeks post-menstrual age that have been developed. The NRN has one that's freely available online. But the challenge the authors mention remains to determine if using the algorithm to guide treatment improves long-term outcome for infants at risk of BPD. I mean, we have to do with whatever we have as well. At some point, we just got to use what we have. But yeah, it's true that what's difficult to decide is, as we were saying earlier, in this graph,
The Incubator (15:20)
Right.
Ben Courchia MD (15:30)
between the use of systemic steroids, especially in the case of dexamethasone, the question becomes what happens to all these kids that are in this in-between rates, right? Like what if a kid has a rate of 50 %? What are you supposed to do? You're not in that 70 % range where clearly you should be using it or you're not in that low range. What are you supposed to do? I don't know. You can decide. I think you can take other parameters into consideration as well. But it's definitely something interesting to think about.
The Incubator (15:41)
Mm-hmm.
Right.
Well, I think we could look at it the other way. Like there's definitely a group of babies that were like, okay, this is a choice we can make and feel good about. And there's a group of babies that were like, we should definitely avoid this. So I think it's exciting. I think it's good news, you know? I think it's good. Yeah.
Ben Courchia MD (16:16)
Yeah, yeah. I love that it's still like hydro-cortisone doesn't go away.
The Incubator (16:22)
No, circling.
Ben Courchia MD (16:24)
It's still remaining. There's still these papers emit the possibility of like, but it's maybe in a case that might be, Now, what's interesting.
The Incubator (16:33)
That's right.
So the steroid saga continues.
Ben Courchia MD (16:40)
Yeah. I like again the editorial by Eric Jensen. I think it takes you back a little bit, especially if you're a trainee, understanding a little bit how we got to where we are today with the use of steroids and understanding a little bit that this is not a niche sort of subject. mean, I think at some point in the end of his editorial, he mentions how it's one of the most widely used drugs in neonatal medicine. And I quote, and it says, although there are true risks and benefit to prevent BPD remain uncertain,
the work by Doyle and colleagues continue to encourage critical appraisal of how the safety and efficacy of these drugs and other therapies may depend on a patient's underlying risks for important clinical outcomes. And it's true that this is basically how we get better patient outcomes, better patient care, if we think of the baseline risk of our patients before we proceed with interventions.
The Incubator (17:34)
I love it.
All right. Thanks, buddy. Well, I had a paper that actually I've been holding on to that we haven't been able to get to. So I'd like to do that one. It's entitled, Most major bleeds in preterm infants occur in the absence of severe thrombocytopenia and observational cohort study. This is from archives of lead author Hilde van Vander Stoijs and senior author Enrico Loprior.
So basically they wanted to look at, I think the study is really interesting. I think it would be nice if you have the opportunity to go and look at this figure. So they wanted to look at thrombocytopenia, but it's sometimes hard to understand is a thrombocytopenia the cause of a problem or the result of a problem. And so they really wanted to look at the nadir, each individual baby's risk.
for bleeding, severe bleed and look at the nadir. And did the nadir occur before the bleed or after the bleed? And so I thought this was a really creative way to look at thrombocytopenia as a risk factor for bleeding. So basically they use this observational cohort study. They used infants with the gestational age less than 32 weeks who were admitted immediately after birth. This was done in the Netherlands. So it included one of the nine
tertiary NICUs and the dates were January 2004 to July 2022. So they included all infants who met the inclusion criteria and then the follow-up started from like the moment of birth and ended at NICU discharge, transfer to another hospital or death, whichever occurred first. They did have some exclusions. all infants, they excluded all infants with no platelet counts.
infants with platelet counts that were thought to be spurious during admission. The date of diagnosis of major bleed was not available. Only platelet counts measured after a major bleed or platelet transfusion and those babies who had an absence of cranial ultrasounds due to transfer within 24 hours after birth. So they did lose out on that group of babies. Okay, I told you about their...
concept of temporal ambiguity. So looking at when the nadir occurred. so specifically they were looking at the lowest nadir, the lowest platelet count before the diagnosis of a major bleed. And of course, some infants received platelet transfusions. So they selected the nadir before the first transfusion since we're still learning about the effects of platelet transfusions. Okay.
The infants were then stratified into nine groups based on their nadir platelet count using these cutoff points, which have been frequently used in other studies of platelet transfusion thresholds. So 10,000, 25,000, 50,000, 100,000, 150, 200, 250, and 300,000. And using thrombocytopenia cutoff as a nadir less than 150.
So they looked at a number of outcomes. The primary outcome was a diagnosis of a major bleed during the NICU admission. So they included major intracranial bleeds, pulmonary, and GI bleeds. They have a cranial ultrasound screening protocol. So infants born at a gestational age less than 30 weeks underwent routine ultrasound scans on days one, three, and seven. And then they had biweekly scans until NICU discharge. For those infants that are slightly older, the 30 to 32 weeks gestation scans were conducted on
one, days one and seven after birth and again prior to NICU discharge. So they looked at kind of major IVH, but they also include other types of intracranial bleeds, things like parenchymal bleeds, subdural and cerebellar bleeds, and they were considered major if they showed any midline shift on the imaging, if they needed neurosurgical intervention.
or if they were associated with hemodynamic instability, things like needing volume, inotropes, or blood products within 24 hours. They called a pulmonary bleed major if it was characterized by acute respiratory deterioration, fresh bleeding from the trachea. Yes, for sure, for sure. That'll get your, hairs.
Ben Courchia MD (22:04)
Call that major.
The Incubator (22:10)
standing. So fresh bleed from the trachea requiring mechanical ventilation or fresh bleed from the endotracheal tube requiring increased ventilatory settings. The dreaded call in the middle of the night. And then GI bleeds were defined as fresh visible rectal bleeds except for mild bleeding caused by neck. Secondary outcomes were mortality before NICU discharge,
compositive major, bleed or death. And let's just get into the characteristics. That's enough. That's enough of the details. So they had 3,138 infants admitted during the study period and they included 2,772 infants. The median gestational age was 29 weeks. So it was kind of an older group, but they did include, like I said, babies down to the lowest gestational age.
Ben Courchia MD (22:46)
Ha ha!
The Incubator (23:07)
And the mean birth weight was about 1200 grams. The incidence of thrombocytopenia, so less than 150,000, was 41%. But severe thrombocytopenia, so they labeled that as less than 50,000, was 8%. So let's get into the bleeding. A total of 224 major bleeds occurred. This was 8 % of the cohort, of which...
79 % were major IVH, 2 % were other major intracranial bleeds, 16 % were pulmonary, and 3 % were GI bleeds. The median age at which a major bleed was diagnosed was two days after birth, and 74 % of all bleeds occurred during the first three days of life, and 8 % bleeds after the first week. Most pre-bleeding nadirs were measured on the same day as the diagnosis of a major bleed.
except for those in the 10 to 24,000 category and the 25 to 49,000 category with a median time from nadir to diagnosis of the bleed of one to two days. Okay. Now, what about the thrombocytopenia? So the incidence of major bleeds did not differ between infants with severe thrombocytopenia.
Ben Courchia MD (24:21)
Mm-hmm.
The Incubator (24:30)
and those within, so less than 50,000, which was 8%, and those with a nadir greater than 50,000. Among infants with a major bleed, 8 % had a pre-bleeding nadir of less than 50,000, and 92 % of those babies with a major bleed had a pre-bleeding nadir of greater than 50,000. The major bleeds in five infants with nadirs less than 25,000 were all bleeds
other than IVH, which was really interesting. There were two pulmonary bleeds, one subdural bleed, one frank rectal bleed requiring transfusion, and one severe cerebellar bleed. Not surprisingly, major bleeding incidents decreased with increasing gestational age. The overall mortality rate was 7 % and was higher for infants with the lower nadir. And of the total 192 deaths, six infants, or 3 %
died in the first 24 hours after a cranial ultrasound was made, including one with a major pulmonary bleed and the other five with no clinical signs of bleeding. So I want to go back to the platelet counts because I think that's what people are really interested in. They have a really neat graph, figure four, about the incidence of the first major bleed per bleeding type. And it's really interesting that it's almost like
As the platelet counts increase, let's look at just major IVH, which is dark blue in this figure. It's almost like the IVH increases as the platelet count increases, which is, I think, totally unexpected. Obviously, number of babies in each group is different, but it's very interesting.
Ben Courchia MD (26:21)
So I'm going to press you a little bit on that because number one, think we'll put that figure on the social media so that people can see. You're right. The IVH really start making an appearance in that dark blue color at a platelet count of like 25,000 or more. However, below, especially less than 10, they have this other category called non-IVH intracranial bleed, which don't make me feel much better.
The Incubator (26:27)
for sure.
No, yeah, they're not great. They're not great.
Ben Courchia MD (26:49)
But it is very interesting. I'm going to let you finish your review because I wanted to dissect this graph for a variety of reasons. So I just want to say that it's not like these kids do fine. If you're not seeing the graph, they're not doing great with Playlet counts below 25,000.
The Incubator (27:00)
Yeah.
No, of course not, yes.
No, there are bleeds, but the majority, and they do have the most bleeds, right? Less than 10,000 have the most bleeds, but it's interesting. mean, some of those other potentially deadly bleeds are pulmonary and GI. And sometimes we don't go looking for them or we're just not thinking about them that much, but those are the things to be looking for in this spontaneous bleeding category.
Ben Courchia MD (27:24)
Yeah.
The Incubator (27:36)
Just all in all, neither univariable or multivariable logistic regression analysis demonstrated noteworthy associations between the nadir and major bleeds. So I think that what they wanted to highlight in the discussion was that the major bleeds, 92%, most major bleeds occurred among very preterm infants without severe thrombocytopenia. Again, they call this less than 50,000. They saw no substantial differences in the incidence of major bleeds between infants with...
or without severe thrombocytopenia except for this higher incidence among those with nadir less than 10,000. And I think this paper is important because obviously we have the new platelet transfusion threshold guidelines. And I think this makes me feel a little bit better about them.
Ben Courchia MD (28:28)
mean, yeah, mean, right? I mean, when you read this paper, my fear was that they were going to find that with platelets less than 50,000, there was a lot of major bleeds. And you're like, shit, like now I'm not transfusing, or I'm not doing anything. When the platelet is 49,000, I'm trying to follow the recent evidence. But first of all, makes me feel better about the recent platelet transfusions, because it sort of reinforces the fact that there's no need to be super aggressive. Now, figure four is so interesting to me.
The Incubator (28:39)
Right, we're missing that group.
Exactly.
Ben Courchia MD (28:58)
because it underscores a few things. Number one, like we said, it sort of highlights what the evidence has shown that below 25,000, it's really becoming a big problem. And you can have a lot of these bleeds, like you said. You can see that the uptick, if you're going from right to left, where 25,000 or less, you get a lot more bleeds. Granted, for the category that has the highest number of bleeds, the highest percentage of bleed with a playlist count of less than 10,
The Incubator (29:06)
Mm-hmm.
Ben Courchia MD (29:27)
the N is very small. I think it's like six kids. So it's hard to draw from that. What's interesting too is that they cut the threshold or the nadir at this 50,000 cutoff, which it's a very interesting thing from a methodology standpoint because they end up taking something that could be looked at more in a continuous fashion where you look at it continuously. But no, they've categorized it and now they have these two categories.
The Incubator (29:29)
That's right, six kids.
Yeah.
Continuous. Totally agree.
Ben Courchia MD (29:55)
I don't know. I don't know if categorizing this and putting 50,000 as the cutoff was the right thing to do. Maybe they were trying to make the point that there's no reason to use, because a lot of people still use 50,000 as a cutoff to transfuse. So maybe they were trying to make the point of saying, no, there's no reason to do so. But I think if you're interested in research and you're interested in methodology, I think this is a great exercise is trying to think about something where what would have been the presentation of the evidence if I had looked at this variable in continuous
as a continuous one versus as a categorical one of above or below that cutoff. But nonetheless, I think the data is there to show that, yeah, most major, like there's not a big, there's not an association between a certain platelet threshold that right now we would not address and major bleed. So makes me feel quite good about it.
The Incubator (30:25)
Mm-hmm.
Yeah. And I think they did a very nice job about saying like the nadir had to be before the bleed, right? Because especially when we're using kind of observational retrospective data, we don't know when the lowest platelet count was for, for, all the babies and all the studies. So I thought this was a really nice way to do that.
Ben Courchia MD (30:59)
Uh-huh.
And it was very interesting to see as well. We've reviewed this on the board review podcast as well, the incidence of IVH, major IVH. It's multifactorial. And so it's not surprising to see that kind of like the platelet count didn't really have any effect on the severe IVH. Like it sort of goes up and down, like it doesn't follow a specific pattern. And that's because cerebral auto perfusion is something that is impaired in neonates. There's all these other mechanisms that contribute to the incidence of IVH. And it's not just what your platelet count is.
The Incubator (31:30)
Mm-hmm.
Ben Courchia MD (31:34)
So it's a good reminder that it is multifactorial. And I'm only mentioning IVH because the others are quite minimal when you're looking at the incidence of these other bleeds in these babies.
The Incubator (31:35)
Yeah.
Right, numbers.
Yeah, I think it's both reassuring and terrifying because what are the platelets even doing? What is even happening with these platelets? And you're right, there's so many other things that we can't measure with the lab value that predict, especially IVH in the babies. Yep.
Ben Courchia MD (31:48)
Yeah, yeah, yeah.
Yeah, yeah.
It's a very interesting paper. I would say if you're a fellowship program, review this paper with your fellows. It's a great paper. I'm not saying it's the most impactful paper. You may say, hey, I'm still going to do everything the same, which by the way, may be the intent of the authors to corroborate the current evidence. But from a methodology standpoint, it's so interesting about, hey, what does that tell us? Looking at the data, looking at how could have this been done in a different sort of...
The Incubator (32:08)
You
Mm-hmm.
Mm-hmm.
Ben Courchia MD (32:29)
study design, right? This was an observational study. What if it had been retrospective, prospective? Like, this is very cool. All right, we're going to take a quick break, Daphna. And when we come back,
The Incubator (32:34)
Mm-hmm.
The Incubator (33:23)
OK, so we are back and we are joined for this EB-Neo segment with two physicians. We are joined by Dr. Sarah Neches, am I pronouncing this correctly? Neches. Neches, I'm so sorry, Sarah, who is coming to us from Seattle Children and with Dr. Rebecca Shay from Children's Hospital of Colorado. Sarah, Rebecca, thank you so much for joining us. We're happy to be here.
I think you guys picked a very interesting article to write a commentary about. The article we're discussing today was published in the New England Journal of Medicine. It's coming to us out of Ireland, if I'm not mistaken. And the paper is called Video versus Direct Laryngoscopy for Urgent Intubation of Newborn Infants. I think this is a topic that is super trendy in neonatology. And I think we did review this paper on episode 214 of the podcast, but I think for
Those of us, myself included, who may need a bit of a refresher. Sarah, do you mind walking us through a little bit what was this paper about? Absolutely. So this was a single centered randomized clinical trial. It was designed to answer the question of whether intubation success is improved when comparing indirect video versus direct laryngoscopy with the primary outcome of being first attempt intubation success. So the study was performed.
in September 2021 through November 2023 at a large university hospital in Dublin, Ireland, informed consent was obtained from families in the cases of anticipated premature birth or congenital anomalies requiring intubation. Otherwise, consent was obtained at the time of randomization or deferred in case of emergent intubations. Their enrollment criteria were neonates of any gestational age who were intubated in the delivery room or the neonatal intensive care unit.
With the majority of those babies, 71 % intubated in the NICU. Once they made the decision to intubate, a sealed envelope was opened and these infants were randomized one-to-one to indirect intubation with a video laryngoscope or direct laryngoscopy. The infants were then stratified also by gestational age being less than 32 weeks or greater than or equal to 32 weeks. And the study team excluded infants if they had upper airway anomalies. A member of their research team attended all of their intubations and collected their data in real time.
At the beginning of their NICU rotations, trainees were provided education on both direct and video laryngoscopy by the trial team, and they had the opportunity to practice with mannequins. The first attempt provider was usually a resident or a fellow and was predetermined before their senior provider opened their randomization envelope. And trainees were allowed up to three attempts before their senior provider would take over.
Similar to other studies, an intubation attempt was defined as any time the laryngoscope entered the patient's mouth, regardless of whether an endotracheal tube has passed, and no direct coaching was described during the intubation. The video laryngoscopes they used in the study were the Karlstorz C-Mac, and prior to that study, they described a low less than 10 % baseline rate of use of video laryngoscopy.
Pre-medication was not used in their delivery room intubations, but pre-meds were used prior to any NICU intubation where time allowed. And the medications they used were atropine, fentanyl, and succinyl methonium. They used standard intubation tools, including uncuffed endotracheal tubes. Stylets were used at the discretion of their clinicians, and no supplemental oxygen was used. Crossover to the non-randomly assigned device was discouraged, but it did occur.
Data for 214 infants were analyzed with 107 infants in each laryngoscopy group. With respect to their practice and provider variables, baseline characteristics were very similar between their two groups, including gestational age, birth weight, the type of delivery, infant sex, percentages of singleton versus multiple births. The vast majority of the babies were intubated in the NICU, and all of the infants that were intubated in the unit, 97 % of the babies
in the video laryngoscopy group and 98 % in the direct group received pre-medications with nearly all of these infants receiving a paralytic. The majority of the infants were receiving nasal continuous positive airway pressure, so nasal CPAP, with an FIO2 approximately 65 % at the time of randomization. First attempts at intubation were made by doctors in training and pediatrics who represented 63 % of their intubations in the video laryngoscopy group compared to 64 % in the direct group.
Neonatologists comprised 8 % of intubations in the video laryngoscopy group and 3 % in the direct group. And the remaining intubations were made by doctors in training in neonatology who were analogous to US NICU fellows. And they will intubate about 20 to 40 neonates during their training. They represented about 29 % in the video laryngoscopy group and 34 % in the direct group. For the primary outcome of first attempt success,
First attempt intubation success occurred in 74 % of neonates in the video laryngoscopy group and 45 % in the direct laryngoscopy group. These results were significantly different with a p-value of less than 0.001. They had secondary outcomes pertinent for a lower median number of attempts in the video laryngoscopy group, one attempt versus two in the direct group, but longer median length of time until successful first attempt of intubation in the video laryngoscopy group.
The lowest oxygen saturation and lowest heart rates were both slightly higher in the video laryngoscopy group compared to the direct group. And the team concluded that the use of video laryngoscopy resulted in a greater number of successful intubations on the first attempt compared with direct laryngoscopy. And they suggested that more thought should be given to the training and use of video laryngoscopy. That was such a good review. Man, we should bring you on more often to review papers. That was very...
Concise and very clear. Thank you for doing that. I mean, what an interesting study. Am I right? It's maybe before we even get into the discussion, I'm curious to get your thoughts on what do you think of the idea of... I was interested... It's interesting that they were needing to get consent, right? I feel like we don't really ask for consent when it comes to intubation. And I feel like these are both valid options for these infants. And so it would have been perfectly acceptable, I feel like, to make the decision. I'm just curious. Did you guys ponder that or do you have any thoughts about that?
Yeah, know, certainly plenty of thoughts about that. I think when I consider the strengths of this study, the fact that they were able to perform an RCT and with the forethought of obtaining consent from all of their enrolled participants is really phenomenal, just as you alluded to. And I think the feasibility of doing that in practice
Many of us think of that as a huge barrier to being able to perform such a comprehensive study like this. I think that they did highlight in their manuscript the opportunities to obtain consent before delivery in anticipated preterm deliveries. So those would be situations in which
you would be already counseling the families likely about a NICU stay and have the opportunity to describe a research study that's being performed in your unit. So I think that's a huge value add to this study that they were able to include that in their prenatal counseling. And then they also included the fact that they would forgo consent if there was an urgent, more urgent or emergent intubation. And so I think that they gave themselves the leeway to
perform their study even without informed consent, just the way that you were describing that we think that these are both really valid options for intubating neonates in current practice and that the ability to obtain consent is just truly not always feasible. So I think that they built themselves in a lot of flexibility there and advanced anticipation of intubation needs. And I think what another aspect of this study that's so interesting is that
A lot of times we can see studies like this and even though it's really meant to include babies who are born preterm, the babies are fairly large and mature and you say, how really applicable is this to the real world? But in this case, we can see that the baseline characteristics of these infants was quite impressive and I would say fairly representative of the babies that we all see that do need intubation in the NICU. Any thoughts on that? And then I have a follow up questions about...
follow-up question about that as well. Absolutely. I think to highlight another strength of this study, there are many studies that have tried to tease out and in many cases retrospectively data related to video laryngoscopy use in certain subsets of infants. And historically, it's really appeared in that literature that video laryngoscopy tends to be reserved for older and more mature infants.
And it's interesting to comment on that because different video laryngoscopy tools come in different sizes. We all know that it feels in our hands a little bit different than a direct laryngoscopy blade. And so this study, I think, really was augmented by the fact that because they performed it in an RCT, they were able to really diminish bias.
as it related to their allocation processes and getting sample sizes of the infants that were similar and also baseline patient characteristics that were really quite similar across the board and maybe Ben to just state it outright. You know, in looking at the two groups, the median gestational age at birth was 29.6 in the video laryngoscopy group and 28.4 in the direct laryngoscopy group. So really not describing a study that
was reserving video laryngoscopy for those more mature infants in the mid-30s weeks gestation. And the majority of the infants were intubated in their first 24 hours of life. And then the birth weight for these babies was 1340 grams in the video group and a median of 1250 in the direct group. So still is representative of that sample of babies that we think will need to be intubated in the premature category as well.
Which is also a testament to how far technology has come. I mean, I remember trying to play around with video laryngoscopy early on and the first tools that ever made it to the NICU are very big, very clunky and would have never fit the bill for babies this small. But today, I mean, we have double zero, triple zero blades with cameras functioning quite well that can really allow us to do a pretty good job at intubation. So that's also, I think, a testament to how far we've come. I'm just curious in terms of...
your collective thoughts on this study in general in terms of takeaways that you can bring to that we can all bring to our respective institutions. I'm just wondering, Rebecca, if you could maybe share your thoughts on what do you think are the main takeaway of this study? Because it is a little bit more nuanced than just, yeah, we should just do video laryngoscopy. think there's more. There's a little bit more than that. Yeah, definitely. You know, I wonder if highlighting a couple of the
obvious strengths of this study, but then talking about some opportunities and takeaways from this body, growing body of literature would sort of be natural next steps. You know, I think, again, I can't emphasize enough. think commending these authors for an outstanding and robust study just adds to this growing body of literature surrounding modifiable strategies to augment intubation safety and procedural safety and success for neonatal intubations.
I think the fact that they were able to collect this data and that they had presence of their study personnel at every single procedure that they studied is just representative of their commitment to this work that we just have to emphasize. again, discussing sort of feasibility of performing this study, this was truly a very robust and well thought out study. And then I think, you know, getting into the benefits of the RCT itself to reduce bias just can't be overstated.
think that within neonatal intubation literature, so many studies are trying to tease out, like, what is that perfect situation in which intubations are optimized? And that is not laryngoscopy alone. Just as you alluded to, one might come away from this study thinking, well, let's absolutely just use this. And I'm thoughtful that it's a little bit more nuanced than that. I think the factors that we have to consider are pre-medication practices,
paralytic use, style at use, certain airway bundles, oxygenation, supplementation during intubation, all of these factors come into play. And I think another strength of this study was that it seemed through their manuscript that the type of laryngoscopy was truly their main difference in practice that occurred during this study period. So otherwise they had similar baseline and study period premedication practices, paralytic use, and no other
mention changes in the way that they approach this procedure. And I think that naturally just makes for less potential confounders in the data and the results overall. And I think the emphasis on trainees being the primary personnel in their study who were intubating is really crucial to mention. And I think we should absolutely highlight that as we continue this discussion, because I think that there is just
a lot of literature surrounding benefits of video laryngoscopy as it relates to the trainee because the majority of their first attempt intubations were performed by trainees, either trainees in pediatrics or trainees in neonatology, analogous to our pediatric residents in the United States or neonatal ICU fellows. And I think that there is a lot of literature surrounding video laryngoscopy use in the training environment. We should talk about that a little bit more discreetly.
but not only as it relates to the use of the tool, which is relatively new, as you mentioned, but the coaching and the teaching and the simulation with that tool, and the ability to have shared airway visualization with a more senior provider who's more familiar with neonatal intubation or can coach through the experience. So overall, think in considering this article, we wanted to discuss a couple areas of potential limitations and or opportunities for continued discussion.
One being the contribution and accounting for adverse intubation associated events in this study and other studies. Kind of the other being that incredible value of VL in training programs at the resident and fellow level. And just a third point of touching a little on study design and some crossover which occurred in this study. Thank you, Rebecca. And I wanted to maybe follow up on that point about training because we talk a lot about how difficult it has become.
to train the next generation of neonatologists with intubation considering the dramatic shift that has happened in the number of intubations that we get to perform during training where in previous years we really had the opportunity to intubate many, many more babies, whether it was because of recommendations regarding management of babies with meconium aspiration and so on and so forth. today it's a much...
more scarce type of procedure. it seems that indirect or video laryngoscopy really could provide this tool. Like we were mentioning a bit earlier for coaching and for maybe a little bit of better guidance for new trainees. Can you tell us what is your perspective when it comes to that aspect of the paper itself? Yeah, I think that's a really great point.
talk about for this study. And, you know, it's interesting because I noticed in reviewing the study, you know, they focused really heavily on trainees, which is excellent. They didn't mention advanced practice providers also being involved in the unit. And that would have been an interesting thing to know about the shape of their unit. But there is, you know, quite a lot less opportunities for trainees.
when it comes to intubation. so having a tool like the Video Laryngoscope is really valuable because everyone can learn from it. I will say, from my own experience as a recent trainee and now junior attending, it really gets to something more, it's deeper. It's like the gestalt of teaching a trainee and teaching intubation. When you, as the instructor, when you can't see the airway, when you're helping a trainee work through a direct laryngoscopy,
you might be less likely to give that trainee a couple more seconds to try to get that tube through. And if you're a senior provider, you can see the glottic structures, you've got the laryngoscope in real time, you might be willing to give them a few more seconds to intubate. And that's where I think that concept of coaching is also really important. It's an important part of video laryngoscopy that
It wasn't described in this analysis, but we're seeing more and more evidence exist about that benefit of coaching, teaching, simulation, using the video laryngoscope for trainees. There's a recent systematic review by McKinnon and her team in 2023. They explored video laryngoscopy and direct for teaching trainees, and they found that that
real-time feedback during video laryngoscopy, that's highly effective. so seeing that, having that shared mental model, that visualization with the senior provider or the coach, it can translate into just that improved experience and confidence and even translate into direct laryngoscopy as well.
Yeah, and I think beyond like we can all always give feedback. We can always try to coach fellows through intubation, but the quality of the feedback is really limited when you're looking at this from an outside perspective, just trying to look at the mechanics. And when you see someone trying to pass a tube, you're not really sure what they're doing. If you have it on video, the quality of the feedback you can give is so much so sharper than the feedback we used to give. So I completely agree with that.
And also understanding where, how far into the process are the people we supervise get to, did they get to visualize the cords and so on and so forth. But like you were saying as well, it's such a procedure that's becoming rarer and rarer in the NICU and so many more people. mean, I think just this week we are having a discussion in our unit about respiratory therapists who need intubations to continue their transport credentialing. So it's the fellows, it's the residents, it's the PAs, the NPs and
even the RITs now. And at the end of the day, we as neonatologists, as the attendings, we often are falling by the wayside. And when it's our turn to integrate, we're like, man, I haven't done this in a while. So yeah, think having these experiences is probably better. Any thoughts on limitations of this study or anything that could have been done a little bit better? Yeah, you know, I think one of the things we really wanted to highlight is surrounding the manuscripts.
focus on tracheal intubation associated events. I think that adverse events associated with this procedure are such a critical part of the discussion surrounding safety because there's been a lot of literature and narrative surrounding the fact that success and safety are inherently linked in this procedure. Increased intubation attempts have been associated with increased adverse events, but adverse events can occur
in any procedure, even on the first attempt. And studies have shown that at least one in five intubations has some sort of documented adverse event, ranging from severe issues like cardiovascular collapse or mortality and death, or less severe problems like oral trauma. And so in this study, the team tracked vital signs and other key metrics during the intubation surrounding physiologic stability, like oxygen levels and heart rates during the procedure itself.
They also commented on the need for chest compressions or epinephrine administration during the procedural attempt. They didn't investigate some of the other issues that are reported in neonatal intubation literature, things like pneumothoraces, esophageal intubations with immediate or delayed recognition, direct airway injury, or emesis with or without aspiration. So those would be some things that we noticed that were
a little bit different in this study compared to others. And I think it's very much worth mentioning and noting that 6 % of the patients in the video laryngoscopy group and 5 % of patients in the direct laryngoscopy group in this study had cardiac arrest requiring chest compressions. And then 3 % of the video laryngoscopy patients and 1 % of the direct laryngoscopy patients received epinephrine during the procedure, which I think highlights
how long the chest compressions may have been occurring to require the need for a cardiac resuscitative medication. And then tragically, there were three deaths between the groups before a chest x-ray could be taken. And they commented on that. I think when we were thinking through this, I wouldn't necessarily call it a limitation, but certainly something that we need to highlight because in a 2022 study, which was performed by Dr. Musa and their team,
Out of a large international airway registry entitled NEAR4NEOS, which is run out of CHOP, there was an analysis of data from over 2,700 intubations, finding that severe complications like cardiac arrest were really extremely rare in that study, about 0.6 % in the VL group and 1 % in the DL group, and the same number of overall documented mortality as in this study with 214 babies.
So with a much larger sample size in that study with serious events that were quite uncommon, it does beg the question of if there's opportunities for further investigation. I think the current study that we're reviewing today acknowledged that they were likely underpowered to detect signals for adverse events, but the data that they do share does raise some questions of whether there were specific patterns in those infants.
who experienced those more severe outcomes or needed more advanced resuscitation associated with the procedure. And then we would be curious if there would be plans to look at any longer term outcomes for the infants enrolled in their study, particularly with emphasis on those that needed post arrest care. And I think one other thing to mention that was involved in their sort of table three as it relates to
intubation associated events is the time that it takes to perform the intubation itself. And Sarah mentioned this a little bit before. And I think video laryngoscopy in some studies is documented to take longer than direct laryngoscopy, though this has not held true in every publication related to video laryngoscopy. In this study, the median time for successful first attempt was 61 seconds in the video laryngoscopy group and 51 seconds in the direct laryngoscopy group.
And though this longer time necessary for successful intubation and video laryngoscopy might be due to either extra seconds needed or allowed to obtain that best view, and that extra time could also reduce the need for repeated intubation attempts and potentially avoid complications that could be associated with repetitive attempts, it would be important to know if that extra time led to more physiologic instability or increased adverse events. And if so,
that would be a concern that would equally be worth addressing. In their supplementary data, they mentioned that they also studied total laryngoscopy time, accounting for all of the necessary attempts. And in that supplementary data, the video laryngoscopy time was 66 seconds compared to 96 seconds in the direct. And we assume that that is related to the fact that in the direct group, there was
more often the need for repetitive laryngoscopy, so a second or third intubation attempt. So I just think those two things are certainly worth mentioning in this study. Absolutely. Definitely. were kind of joking about this saying that what is the correction factor for seconds during intubation? Because these seconds feel like minutes. And if you have premedication and these babies are a little bit under, then it's even worse because every second you're like, my God, my God.
It may not seem to the layperson that the 10 seconds should be a big deal, but in that particular context, 10 seconds are very, very long, very long duration. And, you know, I think one, you know, one additional comment is that in this study, as I imagine all studies surrounding intubation literature, intubation practices and in real life, there tends to not be one standardized reason or collected data related to when you decide to discontinue your attempt.
And so it's just a little bit difficult to postulate how that increased time to intubate really affects ultimately the infants that were enrolled in this particular study. Because it's every provider, likely every supervisor has a little bit of a different threshold of when they advise a trainee to discontinue or stop an intubation attempt. And Sarah alluded to just how much more nuance that gets when you are not able to visualize the airway with the trainee.
Yeah, for sure. Thank you both for this comprehensive review. Any parting thoughts on this paper before we close out this EBNEO segment? If anything, this is an amazing study that's going to pave the way to more data being looked at and I think maybe setting up a framework for looking into this modality further in the future, maybe in even smaller infants and so on and so forth, especially as we said, as the technology allows for as the technology allows for intubation of smaller infants. I think, and I think too,
incorporating a little bit some of also the new evidence. I mean, I know the authors do mention this, that they did not deliver oxygen or any form of other types of supplemental pressure or oxygen during the intubation, which was already presented in other studies, specifically in the New England, as probably beneficial during these resuscitations. And maybe these could help mitigate some of these adverse events. So I think all that is very exciting because there's a lot of potential. And I think if you are a trainee, this is an area that you could definitely dive into.
And I wanted to, again, highlight one of the groups that you mentioned, the Near4Neos group that does tremendous, that they do a tremendous job at really trying to create this collaborative and this big data set for intubation to try to understand the procedure better and get better outcomes for babies. So you can Google them and they're pretty available and ready to collaborate. So Near4Neos is a good team. Sarah, Rebecca, thank you so much for making the time and for a great commentary. We wish you best of luck and thank you for being on the show. Thank you.
The Incubator (1:00:36)
Okay, so we are here today with Dr. Brett Manley. We were just saying off air, Brett, that it's been a while and we have been meaning to have you on the podcast. And so it's so exciting for us to finally welcome you to the Incubator podcast. thanks for having me, Ben and Daphne. It's been terrific watching everything you've been doing over the last few years. And it's great to finally be here and get to chat with you. Yeah, the feeling is mutual and we sure just talking about this.
off air where you just started a new position. So you are now a professor director of newborn research at the Mercy Hospital for Women. Congratulations. thank you. I was moved across town from one big center to the next, but the move was for all the right reasons. And I've got the opportunity here at the Mercy Hospital for Women in Melbourne to really build up the research program in the neonatal space. And I'm really excited to do it and get some trials up and going.
I'm sure, I'm sure. while we are on the congratulatory phase of the conversation, congratulations on the publication of the study we're going to talk about today. You published, I mean, it's now been, I would say a week, two weeks ago, this paper in JAMA called Intratracheal Budesonide Mixed with Surfactant for Extremely Preterm Infants, the plus randomized clinical trial.
And yeah, congratulations on getting that over the finish line. I know it's been a project, a big project for you. we've it. It's a long awaited trial for the community. That's for sure. Yeah. Yeah. Well, thank you. mean, the congratulations, of course, and we might end up talking about this go to what is a huge team across the trial. mean, for people running trials, they know just how many people it takes and how much commitment it takes. And through the middle of COVID and all the rest of the challenges that we faced with this trial and, and,
So it's great to finally be seeing the results in print. But you know, it's seven or eight years of work and maybe this isn't the most efficient way to do clinical trials in neonatology. What comes to that? Well, come to that. I mean, I think I have this feeling sometimes as I read papers, I go through a paper. I would say it takes me like now 20 minutes probably to just read through an entire study if I really sit down and I don't try to get distracted. But you read this and you're like, man, I went through in 20 minutes a summary of what
these investigators years to put together. feel almost like I'm robbing them. It's true. We'll talk about this in the study. I'd like to start getting right into it basically and talk about the study itself. You open up the paper really mentioning some of the great work that has already been done in this subject, some trials reporting the use of budesonide mixed with surfactant.
And really the great promise that these original papers had with a pretty significant reduction in the combined outcome of death or BPD. even showing potentially that at about two, three years of age, neurodevelopmental outcomes are also improved. so you take, obviously we always stand on the shoulders of giants. You take this work and you try then to, with the PLOS trial, to assess the use.
of budesonide mixed with surfactant in really a population that we're always so interested about, these extremely preterm infants, very small gestational age, very small birth weight. Can you tell us a little bit more about how the idea to take on this study came about? Yeah, and it's so important to give credit where it's due, this is not our idea. There have been some terrific scientists and clinical trialists looking at this for quite a few years now.
And I guess the most prominent trials that have been out there are those led by Professor Ye in Taiwan. And there's been two published trials and another that's been presented at several conferences and we're awaiting its publication. And as you say, Ben, they really showed dramatic reductions in BPD, seemed to have much more of an effect on BPD than it did on survival. Although they all had the composite primary outcome of death or BPD or survival free of BPD, whichever way you like to think about it.
So, you know, those couple of published trials have basically shown a one-third to half reduction in BPD. And as you know, if that was replicated in larger clinical trials, that would pretty much revolutionize the way we look after our extremely preterm infants because BPD is such an ongoing problem that's not only not going away, it seems to be increasing because of the larger number of small babies that are surviving. even before those clinical trials, there's
been a, and during there's been a large body of preclinical work done. looking at this combination of Budesonide and surfactant with different types of surfactant, but with similar concentrations and doses of Budesonide. And they've all been super promising as well in animal models. So there really was a strong biological and clinical rationale for undertaking the plus trials. So that was the background we had to it. And there's even been more.
smaller studies published in the intervening years. And there's a couple of systematic reviews out there that I think include more than 10 trials, all of them underpowered for the types of outcomes that we're interested in, but nevertheless, a huge amount of promise in what's out there already. Yeah. studies come out, obviously some people are going to take up the practice and then obviously they create a little bit of a track record of use and then they try to look back and see some of these results. But again, nothing compared to the trial.
that you've undertook this time around. So obviously this is a multi-center, double-blind, two-group parallel randomized clinical trial that basically you had to coordinate over 21 NICUs in four separate countries, mostly in Australia, five in New Zealand, and one in Singapore and one in Canada. I think one of the biggest important...
of the study is that like we said earlier, the illegible infants that you included in the study. So these were infants that were born before 28 weeks of gestation that were less than two days of age and that either were receiving mechanical ventilation, non-invasive ventilation, and basically there was a decision that was made to provide surfactant. You excluded babies that obviously I think we would all agree with had prior treatment with some form of
postnatal steroids for the prevention of lung disease or where survival really was not thought to be in the cards for these poor children or babies that needed to be transferred or other major congenital anomaly. Can you walk us through a little bit what the intervention itself looks like and what were the intervention group and the control group exposed to?
Yeah. And you've really laid out there one of the important principles that we went into this trial thinking about when Omar Kamlin and I were designing the methodology, we really wanted most extremely preterm infants to be eligible for this trial. So really with that list that you've just read through, apart from babies that were thought were not going to survive very long at all, most babies were eligible. Really the only ones that definitely weren't were the babies that were too good. These were the
The 27-weekers, maybe the odd 26-weeker who was doing really well on CPAP or non-invasive support and the clinician didn't think they needed surfactant. Now that's a whole other story whether you think all extremely pre-term babies need surfactant or not. But nevertheless, there were a few hundred babies in that more mature end of the scale that never became eligible for the trial. But we thought it was really important that most of the sicker, extremely pre-term babies could be in the trial.
And hence we made one of the most important decisions in the trial design, which we can debate, which is we allowed babies to remain eligible for the trial, even if they'd received surfactants, such as in the delivery room or in the first hour or two after arriving in the NICU. And there hadn't been the opportunity to obtain prospective consent yet. Yeah, that's a very important point that obviously you mentioned several times throughout the paper. And that again, goes back to trying to include as many babies as possible.
So just to clarify, basically a baby that needed to get a dose of surfactant could be eligible even if it wasn't there first, basically. That's right. So if they'd had a dose, for example, in the delivery room, they were assessed ticks to 12 hours later. And if they were still on a mechanical ventilator or if there was a decision that they needed another dose of surfactant, they could be randomized and enrolled then. And so that's really important to understand and is a contrast to the other trial that will be coming out hopefully in the next little while.
the BDS night in babies trial run out of North America by Dr. Ambal. And the really good distinction between our plus trial and that North American trial is that in their trial, only prospective consent for the first dose of surfactant is used. So this is a big trade off with all of our neonatal trials, isn't it? It's generalizability and getting a truly representative sample of infants into the trial. And if you make it too hard to enroll infants,
All that happens is you miss out on all the sicker and maybe all the wellest babies and you get a quite distinct sample of babies. And we've seen this a lot in our neonatal trials that the sicker babies tend to miss out on the research. So this was the way we decided we could get the sicker babies into the trial. But of course the trade-off there is that if we were to use this intervention in real life, we would presumably mix the Budesonide with the first doses surfactant and give it to the babies.
So it was about half and half of the babies in our trial had had a prior dose of surfactant or hadn't. So I guess, and we've been able to look at that as we'll get to with our subgroup analyses, but that is an important distinction to make. And I think that's such an interesting point. So obviously we've got a lot of early career NEOs, we've got a lot of trainees who listen. And so when people are thinking about study design, I mean, maybe you could just give us a sidebar about like how that discussion went, how your group
you know, went for making that specification in the protocol. Yeah, and I'm sure we didn't get it right, but I think there's some really important principles here. This is sort of opinion based now, but I think it's really important that we limit the number of exclusion criteria in our trials. We want real world scenarios. We want the sickest babies in our trials. And to take that to its greatest extent, please don't exclude the smallest babies from your clinical trials. You know, as you both know,
We have a long history of babies at 23 or 22 weeks not being included in clinical trials. Now that's obviously become a lot more relevant in the last few years as we're seeing more and more of these babies being offered intensive care. But we simply must get the evidence for how to look after these babies and we can't be excluding them. and at the other end, think about why you're excluding babies if they've got certain other criteria. Now there might be obvious ones such as non-survivable or unsurvivable.
lung disease or severe congenital anomalies if you know that that's a different group. But really try and get all the other babies in and try and limit the number of exclusion criteria because we really need to get good real world evidence for how to look after the sickest babies. Very interesting. And so the babies basically in the intervention group received one or two doses of Budesonide at a dose of 0.25 milligrams per kilogram mixed with surfactant.
And obviously the control group received surfactant alone. Interestingly enough, in the methodology is that you had the opportunity to deliver surfactant in a variety of methods. Obviously for babies that were on mechanical ventilation, the installation of surfactant through the endotracheal tube is a no-brainer. But for those who were on non-invasive, you had the opportunity of doing INSUR, which is intubation, surfactant, and extubation, and kind of less invasive surfactant administration with thin catheter. I think this is also kind of very innovative as we are.
doing these studies to have all these different modes of delivery still available as some of them carry potential ramifications on the outcomes, especially the ones that we're looking at in this paper. Yeah, absolutely true. Less invasive or minimally invasive surfactant administration is very common in this part of the world and increasingly common around the world. We certainly didn't, again, want to exclude any babies receiving less invasive surfactant.
Ultimately, it was about 15 % of the population for their first intervention had it via a thin catheter technique. So, you know, not a huge amount or a majority. A lot of these babies were intubated and ventilated, but nevertheless, a good amount of babies. If they needed a second intervention, it was interesting to see that most babies by then received a second intervention down an endotracheal tube rather than a thin catheter. But there were some babies that had more than one dose of the intervention via a thin catheter.
interesting to see how practice changes. I certainly administered a few of the doses myself down at a thin catheter and some of the bigger babies. So no reason not to do that. As long as it goes in the right place, we think that it should work just the same. so these babies are randomized and the primary outcome of the study is survival without physiological BPD. I think it's interesting because you have sort of a hybrid definition of BPD there, which
looks very similar to the Jensen 2019 criteria, but it's not exactly that criteria. You have some potential criteria that involve the level of oxygen support the baby is receiving. So can you tell us a little bit about the primary outcome and how you guys measured or defined bronchopulmonary dysplasia in that case?
Yeah, I think it's, mainly at the bottom end of the scale where the differences might be obvious. And these are the babies that were sort of on low flow or ambient or other types of oxygen, but nearly always these were low flow, cannula or binasal cannula receiving low flows of oxygen. I think it's really important to be sure when you're doing big trials that these babies actually have an oxygen requirement. so we used a physiological or air reduction trial or a modified Walsh trial, whatever, assessment, whatever you like to call it where.
babies that were on little oxygen, we actually turned it down to see whether they could maintain their saturations off the oxygen. And there were some babies that were subsequently shown that they didn't need any oxygen and others that clearly did. Not presented in the paper and it will come out in subsequent analyses, we also undertook something called a shift test, which is looking again at sort of the oxygen hemoglobin dissociation curve of these babies and trying to place them on a curve.
be interested in looking at that test over the coming months to see whether that was predictive of lung disease or not. But that's sort of a side thing at the moment. But otherwise, yeah, the diagnosis was mainly based on the requirement for respiratory support in the 36th week and we kept it to that exact 36th week of post-mental age. we were, know, BPD we could talk about forever.
I think BPD at 36 weeks is on the way out for several reasons. And you'll note that in the paper, we therefore also tried to sort of provide some insurance by looking at outcomes at 40 weeks of post-menstrual age as well, and also important things like home oxygen requirement that matter to parents. I have to find that paper and post it in the show notes. There's that great paper. think Eric Jensen was on it where they looked at the predictive ability and defining BPD at 40 weeks is so much better. And then when you think about it, how many kids do we have?
that we know by 40 weeks are going to be fine, but at 36, it just happened to be categorized already. So I agree with you that, yeah, the definition of BPD is always such a tricky thing. Usually when we do these reviews and we don't have always the privilege of having the first author on, what's interesting, I try to make the review of the statistical portion cursory and I'm really afraid of putting people to sleep, but I wanted to talk to you about this because I was hoping we could geek out a little bit on this because
When it comes to the sample size estimation and the statistical analysis, think that one of the things here that played a crucial role is basically the estimate of BPD free survival and how what was potentially thought to be a reasonable number turned out to be a bit off the mark, which is so interesting because it goes to show a little bit the state of affairs in NICU and maybe the prevalence of BPD that we may be on. Can you tell us a little bit about how these calculations came about?
you guys settled on this original number of expecting 50 % outcome and then what was your reaction when you actually saw the results that we'll talk about in a second? Yeah, thanks. So when we designed the trial, most of the randomized trials and even the population sort of cohorts out there were saying that the incidence of death or BPD or survival free BPD was around 50 % in extremely pre-term babies. Now, of course, that includes all extremely pre-term babies or at least all babies that were enrolled in other trials and they were
some trials of things where more of the well babies would have been included. So what we've done is ultimately enrolled a very high risk population and a very immature population of babies into plus, which we're very proud of. But the offset to that, of course, is that the incidence of death in BPD were much higher than we predicted.
But I also think it's not just that we enrolled the smallest babies. I think it's just a true estimate of what's happening with these babies now. As soon as you have lot of 23, 24, 22-weekers enrolled in trials, the incidence is higher than we think it is. certainly seen similar incidents as a BPD being reported now in other trials. And of course, again, it all depends how you define it and when you look at it and all of those things. But certainly we weren't that surprised.
to see that the incidence was more like 75 % for survival for death or BPD in our trial. And what that did for our sample size, I mean, if you think about it just in absolute risk reduction sort of terms, then it gives us more power with the sample because the incidence is higher. If you think about it in more relative risk terms, it reduces the power. But regardless, given our results, I think we've ultimately ended up with a fairly strong answer.
even though the incidence of BPD was much higher than we originally predicted. Yeah, and that's what I wanted to sort of ask you to go back on just for the people who are interested in study design. mean, we just want to take advantage of having you on. But like, what exactly are the implications of either underestimating the prevalence of the outcome you're looking at versus overestimating and what that does to the power of a study, depending on which mistake you've made?
Yeah, well, that's right. It does depend a little bit on which mistake you make. I mean, if the incidence of your primary outcome is 50-50, as you move away from that and the incidence becomes either more common or less common, it can increase your power to find smaller differences in terms of the absolute difference between two groups. But if you start to think about it in relative risk terms, which is more about comparing the proportions,
then you lose power. since most of these babies now are going to be in that category, it's harder to tease them apart. Basically. Exactly. So, so w you know, we powered our trial for a 10 % absolute difference between the groups, i.e. 50 % in one group, 60 % in another group. and that was the smallest difference that we could find with the power that we had. And we could even argue over whether that's small enough. think,
The prior trials had shown a much greater difference between groups. And so we were aiming to find a smaller clinically important difference. And it's really important that when we design trials that we do start with what do we think will actually change practices? Would a 1 % difference change practice? 10%, 50%. And then work your way backwards. Of course, that's all offset by the feasibility of conducting trials. And you can see how big we needed over a thousand babies to find a 10 % difference.
with an estimated risk of 50%. And, you know, in some cases, it's simply not feasible to do trials that big, especially when you're talking about extremely preterm babies. So you can get caught out, but I do feel strongly that we need to be powering our trials to find what are clinically important practice changing differences. Otherwise we're never going to get the answers unless we put them all together and meta-analyze them and there are issues with that as well. Yeah. Seek the clinically significant finding, not the statistical significant.
It's easier said than done, isn't it? And I know of Cortland, of course. But that's what I think we love about your work. You really have, you strive to have really, what I would say is clean data, right? You're really, really working hard to say like, are we asking the right question? Do we the right groups? You know, are we making the impact that we hope we will have? Which is what we would hope.
for everybody doing research in the community. I really thought of you for that. the question is driven towards meaningful change at the side always, is pretty- Much appreciated. Yes. Very Well, we should have to accept that we work in a really challenging field in terms of creating evidence when you've got such a limited number of the highest risk infants and mothers and
And we're limited by outcomes, you know, using outcomes like mortality is really tricky in high income countries where it's not frequent enough or, know, those researchers looking at necrotizing enterocolitis. So you could pick almost anything where the incidence is quite low and it makes it really challenging to do research. And we just have to acknowledge quite simply that we all have to work together or we're not going to get the answers to these things. And so that's certainly where I like to try and focus my energies, but also thinking about how we can be more efficient. Like even though I've
You know, we've just done this trial and it's great that it's finished, but it took seven or eight years. got one answer. It was no difference between the groups. So now we go back to the drawing board. And of course, you know, as soon as the trial comes out, people email me and they say, what about a different dose of budesonide? What about giving it earlier? And that's absolutely true. But if we're going to do trials for each one of those questions, it will just take forever. And we need to be thinking how else we can do things.
Yeah, what's interesting about hearing your thoughts is that every time you make a decision when it comes to trials, like pulling on this on the string and then something else gives basically, and you're never able to get everything you want. something else unravels for sure. So the results are very interesting. You have a final sample of 1,062 infants.
you have an intention to treat population of 1,059 infants, 524 in the BDS9 and surfactant group, 535 in the surfactant only group. The baseline characteristics are also very interesting. The mean gestational age is 25.6 weeks. The mean birth weight is 775 grams. Interestingly enough, a lot of these babies were exposed to antenatal steroids, I think 95.6 % in the intervention group, 96.3 % in the surfactant group.
That didn't mean that they all got exposed to a full course of antenatal steroids. We know how the delivery of these extreme preterm babies is. Sometimes it's very unexpected and rushed. So about 65 to 67 % of these babies in both groups ended up completing the course of steroids. And as we discussed before, since babies were eligible to enter the trial on their second dose of surfactant,
a significant portion of them, 57 % of the infants received surfactant treatment prior to randomization. In terms of the primary outcome, I would like to start discussing that because I feel like we're going to run low on time. The primary outcome, we were looking at survival free of BPD.
and the difference between the two groups did not reach statistical significance of 25.6 % in the intervention group versus 22.6 % in the surfactant-only group. I'm wondering if you can walk us through the result, and specifically also touching on this post-hoc analysis, which I think was very interesting and maybe giving us a glimpse into
other future directions for this type of study. Yeah, thanks. And so that's sort of three percent-ish difference between the groups in the primary outcome. guess one question for us all to ponder is if there was a three percent difference in that outcome, would it change practice? I'm not sure that it would routinely change practice with that magnitude of difference. You'll also note that the results are presented as risk differences and 95 percent confidence intervals. Most
journals and statisticians are really moving away from P values and they really want us to present the true differences and the confidence intervals around those with our results. so that's an important thing to take away from the paper as well. So we were obviously super disappointed for the babies with this result, given everything that had come before. you know, I remember when I got the result, just how disappointed I was, but
I think it's really important to always ask yourself, well, despite them being secondary outcomes, there's pre-specified subgroups that we would be interested in, especially again, given the results of previous papers. There's evidence out there that steroids in whatever form may be more beneficial to babies exposed to chorioamnionitis, to babies who are small for gestational age or fetally growth restricted, and some sex differences as well. So we knew we wanted to look at those things.
And we had a look at all of those things. And again, somewhat disappointingly for the babies, there's really not a lot going on in any of the subgroups we looked at, including between gestational age groups. So the smaller or more immature babies versus the more mature babies, no difference. And whether they were exposed to surfactant or not, no difference prior to being enrolled in the trial, I should say. And whether they were on mechanical ventilation or non-invasive support, no difference. So that was not particularly helpful.
Interestingly, through the editorial process and the review process, there were questions raised about the differences between our population and the population enrolled in the previous trials by Yay and colleagues. And whilst we enrolled smaller, more immature babies and lots more of them, in the Yay trials, the inclusion criteria were that the babies were in quite a lot of oxygen at the time that they were enrolled in those trials, up to 50, 60 % oxygen and mechanically ventilated. And so.
They raised the question, even though we hadn't pre-specified this analysis, of whether oxygen requirement at randomization might be important. And so as you can see in the paper, the last tacked on subgroup analysis is about the fraction of inspired oxygen at randomization. And in fact, there does seem to be a bit of a signal there in terms of the fact that the budesonide seemed to maybe have more benefit in babies in more oxygen early in their life at randomization.
We just need to be super careful about that. We didn't pre-specify it. It's a subgroup analysis. The numbers are what the numbers are in terms of the babies in each group. There's not a lot. And also the statistical test for interaction there is not quite significant. I think the p-value is 0.07, something like that. So indicating that there's a signal there, but not a definite one.
So it just is a hypothesis generating is all I would say about that particular outcome. But maybe there's something in it that the babies who seem to have worse lung disease, more oxygen requirement early in life may be ones to benefit more. So look, we're really interested to see the North American trial results whenever they come out to see how that might change any of this. Certainly keen to put our data together with theirs. And we've already been talking about that.
to make sure we don't miss any subgroups in whom Budesonide may benefit. Yeah. I think it's so interesting what you're highlighting. We talk about this all the time that there are these different like phenotypes of babies. It's not just gestational age. It's a combination of the prenatal factors, the birth history, the individual baby — you know, sepsis, infection, inflammation. And it's hard to study
the different groups of babies. It's almost like we haven't even totally outlined the different types of babies that there are that we care for, that we're trying to treat all with the same stuff. And there'd be a lot of people out there right now going, my gosh, I totally agree with you. And there's some very clever people looking at phenotyping preterm babies and lung disease. There's a group here in Australia led by David Tingay that's...
interested in doing that. I'm sure many other groups around the world and you're right, that might be more part of the answer. Of course, we're still left with a huge challenge, which if you narrow things down further and further and further to the group that may benefit, that's terrific. But then to get the evidence in that limited group of babies becomes exponentially harder because of the numbers. So there are challenges either way. is like pulling the string, isn't it Ben? know, something's got to give, but you're absolutely right. I don't for a second, you know, say that every baby in the plus trial was equal.
and no doubt there's some babies in there that personally may have benefited from budesonide and some that didn't.
Yeah, but it's always so interesting to me because it is through the work that you do that other investigators are doing that we are getting a glimpse into the potential, like this discussion about, maybe there is a different phenotype and it's only through this work and through these results that we do learn. So, I mean, I'm really appreciative of all the work that goes into it in order for us to acquire more knowledge. And so, I mean, obviously we're coming to...
We're coming to the end of this conversation. But I don't really have anything else to add except that the paper is really worth a thorough read because it's always very transparent into the process that went into the research itself. I think if you are an amateur like me, you will learn a lot of things about research methodology. And I think that it is very interesting.
to look at the data granularly and look at the potential different signals that might be there, might not be there. Because again, this is the frontier of neonatal medicine right now. And yeah, thank you. Thank you for this great work. Do you have any parting thoughts on what does the future hold for Budesonide and surfactant? I know you mentioned, I think the North American trial is the BIB trial. Is that correct? Like the IB trial? Yeah.
But aside from that, any other thoughts about what might be coming next or what might be looked at in future studies? Well, in terms of Budesonide, like I say, I think we really need to see these results replicated just like we needed to see the results of prior trials replicated. Unfortunately, we haven't seen that with this larger trial. I've had questions about giving Budesonide earlier.
higher dose more frequently, they're good questions. Can we personalize this medicine a little bit better? We've thought about whether Budesonide given intra-key could be useful in babies with established BPD, which is an entirely different question. The baby you're really struggling with stuck on the ventilator, you're thinking about systemic steroids, is there any role of intra-key or Budesonide? That's an interesting question. Probably for someone else, I don't think I've quite got the energy for that one. But I might leave you with just again, stressing to everyone,
I think we really need to work together internationally to answer these questions, but we also have to think about how we can work smarter and more efficiently. These trials take forever. They're extremely expensive. They answer one question at a time. Something we've been really interested in Australia is the use of the adaptive platform trial methodology that's been used very successfully in other fields like cancer research and even during COVID. And we've been looking at whether we can
be looking at more than one question at a time and adapting the results once we have answers within those to move on to the next question or the next dose or the next intervention. And so I think that adaptive platform trial type of methodology is extremely promising and something we're trying to get up and going in Australia and New Zealand with the platypus trial.
You know, it's not easy again, these trials are a huge amount of work from a huge number of people. cost a huge amount of money, but we just need to be thinking how can we do it better than one trial at a time, one question at a time. And this potentially has the promise of delivering more information to the bedside faster, right? mean, which is ultimately the goal you set out for yourself. Exactly. think part of a big part of things like adaptive platform trials or any platform trial is
is the value add around it. So the ability to immediately trans, put, put new evidence into practice at the bedside, for participating centers and babies, but also, you know, lot of the other methodology that can go along with the infrastructure for such platforms, like statistical expertise, health economics, consumer input, all the sorts of things that, you know, you have to set up once at a time, every time you do a large randomized trial. But if in developing a platform that
has ability to adapt and translate into practice more quickly. Maybe there are lot of other efficiencies that can be built around such things as well, but perhaps a topic for another time because I can talk about that for hours. Yeah, we'll bring you back on to discuss that. It's very exciting. Brett, thank you so much for making the time to review the study with us. Congratulations. It is impressive work. It is done so well.
For people who are doing research, the ability to conduct research so neatly is beyond the skill. It's a talent. And we really recognize that in you. So please, we're looking forward to your next paper. Thanks so much for having me. It's been an absolute pleasure. Thank you.
Ben Courchia MD (1:35:23)
OK, this was great. Another great work from Brett Malley. I mean, I'm kind of jealous of Brett. If you go in PubMed and you type his name, like he has his name on such great studies. And he is so young. And you're like, man.
The Incubator (1:35:29)
Sure.
Hmm.
Ben Courchia MD (1:35:39)
He's really crushing it. So it's an honor to have him on the podcast and we wish him the best of luck on his new position. I think we're going way over time today as it is. I have one sort of small study that I found in the Journal of Pediatrics that I wanted to mention because the title sort of was appealing and I read it. I'm like, going to talk about this. It's published in the Journal of Pediatrics and the title is Chorioamnionitis and Two-Year Outcomes in Infants with HIE.
The Incubator (1:35:44)
sure.
you
I see. Mm-hmm.
Ben Courchia MD (1:36:09)
The first author is Marie Coralie-Corne, which I don't know if she's French, but she has a very French sounding name. And there's a lot of, it's a who's who this paper, Hannah Glass is on it, Sandra Jewell is on it. So it's a who's who of the HIE world and neonatology world. The background is interesting. It talks about chorioamnionitis, basically the inflammation of the placental membrane. does increase the risk of HIE and the likely mechanism there is...
reduction in the fetus' ability to tolerate the hypoxic ischemia during labor and delivery. And that's about 10 to 30 % of infants with HIE have a history of exposure to clinical chorioamnionitis. Now, it's going to be very important for us to make sure we talk about these things carefully because we have clinical chorio and we have histologic chorioamnionitis, which is basically defined as finding chorioamnionitis on placental pathology. Now, when it comes to histological chorio,
They're saying that the incidence in infants with HIE does vary between 10 % and 60%. So basically, it's all over the place. Now, studies they mentioned have shown that fetuses exposed to clinical Chorio are at an increased risk of adverse neonatal and long-term Neurodevelopmental outcomes, right? That's just straight up Chorio . And so what's interesting to them is that they're asking, does chorioamnionitis increase the risk of adverse Neurodevelopmental outcomes in infants who have moderate or severe HIE?
who are receiving therapeutic hypothermia? So I thought that was a very interesting question. And so this is a secondary analysis of the infants who were enrolled in the HEAL trial, which we reviewed on the podcast before. It's the high dose erythropoietin for asphyxia and encephalopathy trial. It's a big study. mean, I'm sure you've all heard about it. It's a multi-centered, randomized, double-blind placebo control trial that basically tested the use of EPO for neuroprotection in babies with moderate to severe neonatal HIE.
They included infants who basically met the criteria for cooling above 36 weeks of gestational age, had a history of perinatal depression defined as agars of less than five at 10 minutes, a need for resuscitation at 10, a pH of less than seven, or a base deficit of over 15 within the first hour of age. They also included a Sarnath exam and the reception of therapeutic hypothermia.
exclusion criteria are fine. There's a hematocrit value for the EPO components, but otherwise they'll go straight forward. So the primary outcome of this study was at two years between 22 and 36 months of age to look at whether babies developed either no neurodevelopmental impairment, mild, moderate, severe NDI, or death. Now the degree of neurodevelopmental impairment NDI was defined as
The worst severity of the cognitive or motor outcomes as they had previously described, they're using the Bayley third edition for the cognitive scores that they are categorizing as normal. If you have a score above 90, mild, 485, 29, moderate, 70 to 84, severe, less than 70, they have a validated standardized neurological examination for the definition of cerebral palsy. And then they have motor impairment that they defined as mild, moderate, severe, depending on the presence or absence of CP or ability to walk a certain number of steps, cetera, et
So what are some of the results? So of the 500 infants that were enrolled, 13%, 65 were exposed to clinical chorioamnionitis. A total of 317 infants, 63 % of the entire cohort, had available placental data. So when they looked at the placenta of these 300 infants, they found that 39%, 125 infants, had histologic chorioamnionitis, and 42 % were
in the end. So in the end, % of the cohort, 42 % of the 317 cohort were diagnosed with actual chorioamnionitis, whether it was clinical or histologic. So they have basically divided the variable into these three. You either had clinical, histologic, or just any chorioamnionitis. So among the infants with placental data available, the presence of clinical
was accompanied by a diagnosis on placental pathology in 84 % of cases. So it's interesting to see that relationship, right? Both the infants who were exposed to clinical Chorio and those exposed to histologic Chorio were more likely to be born to mother and to be exposed to rupture of membrane for more than 12 hours, which is of something that we expected. So among...
The Incubator (1:40:31)
Mm-hmm.
Mm-hmm.
Ben Courchia MD (1:40:51)
480 infants, the 96 % of the cohort that had two-year follow-up data, 236, about 49%, had no Neurodevelopmental impairment, 12 % had mild, 13 % moderate, 12 % had severe, and 13.5 % had died. So this gives you an idea of the spread of the original data. Now, what they found was that both the presence of clinical chorioamnionitis and the presence of histologic chorioamnionitis
were associated with lower rates of adverse outcomes. Almost like it was better to have. That's great. I was very afraid. So we'll talk about that. So infants exposed to clinical chorioamnionitis had less evidence of brain dysfunction as evidenced by lower severity of EEG background abnormalities and a lower frequency of central pattern of MRI brain injury compared
The Incubator (1:41:26)
no.
It's very confusing.
Ben Courchia MD (1:41:46)
to the infants who were unexposed to clinical chorio. Infants exposed to clinical chorio also had a decreased risk of severe encephalopathy and a higher mean base excess than the unexposed infants, but no significant difference in their needs for resuscitation or end organ injury. Now similarly, looking at the other types of chorio, the histologic chorioamnionitis, the infants had lower severity of EEG background abnormalities.
compared to the unexposed. They also had less brain injury on MRI as evidenced by lower frequency of central pattern of injury. They had a higher frequency of normal MRI and the infants who were exposed to histologic chorio had a higher mean base excess and a mean pH than the unexposed infants. There was no significant difference in the risk of neonatal seizures between the infants who were exposed and unexposed to either clinical or histologic chorioamnionitis. So it looks like the immediate course while
Maybe the basic success is a bit better with chorio like with clinical chorio may not be dramatically different It really seems like this has better prognostic effects down the road now they mentioned and I think that's important that after adjusting for HIE severity for infant sex and exposure to sentinel events the association between histologic chorio and lower severity of the primary outcome persisted but the association between the clinical one and the lower severity of primary outcome was no longer statistically significant, so really
The Incubator (1:43:02)
Hmm.
Ben Courchia MD (1:43:10)
Again, going back to this idea that our definition of clinical chorio is never really a perfect one, but that histologic chorio was quite sensitive when it comes to that. Among the 317 patients with placental data available, 42 % had actual chorio, whether it is clinical, histologic, or both, right? And the presence of actual chorioamnionitis was again associated with lower
The Incubator (1:43:15)
Mm-hmm.
Ben Courchia MD (1:43:37)
severity of EEG background abnormalities, lower risk of central injury on brain MRI, lower severity of the primary outcome, and after adjusting for the severity of the encephalopathy, for the infant sex, for the exposure to central events, the association between actual coronary amnesties, so any type of coronary amnesties and lower severity of primary outcomes, persistent. So I think that's very interesting. The conclusion by the authors is that in infants with HIE who receive therapeutic hypothermia exposure,
to chorio was associated with lower severity of outcomes at two years. This finding is likely explained, they say, by a lower severity of brain dysfunction seen on EEG and a lower rate of central pattern of brain injury on MRI among infants exposed to chorioamnionitis, a better understanding of how the maternal infection and the inflammation affect Neurodevelopmental outcome in term infants may allow for developing targeted neuroprotective strategies for this high-risk population.
So sorry that we don't have a clear, you wanted the paper to follow up with a animal study that tell you exactly what is the mechanism here, but unfortunately we don't have an exact understanding of how that is. Now, I must say it goes back to the authors are trying to give us some clues in the discussion about like how we should at least start to think about this. And one of the ways that I really liked is that
The Incubator (1:44:43)
Thank
Mm-hmm.
Ben Courchia MD (1:45:06)
They're trying to basically recenter the conversation around neonatal encephalopathy and saying that neonatal encephalopathy, they say, is very heterogeneous. It's a clinical syndrome. we don't really understand all the intricacies of how, are all the possible causes? What are the factors that can play more or less of a role in how the diagnosis is presented to us in the form of a clinical presentation?
The Incubator (1:45:16)
Hmm?
Ben Courchia MD (1:45:35)
And so they're saying that the pathogenesis leading to encephalopathy and to HIE is multifactorial, involving various degrees of hypoxia, of ischemia, of inflammation, and of genetic susceptibility. And that the idea that if you tweak these knobs a little bit, where maybe the genetic susceptibility is not there, but the inflammation is higher because you have chorio, but maybe there's less hypoxia, maybe that's what plays a role in what you see in these infants after birth. But again, they're not committing to a formal...
formal ideology because I think it would be kind of a stretch.
The Incubator (1:46:08)
I don't know, it's blowing my mind right now. I don't know. Does it maybe prime the body to be ready for inflammation? I don't know. It's very interesting. Very interesting.
Ben Courchia MD (1:46:10)
Ha
It's very interesting. And the study is relatively small. It's a secondary analysis. I think this is like, to me, I see this as like a prime sort of study for a group like the CHNC to take on or something where it's kind of a small, like finding the kids who have HIE is already a subpopulation of our NICU thing. Finding the kids who have HIE who were exposed to Chorio is a sub, sub, subpopulation. So you might need to have like a bunch of hospitals that need to get together, share their data to then see if that holds true.
The Incubator (1:46:34)
Mm-hmm.
Mm-hmm.
work together.
Ben Courchia MD (1:46:51)
Yeah. Yeah.
The Incubator (1:46:52)
Well, more to come then, I
hope. Nothing is understand that. I've got another quick one. You said yours was quick, but it wasn't that quick. So, I'll go. And then we'll wrap it up for the day. This one is in the journal of perinatology. It's called somatic growth outcomes in response to an individualized neonatal sodium supplementation protocol. Lead author, Elliot Stalter, senior author, Lindsay Harshman.
Ben Courchia MD (1:47:01)
Hahaha!
The Incubator (1:47:19)
And this was a retrospective cohort study of infants between 26 and zero to 33 and six sevenths weeks gestation. And they were cared for in a unit that began this sodium supplementation protocol. And I'll tell you about that. So they look at these two cohorts of babies, the first between 2012 to 2015. So the babies did not participate in the protocol.
and then those between 2016 and 2020 that were part of the new protocol. The protocol uses serum and urine sodium measurements, and the supplementation is initiated if serum sodium is less than or equal to 132, or the urine sodium is less than the threshold by gestational age and postnatal age, starting at two weeks postmenstrual age. So basically what they do, they have this nice table that has different
thresholds, thresholds, urine sodium thresholds by gestational age and postnatal age. So if you're 24 weeks and you're four weeks old, you have a different threshold than a baby who's 26 weeks and six weeks old. Basically, if any baby drops below either of these thresholds, they are initiated on four milligrams per kilogram per day.
Hold on. I just want to make sure that that is correct. Four MEQs. They have four MEQs per kilogram per day. And then urine sodium was reassessed every two weeks and sodium supplementation was then increased by an additional two MEQs per kilo per day if the urine concentration was still below the anticipated value for the gestational age and the postnatal age. They did give us some insight to their nutrition protocols, which is always fun to discuss.
The nutritional policies were pretty consistent. So I think this is important because they have these two epochs where they, you know, they're a decade apart. So I think that's important to know. But basically they have parental nutrition at birth for infants less than 33 weeks gestational age, they have early utilization and relatively conservative advancement. So about 20 mls per kilo per day of maternal or donor milk.
caloric intake goals of 90 kcal per kilo per day or 120 for parental nutrition or 120 to 130 kcal per kilo per day of enteral nutrition. The goals for protein were 3.5 grams per kilo per day and for fat are 2 grams per kilo per day. Human milk fortifier typically added when total milk volume was greater than or equal to 25 mls per day. In general, they avoid chronic diuretics.
until after diagnosis a BPD was made. And when used, were used chlorothiazide and hydrocortisone, preferred diuretic and preferred systemic corticosteroid when needed. I didn't tell you where this study came from. This is from the University of Iowa. So of course, always nice to see some of their protocols outlined and they use this retrospective EMR data.
So they had 461 infants born between this 26 and 0 7th and 29 and 6 7th weeks. And they had 357 born between the 30 and 0 and 33 and 6 7th weeks gestational age during those cohort time periods.
They did exclude some babies, infants with conditions associated with delayed growth or those where sodium supplementation was contraindicated. So babies with underlying cardiovascular disease, with underlying kidney disease, and they go into these. I'm not going to go into those, but just know that there were some exclusion. They also excluded babies with ostomies, okay?
Ben Courchia MD (1:51:23)
Mm-hmm.
The Incubator (1:51:31)
So after application of the exclusion criteria, like I said, they had these two groups. They had this 26 and zero to 29 and six sevens. They were then stratified into pre-protocol and post-protocol. So they had 157 in the pre-protocol, 225 in the post-protocol. In the older group, the kind of 30 to almost 34 weeks were divided into 153 pre-protocol and 157 post-protocol. And they wanted to look at the growth outcomes, length of stay,
Advert-GAS outcomes, included hypertension requiring antihypertensives, sepsis, NEC, BPD. They also looked at hypernatremia greater than 150 and the requirement of postnatal steroids. So the baseline demographics, there were no significant differences in birth weight, in gestational age or percent of SGA. They used the less than 10th percentile for birth weight identified between the infant cohorts within either gestational age group.
Now into some of the results. So within this 26 to almost 30 weeks gestational age cohort, weight and head circumference at two weeks postnatal age were greater in the post-protocol compared to the pre-protocol infants. Now notably, they would not have had that much supplementation at that time point. There were no differences identified at
Ben Courchia MD (1:52:51)
Hahaha
The Incubator (1:52:57)
at that time between the 30 and the 34 weeks gestational age group. So within the smaller group, more post-protocol infants were exposed to antenatal corticosteroids, that's interesting, compared to pre-protocol infants. No difference in exposure was identified within the older cohort. So more data within this younger cohort, the post-protocol infants experienced significantly increased positive change in mean weight Z scores
between two and eight weeks postnatal age and an increased positive change in mean head circumference Z score between the two and 16 weeks postnatal age periods. The post-protocol infants spent significantly fewer days on invasive mechanical ventilation than pre-protocol infants. And there was no significant difference in length of stay between pre and post-protocol infants in this age group. they did have a little higher weight
weight and head circumference to start, but they had a bigger, a significant increase between this two and eight weeks for weight and two and 16 weeks for head circumference. Within the 30 to 33 and six sevenths group, there were no differences between pre and post protocol infants with respect to weight gain, head circumference, time on invasive mechanical ventilation.
However, interestingly, the post-protocol infants experienced a greater length of stay. Now, when we look at the adverse event outcomes, the use of the protocol was not associated with increased incidence of systemic hypertension, hypernatremia greater than 150, BPD, NAC, or culture positive sepsis in either gestational age cohort. Interestingly, within the lower gestational age cohort, the post-protocol infants were less likely to require postnatal steroids.
There's also an accompanying editorial. So that's something that people can also take a look at. But it's an interesting paper. I think there are some takeaways there. Go ahead.
Ben Courchia MD (1:55:09)
Yeah, I was going to ask you what made you want to review this paper on the podcast. I have some thoughts as well. Yeah, I'm sure this will be interesting.
The Incubator (1:55:15)
Okay, a few things. One, I feel like we're seeing a lot of hyponatremia currently in our unit and the units we've previously worked in. Lots of hyponatremia. And we are supplementing babies now.
we still as a community don't know what the right thresholds are. So that's an interesting underlying question when we evaluate any of these articles. Like we're still not positive about what the thresholds should be for babies. And I like how they have this kind of staged approach at Iowa where it depends not just on your gestational age, but also your postnatal age. Because I think that one day that will dictate a lot of interventions in the NICU because
These babies are such a dynamic system. Obviously, we're looking for all the best ways to improve growth in babies. And this seems like a pretty non-invasive, well-tolerated intervention. So I was hoping that it would show improved outcomes. So that's why I picked the paper. I don't know if that answered your question.
Ben Courchia MD (1:56:29)
That's so, that's, yeah, no, it does. It does. think, because I mean, I think this is a very interesting paper. if you look at the study itself, I don't know if you, like, it's not like a big randomized trial where you can take an intervention and say, like, we're going to take this intervention and roll it out. And it's pretty much been trial-tested. However, it raises so many interesting questions. So the first one obviously is, the first one obviously is,
The Incubator (1:56:35)
Mm-hmm.
course.
Ben Courchia MD (1:56:55)
what are we doing when it comes to our sodium? And how do we think about this from a more holistic standpoint? One of the things you mentioned about this study is that this group does not use diuretics. And so that's a very interesting point. I think that for many NICUs, ours included, the question becomes, are we dealing with hyponatremia because we have these kids on diuretic and we're just trying to basically correct a nitrogenic hyponatremia. And that's something that may be interesting because are you just correcting what you caused or is there a need for additional sodium?
The Incubator (1:56:57)
Okay.
Mm-hmm.
Yeah, we did it, right.
Ben Courchia MD (1:57:25)
The other thing too is how do we assess our sodium balance in our babies? If a baby is not growing well and you've addressed pretty much everything, you have the right amount of calories and so on, like you check your in sodium levels and do you start trying to create a little bit of a more precise control over the ins and outs of renal losses and so on and so forth. I think that's that to me is very, very interesting.
The Incubator (1:57:30)
Mm-hmm.
Mm-hmm. Mm-hmm. Mm-hmm.
I think it's exciting. think we're finally at this place where like, gosh, nutrition is absolutely critical to like everything, right? Yeah. Renal. For sure.
Ben Courchia MD (1:58:02)
Yeah. it touches on both nutrition, it touches on renal, it touches on pulmonary. Because if you're using diuretics, I mean, I'm assuming you're using them for pulmonary reasons. Like these are all, it's a big interplay. And the data, by the way, they're not coming up with data that we haven't heard before. the idea that babies who have better optimized sodium to grow better is something that has been echoed in previous studies. So it just reinforces
The Incubator (1:58:22)
Right.
Ben Courchia MD (1:58:28)
this idea that we need to do a good job at making sure that these infants are optimized. I'm going to link to the editorial, which you mentioned. I wanted to give a shout out to our good friend, Dr. Satyan, because the editorial has two beautiful illustrations. And I think that if I'm not mistaken, I'm going to pull this up right now.
The Incubator (1:58:33)
optimized.
Mm-hmm. Beautiful picture.
Ben Courchia MD (1:58:54)
But Satyan recently made an announcement that he's going to try to basically release illustrations on a weekly basis, where he's going to attempt to release an illustration every week, and it's going to be available on his social media. We're going to try to use some of these illustrations for our social media posts to try to amplify the work he's doing. When you look at these illustrations, clearly a lot of work goes into it. So...
I think it's nice that someone is dedicated enough to medical education. He's a busy man. So the fact that he's taking time to draw these out for us is so helpful. He's not doing it for us. He's doing it for all of us, the community, right? So I just wanted to give him a shout out. He's at NeoSatyan on Twitter, formerly X. I'm sure he has other social media accounts on LinkedIn, Blue Sky, Mastodon, all the other alternatives.
The Incubator (1:59:26)
That's right, busy guy.
That's right, the community, the collective, for sure.
the things.
Ben Courchia MD (1:59:50)
So check him out, give him a thumbs up, give him a follow because he's doing good work. So yeah, I'm happy to end it. And by the way, you mentioned something about Iowa. I wanted to interrupt you, but I was muted. That's right. The Iowa healthcare system has their handbook available online. if you ever want to know, like they don't have everything. Let me just tell you, like they could publish more obviously.
The Incubator (1:59:58)
Mm-hmm.
love it when that happens. You can't interrupt me.
Hmm
Ben Courchia MD (2:00:19)
but it's really, really good. So if you go the Iowan Neonatology handbook, it's freely available online. So go check it out. If you want to look at how they manage their PDA and so on, you can look it up. It's kind of neat. I went to look. I don't think I've seen anything in their handbook about sodium supplementation management and so on, but there's a lot of stuff. There's a lot of stuff there. You should go check it out. Yeah, absolutely. All right, Daphna, it was fun. It was a long journal club today.
The Incubator (2:00:25)
Mmm.
to peruse it. All right.
Yes. Thanks for everybody for hanging in there.
Ben Courchia MD (2:00:49)
But we had, for sure, but we had a lot of interesting articles. All right, buddy, I'll see you later. Bye.
The Incubator (2:00:55)
Sounds good.
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