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#201 - 📑 Journal Club - The latest research in neonatology (April 13 2024)






Hello Friends 👋


In this packed episode of The Incubator, Daphna and I dive into a diverse range topics. We start by discussing a compelling article on bilirubin encephalopathy, exploring the relationship between unbound bilirubin levels and the severity of acute bilirubin encephalopathy in late preterm and term infants. Next, we review a study on the long-term neurodevelopmental and respiratory outcomes of infants with varying grades of bronchopulmonary dysplasia (BPD), emphasizing the importance of considering BPD severity in follow-up studies. We then shift gears to discuss the impact of early milk expression on milk quantity in mothers of very preterm infants, highlighting the significance of pumping within the first six hours after birth. We also touch on a recent study investigating the potential link between acetaminophen use during pregnancy and the risk of autism, ADHD, and intellectual disability in children. Additionally, we explore the safety and potential neuroprotective effects of caffeine in infants with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia. We also briefly mention studies on the association between time to regain birth weight and neurodevelopmental outcomes in extremely preterm infants, as well as the use of vibratory stimulation to mitigate pain responses during skin-breaking procedures in neonates. Join us for this informative and wide-ranging discussion on the latest research in neonatal care.

Have a nice sunday!

-Ben

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


Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability. Ahlqvist VH, Sjöqvist H, Dalman C, Karlsson H, Stephansson O, Johansson S, Magnusson C, Gardner RM, Lee BK.JAMA. 2024 Apr 9;331(14):1205-1214. doi: 10.1001/jama.2024.3172.PMID: 38592388

 

Unbound Bilirubin and Acute Bilirubin Encephalopathy in Infants Born Late Preterm and Term with Significant Hyperbilirubinemia. Amin SB, Saluja S, Kler N.J Pediatr. 2024 Mar;266:113880. doi: 10.1016/j.jpeds.2023.113880. Epub 2023 Dec 20.PMID: 38135027

 

Relationships of Severity of Bronchopulmonary Dysplasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function at 7-8 Years of Age. Doyle LW, Ranganathan S, Mainzer RM, Cheong JLY; Victorian Infant Collaborative Study Group.J Pediatr. 2024 Mar 5;269:114005. doi: 10.1016/j.jpeds.2024.114005. Online ahead of print.PMID: 38453001 Free article.

 

A phase I trial of caffeine to evaluate safety in infants with hypoxic-ischemic encephalopathy. Jackson W, Gonzalez D, Greenberg RG, Lee YZ, Laughon MM.J Perinatol. 2024 Apr;44(4):508-512. doi: 10.1038/s41372-023-01752-y. Epub 2023 Aug 16.PMID: 37587184 Clinical Trial.

 

Does extremely early expression of colostrum after very preterm birth improve mother's own milk quantity? A cohort study. Levene I, Quigley MA, Fewtrell M, O'Brien F.Arch Dis Child Fetal Neonatal Ed. 2024 Mar 4:fetalneonatal-2023-326784. doi: 10.1136/archdischild-2023-326784. Online ahead of print.PMID: 38442953

 

Provider moral distress in caring for tracheostomy and ventilator dependent children: A single institution cross-sectional evaluation. Redmann AJ, Hart CK, Smith MM, Martin C, Borschuk AP, Cortezzo DE, Benscoter D.Pediatr Pulmonol. 2024 Apr;59(4):880-885. doi: 10.1002/ppul.26839. Epub 2024 Jan 2.PMID: 38165151

 

Vibration-based mitigation of noxious-evoked responses to skin puncture in neonates and infants: a randomised controlled trial. Relland LM, Kjeldsen CP, Jeanvoine A, Emery L, Adderley K, Srinivas R, McLoughlin M, Maitre NL.Arch Dis Child Fetal Neonatal Ed. 2024 Mar 13:fetalneonatal-2023-326588. doi: 10.1136/archdischild-2023-326588. Online ahead of print.PMID: 38479794

 

Good Enough. Rissman L.JAMA. 2024 Apr 11. doi: 10.1001/jama.2024.2937. Online ahead of print.PMID: 38602672

 

Time to regain birthweight and association with neurodevelopmental outcomes among extremely preterm newborns. Valentine GC, Perez KM, Wood TR, Mayock DE, Law JB, Kolnik S, Strobel KM, Brandon OC, Comstock BA, Heagerty PJ, Juul SE.J Perinatol. 2024 Apr;44(4):554-560. doi: 10.1038/s41372-024-01869-8. Epub 2024 Jan 9.PMID: 38195922

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

Ben Courchia MD (00:00.694)

Hello everybody. Welcome back to the incubator podcast. It is Sunday. We're doing journal club. Daphna, how are you?

 

Daphna Barbeau (00:07.041)

I'm doing great. We have a lot of great articles, like a grab bag this week, I think. So I'm excited to get into those. But how are you doing?

 

Ben Courchia MD (00:16.842)

I'm doing good. I've been on service this week, and I'm finally flying back to France next week. So that's exciting. No, things have been... I mean, we've been very busy, but we can't complain. Things are good. What have you been up to? You've been busy as well.

 

Daphna Barbeau (00:18.785)

That's right.

 

That's exciting.

 

Daphna Barbeau (00:33.961)

Well, you know, we've been doing some visits, right? We got to go to nationwide. We're planning, like, lots of people are to go to PS, and before that, we'll stop at CHOP. And we just, you know, we love interacting with people. We've had such a good domino effect. You know, every time we visit somewhere, we've got a cool domino effect about people that we get to chat with and meet with and see what they're up to, and that's so fun for us. We have more projects that we know what to do with, I guess.

 

Ben Courchia MD (00:59.647)

Yeah.

 

Ben Courchia MD (01:03.271)

Absolutely.

 

Daphna Barbeau (01:06.238)

So that's good.

 

Ben Courchia MD (01:07.414)

Journal Club waits for no one, so we will get underway. Should I begin? Do you begin? What do you want to do? I don't care. All right, I'm going to start with Biller Rubin. I think this is a topic that everyone seems to love. Every time we talk about Biller Rubin, people really tune in. So I'm going to give the people what they want.

 

Daphna Barbeau (01:09.229)

That's right.

 

Daphna Barbeau (01:17.194)

You start, buddy.

 

Daphna Barbeau (01:21.087)

Mm-hmm.

 

Daphna Barbeau (01:24.569)

Mm-hmm.

 

Daphna Barbeau (01:29.622)

Well, it's an everyday issue, right? The bread and butter of being intelligent.

 

Ben Courchia MD (01:31.48)

Mm-hmm.

 

I found this article in the Journal of Pediatrics. It's called Unbound bilirubin and acute bilirubin encephalopathy in infants born late preterm and term with significant hyper bilirubinemia. First author, yeah, Sanjeev B. Amin and colleagues from India. So the paper really talks about something we've all known, right? Talks about severe hyper bilirubinemia.

 

Daphna Barbeau (01:44.885)

It was a very intriguing article.

 

Ben Courchia MD (02:00.682)

And it talks about the feared complication of acute bilirubin encephalopathy. And in the context of that neurological dysfunction, and it mentions this concept of bind bilirubin induced neurological dysfunction. And so they're talking about the fact that clinical manifestations of acute bilirubin encephalopathy in late pre-mes and term infants is really characterized by progressive abnormal neurobehavior that changes across time.

 

And they're mentioning this bind protocol from this paper that they referenced in the journal where co-written with Dr. Bhutani, that is basically a neurological evaluation. It's a fairly straightforward table. I'm going to walk you through it right now, where you can actually give a score and determine if the baby has mild, moderate, or severe acute bilirubin encephalopathy. And so the score...

 

is basically done on three metrics. You have mental status, where based on mental status, you could be sleepy but arousal and poor oral feeding. Then you could get lethargy and irritability. That would be two points. Or three points, you have semi-coma, apnea, unable to feed or seizures and coma. Then you have muscle tone. You get hypotonia, one point.

 

Hypertonia alternating with hypotonia arching of the neck and trunk unstimulation, that's two points. Persistent and opistotinous, I hate pronouncing that word. And retrocollis, bicycling, twitching of the hands and feet, that would be three points. And then they look at the cry. One point would be high pitched with arousal, you would have two points if you had just a shrill, and then three if you're

 

inconsolable or if you have a weak or absent cry. And so basically you rate mental status, muscle tone and cry on a scale of one to three. And then depending on the cumulative score, you get a bind score. So a score of one to three would give you mild, four to six would be moderate and seven to nine would be severe. And so they bring in the introduction, they bring the relationship between bind and the serum measurements that can be done on a baby with severe hypervalorobinemia.

 

Ben Courchia MD (04:25.354)

Question they're trying to answer is whether total serum bilirubin or unbound bilirubin or bilirubin to albumin ratio are associated with acute encephalopathy measured through the BIND protocol in late preterms and term infants. So far so good. So this is a single center study.

 

that was done in India, level three NICU at Sir Ganga Ram Hospital in Delhi. And basically they included every infant that was born after 34 weeks of gestational age that had severe hyperbola rubinemia. They said severe as like a total serum of 20 milligrams per deciliter or more, or that they met criteria based on the AP for exchange transfusion.

 

And that had to be in the first two weeks of life. They had some exclusion criteria, craniofacial malformation, chromosomal stuff, torch, surgical intervention, and so on. They were following, even though they're in India, they were following the American Academy of Pediatrics guidelines. And some of the things that they did is an evaluation on admission using this BIND protocol score that I just presented, and serum measurements of total serum belly, unbound Bayley-Rubin, and albumin to Bayley-Rubin.

 

ratio.

 

So in terms of what they found was the total of 151 infants were studied. The mean gestational age was 37 weeks and five days. Mean birth weight, 2,800 grams and change. The mean serum belly was 23.9. And the mean unbound bilirubin was 1.93 micrograms per deciliter. 37 infants, so 24% of the cohort.

 

Ben Courchia MD (06:24.966)

was diagnosed with encephalopathy on admission. And the mean score on the BIND protocol was 3.6, which would put that in the moderate category. And what they found was that the BIND score correlated well with both total serum bilirubin, unbound bilirubin, and albumin to bilirubin ratio. But what's even more...

 

interesting is that the unbound concentration of bilirubin was significantly higher in the infants who developed acute bilirubin encephalopathy compared to those who did not. And they did not see a significant difference when it came to total serum belly or the bilirubin to albumin ratio. Even when they adjusted for co-founders, which in this case for this study was gestational age and

 

unbound bilirubin concentration was significantly associated with acute bilirubin encephalopathy. So for the babies that had no encephalopathy, the levels were 1.39 micrograms per deciliter, but 1.84 if they had the encephalopathy, the p-value on that was 0.004. Now among infants with encephalopathy, 19 had mild, 14 moderate, and 4 had severe.

 

And unbound bilirubin was associated with severity of encephalopathy, again, for each one of them. And total serum bilirubin was not, albumin to bilirubin ratio was not either. When we're looking at that, the levels were what? 1.39 for no encephalopathy, 1.31 for mild, 3.41 for moderate to severe.

 

So that was also very significant, less than 0.01. And so what's interesting is that in conclusion, what they're talking about is that it's difficult really to assess these infants with acute bilirubin encephalopathy. And measuring unbound bilirubin is something that could be very useful. I mean, we always wonder what is exactly gonna be the threshold at which the bilirubin is gonna cross this, the blood brain barrier. And really unbound bilirubin is what you wanna measure. But I don't know.

 

Daphna Barbeau (08:33.304)

Mm-hmm.

 

Ben Courchia MD (08:42.378)

I don't think we could, I don't know if our institution would run an unbound bill of Robin. I have not tried, but what's interesting is that the paper shows that this measurement of unbound bill of Robin does correlate very nicely with the bind protocol, which seems fairly straightforward to administer on admission. And so

 

Daphna Barbeau (08:47.665)

That would be a send out.

 

Daphna Barbeau (09:01.465)

for sure.

 

Ben Courchia MD (09:04.222)

They mention in the conclusion as unbound bilirubin measurements is not easily available, a standardized approach to evaluate and monitor encephalopathy using the BIME protocol in conjunction with AEP guidelines will be very useful to reduce variation in the use of exchange transfusion and decrease associated adverse outcomes, thus improving quality of care. And they're not, it's not lost on them coming from India that this standardized approach may be extremely useful for resource-limited settings where severe hyper bilirubinemia is common.

 

and routine measurements of bilirubin biochemical measures may not be easily available. So I thought this was a very compelling article, talking about something that I'm gonna say, like our appreciation of bilirubin encephalopathy is not great. Like I think we treat the number very aggressively, but yeah.

 

Daphna Barbeau (09:52.605)

Exactly. Well, and I mean, I think in a high resource setting, we are thankfully shielded from some of that because, you know, we were able to stick to the protocols and treat babies. And so we thankfully don't see a lot of it. But you know, it's good to have this additional information and resources. Okay, my turn. Okay.

 

Ben Courchia MD (10:20.266)

Yeah, tell us what you're looking at.

 

Daphna Barbeau (10:22.581)

Well, I thought this was an interesting article. It's definitely something we are always talking about in our unit. This was entitled Does Extremely Early Expression of Colostrum After Very Preterm Birth Improve Mother's Own Milk Quantity? A Cohort Study. And this is in the archives. Yes. OK.

 

Ben Courchia MD (10:45.098)

Archives, yeah.

 

Daphna Barbeau (10:47.697)

Lead author, Alana Levine, senior author, Francis O'Brien. And so they were basically, they wanted to look at a number of things and looked primarily, what does the study add, is looking at that timeframe in the first six hours of initial expression. Does time to pumping initial expression improve outcomes throughout? So they looked at 4, 14, and 21 days after birth.

 

They also wanted to look at what are some of the other characteristics that might improve those milk yields at those time. So basically, the background really is that we have a lot of information about first breast feeds and long-term breastfeeding outcomes, so time to first breastfeed. But is it the same for time to pump? And so there have been...

 

other trials with kind of mixed results about this first six hours. Is it just the first six hours or is it the first hour? What's mostly important? So that's what they wanted to look at. This paper is actually part of another randomized controlled trial that looked at a relaxation intervention and milk yields. So that's also exciting and that data is not out yet that I can find. That's right. And seeing if that improves milk yields. And I mean...

 

Ben Courchia MD (12:03.722)

like relaxation intervention on the mother.

 

Daphna Barbeau (12:09.609)

This is up our alley, right? I totally believe that would work, so I'm hoping we get to review that soon.

 

Ben Courchia MD (12:15.637)

Do you know what the intervention was?

 

Daphna Barbeau (12:18.057)

So it was like a mindfulness relaxation intervention. So I'm excited.

 

Ben Courchia MD (12:21.26)

Ha!

 

Ben Courchia MD (12:26.019)

Yeah, there's all these studies where the premise resonates so much with our belief system and what we do that I really hope results are significant.

 

Daphna Barbeau (12:34.35)

For sure.

 

Daphna Barbeau (12:38.553)

I know. And we're not biased at all then, I guess. So basically they recruited birthing parents who delivered infants between 23 and 0 and 31 and 6 weeks in the UK across four NICU units. They were recruited in the first 72 hours and the primary outcome was milk yield on days 4, 14, and 21. So this was overall an observational study.

 

Ben Courchia MD (12:41.066)

Absolutely not, no, completely impartial.

 

Daphna Barbeau (13:05.489)

So the mean maternal age was 32 plus or minus six years, and the average gestation at birth was 27.8 plus or minus two to four weeks post-menstrual age. So in total, they had 103 participants at day four after birth and 91 participants at both days 14 and 21. So for the group as a whole, the milk yield increased over time from a median of 155 grams on day four

 

to 490 grams on day 21. And the median expressing frequency, so how many times per day did they pump, was five on day four and six on days 14 and 21. And still, they documented minimal breastfeeding attempts on any of these days, even out to day 21. At 36 weeks post-menstrual age, when infants were on average 8.2 weeks of age,

 

65% of participants were giving exclusive mom's own milk, and 86% were giving any mom's own milk. So they were doing, I think, a reasonable job of getting expressed milk. They looked at the median time to first expression attempt after birth. So that median time was six hours with a strong left skew. Overall 20.8% of participants expressed within two hours of birth.

 

30 expressed between two and six hours of birth, and 48% expressed more than six hours of birth. So 50%, even though they were doing this, 50% were expressing more than six hours after birth. So they wanted to look at time to first expression and the milk yield. So they created these kind of three categories. So they looked at less than two hours, this two to six hours, and then greater than six hours.

 

Ben Courchia MD (14:57.806)

they categorize the continuous variable. Dum dum dum.

 

Daphna Barbeau (15:00.385)

That's right. I actually encountered many statistical terms and research terms in my review of articles this week, but we won't get into all of those. Okay. So basically, actually, they have this beautiful graph that shows day four, day 14, day 21, and then each of these groups, less than two hours, two to six hours.

 

Ben Courchia MD (15:10.346)

I'm going to go.

 

Daphna Barbeau (15:24.329)

and greater than six hours from birth, which I think really helps explain the data. A picture is worth a thousand words as they say. So expressing within two hours of birth was associated with greater milk yield at day four than expressing more than six hours after birth, but no greater milk yield statistically than expressing between two and six hours after birth. And at day 21, there was no association between time to expression and milk yield.

 

So in all three time points, there was a statistically significant interaction between expressing frequency and time to first expression with increased expression frequency associated with higher yield, only in those who expressed within six hours of birth. So yeah.

 

Ben Courchia MD (16:10.73)

So we have to say that again because that's going to... So now we're talking no longer about how early they pumped, but we're talking about how frequently they... Yeah.

 

Daphna Barbeau (16:19.393)

Right. So they were looking at different variables to see what would provide the most milk at those days. So what they're really hoping to convince you is that you really need a pump by six hours, but pumping less than two hours is not necessarily providing a higher yield. And that, it still mattered, even if you were pumping less often, if your first pump...

 

Ben Courchia MD (16:26.486)

All right.

 

Daphna Barbeau (16:48.981)

was less than six hours. So I thought that was really interesting. But I will note on the graphs, even though they say there's no statistically significant difference, you can tell by the time points that certainly, and that's what some studies have shown, pumping in the first two hours did have higher milk yields, even a trend toward higher milk yields at every time point. But that's why they wanted to look at some of these interactions.

 

Daphna Barbeau (17:19.365)

number of expressions. There's a significantly higher milk yield for those expressing within six hours of birth when expressing at a frequency of five or more times on day four and seven or more times on day 14 and 21. So the interaction of both of those pumping early and the frequency made the biggest difference. They also wanted to look at association between time to first expression and milk feeding outcome.

 

And there was no significant difference in exclusive moms own milk or any moms own milk at 36 weeks post-menstrual age for those expressing within the first six hours after birth compared to those expressing more than six hours after birth. So then they wanted to look at which birthing parents were able to express within the first six hours, since again, nearly 50% were not able to express until after six hours. Adjusted analysis showed that expressing within six hours of birth was more likely for those who had given birth vaginally.

 

those who were multiparous and those living in less, quote unquote, deprived areas because they were using this index of multiple deprivation. So I think this is an interesting study, especially in units like ours who are still working on this first pump. I think for a lot of people, it seems intimidating to say, you got to pump within the first two hours, especially when that mom's in the initial recovery. But

 

Having this goal of six hours, I think, is reasonable for us to do and may not cause too much difference in outcomes. Though, it does seem like the earlier, the very earlier you can do it, the better.

 

Ben Courchia MD (19:01.606)

Um, yeah, I have a lot of thoughts about this because I think, like you said, um, it's a big ask. Um, I'm not a, I'm not a birthing mother, but I can only imagine that like you've given birth it's first of all, you delivered a preemie baby. So it's stressful cause this was not the plan. And now it's like, as soon as you're done, like you don't even get time to rest. And it's like, can you start pumping? And it's like, can I just catch a break? Like, can I get a little bit of a break? Um,

 

Daphna Barbeau (19:18.838)

Yeah.

 

Daphna Barbeau (19:27.026)

I know, I know.

 

Ben Courchia MD (19:30.39)

But it's interesting, number one, that the fall off is not so significant for mothers who've pumped after six hours. Because that's the fear, right? If you wait till six hours, it's negligible. But it's not. So that's a hopeful message. But then again, even the ones that are not statistically significant, the comparisons, I think it may be clinically significant. So I'm gonna piss off a bunch of dieticians here

 

Daphna Barbeau (19:42.617)

You're done. Yeah.

 

Daphna Barbeau (19:57.273)

Correct.

 

Ben Courchia MD (20:00.838)

Because they looked at the milk yield in grams. If you assume that the density is one to one, like if one gram is an ml or something, because we don't think of how much gram of milk we give babies, we think in ml's. It's like how many ml's are we feeding every three hours. But look at on day four in that graph, the difference between a mother that pumped less than two hours from birth versus one that went from like two to maybe up to six. It's like...

 

Daphna Barbeau (20:05.138)

Uh-huh.

 

Daphna Barbeau (20:15.134)

right.

 

Daphna Barbeau (20:26.169)

Mm-hmm.

 

Ben Courchia MD (20:28.846)

284 versus 249, which it's a difference of about 45, which could be like, if you don't have donor milk and so on, like that could be, that could, on day four on an extremely low birth weight infant, that could, yeah, right? It's exactly right. Cause that's always the way I think about it. It's like, well, is it statistically significant? Yes, no. But what about clinically significant? But in that case, considering that we feed these babies on day of life for maybe like four ML every three hours, maybe.

 

Daphna Barbeau (20:35.278)

Mm-hmm.

 

Daphna Barbeau (20:41.373)

Yeah, let me get you a week.

 

Ben Courchia MD (20:58.306)

five, six, seven MLs, like the difference of 40 ML is significant. So it's interesting. And I think if you have donor milk, I think you can bridge that gap still fairly well. But if donor milk is an issue or accessing donor milk is an issue, this might be a good QI project.

 

Daphna Barbeau (21:18.649)

I also think to your exact point, the way we discuss this with families and people who are doing all the pumping, when we think about how stressed out a mom is at four days or at a week or at 14 days because they don't have enough milk or what they perceive to be enough milk or they have one ounce more than one ounce more or one ounce less.

 

I mean, I think that's huge in giving them some control over what's happening in the NICU and as they are doing this role. So I think our education of families is almost more important than our education of like our labor and delivery teams. We have to say like, you know, if we can do this intervention, the yields are impressive. And I think that helps mitigate stress. When a mom says, I'm doing the work, I'm putting in the pumping, I can see the more milk coming versus a mom who...

 

Ben Courchia MD (21:47.758)

Mm-hmm.

 

Daphna Barbeau (22:14.933)

maybe we see what doesn't pump for the first 24 hours for a number of reasons. And then they're saying, I'm working around the clock. I'm exhausted at this week and I still don't have, I still don't have milk. You know, we're setting these moms up for extra guilt and trauma and anxiety if I think we don't.

 

Ben Courchia MD (22:35.018)

Yeah. And if you're, I mean, listen, we work in the United States where resources are measured out, everything is measured. The cost of having donor milk is significant. Like, again, by day 21, you could reduce how much donor milk you would need to use from the milk bank by just by just maybe supporting mothers earlier on. Yeah. So that's very interesting.

 

Daphna Barbeau (22:43.039)

Mm.

 

Daphna Barbeau (22:58.986)

Mm-hmm.

 

Mm-hmm.

 

Ben Courchia MD (23:04.695)

Very, very interesting.

 

Daphna Barbeau (23:06.009)

Mm-hmm.

 

Ben Courchia MD (23:07.426)

Thank you for reviewing that. Before we get into some of the other articles, I just wanted to, did you see this paper in JAMA that came out called Acidaminophen Use During Pregnancy and Children's Risk of Autism ADHD?

 

Daphna Barbeau (23:20.129)

Yeah, I did. I was supposed to review that paper, not you. No, you can do it. I know you were excited about it.

 

Ben Courchia MD (23:23.794)

Oh, you're going to review it. I'm sorry. No, no, no. No, no, I'll let you do it. So then the next paper I'm going to go to is going to be talking about BPD. Very interesting paper. If you're a BPD nerd like me, you're going to enjoy this. If you're fed up with BPD, please skip the next nine minutes. But it's a paper in the Journal of Pediatrics called Relationships of Severity of Bronchopulmonary Displasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function.

 

at seven to eight years of age. The first author is Lex Doyle, and this paper is obviously coming out of Australia. Now, what's interesting is we all know the dilemma around BPD, the definition, et cetera, et cetera. But if we abstract the problem of the BPD definition, we're still all measuring whether a baby has BPD or not in our respective units.

 

whether you use definition A, B, or C, it doesn't matter. But at 36 weeks, you're going to make an assessment. And our ability, the authors say this from the paper, our ability to identify more accurately children's who are destined for long-term neurodevelopmental or respiratory dysfunction would really help us in terms of targeting scarce early intervention resources towards those with the highest risk.

 

and provide more accurate counseling for families of children who have BPD of varying severity. And I think that is a concept that resonated with me pretty significantly because we have these parents in the unit and we say, oh, it's 36 weeks and your child is requiring 29% oxygen. So you meet the criteria for BPD and parents most of the time look at you and say, well, what does that mean? What does that mean for the future? And

 

I think we have a vague idea of what the implications are for patients who have BPD. We say, oh, you know, maybe they'll have more respiratory complications. We know that the neurodevelopmental outcomes are worse. But I don't think we've given so much thought as to what Lex Doyle and his team are talking about here, which is, well, can we be a bit more granular? Can we look at, depending on which definition and which grade you have, what does that mean practically so that we could counsel patients more appropriately?

 

Ben Courchia MD (25:49.214)

This is a more researchy type of comment, but it's a metric and an outcome that's being used in so much research. So shouldn't we understand this better? And I think that was a very interesting question. So I think we stated indirectly the question being asked by the paper, relationship between severity of EPD and neurodevelopmental and the respiratory function at school age, so seven to eight years of age, which is also data that we don't often see.

 

So they looked at consecutive survivors to seven to eight years of age in infants born extremely preterm or extremely low birth weight, which was a cohort of about 220 infants in the state of Victoria in Australia in 2005. And they looked at BPD in the form of four grades. There's no BPD, grade one, grade two, grade three. And they parsed out all their patients and identified them based on various definitions. So the three definitions they gave.

 

And we're going to review them because I think it's always fun to review the BPD definition because you may forget them. But the first one are obviously the 2001 Job criteria, which basically says that you get oxygen. So grade one BPD means that you have oxygen for 28 days or more, but not at 36 weeks post menstrual age. And you have no other respiratory support at 36 weeks. So you just got oxygen for almost a month.

 

Grade 2 means that you got oxygen for 28 days, and you have an FIO2 of 21 to less than 30% at 36 weeks with no other respiratory support. And grade 3, meaning that you got oxygen for 28 days or more, and your FIO2 is above 30% at 36 weeks, and you have some other form of respiratory support. Then they used the 2018 Higgins definition.

 

which looks at BPD in a different manner. I think to me, that's one of the most complex one because it involves a lot of different criteria. But basically mild BPD or grade one is assessed at 36 weeks. And for grade one, you're either on CPAP, NIPPV or nasal cannula, three liters or more, but your FiO2 is 21%. Or you're like on nasal cannula less than three liters, but still more than one liter. And you're on like less than 30% oxygen or you're on an oxyhood.

 

Ben Courchia MD (28:08.222)

less than 30%, or you're on what we know here in our unit as like a micro flow, like a PD flow, like less than a liter per minute, and you are on anything less than 70% FiO2. And then they looked at grade two, which was you have invasive positive pressure ventilation, but your FiO2 is 21%, or you're on CPAP, nasal cannula, NIMV, nasal cannula, three liters or more, but now your FiO2 is up to 30%.

 

Or you're on the low flow nasal cannula, like one to two liters, but your FiO2 is more than 30%. Or you're on a PD flow microflow, but you're above 70%. And then finally grade three, you're on invasive mechanical ventilation at more than 21% or you're on C-PAP, NIMV, NIV, NAVA, nasal cannula, more than three liters, and you require more than 30%. And then the last definition they used was

 

the Jensen criteria. However, they mentioned something that to me is very interesting. They said, well, we don't really have high flow nasal cannula. So they basically created this new definition that they called the VICS 2005, which basically substitutes nasal cannula flow for FiO2. And basically, grade one, you have an FiO2 less than 30% into the incubator or a nasal cannula 100% oxygen.

 

at less than 100 ml per minute. In grade two, your FIU2 is more than 30%. And in grade three, you have invasive, or you have nasal CPAP at 36 weeks, and grade three, you have invasive IPPV. There's table one that describes them all, but I feel like I just wanted to, since we're gonna go into it, we might as well just review them. So they did neurodevelopmental assessment. The IQ was assessed using the differential ability scales, second edition.

 

Academic achievement was done with the wide range achievement test fourth edition and the motor function was assessed using the movement assessment battery for children second edition They defined major neurosensory disability as having one or more of the following moderate to severe cerebral palsy, blindness, deafness or an IQ Z score of less than two standard deviation They also did pulmonary function test, FVV1, FVVC ratios and so on and so forth

 

Ben Courchia MD (30:31.35)

The results for these 218 infants was quite interesting. Looking at the breakdown of BPD, most of them always end up not having, most of them don't end up having BPD. So looking at the definitions, looking at the job definition, 39% had no BPD, 11% had grade 1, 24% grade 2, 26% grade 3. And what I want you to pay attention to is how they separate over the three grades.

 

So you can see that very little grade one and a significant amount of either no BPD or a grade two or three. Looking at this Higgins definition, 48% no BPD, 29% grade one, 11% grade two, 11% grade three. So as we get to the higher grades, there's less and less babies. And then this modified Jensen criteria, 48% no BPD, 25% grade one, 24 grade two, 3% grade three. And then...

 

you obviously have to ask the question, when these definitions were released, are they more appropriate now? Like, did the 2001 definition just not age well, quote unquote, and that's why it's not as representative. Anyway, these are all questions you can ask. So they were able to assess 88% of their cohort at eight years of age. 16% had major neurodemental disability. And what they found is something we all know, which was that the lowest rates of long-term neuroimperament

 

applied to the no BPD group and the highest were found in the grade 3 BPD group. So we know that BPD is associated with poor neurodevelopmental outcomes. So that was not really surprising. What we wanted to find out was how do these grades break down? Interestingly enough, grade 1 on any criteria, no matter the definition, was not associated with any adverse neurodevelopmental outcomes.

 

Grade 1 for the Higgins and the modified Jensen criteria was, however, associated with worsened respiratory function. So no effect on neurodevelopment, but some effect on respiration and spirometry for the Higgins and modified Jensen. Looking at grade 2, there was little evidence that grade 2 on the Job criteria, the 2001 definition, was related to the risk of any.

 

Ben Courchia MD (32:55.91)

adverse neurodevelopmental outcomes but was associated with worse respiratory outcomes.

 

Grade 2 on both the Higgins and the modified Jensen, and grade 3 on all criteria were associated with increased risk of both neurodevelopmental and respiratory outcomes. So I think this is very interesting, because you see that grade 1 doesn't have bad outcomes, technically, from a neurodevelopmental standpoint. You can see that grade 2.

 

is very different whether you look at it from the 2001 definition where it's not as bad as having grade two in these more modern definitions and grade three on all these definitions is quite bad. So I think this is quite interesting. The authors conclude that with extreme

 

Daphna Barbeau (33:49.098)

Yeah.

 

Ben Courchia MD (33:58.826)

with increasing severity of BPD for survivors born extremely low birth weight. Regardless of the criteria for defining BPD, however, only those receiving oxygen or pressure support at 36 weeks were at increased risk compared with no BPD. And the risk rose with increasing requirements for oxygen and pressure support at 36 weeks. And as long-term follow-up studies continue to increase their focus on school-age and older children.

 

it will be important to incorporate BPD severity into their analysis. And maybe not just BPD yes or no, I think. I added that last part, but I think, yeah, looking at it on a more granular standpoint.

 

Daphna Barbeau (34:37.705)

Yeah, I mean, this makes sense, right? Kind of intuitively and kind of what we see, right, for those of us who do follow up or follow our kids up. So, I mean, I guess it's good. I guess it's good news.

 

Ben Courchia MD (34:40.072)

Yeah.

 

Ben Courchia MD (34:53.566)

Yeah, I think it's interesting and it's very helpful for, it's very hard to counsel families with BPD. We don't have a lot of data on what that looks like in the future. And telling parents, oh yeah, it looks a bit like asthma. Like that's not enough. That's not enough. All right.

 

Daphna Barbeau (34:56.713)

Yeah, counseling.

 

Daphna Barbeau (35:06.057)

Yeah. Okay. Thanks buddy. Well, should I tell you about acetaminophen now?

 

Ben Courchia MD (35:12.594)

Yeah, yeah, sorry about that. Sorry about that.

 

Daphna Barbeau (35:16.657)

Okay, this was actually a paper in JAMA, Acetamin If In Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability. Lead author Victor Alkvist, senior author Brian K. Lee, and then here in the middle of the authorship, we see Dr. Johansson, our friend from Karolinska University. So...

 

If you're not aware, in the last handful of years, a number of studies have come out saying that acetaminophen use and the dose response of acetaminophen use has been linked to some of these neurodevelopmental outcomes. This has been very concerning to people because acetaminophen has been one of the only things that people can use during pregnancy for all of their symptoms of everything. To take that away from pregnant people is no... It's a big deal.

 

Ben Courchia MD (36:06.462)

Yeah.

 

Daphna Barbeau (36:12.805)

So that's what this group wanted to look at. So they did something kind of unique. They felt like maybe there are some other confounding factors that we can't account for. So they wanted to look for, again, unobserved kind of genetic and environmental factors that might be shared between siblings.

 

which would increase the risk of some of these neurodevelopmental outcomes. So basically what they did is they took this entire cohort, they looked at babies who were exposed, or children who were exposed to acetaminophen versus children who were not exposed to acetaminophen. But they also included the sibling cohort. So the sibling analysis was also adjusted for a number of confounders that could differ among siblings.

 

And then they wanted to compare the sibling cohort to the non-sibling cohort and see what they found. So this is just a review for us since we actually don't manage things in pregnancy, but it's an interesting study of nearly 2.5 million children, 7.5, what, what?

 

Ben Courchia MD (37:24.467)

But you need to know, you need to know this. Like, I mean, we get phone calls all the time from people who are pregnant who say, what can I take? What, is it harmful to the baby? Like we...

 

Daphna Barbeau (37:30.433)

That's true. Yeah, when you're the pediatrician in the group or the family, right, everybody's calling you. Yeah, you're absolutely right. So of nearly 2.5 million children, 7.5% were exposed to acetaminophen. Now I had to say that I think that number is quite low. I think it's potentially bigger than that. But anyways.

 

Ben Courchia MD (37:36.398)

That's right.

 

Daphna Barbeau (37:51.469)

Acetaminophen exposure was more common among children born or birthing parents with lower socioeconomic position, a higher early pregnancy BMI, those who smoked during pregnancy, those with diagnoses of psychiatric conditions, neurodevelopmental disorders, a number of indications for acetaminophen and co-prescription of related therapeutics. So they wanted to see what might have some of the other factors that might be contributing to this finding.

 

So then they looked at the whole group. So during a median follow-up of 13.4 years, amazing, 188,929 children, so 7.62% were diagnosed with at least one neurodevelopmental condition. This included ADHD, autism, or intellectual disability. 2.76 with autism, 5.9% with ADHD, and 0.99, just under 1% with intellectual disability.

 

And in the final adjusted models in the whole population-based sample, children exposed to acetaminophen were slightly more likely to be diagnosed with autism, the hazard ratio of 1.05, slightly more likely to be diagnosed with ADHD, a hazard ratio of 1.07, and slightly more likely to be diagnosed with intellectual disability, hazard ratio of 1.05, compared with children who were not exposed to acetaminophen. The differences in the absolute risk between acetaminophen users

 

and non-users were small. Now, in the models without sibling control, in the full sibling cohort demonstrated that sibling sample kind of had the same apparent acetaminophen associations as a total sample. But in contrast, those models with sibling control, where they controlled for this family network, acetaminophen was not associated with children's risk of autism.

 

And as with acetaminophen, the association between non-aspirate NSAIDs, opioids, anti-migrant medications and neurodevelopmental disorders all diminished to null using the sibling analysis. Interestingly, aspirin in the sibling analysis was inversely associated with neurodevelopmental disorders in the sibling group. So they actually saw less neurodevelopmental conditions in the aspirin group, which I think was totally unexpected.

 

Daphna Barbeau (40:12.969)

So they also wanted to look at this dose response pattern. So in population-based models, a dose response pattern was seen with the partially adjusted models attenuated with the covariate adjustment. But these fully disappeared again in the sibling analysis. So, yeah.

 

Ben Courchia MD (40:29.662)

So can you tell us again, this sibling analysis, like is that a valid way of doing this?

 

Daphna Barbeau (40:34.965)

So basically they wanted to say like, maybe there's some genetic features or maybe there's some environmental factors that put people at risk for neurodevelopmental outcomes. So how can we study that? Well, we can look at families. We can look at one family versus another family. And so basically when they grouped these kids that had siblings in the analysis, they were able to potentially control for some of those things that are related to...

 

genetics or home life that you might see in certain families. We know that these neurodevelopmental conditions have some genetic predisposition. When they controlled for siblingship, they saw these differences in acetaminophen exposure basically go away, thinking that there might be some other genetic, familial, or environmental factors that might be behind.

 

Ben Courchia MD (41:20.59)

posting.

 

Daphna Barbeau (41:32.289)

this acetaminophen claim.

 

Ben Courchia MD (41:33.662)

And it's kind of tricky, right? Because we kind of know that there has to be some genetic component, especially when it comes to autism. That's something that's been described, but we haven't really been able to put our finger on exactly what kind of exactly. So it's like kind of a Schrodinger's cat. We know it's there, but we can't really know its position. We don't know exactly. Yeah. Interesting.

 

Daphna Barbeau (41:36.564)

Oh yeah.

 

Daphna Barbeau (41:46.209)

what it is, yeah.

 

Daphna Barbeau (42:00.377)

So hopefully we can let people keep using acetaminophen. I'm not sure if this is the study that will allow for that, but at least it's good that people are re-evaluating it. People are re-evaluating it for sure.

 

Ben Courchia MD (42:02.486)

That's it. Yeah.

 

Ben Courchia MD (42:09.73)

At least you feel better.

 

I mean, I forget who I had this discussion with. Maybe my sister-in-law who was recently pregnant. Like what's out there that we can use then? It's like, if you feel like crap, like what can, no ibuprofen, no, it's like, yeah, it's terrible. Yeah. I don't have a lot of other papers. I just want to mention two articles that I read with great interest. The first one was in the journal of perinatology. It's called Time to Regain Birth Weight, an Association with Neurodevelopmental Outcomes Among Extremely Preterm Newborns.

 

Daphna Barbeau (42:21.62)

Nothing.

 

Nothing. It's tough. It's really tough.

 

Ben Courchia MD (42:42.358)

First author is Gregory Valentine. Last author is Sandra Jewell. And this is basically a paper that looked at the cohort secondary analysis of the peanut trial that looked at the use of EPO. And they wanted to know if you'd.

 

Daphna Barbeau (42:52.302)

Mm-hmm. Man, they've been able to give us a lot of information from that trial. It's not what we wanted, but we've got a lot. Well, I think we've had some very useful papers come out of the cohort, so that's good.

 

Ben Courchia MD (42:57.378)

They've, they have, they have milked this data to the bone. Ha ha.

 

Ben Courchia MD (43:08.254)

Yeah, that's a good thing about well-designed studies. So they wanted to determine the association between time to regain birth weight and two-year outcomes. And I think what's interesting is that they're saying in preterm infants, we're really not sure, based on the data, whether they should regain quickly, whether we shouldn't let them lose too much. It's very unclear as to what's bad for these very preterm infants, especially in the first few days of life.

 

Daphna Barbeau (43:11.734)

Yeah, that's right.

 

Ben Courchia MD (43:34.986)

And so they made this very nice figure, which basically explains what they're talking about. So obviously, there's the time to regain, which is from birth to the time you regain your birth weight. But then they define three parameters, which is the birth to the nadir, which is to the lowest birth weight, to the lowest weight you will reach in the first couple of days. And then they have the nadir to the regain, which is how long it takes you from that point to regain your birth weight. And then they have the cumulative...

 

weight loss, which is how much in proportion have you lost of your birth weight. And what they were able to do is in a cohort of about 650 neonates, what they found was that those with the shorter nadir to regain had lower cognitive scores, lower motor scores in an adjusted

 

Ben Courchia MD (44:33.542)

Increasingly cumulative weight loss was associated with lower cognitive scores, motor scores, and language scores, which seems to show that a faster, and again, I'm really breezing through, but people should read it. It's quite a technical paper. So it does require a little bit of attention, but the faster nadir to regain and an excessive cumulative weight loss are associated with

 

poor neurodevelopmental outcomes at two years. So yeah, I thought that was very interesting because you would think the sooner we can get them back to birth weight, the better, right? But may not be so.

 

Daphna Barbeau (45:17.057)

Very interesting. And yeah, those are tough papers to read. All the deltas, right? They're very... Ha ha ha!

 

Ben Courchia MD (45:21.626)

Oh my God. Oh my God. I mean, it was not poorly written. It was not. It was really very well written, but it's very technical. And it's like the confidence intervals and the percentages and so on and so forth. So it was it was it was it was it needed some attention. And the last paper I'm going to mention today is something I found in which journal was that? Damn it. I forgot. Pediatric pulmonology.

 

Daphna Barbeau (45:25.225)

No, yeah, it's just tough math.

 

Ben Courchia MD (45:45.302)

which looked at provider moral distress in caring for tracheostomy and ventilator dependent children, a single institution cross-sectional evaluation. First author is Andrew Redman. It's coming out of Cincinnati Children. Basically, at Cincinnati Children, they have a 25 bed unit of patients that are trache, but they don't really need ICU care. Like they're sort of on their way out the door, you know, but they need more, they need more,

 

Daphna Barbeau (45:48.696)

Hmm. Mm-hmm.

 

Ben Courchia MD (46:15.378)

support than a patient on the floor, for example. So it's a very interesting intermediate type of unit. And they sent this survey to try to find out a little bit about moral distress and burnout. They sent it to the docs, to the therapists, to the advanced practice practitioners, to the nurses, and so on. And what's interesting is that these are the patients that are not

 

They're complex, but they're not sick, right? I want to make sure that this is coming across loud and clear. Because, yeah. And what they found was that moral distress levels in their unit, caring for long-term tracheostomy and ventilator-dependent patients, was high. And even though this was not an intensive care unit, the responses were comparable to levels in pediatric and neonatal ICUs. And that advanced practice

 

Daphna Barbeau (46:47.769)

Uh huh.

 

Daphna Barbeau (47:07.595)

Wow.

 

Ben Courchia MD (47:11.362)

Practice practitioner, I messed that up, I'm so sorry. Advanced practice practitioner, okay, it is repetitive, it's not me, advanced practice practitioner had a higher level of distress compared to other groups. And I think they go into an interesting conversation about how the doctors didn't have such a high level of distress and they were saying it's maybe because they rotate off units more and...

 

the APPs do go off unit, but for a very short while and come right back. And they were talking maybe about the beneficial effect of this buffer being off units that can allow you to almost a little bit reset and come back and not experience so much distress. I thought that was very interesting. And it goes back to show that these patients, which often can be some of our more complex, severe BPD patients, do take a toll on us and on our team. And I think...

 

Daphna Barbeau (48:05.011)

Mm-hmm.

 

Ben Courchia MD (48:10.53)

I'm not saying that we should not care for them. I'm saying we should recognize that in our teams and support our team appropriately.

 

Daphna Barbeau (48:14.614)

Yeah.

 

Yeah, and that, you know, the… we call the primaries in our unit, right? The people who are, you know, staying with that family throughout an admission or, you know, dealing with the… you know, we feel like the admissions should get easier for families when they're closer to discharge, but that's not always surprisingly the case, right? Sometimes it becomes much harder the longer families have to be in the unit. And so…

 

Ben Courchia MD (48:37.004)

Yeah.

 

Daphna Barbeau (48:42.685)

It's, and you get attached to the patients. I mean, there's so many factors that, that are underlying.

 

Ben Courchia MD (48:45.822)

And there's this, the, yeah, the sense of impending doom of like, if this kid, if this kid who's now okay, were to get sick, holy shit. It's like, I'm gonna, I'm gonna be in so much trouble because he's doing fine now. But what if he spikes up?

 

Daphna Barbeau (48:50.27)

Always. Yeah.

 

Ready. Yeah. It'd be like starting over, right?

 

Daphna Barbeau (49:03.633)

What if? Yeah, I know. I had a few more, okay. Now I'll do my rapid review. I thought this was an interesting paper in the Journal of Perinatology. I'll just kind of just briefly run through it. A phase one trial of caffeine to evaluate safety in infants with hypoxic ischemic encephalopathy. Lead author, Wesley Jackson, senior author, Matthew Lohan. So this is a phase one.

 

Ben Courchia MD (49:07.979)

Yeah.

 

Ben Courchia MD (49:32.332)

You're on your own on this one

 

Daphna Barbeau (49:34.625)

This is a phase one open label trial designed to evaluate the safety of caffeine in infants receiving therapeutic hypothermia for HIE and to look at the pharmacokinetics of caffeine. So I mean, trial phases have been like a big talk during the COVID times. But as a reminder, phase one is really trying to determine like, is this treatment safe?

 

to test kind of novel therapies for safety, toxicity, and dose. And hopefully, you can move into phase two, which does the treatment work. Phase three, is it better? That means putting it kind of head to head towards the gold standard. And then phase four is that kind of it's already gone to market, patients are taking it, and then looking at like what else can we still learn from what's going on?

 

So this is a very small trial because it is a phase one. So it's a single center open label dose escalation study. They've enrolled 17 infants greater than or equal to 36 weeks undergoing therapeutic hypothermia. So.

 

Ben Courchia MD (50:42.986)

And the idea is that caffeine is going to be neuroprotective.

 

Daphna Barbeau (50:46.821)

That is the hope based on what we know about caffeine, say, in the preemie population, but also on a lot of animal data in, what is it called, models of HIE. Yeah. That's right, and traumatic brain injury. Absolutely. So this is exciting. What did I want to tell you? I don't want to get into all of the details.

 

Ben Courchia MD (51:01.002)

And in the dot, and the dots as well. I mean, caffeine has been shown to have, yeah, so.

 

Ben Courchia MD (51:12.962)

Does it work? You wanted to tell us if it works.

 

Daphna Barbeau (51:15.897)

But so the goal is that the patients would get three doses of caffeine, the first dose within 24 hours, subsequent doses given at 24 hour intervals, all given IV. So some patients got this, everybody got this 20 mg per kig loading dose, and then they were either to get two subsequent doses of caffeine of five milligrams per kilogram, which is low dose, or 10 milligrams per kilogram high dose. Okay.

 

So basically, they looked at a number of adverse events. I'm not gonna give you all of them, but I'll tell you kind of the major adverse events that they were looking for. Interestingly, they did not achieve target enrollment. They were looking for 18 infants and they only had 17 infants. And that's because the funding period ended following the enrollment of 17 infants. The major barrier was COVID restrictions, basically. So just know that.

 

Enrolled infants had a mean gestational age of 38 weeks. They had a mean birth weight of 3.3 kilograms. Four infants or 24% had severe HIE. 71% had moderate HIE. And they did enroll one infant with mild HIE. All the infants received therapeutic hypothermia. 35% of infants had a 10-minute Apgar score of less than or equal to three. And five infants, 29% received chest compressions in the delivery room.

 

12% two infants had EEG confirmed seizures and received one anti-combulsive medication prior to the administration of the first dose of caffeine. So this is a pretty sick group, I would say. All infants received analgesia and sedation with morphine or fentanyl during therapeutic hyperthermia. The mean duration of hospitalization in surviving infants was 38 in the low dose and eight in the high dose, which I think is interesting. They don't comment much on that, but I thought it was interesting.

 

Ben Courchia MD (52:52.608)

Mm-hmm.

 

Daphna Barbeau (53:11.649)

They had 30 adverse events reported and 71% had at least one adverse event. Now many of these adverse events are also common in therapeutic hypothermia. So that's kind of what they were looking to do. Five serious adverse events including seizure activity requiring greater than one anti-combulsant medication, three occurrences of ECMO for hypoxic respiratory failure, and one spontaneous bowel perforation.

 

No adverse events were determined by the investigators to be related to the drug. However, one infant had persistent seizure activity. They needed a second anti-combulsant medication. So that's actually one of the exclusion criteria. So they didn't receive the third dose of caffeine. So then they looked at all of these adverse clinical events in this trial and they compared them to the frequency of those adverse events reported in the hypothermia arm of the whole body hypothermia for HIE trial.

 

conducted by the NICHD. And there were no statistically significant differences in frequencies of clinical events of these babies who got therapeutic hypothermia and caffeine and those babies who had hypothermia alone. So hypoglycemia was higher in the caffeine group with a p-value 0.05. However, two of the infants with hypoglycemia in the caffeine group experienced hypoglycemia prior to the first dose of caffeine. It did not recur following caffeine exposure.

 

Two infants died in the caffeine population. One infant in the low dose cohort died during therapeutic hypothermia. And this was kind of a redirection of care. And one infant in the high dose cohort died following hypoxic respiratory failure and sepsis on day 19. Now it should be noted that in the whole body hypothermia trial, 19% of babies died. A more recent...

 

Ben Courchia MD (54:59.946)

Yeah, so that was like 12% in the caffeine group, which these two ended up representing like 12% in the caffeine group compared to 19% in the, yeah.

 

Daphna Barbeau (55:06.361)

Correct. That's it.

 

Daphna Barbeau (55:11.097)

That's right. Now, more recent mortality estimates are about 7% in the standard hypothermia group. There were no episodes of neck, and one infant in the caffeine group had SVT. 18% had acute kidney insufficiency, another thing that they were looking for specifically. They did have some preliminary effectiveness. So brain MRI was performed in 15 infants at a median age of five days.

 

Ben Courchia MD (55:17.55)

Mm-hmm.

 

Daphna Barbeau (55:37.997)

Two infants died during the hospitalization. They did not have neuroimaging. And in the standard of care clinical interpretation, MRIs demonstrated diffusion restriction in 53% of infants. In the whole body cooling for HIE trial, 48% of MRIs were abnormal in the hypothermia group. Then they looked at the NICHD MRI scoring strategies. So they applied that to the babies.

 

33% scored zero, which is quote unquote normal. 27% scored 1A or minimal cerebral lesions. 27%, 1B, more extensive lesions. And 13% scored 2B, basal ganglia thalamic anterior or posterior limb of the internal capsule or watershed infarct with cerebral lesions. 20% of surviving infants had abnormal neurologic exams at discharge.

 

33% were discharged with a G-tube, and all infants undergoing therapeutic hypothermia received neurodermal to follow up at six month intervals, and that long-term follow-up is ongoing. But basically what they concluded was that caffeine administration was well tolerated, and then they are hopeful to proceed to phase two. So not enough information yet.

 

But it's always exciting when things are being studied.

 

Ben Courchia MD (57:03.227)

Yeah. I think it's our job as an information podcast to make you aware of these phase ones. So you can see where we're going. I think for HIE, the two things, I think EPO was the last drug that was big hope, but I think now we're seeing based on the current phase one trials that have been published, sildenafil and caffeine potentially as these new drugs that might be part of the bundle that we use in our HIE patients.

 

Daphna Barbeau (57:09.27)

Yeah, upcoming.

 

Daphna Barbeau (57:16.577)

Yeah, big, big hope.

 

Daphna Barbeau (57:31.917)

Yeah. I've got another quick paper, a vibration-based mitigation of noxious evoked responses to skin puncturing neonates in infants, a randomized control trial. This is also in the archives, lead author Lance Relland, senior author, Natalie, I looked like a French name. Thanks, buddy, thanks. So basically what they wanted to do and

 

Ben Courchia MD (57:38.71)

I've been waiting all episode for this one.

 

Ben Courchia MD (57:51.477)

Maître.

 

Ben Courchia MD (57:54.774)

Ha ha ha!

 

Daphna Barbeau (58:00.885)

This makes me very excited because I think if you did a lot of pediatrics work, you know that they're using this in pediatrics all the time. So, why not our babies, right? So what they wanted to do is if they could apply a vibratory stimulus at the site near where they were going to draw blood, would this help with some of the pain mitigation?

 

Ben Courchia MD (58:27.447)

Mm-hmm.

 

Daphna Barbeau (58:29.117)

So there's actually even, I mean, there's a device that you can buy just on the market to take to your pediatrician's office or to use if you have to do injections at home. And parents love this thing. So it's already out there. I did not evaluate the vibratory frequency, though. Now I'm going to go back and do that. The background is obviously that preterm infants in the NICU are exposed to a high number of skin breaking procedures.

 

some experience on average 14 painful procedures per day. So this was a single center randomized controlled trial where infants between 36 and 52 weeks post menstrual age who already had a clinical need for a lab draw were randomized either to a lab draw with or without simultaneous vibratory stimulation. I'm not gonna get into all of the details, but they did two, I think, very cool things.

 

The first is since we're so bad at visually identifying pain, they used EEG actually to look at kind of evoked potentials to look for that as the pain response. They also did use a facial pain scale basically to see how that correlated with the EEG potentials. So that was a cool thing. The second cool thing I think they had is this handheld device. Okay.

 

Ben Courchia MD (59:47.094)

Yeah.

 

Daphna Barbeau (59:51.957)

So basically the only person that's not blinded is the person who does the puncture and they're supposedly not part of the rest of the clinical team. But because this handheld device is an all-in-one, nobody else knows what's happening. And it's easy to both provide the vibratory stimulus and do the heel lance. So it does the vibration, yes or no, it does the heel lance and yeah.

 

Ben Courchia MD (01:00:14.678)

Hold on, hold on, hold on, hold on. How are they blinded?

 

Daphna Barbeau (01:00:18.873)

the rest of the people? No, the person who does the blood is not blinded. But because they know. They have to turn the switch on. Vibratory yes or no.

 

Ben Courchia MD (01:00:21.504)

So the person drawing...

 

Okay, that makes sense because this is basically this... Right, and it's like a remote, basically. The device looks like a remote that has the lense inside of it. So basically, you turn it on, you put it near the heel, and it does everything together. I was going to say, the person will know if the thing is shaking or not.

 

Daphna Barbeau (01:00:32.266)

That's it. Yeah.

 

Exactly.

 

Yeah. Doing it, yeah. But the other people don't theoretically don't know because it's all in one device. The other cool thing this device does is it's a link to the EEG. So it time marks on the EEG exactly when you started the vibration and exactly when the Lancet deployed. So I thought that was like pretty cool. I also think that like, if this takes off, a one all in one thing is the best case scenario.

 

Ben Courchia MD (01:00:47.382)

The VIP, I see.

 

I see.

 

Ben Courchia MD (01:01:02.972)

Yeah.

 

Ben Courchia MD (01:01:09.794)

Mm-hmm.

 

Daphna Barbeau (01:01:09.837)

Okay, they enrolled 134 infants, no serious adverse events, half were allocated into each group, all were analyzed for facial expression, and they had data on all the babies for facial expression. Now, notably, they had a very large proportion of enrolled infants that were excluded for the EEG data because there was so much artifact. So you can take with that what you will, but they had almost an even number in the control and the intervention group, total 81 babies with EEG data.

 

Okay, there were no statistically significant differences between groups at baseline, though I will say, I think our hope was for the preterm infant who theoretically has longer stays, may have more pain-front procedures, but this cohort had a mean gestational age of 36 weeks in the control and 35 weeks in the experimental group. So it's a good place to start, especially because they wanted to look at those visual pain cues.

 

There was no difference in the EEG voltage at rest. So before they provided any stimuli, both groups were comparable in their EEG voltage. And then they had these cool graphs about the EEG voltage in the frontal, the central, and the central parietal and repeated measures on the area under the curve between resting state and immediately preceding skin puncture. So this means that

 

the device is on the baby and it has plus or minus stimulus and has, sorry, this is contact with the device, didn't have any significant noxious evoked response. And then the device plus stimulus also did not have any significant noxious evoked response. So they wanted to make sure that the baby didn't have a kind of...

 

Ben Courchia MD (01:02:45.828)

Mm-hmm.

 

Daphna Barbeau (01:03:05.129)

elevations in the voltage just from the vibration, and they didn't. That's important when we talk about the facial findings later. Now, skin puncture itself resulted in a significant noxious evoked cortical response compared with baseline. There was a significant effect of group assignment on the response. So that means that the experimental group had a much lower noxious evoked...

 

potential than the control group. And this was true in all areas of the brain, frontal, central, and the central parietal. So in the graph, you can see that the babies who had the vibratory stim had lower voltage. Now for this behavioral component analysis, they had good agreement, both intra-reliability and inter-reliability. So that was good.

 

They found that the individual facial component present in the video clip at rest was also expressed during the 10 second period following the skin puncture. So the baby had some facial feature findings, behavioral response that persisted throughout the procedure. The most commonly expressed behavioral components include brow bulge, eye squeeze, deepening of the nasal label, furrow, and mouth opening.

 

But the important interesting thing is that baseline, there were no differences in facial expression between groups. And they found that there were differences when using the vibration. So it was hard to tell. The point was that the baby's facial expressions changed even just with vibration. So it's not really a good marker of pain response since there were no EEG changes for vibration, but there were EEG changes with the skin puncture, even though

 

the behavioral findings were there just with a vibratory stimulus. And so they found a statistically significant correlation between the expression of facial components and both vibratory stim and the noxious evoked brain activity. So this was interesting, I think. It just shows that we're not very good at saying what the pain response looks like in babies, especially the more preterm that they get.

 

Daphna Barbeau (01:05:27.297)

but that this vibratory stimulus may help mitigate some of the pain response with skin puncture. So I thought that was cool.

 

Ben Courchia MD (01:05:34.346)

Yeah. And I always wonder like, how much data do you need? We were talking about this with, with Gabriel, like, how much data do you need for an intervention that pretty much is, there's not, it's low risk and, and has a lot of follows common sense, just a bit like music therapy and so on. Like, do you, how much studies, how much money do we need to invest in studying these when it's like, just turn on the fucking Mozart when you're doing it's like,

 

Daphna Barbeau (01:05:37.592)

Right.

 

Daphna Barbeau (01:05:42.469)

is low risk, no risk.

 

Daphna Barbeau (01:05:53.525)

Yeah, no, I totally agree with you.

 

Daphna Barbeau (01:06:00.658)

I totally agree with you. But that being said, we still have units who aren't swaddling during procedures. They're not giving milk during procedures. They're not doing kangaroo care during procedures. They're certainly not doing vibration during procedures. But I agree. It's a low bar that we could do. It doesn't cost much. We should be doing it for sure, for sure. Thank you for saying what I...

 

Ben Courchia MD (01:06:24.64)

Very cool.

 

Daphna Barbeau (01:06:29.961)

I only have one. It's not even a research paper, I should say, but I think people should read it. It's called Good Enough. It was published in JAMA. It's getting a lot of traction online. I just wanted to recognize Dr. Rissman is a pediatric intensivist, also pediatric palliative care physician.

 

She's a physician mom. And certainly, I think if you've been feeling like imposter syndrome or being overwhelmed or like you aren't balancing all of your plates the way you had hoped that you should definitely take a read. And I think even if you haven't been feeling this way but want to support your colleagues, you should also take a read. Obviously, the article was targeted, I think, to being a woman in medicine, particularly a mother in medicine. But I think this message applies to everybody.

 

We were just talking before logging in about how many plates that we're trying to balance. And I think also kind of this discussion about being open and vulnerable and talking about the weight of our work applies to everyone. So I hope everybody will take a look at that piece.

 

Ben Courchia MD (01:07:41.654)

Is she a NICU mom as well? I want, has she, she may? I follow her on Twitter and I remember her posting something about some experience in the NICU. I may be wrong. Now I.

 

Daphna Barbeau (01:07:45.094)

Ah, you know...

 

Daphna Barbeau (01:07:49.931)

I should know.

 

Daphna Barbeau (01:07:55.569)

No, I think you're absolutely right. She, uh, I think you're absolutely right. She wrote a number of articles that JAMA have published, Becoming a Mother and Gaining Perspective. Yep, they are proud parents of a NICU grad. So she's written a number of things, which I encourage people to take a look at. And I guess speaking of the humanities, as a reminder, we are hosting a night of Stories from the NICU.

 

Ben Courchia MD (01:08:12.642)

There you go.

 

Daphna Barbeau (01:08:23.181)

during the Delphi Conference. So if you're a writer or you're not yet a writer, you just have a story percolating or you wanna be mentored in writing a piece for our event by the amazing Dr. Rachel Fleischman, who's a Neo and a writer, then please email us. Let us know.

 

Ben Courchia MD (01:08:38.966)

Yeah, I mean, that's going to be the theme of the conference, really, not the storytelling. That's one of the big themes that we're approaching. But this idea that through Delphi, if you haven't registered, you should. We're going to have we're going to give people who attend Delphi the opportunity to interface with really exceptional speakers and mentors and things like that. So, Rachel, that you may have listened to the episode already last week on the podcast is an author.

 

published in some of the biggest publications in the US. And an opportunity to work with her on a little essay is not something that's gonna come by every time. We're gonna have workshops where we're gonna give you the opportunity to do some point of care ultrasound stuff with Dr. Gabriel Altit, with Dr. Lauren Ruas and others. This is another cool opportunity to just interface with these guys who are leaders in the field. And...

 

You could ask questions. And really the point is really to make this a meaningful experience, potentially opportunities for future collaboration. Dr. Ryan McAdams and James Berry from the artificial intelligence collaborative group, NeoMind AI are going to give us a workshop on leveraging AI tools in the NICU. And again, the goal is that if you're coming to Delphi, you're going to make connections and not like the business type of like, Oh, you make a connection. You got their emails.

 

But a meaningful connection that hopefully can lead maybe, who knows, could be a career defining interactions where you say, I met this person at this, we really hope so. We really hope so. So yeah.

 

Daphna Barbeau (01:10:12.629)

We hope so.

 

Yeah. And we were talking about dominoes at the beginning of Journal Club, but we've seen a lot of domino effects from the last Delphi. So we hope that everybody can experience that.

 

Ben Courchia MD (01:10:26.014)

Absolutely. So just consider registering. We're not full yet. There's room. Also, if you're a fellowship program and you want to participate in the trivia contest, sign up. There's a nice award. And yeah, all the information is on our website and on the Delphi agenda. So if you have any questions, email us. We're slow to respond, but we respond.

 

Daphna Barbeau (01:10:40.333)

Mm-hmm.

 

Daphna Barbeau (01:10:52.369)

I mean, I don't think we're so slow to respond. We've had some scheduling, some scheduling trouble, but now we're back on track. So email us, email us questions, concerns. You'll hear from us directly. Okay, that's it. You too, bye.

 

Ben Courchia MD (01:11:00.266)

back on track. Sounds good.

 

Ben Courchia MD (01:11:05.63)

All right, Daphna, have a good rest of your Sunday. Bye bye.

 


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