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#034 - 📑 Journal Club 17

NICU journal club the incubator podcast

Hi there 👋

A busy week for the incubator with a number of recordings done and coming to you soon. We have a nice variety of articles today. We reviewed a cochrane review on high vs low cpap, which underscored how little data is out there on the topic. We discussed NAS, which has been rebranded as NOWS, and its effect on cerebral perfusion on brain MRI. We have a bunch of pulmonary articles, looking at NAVA vs SIMV, and this very cool article from germany where researcher constructed a digital model of a BPD baby's lung using MRI and pulmonary function testing. Daphna discussed this great article about parental perspective of their preterm baby's health outcomes, and so much more.

Enjoy this journal club and let us know if you have any feedback or recommendations.


Articles discussed in this week's episode are listed below (in chronological order).

Nasal continuous positive airway pressure levels for the prevention of morbidity and mortality in preterm infants. Bamat N, Fierro J, Mukerji A, Wright CJ, Millar D, Kirpalani H.Cochrane Database Syst Rev. 2021 Nov 30;11(11):CD012778. doi: 10.1002/14651858.CD012778.pub2.

Cerebral perfusion and neurological examination characterise neonatal opioid withdrawal syndrome: a prospective cohort study. Benninger KL, Peng J, Ho ML, Newton J, Wang DJJ, Hu HH, Stark AR, Rusin JA, Maitre NL.Arch Dis Child Fetal Neonatal Ed. 2022 Jul;107(4):414-420. doi: 10.1136/archdischild-2021-322192. Epub 2021 Nov 1.

Early arterial pressure monitoring and term-equivalent age MRI findings in very preterm infants. Butticci R, Habre C, Hernandez A, Barcos-Munoz F, Pfister R, Hanquinet S, Beuchée A, Baud O.Pediatr Res. 2022 Sep;92(3):822-828. doi: 10.1038/s41390-021-01839-2. Epub 2021 Nov 19.

Effect of prophylactic dextrose gel on the neonatal gut microbiome. St Clair SL, Harding JE, O'Sullivan JM, Gamble GD, Alsweiler JM, Vatanen T; hPOD Study Group.Arch Dis Child Fetal Neonatal Ed. 2022 Sep;107(5):501-507. doi: 10.1136/archdischild-2021-322757. Epub 2021 Dec 2.

Oda A, Parikka V, Lehtonen L, Azimi S, Porres I, Soukka H.Pediatr Pulmonol. 2021 Dec;56(12):3857-3862. doi: 10.1002/ppul.25639. Epub 2021 Aug 26.

In silico numerical simulation of ventilator settings during high-frequency ventilation in preterm infants. Förster KM, Roth CJ, Hilgendorff A, Ertl-Wagner B, Flemmer AW, Wall WA.Pediatr Pulmonol. 2021 Dec;56(12):3839-3846. doi: 10.1002/ppul.25626. Epub 2021 Aug 25.

Parental perspective on important health outcomes of extremely preterm infants. Jaworski M, Janvier A, Bourque CJ, Mai-Vo TA, Pearce R, Synnes AR, Luu TM.Arch Dis Child Fetal Neonatal Ed. 2022 Sep;107(5):495-500. doi: 10.1136/archdischild-2021-322711. Epub 2021 Nov 23.

Association Between Early Amino Acid Intake and Full-Scale IQ at Age 5 Years Among Infants Born at Less Than 30 Weeks' Gestation. Rozé JC, Morel B, Lapillonne A, Marret S, Guellec I, Darmaun D, Bednarek N, Moyon T, Marchand-Martin L, Benhammou V, Pierrat V, Flamant C, Gascoin G, Mitanchez D, Cambonie G, Storme L, Tosello B, Biran V, Claris O, Picaud JC, Favrais G, Beuchée A, Loron G, Gire C, Durrmeyer X, Gressens P, Saliba E, Ancel PY; Nutrition EPIPAGE-2 Study Group and the EPIRMEX Study Group.JAMA Netw Open. 2021 Nov 1;4(11):e2135452. doi: 10.1001/jamanetworkopen.2021.35452.


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


babies, infants, cerebral blood flow, mri, studies, weeks, paper, ventilation, preterm infants, talk, group, neonatal, day, gestational age, thought, parents, score, dextrose, nava, amino acid


Daphna, Ben

Daphna 00:00

Ben 00:51

Hello, everybody, welcome back to the podcast Daphna. What's going on?

Daphna 00:54

Well, we've had a busy week on the podcast, I feel like we're recording recording recording, but

Ben 01:00

we're, yeah, we're definitely stocking up on episodes. So the guests have been have been tremendous. And what is what is some of them I think, because today, today's Journal Club has some hints as to who our next guest will be in. So that's, that's exciting. How are things with you?

Daphna 01:16

I am good. I know,

Ben 01:21

that's a family at home.

Daphna 01:22

The puppy was sick, the puppies better. My daughter had a birthday. It's been a it's been a busy time, you know, with the holidays. How these finishing holidays coming up? You know, it's it's busy time for everybody. Right? Yeah. How about you?

Ben 01:39

It's busy time I've been very much engulfed into the feed a world chess championships. That

Daphna 01:47

for people who, for listeners who don't know that you're like a chess fanatic.

Ben 01:52

I love chess.

Daphna 01:54

Every time you share your screen, you have chess on this

Ben 01:57

chess board on fine. But yeah, so today Yeah, today was not the last game of the championship. But the Norwegian Magnus Carlsen won again, and basically defeated his opponent and is now staying the world champion for another couple of years. So it was it was crazy. You know, it was crazy. Let me talk to you about this for a second. Let's hear a journal club. But

Daphna 02:19

you know, I know the names of the pieces. I know where they board. Yeah,

Ben 02:23

that's a good start. That's great. That's it's very irritating when you get to a place and you see that the pieces are not set properly. And the board is sort of very irritating, some for some reason. But it's but I don't want to be a chess. Now, what I wanted to share was that

Daphna 02:36

the US championship,

Ben 02:39

this chess championship was very interesting, from a stamina standpoint that I think I was reflecting on it from the NICU perspective, that so they played, they played something like 1011 games. And the first six games were very competitive. And the game six lasted eight hours. And they played for eight hours. And it was not, it was so close. People thought it was going to be a draw until the very end and and Carlson won that game. And after that game, the Russian opponent Nepo lost pretty much a lot of games making very silly mistakes. And it was really a tale of two halves, where he really fell apart after this game that was so demoralizing. And I was thinking about that from the NICU perspective, when you really work with a baby for days, and then and then it doesn't work out. And then you've I felt what he was going through. And people were saying, Oh, he's so good. How come and I'm like, I know exactly what he's going through. Were like, yeah, and you're forced to come back to the to the table after these types of events and you're not given the room to breathe because they play like right back like they played for eight hours and came back the next day for another one. It's it's impossible. So it was it was interesting to reflect on the decision

Daphna 04:01

fatigue and it's mentally taxing and so then I'll share you you gave me a piece of of chess wisdom the other day, right? So I'm, I'm at a I'm sit at the bedside kind of clinician, I'm leaning up against the wall and just watch the baby, watch the monitors, watch the ventilator, watch watching the nurses know pull up a chair and I'll stay all night. And it can be exhausting. But you brought up a good point that in chess in these big, you know, championships, they get up, they walk away, they reset, they breathe a little and they can they can look at the problem with with fresh eyes. So

Ben 04:41

yeah, they have like a little rest area so they get off stage and, and for most of the championship. It's like one guy in front of an empty chair just like staring at a board. So it's Yeah, but it's something also that I think is very valuable for us at the bedside, make a move and walk away. Let the position sit for a little bit and then think about your options because it and you can get so wrapped up in what your thoughts are that you don't see some of the alternative routes or variations. And I think that's alright, enough chairs for today.

Daphna 05:11

Fine. I'm willing to, I'm willing to consider this practice change, I think about it. What I hear you saying is that you're playing chess with us is when you are playing chess with your babies or playing chess with it.

Ben 05:29

Or with the pathologies, there's, there's a discussion about are you playing the baby? Are you playing the pathology but anyway, so today's Journal Club, there's a lot of super cool articles. And I'm going to start with the list. Now this this week, they're like, they're, they're kind of cool from the techie standpoint, like there's one particularly that I want to go over, but I'm going to start off with the Cochrane Review. Because every time a Cochrane publishes something on neonates, we should, I think, review it. So this was published in the past two weeks, it's called nasal continuous positive airway pressure levels for the prevention of morbidity and mortality in preterm infants. first author is our good friend, Nick Babbage from from chop. And so this is a very interesting, this is a very interesting Cochrane Review, because of what they were really trying to, to assess. They wanted to assess the effect of low CPAP versus moderate to high CPAP. And they really defined that as you were on low CPAP, if you were on five centimeters of water, or less, and moderate to high CPAP, if you were on more than five centimeters of water, and they looked at that for two particular time points, which are initial respiratory support, and following mechanical ventilation, so after extubation, and they wanted to look at these parameters in preterm infants. So they looked at studies that included babies with birth weight, less than 2500 grams, or a gestational age at birth, that was less than 37 weeks. They, they were very honest about the levels of CPAP. They say that this is not it feels arbitrary, but they said it is arbitrary. And it sort of reflects how everybody else is thinking about these things. And I thought that was that was reasonable. Their primary outcomes were very interesting. So they were looking at death or BPD, at 36 weeks, using the NIH definition, they were looking at mortality at 28 days hospital discharge, and at one year, they were looking at moderate to severe neurodevelopmental impairment at 18 to 26 months and three to five years. They were looking at treatment failure and need for mechanical ventilation, they also had a very long list of secondary outcomes, I'm not going to bore you with the list of secondary outcomes. And the reason why I'm not going to bore you is because you will find out very quickly that this, that their their their endeavor was not as fruitful as they wish it was. They had planned a lot of subgroup analysis, which I will skip. And in the end, looking at studies between 2001 and 2016, they were able to include 11 trials. And unfortunately, they had to remove they had to exclude a lot of these trials. Because based on the outcomes that they wanted to report on, only four studies reported health outcomes that they had pre selected as being relevant to nasal CPAP levels, and to the overall health of preterm infants, while the remaining studies reported on short term, physiologic stuff, you know, like oxygen level, heart rate and blood pressure. And the key result of this study is that of the four studies that are reporting on the pre selected health outcomes, they could only combine data from two studies. And I'll just tell you briefly about those studies comparing these or CPAP levels for initial respiratory support, and two studies comparing level for post extubation. And based on the data from these studies, there's there's too much uncertainty as to whether low or moderate to high knees, or CPAP, will help improve outcomes. And so at the end of the day, this is out there, unfortunately, there's not much data, it felt like it felt like a bit of a frustrating endeavor when you're supposed to do a Cochrane Review, and you ended up reviewing single studies. It doesn't make too much sense. But it shines a light on the lack of I thought there was going to be more studies, I tend not to read the abstract, I tend to just like get dive into the paper. And, and shockingly, as like, really, there's not much more first of all, when they said 11 studies, I was like that seems low. But then after that, when they had to exclude all these other studies, it was like

Daphna 09:37

yeah, God, and the studies are very different. Right? So when we're talking about, you know, a meta analysis and doing a review, is it is it apples to oranges can can we make comparisons and it it really, I think, goes to show how far academic medicine has swung where we're really not trying to replicate anything anymore. So how can we even you No combine studies to do to do big reviews and a reminder for you know, trainees who are confused and they feel like, Where does the dogma come from? Well, there is there. We don't know. There's still a lot we don't know. Isn't that right?

Ben 10:18

So, so that's out of the way. Should we? Do you want to do you want to go next?

Daphna 10:24

Yeah, I wanted to review this. cerebral perfusion and neurologic examination characterize neonatal opioid withdrawal syndrome, a prospective cohort study. This is from the archives nationwide,

Ben 10:40

from my archive of

Daphna 10:44

Yeah. Lead author, Kristin, Ben injure. And again, like you said, it's coming from Nationwide Children's Hospital. And so they really, I wanted to talk about this paper because you know, that I love functional MRI. I think that we have so much to learn from the psychology, psychiatry literature, neuro imaging, that will tell us more about disease processes and babies. So that's something they wanted to look at, they wanted to see was the brain blood flow cerebral blood flow in babies with their calling it now is neonatal opioid with withdrawal syndrome. Different so they did a prospective cohort study, they looked at subjects who were newborns, greater than equal to 36 weeks gestation at birth and less than 14 days postnatal age. They looked at a group of exposed infants, so they had in utero opioid exposure confirmed by toxicology testing, either in maternal urine, infant urine, meconium, or umbilical cord, and all of the babies were receiving more at least morphine treatment for their symptoms based on the Finnegan score. Again, like I said, all the babies were exposed to or were being treated with morphine. As a first line, some babies needed a secondary medication. Infants in the control cohort had no in utero exposure to opiates, illicit drugs or other illicit drugs or alcohol. And then they did a really a matched cohort also. So they looked at gestational age of birth, postmenstrual, aged MRI, and some of the inclusion criteria. Not surprisingly, babies with HIV, other central nervous system problems and other major congenital anomalies, the measures they used, they wanted to look at both cerebral blood flow, so they were using an MRI, and they wanted to compare basically the neonatal neurologic exam, so they were using the Hammersmith neonatal neurologic exam, the H and N E. And for people who aren't familiar with it, it's really looks at kind of newborn state tone, reflexes, irritability, response to sort of interaction.

Ben 13:13

I was not familiar with that. And I had to look it up. Did you know about it before, too, so I, I looked it up and it kind of looks like the the gestational age assessment tool a little bit. Right.

Daphna 13:25

So it the you mean, the duvets because, yeah, that's right. Well, the the dooba witnesses are, are they developed the Hammersmith so. So it's a lot of the newborn steet physiology that they look at. So he had 67 infants 31 exposed 36 control. And then they had really 30 and 31. So 30 Expose 31 control who were able to complete both evaluations. The groups were comparable otherwise no major differences in gestational age, they mean gestational age in both groups was 38 weeks, the age at MRI 10 days versus 9.3 days, no difference. The agent there ah, and Annie was about nine days for both, and no major differences in the groups in terms of sex. Interestingly, though, it's something you know, I think we've we've done so many articles now about how being growth restricted is impacting development. So three of the babies in the exposed group were also growth restricted, which is not uncommon, right. A lot of babies who are or have been exposed to things in utero are also growth restricted. And that may give us a hint about, you know, why the cerebral blood flow looks the way that it does. 93% of the exposed group, we're actually in the weaning phase. As at the time of MRI, I think that's important. So it says to me that the babies at least got to some sort of steady state, and they were able to start coming off of their medications for most of them. So and the groups when they just look at the newborn exam, so the H and N, a total optim optimality score was lower in the exposed group compared with the control group. Infants who had been exposed had lower domain total optimality scores for spontaneous movements, abnormal signs, and behavior and orientation. So that those are some of the major categories in the assessment tool. And interestingly, the MRI quantitative scores, so brain size really were not different. And they actually did a good job. They not only did total brain volumes, they looked at white matter, they looked at different brain regions. And they were pretty similar. But what was different was that the cerebral blood flow was was very different. So the global whole brain cerebral blood flow was higher in the opiate exposed group. And then they looked at the regional cerebral blood flow in infants with opiate exposure, and it was higher almost everywhere, which makes sense. That's why the whole brain blood flow is different, but specifically let leptomeningeal on perforating anterior cerebral arteries leptomeningeal and perverting middle cerebral arteries, the posterior cerebral arteries, the anterior choroidal arteries, posterior communicating artery, the insula, the caudate nucleus, the lead to form nucleus and the M one, M three and M six territories. And so when you think about some of the downstream effects of opiate exposure, and what that looks like, clinically, and it's not surprising that they have changes in blood flow, I will say at the onset, and I'm getting ahead of myself, but I expected the opposite, right, I expected we'd see decreased cerebral blood flow. And so they talk about this a little bit about how much like in hypoxia ischemic encephalopathy, we what we may be seeing is really reperfusion. And so now we see increased cerebral brain blood flow, but potentially previously they had altered cerebral blood flow. So I thought that was really, really interesting when we talk about the pathophysiology. The other thing that group did is they tried to use modeling, using different combinations of cerebral blood flow, and the physical exam each and any, and the best performing model, kind of to predict babies that had been exposed was the combination of the cerebral blood flow, MRI variables plus the exam, but it really only slightly outperformed the physical exam alone. And so it just goes to show how how the babies even just on physical exam, you know, has such characteristic clinical findings, I think that that were able to really pick this up on clinical exam. Anyways, I got ahead of myself, what do you think?

Ben 18:31

Yeah, you touched on a lot of stuff. I think, to go back to a few things you were saying the cerebral blood flow maps that they have in figure one, it was super cool. And and like, like you said, sometimes it can be difficult when they talk about these MRI findings to as neonatologist really to, like you have experience with it. But for me, I'm not as comfortable with MRIs. It's difficult sometimes to interpret there. But this is a picture with a worth 1000 words, like you see.

Daphna 19:01

That's different than that. Right?

Ben 19:03

Yeah, easily. So that's that's the first thing. And then you touched on something that they mentioned in the discussion, which is this association Association. Equating no ws first of all, I thought that was an interesting, let me start there. It was interesting that now it's right instead of any Yes. And I feel like it might be a more appropriate term right. To not call this abstinence. I mean, the baby did not have abstinence from no doubt abstain from anything. But anyway, I think equating this to HIV was very, very interesting, because we tend to dismiss it as I mean, and maybe I'm generalizing a bit too much here, but we are I mean, at least I'm dismissing it very often where I think, well, the baby is now out of this environment, and there's a time component where the baby will eventually get over this withdrawal symptoms, and then things will be back to normal. And it's, first of all, I realized, as I say it, obviously it's completely wrong. But this is wrong and should affect how we manage these babies. We would never say those things with a baby with HIV, right? We, we do encephalopathy screenings with with serial physical exams, they are all subjected to MRI, before discharge, and they all get neurology follow up.

Daphna 20:30

Neurology and support physical therapy, occupational therapy, early developmental screening. So

Ben 20:37

yeah. And so it made me wonder whether maybe we have to reframe how we see these babies and like start establishing these frameworks to give them proper follow up proper assessment of potential long term issues down the road. And that was very interesting to me, because I never thought of now's as we say no, in those terms, and for that, for that alone, I think the paper is extremely valuable.

Daphna 21:05

Yeah, it's interesting. For me, this is something that's very in the forefront of my mind when I see these babies, and I think about what will school look like for them, you know, what, what will day to day life? Look for them? You know, they have such high levels of attention deficit, things like that. But do I do a great job with the anticipatory guidance for that? No, I don't. And I think that we could do a better job supporting families who may already have a resource limitations, right, or additional stressors that they're dealing with, do we do our best job to set them up for success and follow up are most of us even following them up in our follow up clinics, we're not as a whole. And so maybe that's something that we can do differently.

Ben 21:55

And that goes back to bias and maybe confounding variables, because of the fact that these babies are the product of a gestation that is affected by substance abuse. For babies who are born to mothers who have issues with substance abuse, it's difficult, it's a very complicated social context. And and that alone has a lot of long term consequences. And add on top of that potential cerebral changes at the cellular level than that yet it makes things even worse. And that's why I think, rethinking how we follow these babies up, no matter how they do in the NICU. No matter how things go is might be very interesting.

Daphna 22:34

Yeah, I agree. I think it just goes to, you know, when we what is our role in transitioning babies to home and the rest of their lives? You know, how can we set these families up for success, we have a real let, we have a real trauma informed mindset that we just we just say, because we, we just I guess we can talk about will tease we just recorded with with Mary Coughlin, who if you're not familiar with her work, we hope you will tune in after the start of the year. So that we can, we can engage you a little bit in that regards. So we digress, where do you want to

Ben 23:12

progress? I want to go to pediatric research. And I want to talk about this paper called early arterial pressure monitoring and term equivalent age MRI findings in very preterm infants, since we're talking about MRI, first other is Roberta buchi. And this is from a group at the University Hospital of Geneva, which I visited not too long ago. So it also reminded me of my vacation, so that was fine. I was puzzled by this paper because of the objective. Obviously, this pilot study investigated whether invasive blood pressure, arterial blood pressure monitoring, in a continuous fashion during the first postnatal days can predict term equivalent MRI findings in infants born preterm and what was the lowest sort of mean arterial pressure with the subsequent development of brain lesions? I thought that was very interesting, obviously, because they're trying to do something that's challenging to connect a very specific item, a physiologic item early on in life to the term corrected MRI. And making that connection point is, is puzzling. I was wondering if in the background, they would substantiate this with any theories. They obviously mentioned the potential of blood pressure disturbances causing ivh, that potentially being a modulator for long term MRI issues. But otherwise, they don't have much else in the background. And they're just saying, well, there's also not much else in the literature. So it's not completely unreasonable to try to bridge this gap.

Daphna 24:39

And this is why I sit at the bedside continuously because I have this fear this, this sense that, you know, a few low blood pressures will say,

Ben 24:50

and we'll talk about that. It's actually a bit. I mean, the, the data is retrospective, so everything we're going to say has to be taken with a bit of a grain of salt because it's not perfect and that's fine. But for babies born before 28, and sick 28 weeks and six days, and they were all born at the Geneva University Hospital NICU, and they all had invasive blood pressure monitoring through an umbilical artery line. They. So they, I was wondering if they were going to get into the thorny subject of normal blood pressures,

Daphna 25:24

which was a hot topic, just just on Twitter.

Ben 25:28

And they've avoided they avoided the topic very cleverly by just looking at what were the lowest right? They just picked up on the lowest blood pressure measurements for these babies.

Daphna 25:36

Oh, and studies like this may help us establish, you know, parameters, right. So

Ben 25:44

and they did. And they did use physiological markers of low blood pressure, which I think was very, very good. So interventions to treat low blood pressure were generally initiated upon observing upon upon observing of a mean arterial blood pressure lower than that appropriate for the gestational age of the infant. So they're staying vague on that point. But that's fine, associated with other evidence of reduced organ perfusion, reduced urine output, lethargy, abnormal skin color, et cetera. And they were using either volume expanders or I know troops parenthesis, dopamine as first line agent. I know, I know, Kellyanne is going to be pissed that. But that's just no, but I mean, at the end of the day, the one thing even we talked about this on Twitter, when people were talking about what is a hypotension, everybody agrees that there must be some physiologic and organ dysfunction that you must document, right. I mean, it's not just a number. It is low urine output. And so So I think that was good. So they were trying to get data on day of life, one day of life today of life three, I will spare you the detail because of the of life three, they were not always able to get good measurements. So we ended up having the of life one and two, only. The MRIs were done using a 1.5 Tesla and a 3.0, Tesla, MRIs. And they were reviewed by two independent radiologist and they had this, you may be familiar, you're definitely going to be familiar with the Keto keto coro scale to assess the cerebral white matter, cortical and the gray matter and cerebellum abnormality. So they use this scale, which I'm going to be honest, I was not super familiar with. And the primary endpoint was associated with the Association of the trends in arterial blood pressure, and the variability with the occurrence of brain abnormality. According to this kiddo, Choros score calculated as the sum of the four regional sub scores. So obviously, the clinical risk scores look at those different regions that I just mentioned. And the brain abnormality on MRI was defined as a Keto Cora score of one or more. I feel like explaining, I wouldn't be able to explain the Keto Cora score. So let me just preface it by saying this, but I feel very, I can cleverly get out of this by saying it's outside the scope of this review. So in terms of the results, they were their entire cohort was composed of 99 infants and 78 of which had abnormal MRI 21 of which had what unquote, normal MRI so the overall overall for that, so let me just talk quickly about the cohort. The gestational age for the cohort was 26.3 weeks, the birth weight was 870 grams, and they have a lot of other a lot of a lot of other factors mentioned in the in the baseline characteristic. Overall, the median kiddo Cora score was two and 79% of the infant's had an abnormal MRI, as we just mentioned, aside from birth weight and gestational age at birth comorbidities significantly associated with the evidence of brain injury, where fetal growth restriction, which as you mentioned in the prior paper, we've sort of discussed on the on the podcast late onset sepsis, and bronchopulmonary dysplasia. So then they did this lasso procedure, where they basically allowed the computer to connect the dots and seeing what kind of measures of low blood pressure are associated with long term abnormal MRI. So the lasso procedure, selected 30 consecutive minutes on day of life one and 10 consecutive minutes on day of life to as the most relevant durations of lowest mean arterial blood pressure to be associated with brain MRI findings. And so the crude or was 1.11 with a P value of 0.03. And that's for the first day and the or for the second day was 1.13 with a P value of 0.03. And this significant association persisted after adjustment with covariates including birth wages stay Should age sex. And I know trope exposure. So very interesting that in conclusion, basically, they found so and they also, I'm going to before I go into the conclusion, they found that they had like a threshold for the mean arterial blood pressure. I don't know how useful that is, I'm just going to mention it because obviously these are babies are very interested in all ages, but they're all taken on to life one and two. So the ROC curve analysis showed optimal thresholds at 30.25 millimeters of mercury on day one, and 33.25 millimeters of mercury on day two. And so these were the thresholds below which you started getting abnormal stuff on MRI term equipment, their conclusion was at early continuous arterial blood pressure monitoring me predict brain brain MRI findings, a term in very preterm infants. Just one last thing in the discussion that was hoping that maybe they would really try to postulate a mechanism. But the mechanism they mentioned in the introduction, being talking about ivh, was actually quite rolled out because they are rates of babies with abnormal MRI. So seven, eight babies, only one of them had actual severe ivh and 12 had grade one, grade two, so really cannot truly be explained by the overwhelming presence of AVH, when that was really not the case. And then at the end of the day, they they're making, they're not committing to a potential pathway as to how this happens. They're making a general statement in my opinion about how hemodynamic fluctuation could affect cerebral perfusion and eventually cause white matter injury. But there's not really an interesting cellular pathway that they're explaining just in case, you're wondering whether that's that this is sort of buried somewhere in the discussion. I think that's fine. If they if you if you don't have a good mechanism to explain the the path, the the association, then there's no, there's no need to postulate uselessly. What did you think?

Daphna 32:01

Well, I think we know that cerebral blood flow, like in this previous article, you know, has some impact on our long term MRIs. And does our blood pressure modulate our cerebral blood flow? Yeah, we know to some extent that it does. So. I don't think that's such a stretch. I would have liked, like you said, to really see it broken down by gestational age because I I believe that matters. I don't know what the cutoff is. But I think there are different cut offs for different gestational ages. And but I think if there was a there was a point, you know, that you start to see brain changes that will that would certainly change? How we looked at it at blood pressure for sure.

Ben 32:48

So did it freak you out that you have only that you only have on device? One, you have about 30 minutes? And then on the other life, too, it's 10 minutes? Are you going to manage? Now

Daphna 33:00

you have a question about about blood pressure and choosing those first few days, right if you're in that transitional circulation, transitional physiology, and you're much more at risk for ivh. But you like you said the ivh wasn't a huge problem in their cohort. But that's the other thing. Like, should our blood pressure parameters change by day of life week of life? Probably but we don't we don't

Ben 33:25

know. We don't know. That stuff I think will come out as more and more hemodynamics point of care ultrasound stuff is published.

Daphna 33:35

Did all right, I was going to do this effective prophylactic dextrose gel on the neonatal gut microbiome. first author, Sophie St. Claire. This is coming to us from New Zealand and is also in the in the archives. So while I leave my opinion, I see I always get ahead of myself. Anyway, their objective was to do

Ben 34:01

what's your opinion? No, I'm actually curious about

Daphna 34:05

my opinion. Here's my opinion. I am. I am a mother I breastfed, I really believe in breast feeding as a source of nutrition. And when we bring in these babies for hyperglycemia you wonder like, what is the right thing? Like I know that some formula exposure for baby who otherwise would get exclusively breast milk could potentially change the microbiome. Yes. So is there an alternative that we could use that wouldn't change the microbiome? That's intriguing to me. That's my opinion.

Ben 34:45

And when you read the title, did you think that the extra style would impact the microbiome?

Daphna 34:49

Hey, did not think it would because I thought it

Ben 34:53

was for sure you did. Yeah, I'm like you're providing sugar. Look,

Daphna 34:57

it's it's dextrose

Ben 35:01

Yeah, but I'm saying shouldn't that provide like I was thinking, Should I provide a medium for some some bacteria? That's crazy. Yeah, I was just thinking anyway. So let's now we can now we

Daphna 35:12

now will find out what happened. This was part of a nested observational study within the hyperglycemia prevention in newborns with oral dextrose, or the H pod, multicenter randomized trial to evaluate 40% dextrose gel compared to placebo, and in neonatal hypoglycemia. So these were babies who were at risk for hypoglycemia. Infant, a diabetic mother, babies who are preterm less than 37 weeks babies who were small, or large to less than 2.5 kilos, or greater than 4.5 kilos. And they were randomized to receive either dextrose gel or the cellulous placebo gel massaged into the buccal mucosa as a prophylactic therapy to avoid neonatal hyperglycemia. And so the study of that the original study actually didn't find a difference in using the prophylactic gel. But the studies that looked at glucose gel as treatment, you know, did seem to does seem to improve neonatal hypoglycemia, so many of us are using that in our in our hospitals already. So then they wanted to look at the stool of these babies who received dextrose gel versus the placebo gel to see did it change the microbiome. So they collected stool, a day of life one, a day of life seven plus or minus three days. And then again, at four weeks, plus or minus seven days, the primary outcome was to look at the microbiota, beta diversity. And if you're not familiar with the terms, beta diversity is really looking at diversity between samples. So between different communities, and alpha diversity is looking at the diversity within a sample. So an individual patient or community,

Ben 37:07

thank you for doing I had to look it up.

Daphna 37:10

See, I told you, I had some experience in stool sample and never took off. But

Ben 37:17

you have to be careful not to say those types of things in outside the neonatal context. Because

Daphna 37:23

anyway, so they really wanted to look at the beta diversity. So looking between, you know, the two groups at four weeks of age, they also wanted to look at the beta diversity at a week, and then the microbial community stability, and again, the microbial Alpha diversity at seven days. And at one month, they also wanted to look at the kind of total microbial load at all time points to see what is the total bacterial load, and the taxonomy differences. So all in all, it 165 infants providing at least one stool sample 45 in the dextrose gel 49 in the placebo gel and 72 in the control group. And the groups were well matched for baseline maternal and neonatal characteristics. Some babies had multiple samples, obviously, the goal is to have at least those three samples. And so they use 434 samples for analysis, what they found is that there's actually no difference in the beta diversity between groups at four weeks before or after adjustments for a variety of variables. There was no difference even when excluding infants who received antibiotics, or probiotics, which I thought was interesting, it was interesting. There was no difference in total DNA concentration or relative abundance. And then there was no major difference between diversity within those groups at the day seven and the week for samples. Which was interesting, because I might have expected some diversity there just given other studies that have looked at diversity over over age. So to close that loop, there were no significant differences in beta diversity at any time point, alpha diversity, or DNA concentration or relative abundance of individual genera. But interestingly, they looked at some of the other neonatal characteristics, so beta diversity was significantly different between infants born vaginally and those born by C section on day one, and week four, which is something that has been shown right. At ease. It's one of the major criticisms for too many cesarean sections right? But interestingly, no significant differences in alpha diversity at day seven and week four. So within the same baby or in DNA constant ration. They also found not surprisingly, that beta diversity was significantly different between infants who received breast milk and those who received formula with or without breast milk on day one. And week four, but not on day seven, formula fed infants exhibited greater Alpha diversity than those who are solely breastfed, which again, has been shown in research before. There's no significant differences in DNA concentration between groups. The other thing they found was that beta diversity was significantly different between babies born at the different recruitment sites, which is not surprising, but it's interesting. And obviously, your your Flora would be different depending on where you are born. So I thought it was an interesting study. I'm glad that it seems like giving them dextrose gel will not change their microbiome. So same here.

Ben 40:53

To me, I don't have much to add, I want to I want to I want to take the I would like to be allowed to move on just because I want to get to like three more papers. And and I felt like you went you went through this one pretty well. Thank you. That you don't go through them well before. Just make sure I don't misconstrue it. The next one I want to talk about is this novel paper. Yeah. So this paper is published in pediatric pulmonologist called neurally. Adjusted ventilatory, assist in ventilated, very preterm infants a crossover study first author is Radha Oda. This is from a group at in Finland. So this paper, study the incidence of hypoxemic episodes during novel ventilation and during si n v and pressure support ventilation, so si n V is for those who still need to be reminded synchronized intermittent mandatory ventilation and pressure with pressure support in preterm infants. And they wanted to see a little bit of the differences between the two modes, right. And obviously,

Daphna 42:01

people were novice.

Ben 42:02

Yes, yes, that was I was going to do that the two modes are in intubated patients. And Nava is basically neurally driven mode of ventilation where a catheter, like a like an OG tube with electrodes at the tip bar is being placed in the baby's esophagus captures the electrical activity of the diaphragm. And when the baby sends a signal to take a breath, the electrical activity of the diaphragm is picked up by the ventilator and the breaths are delivered in a proportional fashion. So this was a single center study of this level three unit in Turku University Hospital. I hope I pronounced this correctly. Sorry, if I did not. It used a convenience sample of 19 infants. And this was an observational study that took place between August 2016, and February 2018. All the infants with a gestational age of less than 30 weeks at birth and who needed invasive ventilation and had some saturation events at the saturation events were eligible for the study. The protocol involved two options. And the options were to assess the differences between the modes of ventilation depending on which mode they were on. So if you were on si NP with pressure support, you were left on that for three hours, you had like a 20 minute wash out period and then you were switched to Nava for another three hours. If you were already on Nava, because that's the standard mode of their unit, it would watch you on three hours, transition you to si MV and then put you back on level for three hours.

Daphna 43:31

Can I Can we just say how useful these little diagrams are? For Understanding the methods of a paper?

Ben 43:37

I could not emphasize that enough. Still to Jensen, Dr. Jensen said that saying a paper will pop if you have a good figure. He's 1,000%. Right?

Daphna 43:48

I could replicate this easily. Right? So

Ben 43:51

yeah. And they're not sophisticated. I mean, this is not something you need a designer to do. I mean, this is like a bunch of boxes. And it tells anyone can do it, of course. But what I'm saying is that sometimes you think oh, I don't know how to use the software. I don't know how to draw. It's like anybody could do this. So the settings, they don't really go into that though. They said that that was based on whatever the neonatologist on duty was deciding, and

Daphna 44:16

presumably different for each baby. Right. So

Ben 44:19

yep, yep. The they also something to mention that skin to skin care was not done during these recordings, just so that they could, I know you were very happy about that. But for physiologic testing purposes, it makes sense. And what's interesting is that even though the patient's that's the other thing that's important is that they measured a lot of different variables, but what's important to know is that they left another catheter in those babies all the time. So they were able to capture electrical activity of the diaphragm, both when they were on SIV and when they were on Nava, and obviously that's important because of the outcome. So the primary outcome of the study was the proportion of time with saturations within the clinical range, the clinical target range of 90 to 95%. secondary outcomes there were multiple but included the time with auto set above the target range, time with auto set below the target range number of the saturation, the saturation Severity Index, the number of manual fit adjustments that were made and the time that the near infrared spectroscopy was within the target range, above the target range and also below the target range. They also looked and that's very important at the neuro respiratory parameters, EDI, Min EDI peak and respiratory rate. So before we go into the results, this this is something that I was asking myself, What is this d saturation severity index. And so the D saturation Severity Index is calculated as the sum of the area under the curve below the threshold of 86% of each D saturation episode divided by the study time in minutes. Okay, so that's done results. So the infants were born at a median age of 26 weeks and four days and the range went from 23 to 29, and three, the median birth weight was 610 grams with a range of 400 to 1160 grams. All infants except one received caffeine. And the infants were recorded at a median age of 20 days, the range being one to 82 days, one infant was recorded twice, 14 infants were switched from novice to assign nvn Back to Navah. And six infants were switched from si n v to Navah. In each mode, let's go into the results the proportion of time in the proportion of the time the saturation was within the target range did not differ between the ventilation modes, either when comparing Nevah versus si MP press pressure support 38% in Navarre versus 29% In SI MV, P value point two nine or si n v vs Nava periods 30% versus 41% P value point two nine, the median number of desaturation was 13 per hour and did not differ between the modes. That was kind of surprising, you know, like 13 desaturation per hour makes you think,

Daphna 47:05

yeah, however, no matter what, what the baby was on, it's a lot, right. Yeah. And for people who, you know, we have the experience right in our last unit where we, our desk was in the unit right by the sickest patients. They do sound a lot. Yeah, sometimes I think we don't notice.

Ben 47:23

However, the desaturation Severity Index was significantly lower during Nava ventilation than assigned depression support when SIV came before Nava 152 versus 131 with a P value of point 03. In addition, fewer manual fit adjustment by the nurses were performed during Nava ventilation. The last thing I want to mention is the EDI peaks, meaning the maximal activity of the diaphragm was significantly lower during Nava ventilation than during assembly, the minimal electrical activity of the diaphragm decreased significantly during novel ventilation after a period of SMD. Ventilation. And the tip the peak inspiratory pressure was considerably lower during Nava ventilation compared to si MV. And so these are the findings. Although another ventilation did not increase the proportion of time with optimal saturation, it was associated with decreased diaphragmatic activity lower pap is less severe hypoxemic events and fewer manual oxygen adjustments in very preterm infants. Which the conclusion there are underwhelming. It seems like it's like, oh, there's no difference. But I mean, if you get the same outcome, it's a huge deal. I thought that the author should have done a better job at being boasting more about their findings, because I thought you could say, well, there was no difference, except that like pressures or lower diaphragmatic activities lowers like, that's huge.

Daphna 48:43

Yeah, that's all the things, right? lower pressures, prevents the development of VPD. Right? Like, we know that if we can keep babies on lower support that that they will have less lung injury. So I mean, I thought this was a very positive paper.

Ben 49:03

Yeah, this is a very cool paper, again, showing the benefits of Nava and it's a great paper to review this week because we had the privilege to record yesterday with Dr. Beck and Dr. Cinder B, who are the CO inventors of the novel technology. And they came on the show to talk to us about Nava and this was a this was a fun interview. They have they have fun personalities and and it was it was cool to actually get their take on on really what are the merits of Nava and when you think about it, not just as a mode of ventilation but as a mode of as you were quoting them that as personalized motor ventilation it gives you some appreciation for what it does. Any thoughts on this paper?

Daphna 49:49

No, I I mean, you know that I like NOVA I know that you like now but we are not sponsored by knob. Don't say that. We just really like it. We find a lot of clinical applications for it. So this is what I see at bedside, right? There's so many babies, not all babies, but you transition them. And you're able to wean their oxygen even though they haven't weaned in weeks, you know. So that's what I feel at bedside. It's nice, it's nice to see, you know, really paper after paper showing the benefits, especially those lower peak pressures, I think.

Ben 50:24

Right? And and it's not about what the paper for me highlighted is that it's not about the outcome on the monitor, meaning it's not about the target sets only meaning Yes, you want them to be in the range, but like, at what cost cost that you're gonna get those results. So that was very,

Daphna 50:38

yeah, I mean, if you never look at the monitor the ventilator and you never look at the peak pressures that are, you know, pounding away at this baby, then yeah, you can keep them setting, you know, 95 or so.

Ben 50:54

Following up on this paper, I wanted to talk briefly about this other paper in pediatric pulmonology, called the in silico. numerical simulation of ventilator settings during high frequency ventilation in preterm infants. first author is Chi Forster. This is from a group out of Munich in Germany. The paper is, okay, I'm gonna be honest, the paper is not super easy to read. But what they're doing is some of the coolest thing I have ever read. And for that alone, I think I would have probably dropped the paper if the technology was not this. Cool. So I think just for that alone, I think it's worth it's worth reading. The goal of this paper is to compare the effects of different ventilator settings during high frequency and conventional ventilation on oxygen delivery, lung mechanics, and overall compliance of the neonatal airway of a preterm infant. So let me brief you as to what they did. Basically, they this is a study that involves one patient, so they took a baby that they had in the unit in Germany, and this is a baby that was born at 27 weeks and three days, that was diagnosed with grade three BPD. And they put this baby through a few tests, number one, a, an MRI to look at the pulmonary tree, and they put the baby through lung function testing, the lung function testing was done at 36 weeks. And, and it has all the references of the tools that they that they are, they used, the baby's birth weight was 760 grams. And And again, that's why I was saying the paper is not just read, we don't know how old the baby was at the time of the MRI. It's unclear whether the I'm assuming the baby was intubated, but it's not clear either. It says that the baby spent 32 days on mechanical ventilation and 46 on non invasive like CPAP. But it's not clear what the mode was at the time. Again, it's not about the baby, it's about what they were able to do. So we'll gloss over that. And if I missed it, and somebody in the audience picks it up, I'm happy to correct myself. So they did this pulmonary noncontrast, and hence the MRI. And they were able to create a 3d model of this baby's lungs, right. And they created this 3d computational model, and using the MRI findings, mimicking the original lung mechanics required from the pulmonary function tests. And basically, once they had this model long on the computer, they put the model through various settings on high frequency and conventional ventilator and look at the O to N and O to out and I'll explain that in a minute. So, they had three different settings on high frequency, they had HF one HF two HF three high frequency, one was basically using a mean airway pressure of eight centimeters of water, a frequency of 10 hertz and a tidal volume of two mL per kilo, within with an A E ratio of one to two, high frequency to the map was decreased from the frequency was decreased from 10 to seven hertz, and the tidal volume was increased to 2.86 milliliters per kilo, high frequency three, they use the higher media with pressure going up to 12 and tidal volume of 2.0 mL per kilo. Then they had settings for conventional ventilation where they use the restaurant rate of 60 breaths per minute, the tidal volume of five mL per kilo peep of six and an eight, eight E ratio of one to two. And these are obviously models, right? So the baby is no longer in the picture. So they got all the measurements from the baby, the baby was returned to the unit. The baby is not being harmed in any of these settings, right? Because sometimes you could think, Oh, are they doing this on the baby? No, the baby underwent MRI pulmonary function testing, which by the way is would be great if we right. Yeah, pulmonary function testing on RBP babies at 36 weeks. So I think from an ethical standpoint, that was fine. They have all the different settings in table two of the paper and basically they looked at simulated cycles of eight simulated cycles for the high frequency and two simulated cycle was for conventional ventilation. So what they did is that they created this this pulmonary tree where there was oxygen in and oxygen out, oxygen in and you would again, this is why the paper is not the best, the best because you would think oxygen out meaning whatever's returned to during exploration but no oxygen in is what's entering the the airway oxygen out is what's measured at the distal bronchial tree. So whatever's available for gas exchange. And here's what they found. So in, in simulation, one HF one, the amount of oxygen leaving the respiratory tree was 49% of the OTU provided to the distal airway. And again, at an F value of 35%, when they used high frequency 250 8% of the oxygen provided was delivered to the distal airway. In the third model, where the the minute we pressure was a bit higher, they were able to get 58% of oxygen delivery to the distal airway. So

Daphna 56:00

it's still less than I thought,

Ben 56:02

it's very much less than we thought, yeah, when they looked at the conventional ventilation, the amount delivered represented 76% of the oxygen, the OTU, and so much, much better at delivering that oxygen to the distal airway. They have a lot of cool pictures. And the one more one more finding I want to mention is, and it's the one they're highlighting in this discussion, they're saying that the most significant insight into lung mechanic here is that oxygen delivery during high frequency occurs more homogeneously than during conventional ventilation. So what they found was that the because of the harrow heterogeneous nature of BPD, they found that during conventional ventilation, the areas with good Compliance would get over the standard, and the areas with poor compliance will just not get ventilated, something they were able to much better overcome in high frequency. In conventional ventilation, I'm quoting regional tissue variation and inflation is mainly governed by original tissue compliance. This means region of high compliance through a tendency toward inflation slash over inflation, while regions with low compliance exhibit almost no inflation at all. And in contrast, high frequency oscillation settings show a strong tendency toward a rectangular block picture indicating that all regions independent of compliance are ventilated uniformly, this would indicate an outcome and ventilator therapy that could be beneficial in the management of neonates with ventilation perfusion mismatch, you can look at the pictures, the MRI pictures of the inflation model on conventional ventilation is staggering. We'll share that on Twitter. And, again, they're talking about some of the limitations of their study in the fact that they don't know how well this can apply to very preterm infants. But I'm like, it doesn't matter. Like for BPD alone, this is already huge. Yeah. And, and they're not, in my opinion, honing down on something that dimension, which is I mean, actually, they're putting it in the abstract, but they're saying that if we did this on every baby, we could create something they call this digital twin, where you could actually use the model and start test what would work for this patient and find the optimal motor ventilation? And I think this is like, Uber cool. Yeah. So anyway, I'm going to stop rambling.

Daphna 58:15

Yeah, I mean, it's just neat. To use model, you know, they're using modeling and surgical planning. But this is like, in real time lung mechanics. It's really neat. It's really neat. Yes.

Ben 58:26

This is really cool. Hopefully, you know,

Daphna 58:29

for every for everybody soon.

Ben 58:32

Yeah, I mean, it takes an MRI and lung function testing. But I mean, this could be something that's that could change how we treat babies.

Daphna 58:40

The next article, parental perspective on important health outcomes of extremely preterm infants. And so this is coming to us from Montreal. The lead author is Magdalena Jaworski, and she is in Dr. jnb errs group who we are hopeful will be joining us on the podcast very shortly. So keep an eye out for that. So what the team really wanted to do was find out really how parents of extremely preterm children report on their child's well being long term. And so this is part of a larger study the parents voices project, which is a cross sectional survey of parents of this extremely preterm cohort. All infants are born less than 29 weeks are eligible for follow up after discharge in their program for neurodevelopment developmental monitoring, and they engage in this long term longitudinal research. So the group was seen for follow up that 18 months, 36 months, five years and seven years, so they had 248 Parents of 213 Children, so 83% of their eligible children participating, and they had 285 individual responses they had both parents answering the question for 71 children. So that's where the difference in responses versus children come from. And then 428 Children moms only and for 14 children, the paternal answers only. And just for some demographic data among responding mothers and fathers 63% and 82%, respectively, self identified as Caucasian 82 and 87% respectively reported having at least a high school diploma, so the group mean gestational age of 26.6 weeks with a mean birth weight of 907 grams. And based on the 18 month assessment, they evaluated the children for neurodevelopmental impairment. So at that time, 55% met criteria for no neurodevelopmental impairment, 25% had mild to moderate and di, and 20%, severe and Di. So then they asked the families to rate their children's kind of health score. And so interestingly, of all the children, the median score for health, as reported by parents was nine out of 10, which is a very high score. And interestingly, when both parents responded for the same child, the agreement was very strong. So they almost always agreed with each other's assessment of their child. And then they split the group by an impairment. So for the group of no neurodevelopmental impairment, the score, median score was nine. For mild to moderate neurodevelopmental impairment, the score was eight. And even for the severe NDI, the score was seven, which is still, you know, reasonably high score, which is really, when we get to the discussion really kind of their main take home point. They also looked at the children whose parents rated their health as six or less so less than the 10th percentile, the cohort now has 28 babies or 28 children, and of those 28, four had no neurodevelopmental impairment, nine mild to moderate, and so not surprising. 15 had severe neurodevelopmental impairment. So that was the largest group the most neurodevelopmental impairment, and so they had the lowest scores. But again, most parents even with severe neurodevelopmental impairment, rated their kids as seven. And then they asked the parents their priorities for health improvement. So what would parents work on if they could and the main themes identified across the board were development and 55%, respiratory health and fragility, and 25% nutrition, feeding and growth problems and 14% and 19% of parents reported there was nothing to improve. Then they asked parents specifically about development since that was the largest kind of group. So if they describe their child's development of sub optimal, what were they what were their concerns, language and communication, 20% behavior and emotional health 18% motor development and movements 15% and cognitive and learning skills 14%. Development was mentioned equally by all parents growth and feeding were more concerning to parents of children in the severe NDI group as compared with the no NDI group, with an odds ratio of 2.86, which is not surprising. respiratory illness and fragility were more frequently reported by parents in the mild to moderate category as compared to the severe category. And then they tried to look at these groups over time, so parents had 18 month old children were less likely to mention develop development as an area for improvement. In that age group 18 to 36, they were much more likely to express concerns regarding respiratory health, compared to the older groups and growth in nutrition issues compared with parents of older children. Interestingly, there was no difference between mothers and fathers separately, or by gestational age groups, even between the 22 weekers and the 28 weekers. With respect to the frequency of themes, and both by parents. They looked at parental education. So parents who had not completed high school, were less likely to report wishing to improve their child's development compared with parents who had at least a high school diploma. They were also more likely to respond that nothing needed to change. And I liked that they provided us some qualitative data. So in particular, for development things like I was worried about running, she acts like a baby I'm worried about school. Her language I wish she would express herself Have more clearly in respiratory health and fragility. His lungs are still fragile, his immune system has pneumonia, Is he sick all the time. And then in the growth in nutrition, I hope she'll learn how to eat his reflux and frequent vomiting. He does not eat much. So they really tried to evaluate what were the major concerns for parents? And what did they think about their baby's health over time. But really, I think this shows and just like previous reports that in general, parents, even of our kind of sickest, most fragile, post discharge, babies, still really rate their health is pretty good. And I think that's important for us to remember when we're counseling that and we really, it's really the parents experience and not our experience that we should be targeting. Thoughts.

Ben 1:05:54

Yeah, no, I agree with the last statement you just made. And I thought that was very interesting. Figure three of the paper is quite interesting, where they have basically bar graphs and, and in the first figure, basically, they look at the different areas of improvement that the parents have have, have identified. And in graph A versus B, they're looking at this breakdown based on the severity of NDI and the in in the second one, they're looking at it based on age. And what's interesting is that when you're looking at the chronological aspect of things from 18 months, all the way to seven years, you can see that development progressively becomes a more and more prevalent issue, you can see that respiratory illness goes down that growth and feeling goes down, and that the idea that nothing is wrong, actually goes away meaning saying that there's nothing to improve actually goes up with with time. So that's really cool. And I like the narrative examples as well of the parents, quote, so that that was that was cool.

Daphna 1:06:54

And that really mirrors I mean, what you see in the routine, outpatient pediatric clinic, right, the first few the, you know, those early years are really around weight and growth. And then as they enter school age, you know, they're really more starting to worry about development and milestones in school. So you know, it, it's parents of our medically complex babies still have a lot of the same needs as any other family, right? Yeah, absolutely. That was interesting.

Ben 1:07:29

I guess we're way over time anyway. But I wanted to mention this last paper. Just for fun. It's in JAMA Network open. It's called association between early amino acid intake and full scale IQ at age five years among infants born at less than 30 weeks gestation. first author is John Christopher was a from the epi parish to study group and the epidemics Study Group, which is the basically, I tend to think of the patterns like the Epicurious differentiated equivalent of the Epicure group. But anyway, the reason I wanted to highlight this, even though we're over time is because last time on general Club, we spoke about early versus late TPN. And we talked about early administration of amino acids. And so I thought this was interesting that this came in our folder this week, talking about the effects of early amino acid intake in very preterm infant. So the objective of this study was to assist to evaluate the association between early amino acid intake and cognitive outcomes. At five years. They the identified high amino acid intake as 3.5 to 4.5 grams per kilo per day, at seven days after birth. And anything below that as as a slow amino acid intake. I'm going to go through the abstract, I went through the whole paper, there's a lot of stuff that to talk about, but obviously when we're short on time, so they use the epi parish to cohort, which is in that nationwide prospective population based cohort that studies 63, neonatal ICUs, in France. And they created this propensity score matched analysis to compare infants born at less than 30 weeks, who were receiving either high amino acid intake at seven days of birth compared to those who did not. They will recruit between April 1 and December 31 2011. And they were followed pretty far out until 2016 2017. They performed full scale IQs at age five. And the main outcome was at the primary outcome of the IQ score greater than one standard deviation at age five years. And then they did a complimentary analysis looking at all sorts of other stuff, including data from cerebral MRI, a term equivalent. I don't want to spend too much time about that because the percentage I mean, the percentage of kids from this study who did get MRI was quite, it's quite low. It's still a high number, absolutely speaking, but it's it was a small percentage So 1789 preterm infants had data available to determine exposure to amino acid intake. And 938 infants 938 infants were exposed, and 851 were not so 938 had high amino acid intake 851 did not 707 17 infants from each group could be paired, the primary outcome was known in 396 out of 646 Exposed infant and out of 379 out of 644 non exposed infants who were alive at age five years, a full scale IQ score greater than one standard deviation was observed more frequently in the exposed infants to high amino acids versus the non exposed ones. And the percentages were 61.4 infants versus 54.4%. And looking at some of that complimentary analysis where they actually tried to do a matched cohort. So they said that in the matched cohort, a significant correlation was found between amino acid intake for one for one gram per kilo per day at day seven and full scale IQ at five years. And then when they looked at, among all correlated nutritional intake on the amino acid intake level, at days three and seven, were correlated with full scale IQ. amino acid intake at seven days after birth was significantly correlated with carbohydrate intake and lipid intake, but neither carbohydrate intake nor lipid intake was correlated with IQ score. So this is something interesting in terms of lipids and dextrose. Not really, right, it wasn't a board. And so their conclusion is that these these findings are suggesting that early, high dose of amino acid is beneficial when you're looking at long term outcomes. So in this cohort, high amino acid intake at the sevens after birth, was associated with an increased likelihood of a full scale IQ score greater than one standard deviation at age five. And obviously, this is a this is a database study. So they're recommending more more specific studies to be done. I know this was a bit fast, but I thought this needed to be mentioned. Any any thoughts Daphna?

Daphna 1:12:09

Yeah, I mean, I think they did a good job trying to match because infants in the exposed group, the ones who got more amino acids were more likely to be female. We know in general in the NICU, that outcomes are better and female infants, they were more like the mothers with an educational level higher than high school, and more likely to have antenatal corticosteroid, which we know changes outcomes. So in general, they they were the had the better chance for better outcomes to begin with, but they did do all of that matching. But then it makes you wonder, you know, why didn't those kids get all the amino acids? Was it because they were sick? Was it because they had renal injury? You know, which is, you know, one of the few reasons I restricted amino acids is that, you know, the babies have I'm concerned for renal injury. So, and they did say they were less likely to have acute kidney failure, and assisted ventilation, by in the first week of life, the babies who got the most amino acids. And so you know, that exactly what they say it's certainly an interesting trend. We know that early nutrition is important. But it's hard in a in a non randomized situation. And I'm not sure we'll ever randomize babies to

Ben 1:13:27

know amino acids. That's right. You're right about that. Anyway, that's it for us today. Any parting words, Daphna?

Daphna 1:13:39

No, I think that's, that's all. Anybody else who's had a long week. We congratulations. You've made it. Where are we?

Ben 1:13:47

I I just wanted to highlight one of the reviewers that we had on the on the Apple podcast saying love this podcast, the journal clubs are great. And the interviews are always interesting. Keep up the great work. And this is from x e 76. bln. So thank you, and we're working for more great content, more ways to consume information. So look out for what's coming up soon. Sounds good. All right. 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, the queue 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. Dufner 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


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