#009 - Journal Club - ELBW aging, Prongs in the delivery room, Skin-to-skin and Edi, Probiotics and more

As always, feel free to send us questions, comments or suggestions to our email: nicupodcast@gmail.com. You can also contact the show through instagram or twitter, @nicupodcast. Or contact Ben and Daphna directly via their twitter profiles: @drnicu and @doctordaphnamd. Papers discussed in today's episode are listed and timestamped below.
enjoy!



06:05 - Extremely Low Birth Weight and Accelerated Biological Aging. https://pediatrics.aappublications.org/content/147/6/e2020001230

13:48 - Early Determination of Prognosis in Neonatal Moderate or Severe Hypoxic-Ischemic Encephalopathy. https://pediatrics.aappublications.org/content/147/6/e2020048678

19:55 - Use of Probiotics in Preterm Infants.h ttps://pediatrics.aappublications.org/content/147/6/e2021051485

23:20 - Use of Probiotics to Prevent Necrotizing Enterocolitis. https://jamanetwork.com/journals/jamapediatrics/article-abstract/2780228

28:00 - Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks’ Gestational Age. https://jamanetwork.com/journals/jamapediatrics/article-abstract/2780513

40:49 - Parent–infant skin-to-skin contact reduces the electrical activity of the diaphragm and stabilizes respiratory function in preterm infants. https://www.nature.com/articles/s41390-021-01607-2

51:00 - Lung mechanics and respiratory morbidities in school-age children born moderate-to-late preterm. https://www.nature.com/articles/s41390-021-01538-y

59:00 - Early prediction of neurodevelopmental outcomes at 12 years in children born extremely preterm. https://www.nature.com/articles/s41390-021-01564-w

As always, feel free to send us questions, comments, or suggestions to our email: nicupodcast@gmail.com. You can also contact the show through Instagram or Twitter, @nicupodcast. Or contact Ben and Daphna directly via their Twitter profiles: @drnicu and @doctordaphnamd. The papers discussed in today's episode are listed and timestamped on the webpage linked below.

Enjoy!

Transcript

Ben: 0:05

Good morning, everybody, Daphna, how's it going today?

Daphna: 0:52

I'm doing great. You're the one who's on service. So

Ben: 0:55

I've been on service every other day. It's just like, I live in the hospital. But things are good. I can't complain.

Daphna: 1:02

That's good. That's good.

Ben: 1:05

Again, we are very happy to, we have a few announcements, actually, that we wanted to get out of the way before we start Journal Club. Number one. As always, we want to thank everybody for the feedback, we're getting so much feedback on on the podcast, and it's so positive, so constructive. And so we want to thank people for trusting us with their time downloading the episodes and, and giving us positive feedback and constructive feedback. So we're thankful for that.

Daphna: 1:34

Yeah, agreed, you know, engaging with us and letting us know what you think

Ben: 1:39

we like it. Yeah. And continue continue reaching out to us on Twitter. I mean, Daphna is the one doing most of the of the responding on the on the on the Twitter account. It's again at Nikki podcast, but we we are responding to messages, and we are responding to tweets and retweets, and we're doing the best we can. So please, interact with us, we're happy, we're always it's always cool to engage with the audience. On another note, we are introducing a new series of episodes in our podcasts, and these are book clubs. So we're very excited to start book clubs, they're going to take place on weeks where we're usually have an interview. And we will give you guys the lead time to read the book. And we are inviting you to submit questions to the author. And we will interview the author on the podcast and submit a selection of the questions that we receive or all the questions if we have time to get around to all of them. And, and we'll ask them to the author. So the first book we're going to do will be will be released on the episode will be released on August 1. The book is called The Strange Case of Dr. Cooney, how a European showman saved 1000s of American babies. It was written by Don raffel. And she will be on the show with us. At the end of the month, we'll record the episode and we will release it on August 1. So please send us your questions before July 23. And you can send them either directly to our Twitter account at NICU podcast or to the email NICU podcast@gmail.com. This is going to be done in partnership with the Met book club on Twitter at med book club one. So yeah, that's now any thoughts on on the book club.

Daphna: 3:23

But you know, this was your selection. So I'm halfway through the book, I think people really enjoy it. And it's got a lot of, you know, historical reference, I especially enjoyed the descriptions about what life looked like, within their kind of tiny model NICU. So I think it's an interesting choice. I think it'll be really fun to speak with the author, it will be I get to pick the next book.

Ben: 3:50

That's right, you do get to pick the next book. And and this was a gamble. By the way, I have no ties to this author, and we just randomly emailed her and she was so generous with her time to say, hey, I'll be happy to come on the podcast. And, and the book is really cool. It talks about sort of the incubator shows in the early 1920s and 30s. And it's kind of interesting to see the origins of the neonatal ICU. I mean, it's it's, it's not something you would expect, I guess, if you if you don't know the story.

Daphna: 4:19

Yeah, I think it's a fun one. I think anybody who is engaged in neonatology has has to, you know, really learn about the origins. Yeah. And

Ben: 4:27

I think that's the other thing, the book was written mostly for a wide audience. So it's, it's an easy read. It's not a big book. And, and the author writes really well. So it's easy to engage with the book. So please pick up a copy. It's available everywhere, Amazon, it's available in Kindle audiobook. It's everywhere, whatever you need, so you have no excuse, get the book, read the book, and then send us your questions and we'll submit them to the author. All right, any other announcements?

Daphna: 4:59

No, I think you can I've read everything. All right, that's awesome.

Ben: 5:01

We're growing. It's a little, little engine that could you know,

Daphna: 5:05

it's exciting. Yeah, it does feel like that some days doesn't fit, right. We're staying up late reading articles waking up early reading articles, but it's been fun. So we appreciate everybody's energy and excitement. Yeah,

Ben: 5:18

the podcast has made me read articles on a very consistent basis. And in the gems that you find on a, on a monthly basis in various journals is kind of amazing. So I'm very happy that I get to do that now. Anyway, let's begin journal club this. Today, we're gonna start. Should we start with pediatrics Daphna?

Daphna: 5:41

Sure you you always let me pick first pick first. Go ahead. No, no, no, I'm saying it's your turn to pick first.

Ben: 5:48

Well, talking about cool articles, I want to talk about pediatrics. And in pediatrics, this month, there's a new article called early determination of prognosis in neonatal Oh, that's not the one I meant. I apologize. I clicked on the wrong one. Let's start that again. The it's still in pediatrics, but it's called extremely low birth weight and accelerated biological aging. The first author is Ryan Van Lieshout. And the senior author is Lewis Schmidt. They're from Ontario, Canada. Lots of good research coming out of Canada. They're busy, they're busy. And so it's such a cool study, it's looking at how fast do ERP double use a extremely low birth weight infants age compared to controls. So in the article, they say using the oldest known longitudinally followed cohort, a via BW survivors, we compared biological aging in his group, using an epigenetic clock to a sample of matched normal birth weight, infants controls. And they. So the way I was very curious when I read the title, but how do you measure aging. And so they're introducing or at least introducing to me this idea of this epigenetic clock. And it has garnished interest according to them as a novel measure of biological aging. And basically, it looks it indexes Saito zine five methylation within the CPG dinucleotide, also known as DNA methylation, so they're basically they're looking at a marker of DNA methylation, and the the amount of methylation associated with biological aging. And what they were trying to do was to compare the differences in biological age between the group of ELB W's and and, and controls, using that methodology. Were you familiar with that process, because I was I really wasn't.

Daphna: 7:45

Yeah, you may not know this about me, but I have a freezer full full of that my own personal freezer. My mentor freezer is full of beautiful swabs awaiting CPG methylation analysis.

Ben: 8:00

So tell us about it. This by the way, we have to tell the audience this is not a setup, like I am finding this out, as we speak.

Daphna: 8:08

Show I my interest was a little bit different. It was in the serotonin receptor as it relates to kangaroo care. But I mean, this is the same concept looking at the methylation, the epigenetic, you know, changes in in, in our genome as we as we go along. And frequently it relates to stressors that we encounter. And some of these are heritable. That's not what they were studying. But that makes it I think, even more interesting. But they looked at a pretty wide range, they looked at 353 sites known to predict chronological age, or as they call it epigenetic age. So I think they set that up, as well as they,

Ben: 9:00

yeah. So they had a cohort of babies that were born between 1977 and 1982. And they follow these babies until 30 to 35 years of age, which is kind of nuts. And they had about 100, so they had 394 Babies 180 About so 45% survived to discharge, which by the way, just reminds you of how bad mortality was back then. Right. And then they were able to complete follow up on 142 survivors. And at the end of the day, in order to get the glucose swabs, they were only able to get it from 45 patients. So I'm sorry

Daphna: 9:45

30 at 30 to 35 years, though, which is pretty actually not so bad. It's pretty impressive. If you

Ben: 9:51

can get that many patients at 35 years after they leave the NICU. Well, kudos to you. And so they looked At, they looked at various comorbidities, obviously they looked at neurosensory impairment. And they looked at chronic health problems in adulthood, which obviously, when you're looking at aging, these factors can contribute. So they, they adjusted for these. And when they looked at the the differences, well, it appears that your bw is age faster compared to matched full terms. And when they did the stratification, that was actually quite impressive, because they said, stratification by birth weight and sex reveal that ELB W men were epigenetically older, compared to full term by 4.5 years, 3.77 3.7 years older than LBW women, and three years older than full term women. And after all these adjustments, this all these all these interactions remained statistically significant for all these other covariates that we mentioned earlier. And even they mentioned that the epigenetic clock underestimated chronological age in all groups. But even taking that into account, the difference was still very pronounced in ELB W's. And so there's, there's there's concluding that there's a supports a differential rate of epigenetic aging among the LBW men in adulthood as well.

Daphna: 11:24

Well, we're just learning so much more and more about how, you know, our early life experiences, I mean, shape our trajectory, basically, forever. And certainly, you know, why would we think that being in the NICU, which in and of itself is is a traumatic, you know, stressful experience? wouldn't wouldn't, you know, factor in into that. And this also gives us an opportunity to give a little, put a little spoiler alert out for our next and upcoming interview he have, where we talk to, you know, adult adults who are born premature, and what their life looks like. And, you know, we really get to talk about the comorbidities associated with being born prematurely. I think it's great that they have this group that they were able to follow and that they're continuing to follow. To give us more information about that.

Ben: 12:26

Yeah, I mean, this this is an interview that we did with a former 28 weaker that lives in the UK. And it's fascinating, because she's talking about these things as to when you go to your primary care provider, should you mention that you were born at 28 weeks? And these articles clearly state that? Yes. This is this is a risk factor. And the same way that Cardiology is evolving to include now, adult congenital, we're going to need to figure out these babies now are now surviving. And, and there's, there's a lot of work that is left to be done in adult survivors of prematurity. So I was not familiar with this methylation technique to assess epigenetic age, I think this was really cool. And this is something that potentially can become a nice tool to use for other studies. So

Daphna: 13:15

yeah, absolutely. And, and even looking at interventions and how does it protect against the epic, you know, epic, epic genetic changes, I think are really interesting. Yeah. So I think we'll be reading a lot more about that.

Ben: 13:32

Do you wonder the journal,

Daphna: 13:34

the journals this month were full of long term follow up? That's actually

Ben: 13:41

let's, let's, let's go to the next article. And in pediatrics, where this one this is the one that I sort of stumbled upon initially with that it talks about early determination of prognosis in neonatal moderate or severe hypoxic ischemic encephalopathy. This was a study done by the neonatal Research Network. And what they did was trying to determine several things from initial sort of markers, I guess, or risk factors. And they were trying to develop a scoring system to to get a better prognostic model. And so this was a secondary analysis on a trial that was published about comparing usual cooling with deeper cooling and longer cooling. This was published, I think, in JAMA where they looked at cooling over 120 hours, and instead of 33 degrees, I think they went to 32 degrees. And the outcomes were pretty much not very different from one another. Regardless, this is the same data that they're using. And here they looked at weather. The different markers at birth or in the first six hours of age could predict several things, death or disability, and in hospital mortality, and They used, it's interesting, because they use, they identified several markers that were quite predictive of, of these things. And interestingly enough, they did not come up with a singular score for both outcomes. So when it comes to death, or death slash moderate or severe disability, the items that they identified to include in their model was spontaneous activity, Apgar score at five minutes, seizures, emergency C section and the absence or week, or week or normal suck. And they found that these factors predicted death or moderate to severe disability pretty well, when it came to not the other score for death during the initial hospitalization, they found that the most sensitive factor was spontaneous activity. And then the added maternal age, uterine rupture and or an abnormal suck. What did you think about the article?

Daphna: 16:05

Well, I think we're all trying to find any, anything, any kind of predictive bottle to give more prognosis to make a decision about cooling, to give better, anticipatory guidance about the outcomes. And so anybody who's studying HIV is trying to say, you know, what, what can we put together? Is it the clinical history? Is it really the clinical exam? Is it the laboratory bindings? Is it these biomarkers? And can can we put enough of those things together to give some sort of predictive matrix? I think this just follows through, you know, that the clinical exam is important. We know that the star not scoring predicts outcomes. And, and so I mean, I that's really what I took away with it, all three models, were actually pretty comparable. And in predicting death, death or disability, some of them had overlapping criteria. And so

Ben: 17:10

and so that was what was interesting is that this new model was, like you said, relatively comparable to other ways of assessing in hospital mortality or death and disability. But this new model was somehow much better for in hospital death with nearly 7%, correct classification. And they started using, I think, some some machine learning as well. And so I think this is this, the bottom line is, for the clinician, I don't think you're taking any of that stuff to the bedside right now, I don't think you're replacing your SAT score, like you said, but it's starting to, number one, incorporate machine learning into prognosis and sort of risk stratification, number one, number two, starting to look at things a bit more granularly in terms of separating the outcomes, because obviously, disability death and disability is one thing and in hospital mortality is an it's a complete as it is another. So I was interested about how this is sort of opening the approach to HIV to a bit more in a bit more granular level. I think that was that was interesting.

Daphna: 18:20

Yeah, I think we're able to refine more and more, what are the kind of key features that that may help us predict, you know, outcomes, but but, you know, parents do ask that question. You know, will my baby leave the unit? You know, that's their first question. And so, I think any, any information we can give them is beneficial. And we're getting there. I think we have a long way to go. But you know, we're, we're starting to refine that.

Ben: 18:51

And I think what was interesting is that they used machine learning algorithms to sort of detect which factor was really predictive. So for example, in this card model, they said for death, or disability, the top predictor for death or disability variable was spontaneous activity. And I think this is kind of nice to know. Because if you have if you see this, then you can, like, I know, we have our Sarnat score, but which one is more important? Which one is the best predictor? We don't know? But we're getting that information seems to be now trickling in. And so that's, that's really, I think, really helpful.

Daphna: 19:23

Yeah, and what exactly like you said, what parts of the physical exam like the you know, the sack is frequently you know, the first thing that go the last thing to come back and so, you know, it gives you sometimes it's the only thing that's, you know, abnormal also. So I just think it gives you something to, you know, pay paid, like pay closer attention to.

Ben: 19:45

Absolutely, absolutely. All right. I guess the last article that we highlighted for this month was this it's not really an article but it's a it's a statement from the AP regarding the use of probiotics in preterm infants. Do you want to take a stab at it? Or should I go ahead?

Daphna: 20:07

Well, I thought it was well written, I think, you know, we've actually talked about probiotics few times on already in our in our short stint on the podcast. And that, you know, there, there wasn't really a quote unquote, consensus. I'm not sure there still is a consensus, because I think Dr. Poindexter laid it out pretty well, by saying, so what are what are the factors? You know, we need to say that this is safe and effective. So the first is, do we have trials that say it's safe and effective. And actually, we do have trials that show that probiotic use is reducing neck, which is a big cause of morbidity and mortality in our extremely preterm babies and our moderately preterm babies? And do we have a product that has been routinely tested, it's been validated by our kind of Food and Drug Administration, and we don't. And so the the studies that have been done are so heterogeneous about what which bacteria is being used, how much of that bacteria is being used. And so we can't really say which, which is the right choice. And since it's really been used as a dietary supplement, and not so much as a medication, it's just not really been standardized. And probably the other most important point, she makes sense that in those studies, there were very few babies less than 1000 grams, so probably the highest risk babies, both for neck but also complications, you know, that we might be concerned about, with the use of probiotics, we're not totally well represented. And so, you know, I think they took a bold step to say that they don't recommend probiotic use, and that in units that were going to engage in probiotic use, that they were diligent about picking kind of the right patient population. Yeah.

Ben: 22:27

I mean, the this report, we should call this says, quote, current evidence does not support the routine universal administration of probiotics to preterm infants, particularly those with a birth weight of less than 1000 grams. And like you said, it's mostly because of practical, I think issues.

Daphna: 22:45

Yeah, and you and I have talked about this before about how much you know, how much data how much data do we need, there are lots of things in neonatology that we don't have that much data for. And so, you know, probiotics is an interesting discussion, because we, we do have some data, we do have some data that it's potentially protective. But we're just going to have to narrow down what's the safest way to get the most efficacy out of the product.

Ben: 23:15

And I think I think that's where this leads us straight into this viewpoint that was published in JAMA peds so we're switching gears a little bit from pediatrics to John peds. And this this viewpoint was published by I guess we can call him our good friends, Abdul Razak, again, who's on Twitter at Dr. Abdul Razak, underscore MD. And they published something that's called the use of probiotics to prevent any see evidence to clinical practice. And it's funny because I don't believe that they wrote this. It was published, like may 28, I don't believe and I think the statement from the AAP was published May 26, or may 27. So it felt like most like a response and immediate response, which I don't think it was, I think it was written way before, but they're making an argument that I think supports the current clarification that needs to be had regarding probiotics. They're talking about this Cochrane review that included 56 RCTs, that included 10,000 babies, and they're undergoing through pretty much in a very concise manner through the evidence that shows that clearly, there's there is enough evidence to suggest that probiotics reduce the risk of any see, but they are highlighting that they are highlighting a few factors that are going to pull up cause problem in terms of getting into practice. The first one that they mentioned, I'm gonna go through, there's not that many of them, I think there was three. So the first one is what you've mentioned, is that first, unlike pharmaceutical products currently available, probiotics are not regulated as a drug, and we don't really have anything that's FDA approved. The second factor is evidence in quality. And in the Cochrane dimensioned, the Cochrane meta analysis, they they're saying that a lot of the evidence has been downgraded to Quality due to limitations in the trial designs. Third, they're talking about these concerns for systemic sepsis with organisms present in the probiotic preparation something, again, that you mentioned in the AP article where they're like, you know, you're not sure how much probiotic how much bacteria you're getting from sample to sample. However, I think what was interesting is that they, they're saying, it's unlikely that we need more trials, which was one thing that the AAP sort of said, they said, oh, we need we need a bit more evidence. There's their statement here is we don't need more trials. We know it helps. And in order to prove that they did something that was very clever, which is that they they ran a fake meta analysis with potential scenarios. And basically, what they did is that they said, Okay, let's assume that more data is coming out. And let's plug it in, to in addition to the other trials that we have, and they had four scenarios, the first three included a hypothetical trial of 1800 infants in which probiotic supplementation compared with placebo related related resulted sorry, in a relative risk of neck of case number one 0.5. Case number two 0.67. And case number three, one. And so even as the relative risk increased, it still didn't change the main analysis. And then in order for them, they then ran a fourth scenario in which they said, Okay, what is it going to take for the evidence to really switch completely back to midline and not favor the use of probiotics in NEC, and that scenario, D. And they said, that would represent a trial of 80,000 infants in which probiotic supplementation compared with placebo results in an relative risk of neck of one. And so obviously, that's very telling, because this, this shows how unlikely it is. And so I think in In summary, it's showing very well that we now understand that theoretically, by probiotics do reduce neck, we have evidence that it does, now it's up to us to come up with a formulation that we can actually use and regulate and control. And that's really where we're at. It's not that probiotics are not recommended by the EPA, because they are not good. It's just because practically speaking, we do not have the infrastructure in place to deliver that to the babies.

Daphna: 27:16

Yeah, and that's true for a lot of, you know, over the counter supplements, you know, and I, you know, I think there is a pathway for them to be better regulated. And it's something that, you know, I think we can advocate for because because we do have some data that it's protective, and we know that neck is such a potentially catastrophic, you know, consequence of prematurity. Yeah. So it was interesting, interesting, ongoing debate as we as we should we should we stick with JAMA, peds and

Ben: 27:57

lead the way? Yeah.

Daphna: 28:00

So, we wanted to talk about this article comparison of respiratory support after delivery and infants born before 28 weeks gestational age, the core, the core sad randomized clinical trial, lead author Snorri. Donaldson, the trial was conducted in seven ICUs across five countries from March 2016 to May 2020. So Nick, US and Sweden, Norway, Poland, Lithuania and Iceland. So a randomized clinical trial where they were actually able to enroll babies who really moms came in and kind of threatened imminent delivery before 28 weeks, so I thought that in and of itself was a feat of science, that they were able to do that. They they enrolled 365 mothers and 250 infants were able to be randomized before birth. Unfortunately, there were a number of deaths just because of prematurity, and then they were able to actually follow 246 Live born infants. So they follow followed up 72 hours and

Ben: 29:20

this was this was a stillbirth, right, though that was before

Daphna: 29:25

the deaths. That's right. And so the intervention babies were either randomized to kind of the standard T piece PPV system with the facemask so 122 infants were randomized to that arm or a new modification, a respiratory support system with short by nasal prongs that could still provide obviously peep, peep and PPV. So 124 infants were rolled in that arm so we can tell you about a little bit about some of the baseline criteria, the mean gestational age for the infants was 25.9 weeks. So you know, significantly preterm group 5050, male and female, they were looking for a perm a primary outcome of combined death or need for intubation in the delivery room, I thought they did a good job of outlining their criteria for delivery need for delivery room intubation. And I'll list those just so people have that background bradycardia less than 100 beats per minute, despite effective PPE for a minute persistent apnea, poor respiratory effort, inadequate oxygenation and respiratory distress. So those would be the things that would cause them to intubate babies in either arm. And then they looked at secondary outcomes, time to first intubation, if needed, use of surfactant use of PPV mechanical ventilation within 72 hours and respiratory support is 72 hours. In addition, they looked at a variety of safety outcomes, they looked at ivh, they looked at a pneumothorax. And then again, the need for respiratory support up to three days. So all in all, they had 41 infants, or 33%, in the new respiratory support system, who required intubation, or head death into the delivery room compared to 55 events or 45%, receiving the standard care with the TPS resuscitator. So they felt that their their new kind of modification was an improvement over the the tea piece, which is really kind of become the gold standard in delivery rooms, really worldwide. Were available. And in regards to the secondary outcomes, they didn't find any really statistical significance in terms of the need for surfactant, the mechanical ventilation at 72 hours, which I thought was interesting. And safety outcomes, no difference in the safety outcomes. Obviously, you know, I think we're all interested in the the long term effects of respiratory support. And, you know, they didn't even mention this about how many studies are looking at BPD as an outcome measure. And so they were really looking at the short term, respiratory outcomes. What did you think?

Ben: 32:43

I thought it was fascinating. I think it's a big, big article, I think if you have an article that you need to read carefully, this this time around, this is the one this may impact how we do NRP. This, this is the kind of stuff that really leads to changes, in my opinion to practices in the delivery room. What's very interesting is that it's making a lot of different points. Number one, it seems that the mask is just not a good way of it's not a good interface for babies. It automatically made me think of this article about late preterm babies that when they needed face mask sort of resuscitation either with peep or with PPV needed more admissions to the NICU. And there's this cardio. I'm going to butcher this now. This trigeminal cardiopulmonary sort of reflex reflex, where basically if you put pressure on the right spot on the faces, you cause apnea. And so they found that in late preterm, doing applying the mask improperly can cause apnea and then you freak out. You bring the baby to the NICU, when in truth, you could have avoided all this by just a different way of ventilating the patient. So it's not like the mask is not good for the extremely low birthweight, but it's better for the bigger ones, it seems that it's not the best way to ventilate our provide positive pressure. So that's number one. Number two, I don't know practically speaking, if it does spell the death of the TPS, right. The tip is technically you connect to the mask, but can you connect it to a set of OptiFLOW sort of cannula, right? I don't know about that. I don't know. And then you could potentially deliver consistent pressures, using your TPS through the nose in an nimb type of fashion. So that I don't know if it because I'm trying to think of how can we implement this in any NICU without having to purchase new material or having to really change all the equipment? You can? I think the first thing that came to mind was something that we used to do ourselves when we were at GA measure where we had the transport vents brought over to the delivery room. And that's if you have those things and usually if you're not out on the transport, this is very easily achievable. You go to an extremely low birth weight babies delivery, you bring the transport vent and you connect these problems right away. It's not too difficult to do. But let's say you don't have that you could potentially still use the teepees and connected to the, to the cannula. What was interesting is that they, in the introduction of the paper, they start right away talking about some theoretical problems that are, I think, very important for us to remember. And they introduced this concept that I was not familiar with, of imposed work of breathing. So I w OB is the is the acronym that that is being used. And they said, when supporting a breathing infant with CPAP, the infant will be challenged with additional workload that is needed to breathe through the system. And this extra work is called imposed work of breathing. And they say the most commonly used system for respiratory support and the DRS the TPS was in order to have high impose work of breathing during simulated breathing and a bench trial in 2012. And this led to the hypothesis that SIP CPAP support with a lower AWB might increase the number of infants who establish stable breathing after birth. And I think that's true. When you think about the mask, you put the mask on, and the baby is having to breathe through the nose and mouth against the peep. They don't have that release valve that they have, when they have the cannula where if they have their mouth open, you can blow off a little bit of that pressure. So that's why I think I mean, this is a type of article where I find myself sort of highlighting every paragraph, there's something more valuable. And so I think I think this is something that, again, is going to change practices. And this was not a minor change when you're talking about babies. They they did not cop out. I mean, sometimes you have these trials, and they they do these trials, and they have babies for like 31 weeks, and you're like, like, do I really need this for 31 weeks, but they were big. They were small babies, they were 25 weeks, and the difference in intubation. 33% the intubation or death in the delivery room 33% With the new support 45% with the TPS now, big difference. Big difference. Could you look at the rate? I mean, it's a huge difference. It's a huge difference. It's very significant. And it's the type of things where Yeah, I think that that changes practices right away. I want to emphasize one more point is that their outcome was death or intubation in the delivery room. So when we talk about the fact that they had 33% in the one group and 45% It's not like 45% died in the delivery room, right? They were not.

Daphna: 37:38

There were still there still were not very many deaths. That's no,

Ben: 37:41

there were not that many deaths, when you look at their outcomes, the babies who died in the delivery room, I think it was one and three. And that difference was not significant. Now, the bulk of these 30% and 40% were mostly intubation. So I don't want people to say, oh, you know, so many kids died in the delivery Rome. And no, no, no, it was 32% with the new system, who needed intubation in the Dr. Who didn't die 44% Who needed intubation in the DR with a TPS who didn't die. And I think the death rate for like 2% for the new system and point 8% for the TP. So again, it's no sustained inflation as well. They mentioned that but yeah, that was that was that was a big article.

Daphna: 38:26

Well, I think even in the in the short term before we you know, renovate all of our equipment, I think it's just a good reminder that, you know, the TPS and the mask, there's their optimal ways to use them. Right. And so for especially those of us who are working with trainees, you know, I think we can teach really good management and a seal doesn't mean that, you know, smash that poor little baby's face. And in fact, that can be detrimental to the resuscitation. So I think if we can take anything right away to the bedside, it's just optimizing our mask placement. And in teaching others to do that, because it's the difference between, you know, recovery in the delivery room, and, you know, secondary apnea and then in the delivery rooms, and

Ben: 39:23

and hopefully, it's not a big leap. I mean, so many, like so many therapists take the nasal problems with them because of how they're going to need to transport the baby from the delivery room to the NICU. So if the problems are there before the baby's born, it's not much effort to just switch over. So I think it's something to consider. I mean, it's, it's, it was it was a good article.

Daphna: 39:43

And I do think some units have a long transport. We're using the TPS and so that that's something we could potentially, you know, modify, maybe get out of the Dr. Transition to, you know, some sort of transport interface instead of bagging out across the hallways or alleyways or, you know, skyways to get back to the unit was interesting. Yeah, that

Ben: 40:11

was fast. That was that was good. Where are we going next off now?

Daphna: 40:17

Well, you know, I'm gonna want to talk about this article in pediatric research about skin to skin care.

Ben: 40:25

So I was very first of all, we're introducing a new journal to our list. It's pediatric research, which we stayed away from, because again, the pediatric research journal has has a podcast as well, which I invite you to check out but we were invited by one of the editors to start reviewing some of their articles. And we're very happy that this happened this month, because that article was just a breath of fresh air. Go ahead, I'm gonna let you

Daphna: 40:48

so it was entitled Parent Infant skin to skin contact, reduces the electrical activity of the diaphragm and stabilizes respiratory function in preterm infants lead offer Jiang Li, and this was done in Finland. So that's it.

Ben: 41:07

So the one thing I wanted to before you start, because it's so important, let's go over you want to go over what the EDI is, are for people who are not using Java so that when you do mention the outcomes, go ahead. No, go you go.

Daphna: 41:21

You go. You this. I know you have a a minute and a half chalk talk on No, I'm not. We're not it's been well received.

Ben: 41:29

So we're not going to talk about Nava. But the Nava mo uses a catheter that has electrodes in it that are placed in the esophagus and supposed to measure diaphragmatic activity. And this is what EDI stands for electrical activity of the diaphragm. And you have EDI peaks and EDI means which are the peak electrical activity, usually during inspiration. And the main which is the tension in the diaphragm at the end of exploration. So really, it looks at the work of breathing in a very invasive way. The novom ventilator uses that information to then deliver synchronized non invasive or invasive breaths. We're not gonna go into that, but the EDI this is what is this is what we're discussing. Go right. Thank you.

Daphna: 42:14

No, I think that was that was a good point. Since they're their units who aren't aren't using a lot of Nava we, we in particular, like Nava, and I think for the right baby, it can be a really good device, but also that you can get a lot of good information about the baby. And that's exactly what they did in this study. And it's a it's a tall order with what they wrote here and in the title. But that's that's what they found. So they actually they had a small cohort, 17 infants, all less than 36 weeks on Nava, so some of them were invasive, which means infants were intubated still using the novel technology, or non invasive Nava which is CPAP. With assisted synchronized support using the novel device. The median age was 27 weeks range of 23 weeks and four days to 33 weeks and five days and a medium median weight of one kilogram, but the smallest infant 460 grams to 2.8 kilos. And so I think that's an interesting point also because even in the units that are using Nava, there are some units that are avoiding using Nava and very little infants. So I thought it was nice to see that that they were able they were using Nava with success in very, very small infants. So they looked at 167 episodes of skin to skin care recorded from those 17 preterm infants. They had 138 episodes during invasive novice who again intubated babies and 29 episodes during non invasive Nava So another big point is that a lot of their babies were intubated during kangaroo care, which I like to see. And so basically what they did is they monitored the baby looking at the novel levels or looking at the EDI peaks EDI mins the respiratory rate the time in backup ventilation because the novel support does provide for an apnea time after which it will resort to backup ventilation peak inspiratory pressure and mean airway pressure. So they put babies supine or prone skin to skin. So during these periods of skin the skin care they looked at the kind of novel parameters so the EDI peak CBI mins respiratory rate time on backup ventilation because the novice system does allow for an an apnea a set apnea time after which it will trigger a backup support, peak inspiratory pressures and mean airway pressures. So they had babies prone skin to skin, they gave them a 10 minute kind of wash out period transition time. And then they monitored all of these parameters during that episode, and then they return the babies back to their isolettes or to their bassinet. And then the following night, they basically did a match period. So they looked at time from last feed, they looked at time spent in kangaroo care. And so they tried to really control for some of those factors so that they had a similar period of time. And again, they monitored the same respiratory parameters. And and what they found is that especially during invasive Nava, so babies who were intubated using Nava almost all of the parameters the EDI peaks, Edi mins the respiratory rate, the time on backup ventilation, the PAP is the maps all significantly lower in skin to skin care than in kangaroo care.

Ben: 46:19

Or then that was very important. That was very impressive. Yeah.

Daphna: 46:22

But but all of them were lower in during the periods of skin to skin care then in incubator care. Sorry, I misspoke. And then for the non invasive Nava, so babies who were not intubated but still using the novel technology also impressively so the EDI peaks EDI mins the time on backup ventilation, the PAP is all significantly lower during skin to skin care than in incubator care. And so I think, you know, we talk a lot about kangaroo care, you know, I'm a huge fan. But it's, it's more than just bonding, right, which I think in and of itself is is enough to recommend the therapy. But that we can get, you know, some other benefits, some, you know, real statistically significant benefits that may impact the baby during the time they're being held, but also may carry over to, to support them between kangaroo care periods. And so as we're, I'm so glad that people are studying it, and, you know, putting putting, finding all these parameters that are improved. And, you know, I think we so much everybody thinks about the risks associated with kangaroo care, taking babies out of the isolette, taking babies who are intubated. But at some point in time, I think, you know, we're proving that there's a risk to not doing kangaroo care. I said this, just last night, I was imploring the nurse to, to think about the risks of of not doing it. And I think soon we're gonna have enough data to say that we should be prescribing it when, when possible, I imagine that there's some sort of dose response associated with it also, that we haven't proven yet. But that we should treat it like any other medication in the unit and give it its due diligence and study and, and be talking about it every day on rounds. That's, that's what I feel about the study. How about you

Ben: 48:39

know, this? I think about this, I agree with everything you're saying. And I think to me, it speaks on two levels, there's a, there's a scientific level, a very evidence based process, and there's a mystical level. Number one, on the mystical note, there's this idea of synchrony between mother and baby, that happens in utero, where the baby is, is going at the pace of the mother's heartbeat, and so on. And so the baby is used to this sort of homeostasis, and, and the closest thing we can do after preterm birth is doing skin to skin and and it's showing these these these data, this data is showing that it is there is that that synchrony that's almost restored where the baby's work of breathing suddenly gets better. Like it's just, it's just insane. The fact that

Daphna: 49:28

many moms and daddies who, you know, were so nervous to do their first kangaroo, or the second kangaroo or their, you know, seventh kangaroo, but I say, you know, I said, Well, how's the experience? And they'll say, Well, you know, the baby was sat in 100% the whole time. And I said, Yeah, I'm not, I'm not surprised. And so I think now we have some data to really support what we've been observing at the bedside and it's

Ben: 49:55

so it's so cool that we do test it and it works. And it's tangible evidence. From an evidence based standpoint, I'm going to join you in your in your thought about we should do more kangaroo care, I always try to play these games, these mind games with myself where I try to replace the the the intervention with something else. But let's say that this was a paper on a brand new incubator, and you say, Hey, you put the baby in this brand new incubator, and the technology is such that now all the EDI and all the respiratory metrics, or all the way down, we would line up, we would line up to buy this new incubator. And it's not a new incubator, it's just skin to skin. Now, I think this is a strong emphasis on we need to do more of it. But also, I'm thinking, we need to start, I am tend to think of skin to skin at this as this sort of private moment between the mother and the baby. And that, you know, we have to give them space, and so on and so forth. But maybe not, you know, maybe this is also, as we maximize the time during skin skin between the baby and the mother or the father, then maybe this is also a time where we could do certain things and test the baby and try to see when the baby is in its optimal sort of conditions to do a win or to do things like that. I think this is this is where it opens the door, I think to even more trials and more and more interventions,

Daphna: 51:16

when now you're getting fancy. Right. The only thing I would have like, like to have seen is they didn't talk about positioning during the incubator care. And we do know that some of the studies have shown that you know the prone position which is which is the position babies are in during kangaroo care may improve some of the respiratory mechanics. So that's the only thing I don't know if they controlled for for that position, baby supine baby prone during incubator care. But I don't think it takes away anything from from the data. So

Ben: 51:52

no, that was that was such a cool paper.

Daphna: 51:54

Really cool. Well, what would you like to do next?

Ben: 51:58

So let's say let's then pediatric research. And there was another article that I thought was a good one. It's called lung mechanics, and respiratory morbidities. In school age, children born moderate to late preterm. The first author was Fabian dantas. From a should have highlighted from Brazil. This is a study from Brazil. And so what they were trying to do is to investigate lung and mechanics in school aged children who were born moderate to late preterm. So the included school children, male female, between the ages of five and 10 years of age, and all these kids were born moderate to late preterm, which were they, which they defined as 32, to less than 37 weeks. So 37 weeks excluded. And they had a control group of children who were born at term. And what was interesting is that they performed pulmonary function tests on them, and they looked at their pulmonary function. The average the mean gestational age on these babies was 34 weeks. They were 52 infants, they mentioned that the sample was just a convenient sample, they basically get grabbed whoever, whoever they could. And they study them. They did mention a little bit of their, of their birth weights, most of them were between 1500 grams and 2500 grams, that was 67% of the of the population that they studied. And then you had 20% that were less than 1500 grams. So that's most of the population. So they were not really they were not big babies. And they looked at the percentage of babies who received surfactant, there was about 12% 60% had required oxygen therapy, 46%, non invasive ventilation and 4% invasive mechanical ventilation. So not nothing, but still typical sort of late preterm. And what they looked at was pulmonary function. And in this in this group of 52, compared to 71 controls, they found no difference in most of the difference. So they my understanding, again, I am not a pulmonologist, but they put these babies through different resistance and measure their lung mechanics. And they go through these different resistance called R five or 20, and so on. And they found no difference between the two group. And they looked at bronchodilator response, and that in the occurrence of respiratory morbidities after birth, and they were also similar between the two groups. So I think, Okay, so what's the point then? But I think what's interesting is that we find that parents of late preterm babies have tons of questions about the minor what we feel is a minor of respiratory morbidity. And they say, is my baby going to be able to do competitive sports? And maybe we got to do this and do that. And I think this study answers a lot of these questions. 10 year old pulmonary function tests completely the same. That is great information to have when you bring again to the bedside. They do. They do say that they they do try to explain so why is that right? I mean, isn't preterm having any no effect on anything. So they say no pulmonary plasticity without your authorization occurs over a longer period of time, school aged children born modern to late preterm is have lung functions similar to those born a term, prematurity, therapeutic intervention in our bodies presented on birth may have been insufficient in magnitude to impact lung function. So maybe their babies were doing better than the rest, which I don't think so. I think that was quite humble on their part. And, and they said, Okay, maybe our numbers are too small. But this idea that long development is an ongoing process, and that they can potentially catch up is great to know, especially when you're looking at babies that are around 34 weeks of gestation, because it's not insignificant. And it's a question I've had so many times. And and I don't know the answer to can they do competitive sports and all that stuff? I don't know. But at least I can say we've done function testing. And compared to full term there, there's, there's not much difference. So I thought that was really, it was really good and informative.

Daphna: 56:04

Well, we know that late pre terms are not equivalent, you know, to, to the full term, baby and so many parameters, which actually, we've reviewed just in the last few episodes. So why not lung function? Right. So I think it was a good thing to look at. I'm hoping that they will do the same thing with, you know, more moderately preterm, and, you know, extremely preterm babies, because, you know, we use the term chronic lung disease, kind of willy nilly. Right. And when a parent hears chronic lung disease, you know, we kind of have to backtrack and say, Well, you know, we don't think it's forever, right. But but we don't have the data about exactly, you know, how they do we see them evolve clinic, we, you know, our PICU colleagues, give us some report back, but not of the kind of total population. So I think we've got a lot to learn. I think this was a great start, I think it was they did some really concrete parameters that hopefully they'll replicate with younger babies.

Ben: 57:14

Yeah, I think there was one group in Italy that was doing follow up of these kids and doing pulmonary function tests on babies with BPD. And it's like, I'll have to pull up their article, it was fascinating. And they describe pretty much like an asthma like type of picture, react, but the moderate to late term, they always get forgotten somehow, they're like, oh, you know, they're a little bit of CPAP. And that's it. So it was nice to see that people have followed them. And again, when you talk about follow up at five to 10 years of life, that is, that is a big deal. That's kind of nice to have that data, it's not easy data to get access to. So we're thankful for the for the vestigators, who have done this work, I guess,

Daphna: 57:51

I think it's a good reminder, too, that it even in the extremely small, early infant that the lungs are do have some plasticity, and they do continue to grow. And sometimes we need that reminder to write that, that it's time it's nutrition, it's good, you know, optimization of our respiratory management, that they do grow and develop. But we've got to wait for it.

Ben: 58:20

My mentor, who who recently passed away, Dr. Charlie Bauer used to say I always enjoy your paper with a positive spin. And so I think I think that's that's one of those papers that makes you feel good. It's like, Hey, we're where we have good outcomes, and it's what we're doing is worth it. We're coming to the end. Do you have any other article that you really wanted to go over? Or? Or should we just do a quick run through of some of the others that we highlighted?

Daphna: 58:52

Yeah, I there were still a quite a few. These studies on neurodevelopmental outcomes, which I think were interesting to review. There's one in pediatric research, it was. This was the early prediction of neurodevelopmental outcomes at 12 years and children born extremely preterm. A study out of Sweden and Austria looking at a small group of infants, 55 infants less than 27 weeks gestational age, they did really kind of a battery of motor assessments, and looked at the kind of cohort as a group 62% of babies showing some adverse neurodevelopmental outcomes at 12 years. And I go ahead,

Ben: 59:51

I didn't understand this paper at all. Okay. I think right. What they were trying to show was that they had this new have a tool for assessment that they could use that three months that will help you predict outcomes at 12 years, I didn't really understand the tool we talked about this visually movements. And I'm not discrediting the paper by no stretch. I'm not, I'm just saying this was a little bit above my level. And, and so it's, it sounded Yeah, it sounded really cool. If you if you understood any of that, I'd be I'd be happy to hear a little bit of as to what you thought about that, because I never heard of that this these column FM's, especially movements that are supposed to be very, very predictive of infants developing CP. And so

Daphna: 1:00:35

so the first thing they did was kind of this kind of observational information, which I think in and of itself is, is useful. You know, the we had babies less than 27 weeks, but same thing, we feel like 27 weekers do pretty well. So I think it was important just to kind of look at those outcomes. And that there were no difference between the kind of normal quote unquote, and adverse outcome groups with regards to the gestational age or sex. But interestingly, those children with the most adverse outcomes had significantly lower body weights. And actually, that comes up in some other articles this month. So I thought that was an interesting point of their cohort about 26% had some degree of autism spectrum disorder. 14% had ADHD, which actually I thought was kind of a low percentage, based on previous studies. 5% have blindness to 5% had intellectual disabled disability and 2% had epilepsy. And 12%, developed CP, and actually we had a lot of papers this month on cerebral palsy, what they were looking at, it's kind of this kind of neuro irritability, these fidgety movements or FM's, like you said, predicted kind of abnormal development even as old as is 12 years. We work with a neurologist and actually she is concerned for these babies who have kind of excessive neuro irritability and their and their risk for epilepsy. So there's definitely something there. And I think it just speaks to kind of a more immature neuronal development, and so it makes sense that it would predict worse outcomes.

Ben: 1:02:30

I just was like fidgety movements and a three month old. Isn't that what they do? But they're not. So I know, I know, I've just been being dumb. That's it. Anyway.

Unknown: 1:02:43

We see coming to the end.

Ben: 1:02:45

Yeah, we have some stuff from from, listen, there's some stuff from Journal of Pediatrics, which would which could, which we could go over, but most of the articles were pre proves anyway. So they're not yet released? Maybe we live them for next time. That's fine. They're good articles. I think we should do them justice. And well, we can review them next time. Is there anything else otherwise that you think we should quickly mention?

Daphna: 1:03:09

No, you're right a lot. We have a lot of pre proofs that we we reviewed. So there'll be up and coming and

Ben: 1:03:14

if if anybody from the journal Pediatrics is listening, the pre proofs are awful to read. Can you please fix the format a little bit? I know you don't want to put out the nice PDF, but it's not pleasant. It's not that bad. But anyway, you know, if anybody's listening, so before we finish, should we read a review as as we've started doing?

Daphna: 1:03:39

Yeah, love it. Let's do it.

Ben: 1:03:41

So this was a review. So if you want to leave us a review, by the way, you go on the Apple podcast application, and you scroll down on our incubator page, you select the show, you scroll down, and you can leave either leave us number of stars. And at the bottom it says write a review. So you can just do that. So this is a review that was left by dr. D MW, and it says this is the podcast, new intelligence and other neonatal health care providers have been waiting for a place to learn about the latest NICU research and innovation and stories. So glad it's being done. We'll be listening to this regularly. Thank you, Dr. BMW, this is very nice. Anything else that you want to mention? I'm going to have one more thing I guess we can remind people of the Book Club, anything else that you want to leave us with?

Daphna: 1:04:28

Now we again just sprayed us Tweet us. We'll get back to you. One way or another. We'll get back to you and we're looking forward to seeing you all for book club.

Ben: 1:04:40

Yeah, so again, the book is The Strange Case of Dr. Cooney, how a European shaman saves 1000s of American babies, the other will be with us send us questions for the author by July 23. You can email questions to Nick you podcast@gmail.com Or DM us on Twitter or send us a Tweet at NICU podcast. Yeah, this is going to be exciting. Please if you also feel like you have something to share and you want to be on the show? Tell us we're more than happy to have guests on. And so let us know. And this is what makes this platform kind of exciting. Anything else that you anything else that No, no,

Daphna: 1:05:16

no, we're having fun. We appreciate. We appreciate the audience and those of you who are subscribing and who were listening to more than one episode all the episodes. So thanks for hanging with us.

Ben: 1:05:28

People have been very religiously sort of, I've been talking to people who have picked up the podcast and I'm making it make a point to tell them hey, like, just pick, you can pick it up anywhere. And they're like, no, no, no, I want to start with episode one. And I'm gonna go down the list. That's I think that's really cool. Next week, we'll have an interview with Dr. Katherine Horne, who is not just a personal friend of mine, but she is a neonatologist from Massachusetts, and who has worked for some time with Doctors Without Borders, and who ran a bunch of nurseries in, in West Africa. And so she has a lot of stuff to talk to us about. That's going to be very exciting. So yeah, look out for this interview.

Daphna: 1:06:09

Yes, she has a very interesting CV. I'm looking forward to meeting her.

Ben: 1:06:14

Yeah. Alright guys, thank you so much for listening.

Daphna: 1:06:18

You to be well.

Ben: 1:06:21

Thank you for listening to this week's episode of the incubator. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address, Nicu podcast@gmail.com. You can also message the show on Instagram or Twitter at NICU podcast. Personally, I am on Twitter at Dr. Nikhil spelled Dr. NICU. And Daphna is at Dr. Dafna MD. Thanks again for listening and see you next time. This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns, please see your primary care practitioner. Thank you