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#087 - 📑 Journal Club 35

NICU journal club the incubator podcast

Hello Friends 👋

Journal club this week contains many interesting articles. We reviewed several studies recently published that cover a variety of topics. Caffeine for late preterm infants, early ventilatory support for nano-preterm infants, the association between gestational age at delivery and ADHD symptoms, and so much more. We hope you are enjoying these episodes. If you are, please leave us a review onApple podcast. If you have any comments or suggestions to improve the show, feel free to reach out to us via email.

Have a good Sunday and good labor day if you are off tomorrow!


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

Remote ischaemic conditioning in necrotising enterocolitis: a phase I feasibility and safety study. Zozaya C, Ganji N, Li B, Janssen Lok M, Lee C, Koike Y, Gauda E, Offringa M, Eaton S, Shah PS, Pierro A.Arch Dis Child Fetal Neonatal Ed. 2023 Jan;108(1):69-76. doi: 10.1136/archdischild-2022-324174. Epub 2022 Aug 8.

In the grey zone-survival and morbidities of periviable births. Shukla A, Beshers C, Worley S, Chowdhary V, Collin M.J Perinatol. 2022 Aug;42(8):1001-1007. doi: 10.1038/s41372-022-01355-z. Epub 2022 Mar 10.PMID: 35273353

Hospital and Neurodevelopmental Outcomes in Nano-Preterm Infants Receiving Invasive vs Noninvasive Ventilation at Birth. Shukla VV, Souder JP, Imbrock G, Hu M, Rahman AKMF, Travers CP, Ambalavanan N, Carlo WA, Lal CV.JAMA Netw Open. 2022 Aug 1;5(8):e2229105. doi: 10.1001/jamanetworkopen.2022.29105.

Gestational Age at Term and Teacher-Reported Attention-Deficit Hyperactivity Disorder Symptom Patterns. Lingasubramanian G, Corman H, Noonan K, Reichman NE.J Pediatr. 2022 Dec;251:120-126.e4. doi: 10.1016/j.jpeds.2022.07.042. Epub 2022 Aug 6.

Do Pediatricians and Nurses Recommend Vaccines for Preterm Infants? A Survey in Italy. Napolitano F, Miraglia Del Giudice G, Pelullo CP, Di Giuseppe G, Pavia M.J Pediatr. 2022 Jul;246:64-70.e2. doi: 10.1016/j.jpeds.2022.04.026. Epub 2022 Apr 19

Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial. Oliphant EA, McKinlay CJ, McNamara D, Cavadino A, Alsweiler JM.Arch Dis Child Fetal Neonatal Ed. 2023 Mar;108(2):106-113. doi: 10.1136/archdischild-2022-324010. Epub 2022 Aug 29

Brain injury following mild hypoxic-ischemic encephalopathy in neonates-Ten-year experience in a tertiary perinatal center.Imanishi T, Shimizu M, Sumiya W, Kanno C, Kanno M, Kanno M, Kawabata K.J Perinatol. 2022 Dec;42(12):1630-1636. doi: 10.1038/s41372-022-01486-3. Epub 2022 Aug 11.

A Pose-Based Feature Fusion and Classification Framework for the Early Prediction of Cerebral Palsy in Infants. McCay KD, Hu P, Shum HPH, Woo WL, Marcroft C, Embleton ND, Munteanu A, Ho ESL.IEEE Trans Neural Syst Rehabil Eng. 2022;30:8-19. doi: 10.1109/TNSRE.2021.3138185. Epub 2022 Jan 28.


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

Ben 0:54

Welcome. Hello, everybody. Welcome back to another episode of the incubator podcast. It's Sunday. We're doing Journal Club. It is Labor Day tomorrow. Right Daphna?

Daphna 1:09

That's right. That's right.

Ben 1:11

So for us in the US, it means that professions other than doctors don't work.

Daphna 1:17

Well, there are other people who work on Labor Day, but the doctors will definitely be in the hospital.

Ben 1:24

I'm joking. But yeah, you know,

Daphna 1:27

holiday these, these holidays. These like government holidays are always such an interesting time in the hospital. Right? There's like this sense that like, you know, maybe you got to scale it. Maybe you got a skeleton crew, but you got to do in doing the work, right.

Ben 1:45

It's weird when it's on a Monday. I mean, Labor Day is always on a Monday, I'm assuming, like the Monday when the when the Monday is taken away, right? Monday. So it's an important day. It's like, right after the weekend. Right? Right. Right. Right. And studies that that got pushed a little bit because Sunday was like you said Sunday was skeleton crew. And now Monday morning, like I can't do it on like, you know, you know, these IR procedures that I can do, we can do it Monday morning, if you're okay with it. How are you?

Daphna 2:14

I'm good. I'm good. I mean, there has just been really a flurry of neonatal articles. It's, it's it's hard to keep up. You know, when it's when you have a timeline. This is what I say like, this is why we created the incubator, because there's no way to keep up. Just know even even even, we're not getting to all the articles, right? We never get to

Ben 2:38

the folder is pretty packed. Yeah. Pretty pretty packed. But we have a new system where we will let articles carryover, a bit like your rollover minutes on your phone plan. If we haven't gone into articles

Unknown Speaker 2:53

that about rollover minutes, and

Ben 2:57

you don't remember those. Yeah. Oh my god. Do you guys have rollover minutes so that anyway? Okay. Anything that any announcement has no announcements, we're good to go. Who wants to go first? I have. I have very, I'm very excited. You want me to go first. Okay, so I'm gonna first talk about caffeine. This was an article that got a lot of responses on Twitter. And so I was excited to just get to go through the paper. It's called caffeine to prevent intermittent hypoxemia. In late preterm infants, randomized controlled dosage trial. It's first author's Elizabeth and all event and it's from New Zealand. Interestingly enough, this this is this is part of a larger trial that I want to say it's called the latte trial. That's right. Yeah, it's, it's a very cool name. Anyway. So the background information is quite interesting. They're talking about the fact that late preterm infants that for those of you who need a reminder are these babies born at 34 to 36, and six weeks of gestation, do represent a large number of preterm births, and they do also experience episodes of intermittent hypoxemia which are defined as these transient repetitive decreases in oxygen saturation. Not necessarily associated with apnea, right? They're not talking about apnea of prematurity, but could similarly have negative effects on the baby. And based on prior reports that this group from New Zealand has published, these intermittent hypoxemia episodes tend to peak at around two weeks of age in this population and go down thereafter. If you go through the background, this citation citation number 14, to be specific, is that paper that this group has published in the past and 2019 in the Journal of Pediatrics. And and I think what We have to talk about in the background is how do we define saturation? Right? I mean, it's very, very difficult to understand like, what is the saturation? Number one? As we've said on the podcast many times, we don't even know what goal saturation should be. So the 36 weaker that's in deep sleep in the middle of the night, if they're setting 8889, is that is that okay? Is that considered a desert, we don't know. And the group, this group out of New Zealand, what they did is that they defined these intermittent hypoxemia episodes as like a reduction in auto saturation, either by like 3% or 10%, for certain duration of time. Most cases they were they had to last more than two seconds, and they had to be less than two minutes. And so that's mean, we'll see that throughout the paper. I think many people are going to have issues with the definition of desaturations. Not that they use the wrong but I think I think if you try to get a consensus on whatever the saturation is, in definition, you would get as many opinions as individuals. So what they do say is that we know that caffeine works in preterm infants with what about late preterm infants. And so we also know that caffeine is very rapidly metabolized as gestational age increases, and so maybe the if late preterm infants could benefit from caffeine, maybe they would even benefit from higher doses of caffeine. So the question that they were asking was, what is the most effective and best tolerated dose of caffeine seed citrate, to reduce intermittent hypoxemia episodes in late preterm infants? So this was a phase two B double blind five arm parallel randomized control trial. These are for our research scientist in the audience. And the inclusion criteria were very interesting. late preterm infants delivered at two maternity hospitals in in Auckland, Auckland, Auckland, Auckland. And yeah, because Oakland is in California, I don't know if we pronounce it the same way. In New Zealand, and you had to be between 34 weeks and 36 and six at birth. Now, interestingly enough, they recruited kids in any settings. So they recruited babies in their community, babies who were at home, and they put them on caffeine, which is something that if you're practicing in the US, is it can they do that? It can be confusing when you're reading the paper, because we would we have these most units, at least I have worked into, we never send home babies on caffeine. But in this paper, you'll see that some of these patients are at home on caffeine. And they'll talk about about that. exclusion criteria were major congenital abnormalities, minor congenital anomalies that affect respiration growth or development, previous caffeine treatment or contraindications to caffeine. So what did they do? They were they randomized these infants into five parallel groups within 72 hours of birth. And the daily dose was preceded by a loading dose of caffeine. And as most of you probably are doing, caffeine was discontinued at was continued until 40 weeks gestational age, and the different dosages I'm going to give you the maintenance dose first. So they had a group that was given five mils per kilo per day, another one that was given 10, another one that was given 15. Another one that was given 20 mils per kilo per day. And the loading doses were twice the dose of the maintenance. So if you were in the group that received five mils per kilo per day, your loading was 10. If you were in the group that was 10, your loading was 20, and so on. So if you're loading those if your maintenance dose was 20, your loading dose was 40 mils per kilo per day. Okay, so how does that even work, like you said, so the participating infants, whether they were in the hospital or at home underwent overnight oximetry using a motion resistant oximeter, and they have the it's the one of the Massimo products, you can see it in the paper. And, and so they did that prior, they monitor them prior to the loading those at two weeks post randomization and term equivalent age. So they did they did these spot checks that were quite long in duration, but they were not on continuous monitoring. At these time points, data work was collected on the collected data on maternal caffeine intake, infant feeding, sleeping and and throughput Anthro, POM anthropometry. And saliva samples were collected from mothers and infants at the two week time point analyzed to determine caffeine concentration. So what was the primary outcome of the study was the rate of intermittent hypoxemia events on overnight oximetry. At two weeks post randomization, what was an intermittent hypoxia it was an event where the saturation fell to a level that was greater than 10%. Below baseline for more than two seconds, but for less than two minutes, so Forex Simple, you're setting 100%, your O to set goes to 90 for five seconds. That's, that's an episode. Okay. And in prior papers, like I mentioned earlier, they did define D sets as like a drop that is larger than 3%. But they said that might create that might be too sensitive. So they wanted to really use a hefty drop so that it would be quite significant. In terms of secondary outcomes, there was a lot of secondary outcomes. They had respiratory outcomes, where they looked at the frequency of hypoxemic episodes on the overnight oximetry term equivalent. They looked at the mean overnight oxygen saturation, they looked at the use of respiratory support, oxygen, etc. They looked at growth, they looked at some of the side effects of the medication. Tacky cardio, obviously is one of them that they looked at, they looked at the maternal and infant salivary caffeine concentration, they looked at number of readmissions looked at maternal caffeine intake. So anyway, the list is long. And you can take a look at that. So the results, the study, found 131 infants that were randomly allocated to either placebo, or one of the or one of the five, or one of the four categories, right, because I realize now I may have said something incorrect. It's five categories for dosages, and one of them is the placebo, obviously. So we have a group of five minutes, particular 10 per kilo 1520. These are the four treatment groups. And then there's possible primary outcome data was available on 107 infants. And what was interesting was that a significant number of patients were on oxygen or on positive pressure ventilation. And so when when you look in the placebo group, there was 8% of infants who were on oxygen 33% were in positive pressure. But the percentage of kids who are on some form of support is significant, at least in the five minutes particular group, it was 29% in the 10 weeks per killer was 22%. In the 15th. Year was in the 15th year was I think 33. And in the 20 was 22%. Overall, the kids who were on caffeine 26% of them was were receiving positive pressure ventilation. Not exactly sure if this was tracheostomy whether it was nasal IPPV.

But that's that that's going to be the point that's going to be very interesting to discuss in a second. So let's talk about the primary outcome, the rate of intermittent hypoxic episode at two weeks post randomization was significantly reduced among infants allocated to caffeine citrate, at both the dose of 10 weeks per kilo, or 20 minutes per kilo per day, compared with placebo. However, the doses for five or 15, there was no difference, which is quite odd, I guess. I guess it's quite odd that that these two doses would make an effect and not the other to some of the secondary outcome. At two weeks post randomization infants allocated to the caffeine citrate group, doses 10, or 20, compared with placebo, had significantly higher mean or to saturation, less time spent in saturations that are less than 90%. While the kids who give who received 15 mils per kilo per day had a higher mean heart rate, a term equivalent, there were no significant differences between placebo and caffeine groups in the rate of of intermittent hypoxic event, the mean saturation or the time spent less than 80%. And remember, they're doing those checks at two weeks post randomization and term equivalent, right. So there's nothing in between. These are two time points where they're collecting this data. Compared with the placebo, all caffeine groups spent significantly more time with Tachycardia at two weeks, which persisted at term equivalent in the 510 and 20 Mix per kilo per day groups. Looking at growth because we know that growth could be impacted by caffeine, there was no difference between placebo and caffeine groups in the proportion of infants not regaining weight by two weeks, or in the growth velocity for weight or length at any time point. Infants in the 20 mix per kilo per day group compared with placebo had significantly lower length Z scores at two weeks term equivalent. Before I get into the conclusion, what was obviously interesting is you may disagree with the definition of saying hey, if the if the auto set drops, but they do have by 10% or more, you can see this is not a good definition for me. But they do have in the table, the percentage of time spent with a saturation less than 90%. And I think that's interesting, because that's a very objective metric. If it's setting 88 You feel like that's okay, then that's fine, but at least you can you can interpret that a bit better. The conclusions of the paper was that caffeine citrate reduces intermittent hypoxia in late preterm infants with doses of 10 and 20 makes per kilo per day being effective. The They had a whole documentation that's to the difficulty of administering the medication. So that's why some of the outcomes were not available in the population, mostly because it was difficult for the mothers to give the medication to the babies. Side effects at these doses usually include tachycardia and possibly growth. And they're mentioning that a longer larger trial with no other mental impairment as the primary outcome is required. Now, what I think is interesting about this paper is that the groups are kind of I don't want to use messy but they're very heterogeneous, right? I mean, you have some of them were on the street, roomier. Some of them were on oxygen. Some of them weren't PPV. Not even sure if some of the kids one, oxygen couldn't be also on PPV that some

Daphna 15:41

of them were some of them are at home.

Ben 15:45

Some of them were at home. Yeah. And I also wouldn't be surprised if some of them were at home on oxygen or PPD. I mean, it's not impossible. I guess what I'm trying to say is that, for a baby that is on room air, that's like a healthy 35 weaker, it seems a bit far fetched for me to say, Should we put this baby on on caffeine at home, but it's interesting for especially for the babies who are more medically complex. If you can reduce the rates of hypoxemia episode in a baby that has a track that is on oxygen at home. That's something that's quite interesting, even if most of these babies tend not to be discharged that early. That's, that's interesting. Obviously, there's an issue with the definition of auto saturation of the saturation, because you could you could argue I'm not there's no issues with the definition. But you could argue that you don't like that definition. So there's lots of interesting things there. But it's, in my opinion, an important paper because it also hints at what's happening in our field where we're starting to look outside of the cap trial criteria, which are like, what if we give caffeine to babies longer or in different categories? And that was interesting.

Daphna 16:49

Yeah, the other thing I think is important is, you know, this late preterm group, which is a huge population in the NICU, right, we spend a lot of time studying the micro Pierini. This is nano preemie, the LBW when in reality, they don't make up the largest population of our NICU patients. And we know that the late preterm does not have the same outcomes or developmentally as a term infant, and we just kind of like, we're just dealing with it. So, you know, I love to see the neuro, you know, that was one of the that was one of the outcomes of the cat trial was neurodevelopment. And not just lung disease. So I'd love to see. I'd love to see that for sure. And any other iterations of, of caffeine administration, like you mentioned,

Ben 17:44

I mean, you and I, both in our unit sometimes, right, you have a baby, that's 35 weeks, and we do have this discussion, like, should we should we start some caffeine on these babies? Right? We Yeah, the evidence is not great. But same thing. Same thing for

Daphna 17:57

there are some late preterm who really are having, say, you know, maybe some periodic, you know, impressive periodic breathing or events or things like that.

Ben 18:07

Yeah. And then you wonder, you say, Do I just increase my support or churches give him some caffeine, right. And this is, this is interesting data. This is interesting. Yeah. I have to say, it's odd that the some of these concentrations worked. Some others didn't. Yeah,

Daphna 18:23

they didn't. All right, looking at them. They weren't following.

Ben 18:28

They were not leveling. They were not really following through levels. You're right. But they were following the salivary. They were following the salivary concentration. And again, these were these were those two different time points. So yeah, I mean, yeah, it's, yeah. It's definitely something for, for people to look at. Let me just see if I can. Can I rotate this thing? Alright, don't worry about it. But I'll take a look. There's if you wanted to look at the caffeine concentrations. There is there's it's in Table four. And obviously, what's what's confusing is that these are averages. And so technically, the caffeine concentration in the salivary Calif, caffeine concentration in the infants increases as the dose increase, obviously, which is not really surprising. But still begs the question, why is some doses working then not others in a dose response way? Anyway? All right, we need to move on.

Daphna 19:34

Yeah, and there may be some sort of threshold that we still don't fully understand.

Ben 19:39

Yeah, but I mean, right. I remember it from from caffeine level dosing that like there was this, this bell shaped curves, it's like there's like a, there's like a very narrow range where the effectiveness is there and you don't have too many side effects. But in this case, it's like, it's like 1010 and 20 are okay for this and then 15 and 20. Okay, for that. It's like it's just it's just it's not a continuous pattern. It's interesting and definitely probably wants to be investigated further.

Daphna 20:05

All right, buddy, I had an interesting study that I wanted to talk about. So this was regarding Attention Deficit Hyperactivity symptoms. So this is actually looking at gestational age babies, the titles gestational age at term and teacher reported ADHD symptom patterns. Lead author. Let's see Dr. Ling Natsu Rahmani, and I think I did it. Anchoring author, Dr. Reisman. So this is in the Journal of Pediatrics. And the question really was, we know that there is a link between preterm birth and attention deficit hyperactivity disorder symptoms, but it's actually not been, like totally elucidated. And what they were actually looking at is, does it matter if you're delivered in this 37 to 39 week time period, or, you know, this 39 to 41, week time period, which is something that in obstetrics are debating all the time, like the value of waiting those few extra weeks once your quote, unquote, term. So I thought this was interesting. This is actually a secondary data analysis of 1400 children in the Fragile Families and Child Wellbeing study. So this is a US birth cohort study that what they did is they over sampled non marital births. So by design, they enrolled infants so that three quarters of the infants were born to mothers who were unmarried. And what they wanted to look at was a potentially kind of higher risk group of babies. Obviously, that's not true for all babies who are born to mothers who are unmarried. But that's what the Fragile Families study was designed to look at. So the inclusion criteria was basically singleton births, born at 37 to 41 weeks, and the major exclusion criteria was not having teacher reported data regarding ADHD symptoms. So they were looking at the students at age nine who are evaluated by their teachers using the Connors rating scale. And so they wanted what they were really looking for was gestational age and reported scores. So the primary outcome was looking at this early term group 37 to 38 weeks, versus the late term grew 39 to 41 weeks. So the baseline characteristics of their cohort, roughly half of the mothers 48% were non Hispanic black 63% had a high school education or less 76% were unmarried, and 63% of the overall cohort was covered by Medicaid. And what they were, you know, really trying to understand is that this these population statistics of this other group, really shows this strong association between this social disadvantages associated with being a racial minority and in the United States. And so that's why they really wanted to hone in on this group that is affected by this disparity. So, primary outcome, they wanted to look at the continuous measure of gestational age in weeks in both unadjusted and adjusted regression models. The gestational age and Weeks was associated with significantly lower escapes lower scores on the teacher reported hyperactivity, ADHD, and cognitive problems and initate inattention. Subscales at age nine, such that these babies born at early term, so 37 to 39 weeks had significantly higher scores, meaning they had higher symptoms than the full term children the 39 to 41 weeks on the subscales hyperactivity, ADHD and cognitive problems slash inattention subscales. They looked at the unadjusted association between week of gestational age and hyperactivity specifically that score was point nine to indicating that each additional leak of gestational age at term on average was associated with an 8% lower score. So a pretty kind of linear finding. The bet the longer you are are cooking for later your gestational age, the lower score that you have. Similarly, each additional week of gestational age a term was associated with a 6% lower score on the ADHD subscale and a 6% low risk score on the cognitive problems slash inattention subscales. And then adjusting for maternal characteristics reduced the estimates slightly, but they were still significantly associated with hyperactivity, ADHD and the cognitive problem slash inattention subscore. A good thing to note is one of the subscale items is oppositional behavior scores, and gestational age was not significantly associated with the oppositional behavioral score. And then they wanted to look at the two groups separately. So they looked at early term 37 to 39 weeks and full term, this 39 to 41 weeks instead of the continuous measure. And it also showed significant associations between early term and scores on both the hyperactivity and ADHD subscale. So in adjusted models, that early term was associated with a 23% increase or higher scores on the hyperactivity scale and the ADHD scale, and a 17% higher score. Oh, sorry, I'm sorry. Let me say that again. Early term was associated with 23% higher scores on the ad each. That's still wrong. Let me early term was associated with 23% higher scores on the hyperactivity scale, and 17% higher scores on the ADHD scales. There are some other findings that they looked for really related to some of the social markers, and then they look at obstetric markers. But we've got a lot of papers to review. So I definitely think people could take a look at this. And I think when we think about our whole population, we were just talking about the late preterm. So we can anticipate that the late preterm will have even potentially higher scores, and then certainly in our in our ELB, who are very early babies, that risk is likely to increase. And that's been shown in other studies. So I thought that was interesting when we talk when we hear obstetrics talking about you know, delivering it 37 weeks versus, you know, the 40 week mark.

Ben 27:19

Yeah, and it seems right. I mean, this is data that, like when it comes to me, conium also right, the reduction in NICU hospitalization, we call him aspiration found that delivering around 39 is probably is probably a good idea. So it seems like there's a very narrow window. Yeah. Yeah. And but that's that. I mean, that data is quite, it's quite frightening. Yeah. Yeah. Right. Yeah. Like just you said, early term birth, meaning 37 to 38 weeks associated with 23% Higher hyperactivity score. That's right. 17% Higher ADHD scores. Yeah. When you compared to 39 to 41. Yeah.

Daphna 28:07

Something, something to think about, you know, what I mean, and, and kids who are really affected by these ADHD symptoms, it's no small hurdle for for families, you know. And it's something I feel like when we, you know, when we give anticipatory guidance in the NICU, that it's not one of the major things we talk about, but really affects school aged children and adults, right.

Ben 28:33

So much so much pressure on our OB colleagues, I'm so happy and I feel like the next the next evolution, there will be like a referee that will just like blow the whistle be like you can do it now. And then we have a clock ticking anyway. All right. Okay, I have a very interesting paper that I wanted to talk to you about. Okay. Okay. This paper is called Remote ischemic conditioning in necrotizing enterocolitis. A phase one feasibility and safety study. first author is Carlos Ziaja, from the hospital of Sick Children in Toronto. Definite, do you know what is remote ischemic conditioning?

Daphna 29:18

No, I don't I have a like I have a thought about it. And then I read the paper, but I did not before.

Ben 29:27

I had no idea what this was. And it's quite fascinating. So I guess the bulk of my review will be to just introduce the audience to what remote ischemic conditioning is. It's a maneuver that involves the application of brief cycles of non lethal ischemia and reperfusion to a remote organ slash site that conveys protection to distant organs withstanding ischemic injury. So what does that mean? Practically speaking, it means that you're inducing ischemia in the distal limb, usually the legs or the arms. And the way you do that is by just Just inflating a blood pressure cuff and stopping blood circulation distally. Right. And so you're effectively creating ischemia of the limb for a few minutes. And the idea is that all the pathways that are going to be activated in response to this insult, are going to help you deal with ischemia that's going to that, you know, might happen in the future in a different organ, because your body is almost now trained, I guess, to release the chemicals. And

Daphna 30:32

we have a model for that, right? Like when we see these change these physiologic changes in like, babies whose parent has preeclampsia or really bad you know, placental insufficiency. So, yeah, the body does everything it can. Super cool.

Ben 30:50

Right? And so the, there's like, right, so the oldest or the signals that are being generated from an ischemic insult are meant to protect the body, right. And there's, there's a bunch of papers that we can we can reference in the, in the, in the, on the website that talks about the humoral response, the neuronal response, the different types of micro RNA, the five by phosphate three kinase, the protein kinase theory, there's all these these chemicals, the the that are released to protect, to protect against ischemia. And so this group out of the hospital of sexual in Toronto published animal data in 2020, that showed improved intestinal wall perfusion and the microcirculation with the initiation of, of remote ischemic conditioning compared to controls. And that was done I think, in a mouse model. And it's quite interesting right? Now, where it's

Daphna 31:46

when you think about neck it sounds terrifying to, to even consider this,

Ben 31:50

wait until you hear the methodologies but in, in adult medicine, right, if you're on if you're going to undergo cardiac bypass surgery, they do something they use some some institutions use this the remote ischemic conditioning, and it's actually called Remote ischemic preconditioning. So they'll they'll put your limbs through some ischemic insult prior to you going into the operating room so that you can have better outcomes while you are undergoing bypass, right? In the case of neck, obviously, we don't know when neck is going to develop. So it's conditioning meaning we're trying to help the baby deal with the insult using remote ischemic conditioning. So the question is, Is this safe? And is this feasible? To use Ric remote, I'm going to start using it Ric because it's remote ischemic conditioning for infants with suspected or confirmed neck and they suspected that Ric done in a way where they would use up to four cycles of four minutes of ischemia repeated after 24 hours would be feasible and safe in this vulnerable population. This is a phase one feasibility and safety trial. The patients who were included were babies who were suspected or confirmed next stage ones stages one to three per the modified Bell's classification. And they had to be weighing 750 grams or more at the time of recruitment and be less than 36 week of gestation at birth. There's a bunch of exclusion criteria, major congenital heart disease Congenital Diaphragmatic Hernia gastroschisis, and etc. So what is the intervention look like? Right, so how do you induce ischemia and it's basically just a blood pressure cuff, it's limb ischemia reperfusion cycles were applied by placing an appropriately sized blood pressure cuff around the limb and inflating until blood flow distal to the cuff was interrupted with no pause detected by pulse oximetry. And deflating it using a manual sphygmomanometer nailed it. That was the one I was worried about. But right so it's, it's basically just like you're doing your automated automated blood pressure measurements, except that you're the one that decided to Deflate the cuff now, this is terrifying, right? So these kids are going through an ischemic insult and you're going to start creating more ischemia somewhere else. So they were obviously there, the people at the hospital have sexual in Toronto is a very good group and they had all these safety measures. So the monitoring is the continuous integrity and perfusion color capillary refill times were assessed, the presence of grasp reflex was ascertain immediately before right after and again 24 hours after Ric the urine output during 24 hours before and 24 hours, 24 hours after Ric was also recorded. According to the safety protocol, Ric was due to be stopped if there was no return of limb perfusion on clinical assessment and or no return of oxygen saturation to baseline values plus minus 3%. Right so they give themselves like if you're setting 95 And now you're setting 92. They just watched it within four minutes in the hand or foot or the limb receiving Ric if perfusion did not return. The limb was warmed elevated for 10 minutes followed by nitroglycerin patch application and Doppler or For sound if necessary, so yeah, terrifying. They also had a whole process to do this safely. So to determine tolerability of the ischemia period, up to a maximum of four minutes, as well as the feasibility of doing repeat cycles. On two consecutive days they had, they were doing it in three steps. Step A is that you went through four cycles of limb ischemia reperfusion in one day, with increasing ischemia time by one minute in each cycle, starting at one minute, and then you went from two to three, up to a maximum of four minutes in the last cycle. Each ischemic cycle was followed by reperfusion for four minutes rest for five minutes before the next cycle. Then you went to step b, which is for cycle of ischemia reperfusion in one day, in this time, consisting of the longest safe duration of ischemia determined in Step A, so if you only tolerated three minutes, then you only get three minutes of ischemia, followed by reperfusion for four minutes and rest for five minutes. And finally, Step C four cycles of ischemia reperfusion as in Step B, but repeated now on two consecutive days, so 24 hours, plus minus two hours apart. The primary outcome was safety and visibility of Ric feasibility was defined as the ability to apply the Ric maneuver as planned per the protocol. And the safety was defined as the return of limb perfusion to baseline within four minutes after the cuff is deflated. And a clinical assessment of skin color, pulse ox and cap refill time, and they had a bunch of secondary outcomes. And the results of the study are that they were able to get 15 neonates and they were able to do five in five and each step five went through each step of the study. All neonates were preterm with a birth weight ranging from 490 to 2010 grams net was diagnosed usually between seven and 58 days and Ric was performed after a median of four days from NEC diagnosis. 87% of patients were mechanically ventilated at the time of ric 33% were receiving medical treatment 67% underwent some form of surgical intervention. Looking at the primary outcome, they were able to remote ischemic conditioning was completed according to the protocol and all neonates, arterial flow and limb perfusion returned to baseline within four minutes in all patients. So now it's really reassuring to see that kind of data. secondary outcomes show that all patients had normal grasp reflex before and after. Ric there was no new onset of skin lesions, breakdown bruising and chemosis. There was no significant difference in pain scores comparing it to value before and six hours after Ric and really no patient became either oligos slash and uric defined as having a urine output less than one mL per kilo per hour after Ric so in this study, they demonstrated that Ric is technically feasible and safe and small and fragile preterm neonates with any C. And these novel findings are essential to embark and they use the word embark, which I think is a very appropriate use of the term on a multicenter randomized control trial to investigate the effect the efficacy of Ric and reducing neck progression, morbidity, and mortality. So I thought it was a fascinating paper because I was not familiar with what Ric was, I am fascinated that it's like, really, if this ends up working, right? I mean, it's like, Hey, if you diagnose neck, you just like put a blood pressure cuff and you just like, do these little cycles, and that's going to help prevent bad outcomes. That would be insane. Yeah, I have an insane good, insane good, right.

Daphna 38:38

Yeah. No, yeah. I mean, I'm not sold. And that's all but I, but I'm, I'm hopeful. I'm hopeful. You know, it's just interesting, because so many of these babies who are having intestinal ischemia, like, they're, they're like, lower extremities, or, you know, the profusion is not great. there either. Right? So,

Ben 38:58

I mean, I think I was you read the contingency planning, if there's any issues during this. It's like, it's like, you're my heart rate was like, Oh, my God, oh, my God, because I have dealt with limb perfusion issues in the NICU. And it's like, it's terrifying. And so it's terrifying at baseline, right? It's like, please tell me that the kid who has the limb ischemia doesn't have a PICC line in the wrong vessel, right, those kinds of things. And, and to say, like, Hey, I'm, I may have to deal with this, because I'm inducing it. It's like, Oh, my Lord, it's gonna be a tough IRB. Listen, the animal data is I'm going to post their animal data results. It's pretty, it's pretty impressive. compelling. It is compelling. Let me let me actually, let me show that I'm going to share my screen with you. So you can see. Look at that. Can you see this? I mean, this is like neck, neck with Ric as one as to this is also like neck, neck one. Like these graphs are pretty pretty nifty. Okay, definitely. What are you looking at next?

Daphna 40:04

Okay, let's go to well, we're still talking about ischemia, I guess but this article is brain injury follow the following mild hypoxic ischemic encephalopathy in neonates a 10 year experience in a tertiary perinatal Center. This is coming out of Japan. So, I'm the lead author, Toshi Yuki, ima Nishi. And senior author, Ken Cao bada. So this is a journal Perinatology. They were really looking at, they wanted to look at their cohort of babies who had mild HIV over the course of this 10 year period from 2011 to 2020, who were not cooled. They obviously didn't meet criteria for cooling. But they were brought into the NICU. They were monitoring and then they had MRI data on all of these babies. So that's what they're reporting on. And really, the question is, is a diagnosis of mild HIV like a reliable prognostic indicator for MRI findings, and then they did try to do some long term follow up. So again, it's a retrospective study, done in this single center, where they had babies who are diagnosed with mild HIV using the Sarnat scale, underwent temperature, temperature targeted management. So what that means if you're not familiar with it, so for the 72 hours, instead of undergoing cooling, they went underwent temper, temperature target management, which is 36 degrees plus or minus point five degrees. So they were really trying to prevent like hyperthermia. I'm trying to kind of balance right right below. No, you thermia But it's not truly hypothermia. I told you their inclusion criteria were babies again, who by SAR not scoring were found have mild HIV and did not qualify for therapeutic hyperthermia. Their exclusion criteria. If you were admitted to the center, after six hours of life, the baby was still found to have some sort of critical illness or known or known chromosomal anomalies and the primary outcome was death or abnormal MRI as a primary outcome, and then secondary outcomes. They did try to do some developmental screening at five years. But unfortunately, they had a lot of loss to follow up. So they had 337 Babies admitted for possible HIV 149 were diagnosed with mild HIV 93% of the mild HIV cohort had MRIs, and all survived to discharge. So the for the primary outcome 83% of this mild ha group had normal brain MRI findings, whereas 17% had abnormal findings. MRI injury to the basal ganglia and thalamus was identified in two out of the 23. So 8.7% of newborns to the white matter and 17 out of 23. So 74% of the abnormal MRIs actually had this white matter injury,

Ben 43:21

and then found the center of that group of 23 people correct 23

Daphna 43:25

of the babies who had abnormal MRIs, this is where they found it. And it was just to recap 17% of the total mile ha group had abnormal MRI findings. The other thing they found some quote unquote, elsewhere on the MRI was found in 30 30% of the abnormal MRIs. Other injuries included four cases of cerebellar hemorrhage to two of ivh and one of cerebral infarction. The other thing we did is look at the amplitude of EEG patterns for this group of babies. So groups had similar characteristics, except for a discontinuous amplitude EEG pattern. So they typically are they were looking at the groups who ended up having abnormal MRIs versus the groups who had normal MRIs. So so the babies who had abnormal MRIs more were more likely to have a discontinuous amplitude EEG pattern and they were more likely to have the use of inotropic medications. In all cases of discontinuous amplitude EEG pattern that pattern had changed from discontinuous to continuous by 24 hours after birth, even in the group that had abnormal MRIs, but again, discontinuous amplitude EEG patterns again in that first 24 hours were associated with a higher odds of observing abnormal MRI findings and the presence of clinical seizures which was interesting because usually clinical seizures no longer makes you mild, no longer makes you mild ha. So I thought that was an interesting piece of information. And they don't give us a lot of information about that group of which babies had clinical seizures. They did have some, like I said, five year neurodevelopmental follow up outcomes, but they only had 16 Out of the 87 or 18% in the normal MRI group, and five of 18 to 28% in the abnormal MRI group. But neural neurodevelopmental impairments were present in 12%, of the normal MRI group, and 60% in the abnormal MRI group. Again, they couldn't really obtain really true statistical significance because the groups were so small. But it was interesting to note that in this group of babies with mild HIV by or Sarnat scores, still had some MRI findings, and obviously, having the abnormal MRI findings was a higher risk for neurodevelopmental impairment leader and like, I should say, at five years. That's

Ben 46:24

right. And that paper got me frustrated. Yeah, that's fair. Because number one, I thought it was a bit. Okay. I'm going to give my personal opinion here. But it felt a bit click Beatty, right? You know, when when YouTube videos do clickbait it says like, a 10 year experience, right. And then I was hoping to get data of 10 years worth of data, but then I find that the five year northern metal follow up, the follow up rate was like 18, and 20%.

Daphna 46:55

It was that they they enrolled babies for 10 years.

Ben 46:59

Right. And I understand that, I mean, I've done North metal research, like follow up that we tend to praise, right, all these groups that are able to get 93 96%. However, it's so hard. And then and then it's it's like I'm not exactly sure. Then, like it's it's the typical psychological exercise, right of loss aversion. Like if you tell me 85, whatever, 83% have normal MRIs, right? You're like, really good. And then if you tell me 70% have happened on my mind, like, Oh, my God, that's really high. So I was like, oh, man, what am I supposed to do with this? Am I gonna? And then they were not really, they were doing this in between thing, right? They were not really not cooling. They were also not fully cooling. So. So I don't know. It's interesting. I mean, I think he is a is a is a problem. And then, and then I'm sorry, one more thing, the discontinuous AEG pattern. It's like, oh, boy.

Daphna 47:58

Yeah, cuz if I were to see a discontinuous EEG pattern, that would make me very nervous. Right. And it's not one of our cooling criteria, maybe it will be in the future.

Ben 48:09

But but we also don't know how if these babies were to have been cooled with outcomes a bit different, we don't know. It's just lots of

Daphna 48:19

bats. Go ahead.

Ben 48:21

A paper that leaves you with with more questions than answers than answers. And it's not to the fault of the author's obviously, it's just it's just the state of affairs in mild HIE. Yeah.

Daphna 48:31

Yeah, I was curious to see, you know, as we're, as we're starting to review a lot of these mildy je papers, right, as they're, they're up and coming and to see maybe what the experience is on the Japanese cohort. I think my takeaways, as we're learning more and more is that mild HIV is not nothing, right. There's, there's definitely something going on there. And even when I think about our interview, about hope for HIV with Betsy, you know, we knew they know, they're seeing so many families after faxing, you know, my kids not developing the way that I anticipated that they would they had this like little thing at birth, by the way, and, you know, so I just, that's my takeaway. We got to really take a look at this group of,

Ben 49:21

I like to dissect the data a little bit, right. But I mean, when you see that, like, some of these infants, the percentage like 57%, were on inotropes, like 32%. Were on either troops in Vietnam, like some like you said, Something's happening, right. It's there. They're not there. There's an insult there's a there's a there's a there's an injury somewhere of what kind it's complicated. We just don't have a good grasp on the on the pathophysiology of militia in my opinion just yet. Okay. Okay. All right. Next. How much time do we have? Okay, not much. Have to have two more papers, one short and then Another shout out so I have to go quickly. So this is a paper that was published in the Jama open, I think Jama open what is I think called again, JAMA Network open sorry. This is called hospital and northern mental outcomes in nano preterm infants receiving invasive versus non invasive ventilation at birth. first author is the neck Shukla from the University of Alabama in Birmingham. Kent, if you're listening, you see, I do. You can teach an old dog new tricks. And there's a lot of famous people in there, obviously, while he Carlo is one of these is one of the authors on the paper. And yeah, so what is this paper about? The background says things that we've all been saying for some time, where's where resuscitating 22 week preemies. They're a breed of their own, they have a very set of specific needs that may not be similar to the ones over 2425 wicker. So the authors are suggesting that maybe we should rename this category and they're suggesting the term nano preterm like nanotechnologies nano preterm for infants born between the gestational ages of 22 and zero and 23 and six weeks to differentiate and precisely represent this population. And they're obviously underscoring the fact that strong evidence is lacking on whether non invasive respiratory support at birth is beneficial in nano preterm infants. The question they're asking is, is intubation at 10 minutes or earlier after birth associated with a higher incidence of BPD or death by 36 weeks postmenstrual age in nano preterm infants, like you could like why are they even asking that question? Well, they're making the case for saying that, well, if you have a 24 or 25 weaker, you should write your first instinct is going to try to attempt non invasive, non invasive respiratory support Correct. You're going to try to see if the baby is crying and the baby can do a kill Okay, on another CPAP, and I envy CPAP and IMV. And they've never for example, you may not intubate them, and they're saying, Does that practice apply to nano preterm? The intubation after 10 minutes was chosen as a surrogate for an attempted trial of non invasive respiratory support after birth, right. I mean, because these babies don't tend to linger very long. They don't tolerate non invasive, so that's why 10 minutes was chosen. The study design is a retrospective cohort study of actively treated nano preterm infants at the University of Alabama at Birmingham from January 1 2014 to June 31 2021. They extracted data that was collected prospectively from a database that they're keeping locally. The infants were grouped based on first intubation attempt and the timing of it after birth, whether it was after 10 minutes or before 10 minutes. And as invasive and non invasive respiratory support respectively. The primary outcome was the composite of BPD or death by 36 weeks PMA, the definition of BPD was the physiologic definition. And if you do not know what that is, I'm not going to go into it right now. Tuesday's episode of The neonatology podcast definitely gives us a good overview of what the wash definition is. But you see, that's why we did that. That week a board review. That's great. Yeah.

Daphna 53:26

And we were talking about that with the with Dr. Willis is that as the Gosh, for these researchers who are writing papers during this time of changing, changing definitions, you know, where did you decide to go?

Ben 53:43

Yeah, absolutely. secondary outcomes for the study were hemodynamically, significant PDA necrotizing enterocolitis ivh retinopathy of prematurity, and moderate and or severe neurodevelopmental disability and 22 to 30 months. So off 230 consecutively born eligible mental preterm infants were included, of home 88 ended up in the non invasive respiratory support group at birth, and 142. In the invasive respiratory support at birth, the gestational age, the median was 23.6 weeks, and the birth weight was the mean was 500. Sorry, I'm sorry, I'm gonna say that again. The gestational age and the birth weight, were higher in the non invasive respiratory support at birth group compared to the invasive group. So the gestational age was 23.6 and the non invasive versus 23.0 in the invasive, and then the birth weight was 577 grams in the non invasive versus 522 in the invasive in the invasive group. Not not crazy difference, but different nonetheless. 55% in the non invasive respiratory support group at birth were later intubated, so more than half and the timing of that intubation was you within the first hour after birth for most infant who required intubation in that non invasive respiratory support group, in terms of the primary outcome, the incidence of BPD, or death by 36 Weeks was 94.3% in the non invasive respiratory support group versus 91% in the invasive group, so lower in the invasive respiratory support, and something also here to consider, which is that when we counsel these families, the University of Alabama is a great unit, they have great outcomes rate, the rates of BPD or death is 94. Like it's above 90%. It made me reflect a little bit you know as to what the odds are for these babies. So slightly lower in the invasive group, but not statistically significant on multivariable logistic regression analysis, no significant difference was found for BPD or death by 36 weeks. In terms of the secondary outcomes. Very interestingly, severe ivh, or death by 36 Weeks was lower in the invasive respiratory support group at birth. All other secondary outcomes were not statistically significant. Dr. Chu, Clara, and the team concludes that the findings of this cohort suggests that non invasive respiratory support after birth is feasible, but is not associated with a decreased risk of BPD or death. And in the delivery of nano preterm infants, an adequately powered trial is needed to confirm the trends for better short term outcomes in the invasive support group at birth seen in the current study. The big, the big thing that I have, the big issue I have with this paper is that they didn't disclose their surfactant administration protocols, right? So because if you're using Lisa very routinely, then yeah, that makes a huge difference, because these babies will not get intubated. But if you are intubating, to give surfactant, then it's a different ballgame. And in the conclusion, the word like the surf the introduction, right? So in the conclusion, I'm going to, I actually admitted that that word, they said that non invasive respiratory support in the first 10 minutes is feasible, but it's not associated with a decrease in the risk of BPD, or death compared with intubation and early surfactant. And it's like, that was not really well mentioned beforehand. So I'm not sure. Early surfactant, does that mean that the others got delayed? Does that mean that the other got Lisa, that was that was a bit of information that I would have liked to see?

Daphna 57:37

Well, and it's hard to write because we know that surfactant, this is a board review Pearl, is it? It's much more effective than earlier? You know, we can give it and so how does that, you know, that's how does that change outcome if they're, you know, delayed surfactant administration?

Ben 57:56

Absolutely. The other thing that is impressive about this paper is the fact that I was not expecting that their court was going to spend such a long time period, right. So they're looking at nano preterm, being resuscitated and surviving, like since 2014. So that's, that's a long time. Whether the methods of surfactant administration were extremely well established locally in that unit. I don't know me know, maybe Lisa became part of their protocol right? Later. That's, that's not clear. But But yeah, but dimension of surfactant is actually, it's briefly mentioned in the context of the support trial in the introduction, and only then appears in the discussion. So there's no mention of surfactant beforehand. And, and I don't know which, again, their practice very good medicine, I'm sure they had like a protocol in place, but the paper could have given us more info when it comes. I'm

Daphna 58:47

sure somebody will tell us somebody on Twitter. Well, well, I'll close the loop on that. Okay, anything else?

Ben 58:58

No, I have two more. So I'm shutting my mouth now.

Daphna 59:02

Okay, so I'm gonna go. So since we're talking about very little early babies, this article is entitled in the gray zone survival morbidities of Pirrie viable births. Lead author on keto Sheetla and senior author Mark Cullen. This is in the journal Perinatology is coming to us from Case Western in Ohio. And so this was a retrospective study of the preterm infants that had been delivered in their unit. They were looking at babies born between 22 weeks and 25 and six sevens weeks. And so what I actually thought was very interesting about this study is they were very open disclosed what their resuscitation practice is in this, as they call It quote unquote, the grid the gray zone. So the unit has an opt in policy for 22 weeks gestation. And what that means is that palliative care will be provided unless the family expresses a wish for proactive neonatal resuscitation. So, the unit practice at 22 Weeks was sounds like comfort care. The opt out policy at 23 weeks states resuscitation will be proactive, unless a family chooses otherwise. All infants before born greater than or equal to 24 weeks gestation, are resuscitated C section for example, C section for fetal distress is not offered until 23 weeks. And just so we're all talking about the same definitions when they use the term active treatment. This is defined as the use of endotracheal intubation surfactant administration ventilatory. Support chest compressions if needed epinephrine and our volume resuscitation. So they looked at all infants born between 22 and zero and 25, and six, seven weeks. The inclusion criteria, I mean, sorry, the exclusion criteria was infants under 24 weeks or were provided comfort care based on parental preference instead of resuscitation. So they describe that population a little bit, but that's not they were looking at babies that were actively resuscitated. They also clearly babies with congenital malformations. So during this study period, a total of 187 infants that were actively resuscitated and admitted to the NICU were included, based on again, the gestational age of 22, and zero to 25. And six sevens week, they had 18 infants that were born at 22 weeks, they had 39 infants born at 23 weeks, 52 infants, 24 weeks, and 78 infants of this 25 weeks gestation. Of note, a total of three of the 21 infants born at 22 weeks died in the delivery room. And one of again of the group that got active resuscitation in the delivery room, and one out of the 40 babies that were actively resuscitated and born at 23 weeks, also unfortunately died in the delivery room. Some of the maternal characteristics. So chorioamnionitis was different among groups, it was higher in the 22 week group than the 24 week group. The prevalence of C sections was different among groups. But again, mostly because a 22 week group, we had a much lower prevalence of being born via C section because that was their that's kind of their unit practice that they don't offer a C section for fetal distress until 23 weeks, there was no difference in prenatal care, intrapartum antibiotics or antenatal steroids. So they wanted to look at their group. So at 22 weeks, the rate of survival of the live born infants at the center was 31%. But among actively recessive, if you just take the group of actively resuscitated it was 48%. Among those with active resuscitation in subsequent NICU admission, it was 10 of eight teen or 56%. So for 23 weeks, the total survival is 21 of 43. So 49%, those that received active resuscitation 53% and those that were admitted to the NICU 54%. Survival to hospital discharge was significantly higher in the 24 week group of infants where the overall survival rate was 77%. And in the 25 Week events was 92%. So obviously, as the gestational age increases, our survival increases as well. They also looked at mechanical ventilation, and it was long as to the 22 to 24 week group, no surprise as compared to the 25 leave group. And it did show kind of a graded response, but not necessarily statistically significant between the 22 to 24 week group, infants in the 22 to 24 week group also had a longer duration of TPN than the 25 week group. So interestingly, though, I found these details surprising there is no difference in other abdominal related morbidities such as sip, neck or surgical management for these morbidities. Among the group, surgical ligation of the PDA was higher and those born at earlier gestational ages compared to those born at 25 weeks, but in their cohort there was no A difference noted in severe intraventricular hemorrhage or the need for neurosurgical intervention amongst groups. Wow.

Ben 1:05:10

Yeah, as giving us food for thought.

Daphna 1:05:13

That's right. The infants born at 22 to 24 weeks had a higher incidence of severe ROP as compared to 25 weeks gestation. But of note, the incidence of stage four ROP was very low across all gestation. So stage three, ROP was 70% at 22 weeks 62% at 23 weeks, and 65% at 24 weeks versus 29%. In 25 weeks, need for oxygen at 36 weeks and discharge was comparatively much higher and the 22 to 24 week gestation group as compared to the 25 weeks 70% of infants born at 22 weeks required oxygen at discharge, 62% of babies at 23 weeks required oxygen at discharge, and 60% at 24 weeks, in contrast to babies who were born at 25 weeks, 33% days to discharge home or longer for infants born at 22 to 24 weeks compared to 25 weeks duration of caffeine obviously, longer, interestingly, in their group. So they do have babies that go home with trach and G tubes. But in their group that none of the 22 week infants required G tubes or trach. Very interesting. So the takeaway, I think, which was really the gist of the paper is that for a long time we glue, you know, as a, as a whole we weren't offering, you know, we were not offering resuscitation some centers to the 20 to 23 weeks through or actively discouraging resuscitation in that group. But as our clinical practice of caring for these very small babies is improving, the outcomes are improving. I don't think that changes that we need to have this really important shared decision making with parents. But it's nice to see that the outcomes are better are getting better.

Ben 1:07:16

Yeah, I was gonna say that it's important to clarify what you mentioned early on in terms of their practice in terms of this often. Because I'm, it obviously follows counseling, right? It's not like, they don't just go in the room like what you want to do. I think it's like presenting the data and then the parents, they're going to probably recommend that they're going to recommend that their policy is not to offer active resuscitation. And if the parent says no, you do want active resuscitation based on the data you've presented to us, then the move, move forward. I was gonna say this data is interesting. Number one, the groups are it's a lot of babies, but the groups are small, right? So there's like a 1022, weekers, 2123, weekers 4024, weaker 7225 weekers. And, and so I think when you hear that, like there's zero things in certain in the 22 group, it's like out of the 10 kids, there was none. And it's it's impressive still,

Daphna 1:08:13

I'm still surprised.

Ben 1:08:15

The thing that's interesting, though, is that there was this data that we presented on the podcast some time ago, looking at does our does our care of 20 weekers improve our care of older gestation. And what's interesting is that if even if some of the data is not significant, statistically, the trends are interesting, right? So for example, many more of the older gestation kids underwent medical treatment of the PDA, while more of the smaller ones underwent surgical treatment to ba the rates of spontaneous perforations were obviously the percentage wise was still higher in the 22 weekers. compared to older gestation, same thing was

Daphna 1:08:51

true for most of the comorbidities right, that the percentages were still higher in the kind of stepwise fashion, really?

Ben 1:09:00

Yeah, exactly. And I think that's interesting to me is, number one, I think it's nothing to be ashamed of, I think this stepwise progression is what we would ultimately wants to reach first, in our progression of the management of these babies, if we could now have this be this group be the most vulnerable and the others showing more and more improvement in the ideal. So I mean, it's always interesting, like I said, if you dissect some of the table to is is really a fascinating one. But yeah, yeah, it was. It's an interesting study. Again, I think it can be misleading. Sometimes if you if you look at it in percentages, it makes it it's always you have to know what the end was just so that you don't accidentally perceive that these are like hundreds and 1000s of babies.

Daphna 1:09:43

I think that takeaway is that I mean, the 22 weekers still have the highest risk for death and a host of comorbidities and we didn't even address neurodevelopmental outcomes. These are just the NICU During admission, comorbidities. And I think for units, where there may still be, there may be a lot of moral distress for some people around providing resuscitation in this timeframe. The data is changing. So I just think we, you know, and parent parents have access to the data. So, you know, we, they're no longer can be part of the counseling that you know, 22 weekers universally do terribly, or don't make it out of the NICU, that that's just not true. That doesn't mean it's it's not, there's not significant, you know, morbidity and mortality in that group. But, yeah,

Ben 1:10:49

yeah, so the numbers are interesting as well, when it comes to VP shunts or reservoirs or, like, it's percentage wise, it's interesting, but when you look at the actual end itself, like the 22, weekers, are obviously the ones that have, yeah,

Daphna 1:11:03

the and like I said, because the numbers were small, they grouped them together, right, like the 22 to 24 weeks and the 25 weekers. Which when you can look at the tables and look at them individually. You know, it's 22 week or 23 week or 24. week over the numbers are different.

Ben 1:11:22

For sure. Yeah. And you see, like, for example, for ivh, great for it's like about 33 to 37%, from 22 to 24, and then 24%. When you get to 25 years. It's fascinating. We could keep talking about this for hours. It's very interesting. Okay. The police are passing by. Okay, the next paper I want to go to is a paper that was published in the Journal of Pediatrics. It's a very interesting paper that I thought you might like as well definitely called do pediatricians and nurses recommend vaccines for preterm infants, a survey in Italy. first author is Francesco Napolitano. And it's actually very cool that the person's last name is Napoletana, because the group is out of Naples, Italy. So the so the background is I'm going to try to keep this short. But the background is that there's lots of studies that have shown that there's a low level of childhood vaccination coverage among infants born preterm, and they wanted to assess the knowledge, the attitudes and the behaviors of PCPs and healthcare workers working in the neonatal intensive care unit regarding the vaccination of preterm infants. They basically sent out surveys, some of them were electronic, some of them were paper, and they were able to get 191 PCPs 237 NICU healthcare workers to participate in the study, which was about 67% of the population that they were hoping to pull from that region. I just want to go over a few things. I'm not going to spend too much time on this. But the mean age of the people who answered the survey was 51.3 years with a range of 20 to 70 years, the meantime since graduation was 26.1 years. And when they looked at knowledge and attitudes regarding vaccination in preterm infants, there's a lot of interesting data points. 85.3% knew that preterm infants have the same immunization schedule as term infants 70% knew that the timeliness of immunization should not be influenced by either corrected age, birth weight, current weight, and 77%. I mean, actually 70% knew about the timeliness 77 about the birth weight 73% about the current weight and 77% about the fact that clinical conditions had to be considered. The respondents attitude regarding vaccination in preterm infants are shown on table two, I suggest you take a look at that. And they had like a 10 point Likert scale demonstrating a Deaf like six the highest score on that Likert scale the 10 points right, demonstrating that they definitely favorable towards pre vaccination was chosen by 67.4% of respondent for the effectiveness and by 64% for safety. But, but reassuringly, the mean value was 9.4 and 9.3 points respectively. So pretty high numbers. 75% Consider preterm infants to be more prone to acquire vaccine preventable diseases and 91% agreed on the need to improve parents trust in vaccinations. Interesting at third, this is fascinating. The results of the multivariate logistic regression model show that older healthcare workers and those who acquired information on preterm immunization from scientific journal societies and conferences were more likely to consider vaccines as safe in preterm infants. And so this trend that like younger generations are more distrustful is baffling number one because of what it implies but also because of, I mean, it has to do with what the previous generation witnessed in terms of what the vaccine brought, right and 100% I'm going to want to let you rent in a minute. I'm just gonna finish what was done. 16 9.8% stated that when it comes to behaviors that they always recommend that preterm infants, parents vaccinate their children following the same schedule as term infants. And among those who do not, or rarely recommend vaccination of preterm infants 38% were nurses. And that was very interesting because they reported that vaccination should be recommended by physicians and 16.7% of healthcare workers who were considered concerned about the safety of vaccines and preterm infant. So I thought it was interesting that I was almost shouting at my iPad. I was like, No, like nurses, of course not like you can definitely make this recommendation, right. It's not something that you should feel pushed out of the discussion saying, Oh, that's not for me to say. 6.4% reported, recommending a reduced dose of the vaccines 8.8% advised against administering the vaccines and preterm infants of low birth weight. And interestingly enough, the PCP is kicked the NICU pediatricians but on this the PCPs were more likely than NICU pediatricians to always recommend that preterm infants parents vaccinate their children following this immunization schedule as for term infants, and when finally one more thing I'm looking at the source of the information, most of the respondents got information about immunization of preterm infants from scientific journal 59%, followed by scientific meetings, 52% and scientific societies. 43.6% 66% of the respondents expressed interest in acquiring more information on immunization of preterm infants. The conclusions are that there's a need for physicians and nurses in the NICU and in the community to counteract missed or delayed immunization. And there's this finding support the need to improve the education of health care workers providing care to this group of infants. And these efforts should be directed at younger health care workers who revealed a significantly less favorable attitude.

Daphna 1:16:53

Yeah, I'm I'm surprised. But I, if you really think about it, I guess you're right. If you've not seen a vaccine preventable injury, then maybe you don't see it all the time. You see what all the fuss is about? I think what was striking to me is this, like, where are people getting your information? Only? Only 50% of people are getting it from conferences or journals. Right. So that's something area of improvement. I think. I'm not surprised. I think, maybe for our frontline nurses, you know. I think people are scared to talk to parents about vaccines right now. I think. Yeah. I think I'm not a you know, I'm not surprised about that.

Ben 1:17:42

Whether these 38% of nurses who say they do not want to recommend vaccination, because they not because they don't believe or anything that they just say it just feel like it's not their wood. Right? Yeah. They're not opposed to it just like it's not my place. And whether that happened because of the tension around vaccines, or because they felt like they got pushed out of the conversation, something to definitely talk about nurses are an integral part in the discussion.

Daphna 1:18:04

Yeah. And thankfully, our outpatient pediatric providers are doing such a good job. But yeah, I think I think we're, I think we are it's a missed opportunity, I think when you've been with a family for a very long time, and they you have good rapport and trust, to not have the conversation or to not have the conversation about family vaccination, or, you know, keeping the baby on on schedule, I think, I think we underestimate the relationships that and the trust that parents built with us and that, you know, it's part of our career to have this conversation. But interesting, interesting data. We're, we're way over time, not surprised.

Ben 1:18:53

We're way over time, but I knew you were gonna get riled up. I was I was, I was reading. I was, I was, I was, I was like, screaming at my iPad. I was like, no, come on, like, first of all, like, if you look at all these numbers, it's like, why is it not? 100%? Right, it's like why? But it's, it's interesting to for me to hear like the testimonies of my parents who are describing that when the polio vaccine was was rolled out, people were crying, right. People were crying, like like that said, we won't have to deal with this, this this stupidity anymore. And how the tide has completely turned. It's crazy. This is crazy. Crazy. So I mean, it's and it was not so it was it's scary. And it was also interesting to see that yeah, the newer generation is doesn't doesn't have this this experience of, of kids in braces, I mean, the poor your stuff. The polio epidemic was Yeah.

Daphna 1:19:49

Well, and I think I mean, I think the point is, if it's not coming from us, it trusted nurse or trusted physician Well, where are people that are getting their information? You know?

Ben 1:20:03

Absolutely. And it's important that you said, just keep the conversation going, just have a have a concrete conversation, don't draw lines in the sand, I think it's fine. We can all have educated conversation with each other. Okay, we're way over time, I wanted to give a shout out to our friend, Nick Hamilton, who's going to come on the podcast, I don't have the data in front of me, but he's coming on this year. There were two papers in the like, it's an engineering. It's an engineering, it's called Software impacts. And the other one is the i e, transactions on eurosystem. And Rehabilitation Engineering. I know about the ice because my uncle is, is an engineer, and he's subscribed to the ice. So I had seen that journal at his house, I can never read anything inside. It's very scientific. It's very mathematical. And they're basically looking at something called the PCE, PP, right, which is, I'm going to I'm going to tell you that right now. You see, I'm trying to go too fast. But

so they're looking at the PCPP, which is a, which is the pose based cerebral palsy prediction. And they're talking about this algorithm that would basically measure some of the angles of the babies of 25 key points and joints in the baby's movement, in order to predict using machine learning algorithm, the likelihood of cerebral palsy in the future. There's two papers, and it's very technical. I don't have I'm going to be very honest with you. Even if I had wanted to review, I did not have the know how to review that kind of data. It's, it's extremely technical. But it's a very interesting use of artificial intelligence for prediction of cerebral palsy. The initial data that I was trying to get from these papers is that the preliminary stuff looks really promising. And so I just wanted to bring that up, because it's, it's really neat. That's it.

Daphna 1:22:11

Okay. All right, buddy, everybody.

Ben 1:22:17

Yeah, have a great week. And yeah, we'll see you. We'll see you next week for another great interview. Thank you for listening to the incubator podcast. 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 podcast, 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 You can also message the show on Instagram or Twitter, at NICU podcast or through our website at WWW dot d dash incubator, that org 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 professional. Thank you

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