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#133 - 📑 Journal Club 51

Hello Friends 👋

We have a new episode of Journal Club for you this week. We reviewed a series of interesting articles and are very excited that the time has arrived for the EBNEO article of the month commentary monthly segment. This time we spoke to our good friend Dr. Souvik Mitra about his most recent commentary on the article by the late Dr. RE Giesinger on the hemodynamic approach to the PDA in ELBW infants. We are happy to recognize the late Dr. Giesinger for her invaluable contributions to the field of neonatology and send our thoughts and prayers to her loved ones.

Enjoy this latest edition of Journal Club.

Happy Sunday!


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

Lanciotti L, Pasqualini M, Correani A, Burattini I, Giorgetti C, Palazzi ML, Cogo P, Carnielli V.J Pediatr. 2023 Jun 2;261:113535. doi: 10.1016/j.jpeds.2023.113535. Online ahead of print.PMID: 37271494

Miyake H, Chen Y, Hock A, Seo S, Koike Y, Pierro A.Pediatr Surg Int. 2018 May;34(5):491-497. doi: 10.1007/s00383-018-4242-4. Epub 2018 Mar 13.PMID: 29536176 Free PMC article. Review.

Jensen EA, Wiener LE, Rysavy MA, Dysart KC, Gantz MG, Eichenwald EC, Greenberg RG, Harmon HM, Laughon MM, Watterberg KL, Walsh MC, Yoder BA, Lorch SA, DeMauro SB; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.JAMA Netw Open. 2023 May 1;6(5):e2312277. doi: 10.1001/jamanetworkopen.2023.12277.PMID: 37155165 Free PMC article.

Rodriguez NA, Moya F, Ladino J, Zauk A, Prazad P, Perez J, Vento M, Claud E, Wang CH, Caplan MS.J Perinatol. 2023 May;43(5):601-607. doi: 10.1038/s41372-022-01589-x. Epub 2023 Jan 3.PMID: 36596945 Clinical Trial.

Chiruvolu A, Hendrikson H, Hanson R, Reedy A, Reis J, Desai S, Suterwala M.J Perinatol. 2023 May;43(5):635-641. doi: 10.1038/s41372-023-01657-w. Epub 2023 Mar 30.PMID: 36997802

Giesinger RE, Hobson AA, Bischoff AR, Klein JM, McNamara PJ.Semin Perinatol. 2023 Mar;47(2):151721. doi: 10.1016/j.semperi.2023.151721. Epub 2023 Mar 5.PMID: 36882362

Mitra S.Acta Paediatr. 2023 Sep;112(9):2018-2019. doi: 10.1111/apa.16853. Epub 2023 May 28.PMID: 37246268 No abstract available. ----

Find some of our notes here 👇

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

Ben 1:02

Hello, everybody. Welcome back to the incubator podcast. That is Sunday. It is Journal Club Daphna. How are you?

Daphna 1:08

I'm doing well. We both had, you know, busy weeks. But you had a very interesting week didn't

Ben 1:15

you were busy Adam, and you had what you don't know you pulled out like back to back nights and stuff. Now we just came back with Rooney from California. I'm actually just arriving this morning from the artificial intelligence Med, Global Summit. So that was a lot of fun. And we got to speak about AI to a bunch of people who are interested in AI in the field of medicine. It wasn't just neonatology and pediatrics. So we were very excited to be representing the neonatology group there. And we were there with a few colleagues, most importantly, from the Neo mind, AI group, which will feature on the podcast in the coming months, if you are curious, but in the meantime, you can go on Neo mind And it's basically a group of neonatologist who are interested in artificial intelligence. So James Barry was there Ryan McAdams and George. Firstly, was there. So it was fun. It was exhausted right now. But yeah, I'm

Daphna 2:14

sure the red egg. Okay. But I have two questions. I always like to ask people when they go to conferences, what is the coolest thing you learned? And what was the like, most unique thing about the conference?

Ben 2:27

I think the most unique thing about the conference was, and something that you might appreciate as well as was its design like it was it was designed with the same sort of tenants as Delphi. So there were a lot of young trainees, and there was a very collaborative aspect of the conference. It was just everything was in a big room. All the breakout sessions were in,

Speaker 1 2:48

like a, like a warehouse. Like that's what it looked like. Yeah, so cool.

Ben 2:51

That was very cool. And the coolest thing, so there was a lot of discussions about AI and how we're, we're taking AI in medicine. But there were a lot of exhibitors that had a lot of cool tech to present. And so I think some of the some of the most interesting things that we saw were related to NLP natural language processing, where basically AI can just read through notes, and then say, that patient has a more complicated case of diabetes, if you based on what you're writing. And so starting to, you know, act more as a co pilot, which is something that we know is the future of AI. So that was kind of cool. People being able to develop like models like Chad GPT to just help you predict things so like, you can, you can ask a machine learning algorithm to learn from your database of patients. So that the next patient was like, Hey, do you think this patient can have an egg based on what you tell us? To very important thing? Yeah, a lot of this stuff is not tailored towards neonatology, but the applications are. I mean, I think a few steps away, so it's exciting. Yeah, okay. Neat. Yeah, yeah. Yeah, journal club. Journal Club does not wait, you know.

Unknown Speaker 4:15

Journal Club waits for no one

Ben 4:17

waits for no one. Okay. You know what, I'm gonna get started because I have an entire paper that caught my eye, right? It wasn't the Journal of Pediatrics. It's,

Speaker 1 4:30

it's a PRI proof and it's actually hard to impress you. So, no, it's

Ben 4:34

not that it's, that's not what I meant. And don't say that like it's not true. I'm very curious. I get impressed by a lot of stuff. But the title of the paper was, who needs a second dose of exogenous surfactant question mark.

Unknown Speaker 4:45

I was like, no like that one. Yeah, I was like,

Ben 4:48

when who does need a second dose? The first dose the first author. The first author is lutea Lynch yo t. And this is coming out of the group from Italy. And obviously, what's interesting is that in the background, there's a lot of things that is being mentioned where we know that a single dose of surfactant is sufficient to replenish endogenous alveolar and frankly most effective tools and is adequate for the majority of Infants who are born preterm. And yet, about one quarter to 1/3 of patients who receive surfactant eventually require an additional surfactant dose. And they cite a bunch of studies in the background, you can you can review them that basically look at some of the parameters that were identified, possibly as associated with the necessity to get a second dose mostly being low birthweight, small for gestational age having worse RDS less antenatal steroids for the mother. And so and so that that's really interesting. There were also some studies mentioning that maybe multiple doses of surfactants are associated with worse outcomes, maybe because of how sick these babies are to begin with. So the objective of the study is really to try to identify clinical predictors of surfactant reducing in a large cohort of like 24 to 32 weekers. In born in the center in Italy, it is a retrospective cohort study. In the end, the center is like in the mochi region of Italy. And I think I was thinking about that, like, I'm like retrospective, is that going to be an issue. But on the other hand, I had a hard time seeing our prospective, would have been usable as well from from an ethical standpoint, I don't know. But the study is worth reviewing, especially with such a catchy title. So the infants were having a gestational age of like 24 to 31 in six, and they were born between 2004 and 2021. The excluded kids were out born major congenital anomalies that died in the first 48 hours of life, who had or who had surfactants administration for anything other than rds, they were using protectant. And, interestingly, I think how exactly their protocols function is important. So the indication for surfactant are pretty much standard throughout the study period, which is if you're fit to is 30% or more, and you're on the peep, and you have to be on CPAP of six, I didn't mention whether there was an IMV, not an IV, that's, that's left out of the paper, I think. And the sets that we're maintaining were between 90 and 92. So if you needed more than 30%, to be between 90 and 92, you were eligible. Now, what's interesting is that the dose of the surfactants administration changed during the study period. So in the first half in 2004 2009, they gave 100 Mix per kilo, and then they switched to 200 Mix per kilo from 2010 to 2021. So that's interesting. And it's I don't know exactly how people dosed their surfactin but like the 200 mg per kilo is like your 2.5 mL per kilo. Basically, if you're using curiouser. And the 100 meg per kilo is like your 1.5 1.25. Any subsequent dose of surfactant no matter what, at what time point during the study was 100 milligram per kilo. The surfactant was given via insure. And the criteria for giving an additional dose was the same as the criteria for give giving the initial dose. And then they collected a bunch of complications, clinical data and all these were based on definitions provided by Vaughn right. So so your your BPD criteria by Vaughn would be like, how much are you sure you want at 36 weeks? So take that take that in mind. So they overall they looked at a large pool of infants, maybe like 1600 infants, and then they applied all the exclusion criteria, what they ended up with was the excluded like 300 of them. And then in the whatever, 1200 kids that were left 662 received surfactants. So that's what we're looking at 460 to receive a single dose 170 received two doses 30 received three doses. So what were some of the things that they found? So preterm infants who received multiple doses had very specific and peculiar features, they were all lower birth weight, lower gestational age. And interestingly enough, they had higher incidence of SGA diagnosis and the maternal hypertension SGA status versus ADA status with SGA being small for gestational age and eta being appropriately grown for gestational age. And so what they found was that SDS status, and the first dose of surfactant of 100 mg per kilo compared to 200 were risk factor for reducing, while a higher gestational age later surfactants administration and milder respiratory severity before surfactant administration were associated with a reduced risk of surfactant retreatment. So, yeah, it's very interesting that the SGA status obviously, you would want to give a higher dose and the severity of it Yes, play does play a role it looks like. Interestingly, the use of antenatal corticosteroids was similar between the patients who received one or more doses there was like 94 versus 91%. The duration of mechanical ventilation and CPAP was significantly longer and different in infants who received multiple doses of surfactant versus one, the FY two, before the first surfactant administration were significantly better in the infants have received only one dose compared to those receiving multiple dose again, could be related to the severity of that RDS status. The s the SATs, the FY two at six hours after the first surfactant administration, we're also better and the infants have received a single dose compared to multiple doses almost as if they're like better, they were better responders right from the beginning. The median postnatal age at the time of surfactant administration was significantly higher in the infants who received one dose versus those who received multiple doses. So if they were able to be, I guess relatively stable for longer, and they then then got their Joseph surfactant, then they were less likely to need to re dosing. And the infants who received multiple surfactant doses had significantly higher incidence of BPD death and the combined outcome of BPD or death than those who were managed with a single dose. The conclusion of the authors of that this is a study of a large cohort of preterm infants identified in that identified the following variables as risk factor for surfactant reducing and those included small for gestational age diagnosis, pregnancy induced hypertension as a lower initial surfactin dose or lower gestational age, or higher respiratory severity before surfactants administration. And earlier time of the first surfactant administration, they mentioned in the conclusion that SGA and pregnancy induced hypertension seem to be unmodifiable risk factors in the NICU for surfactant free treatment and in turn, or BPD. And that study is focused on the pathophysiology of this condition may help understand the underlying reasons for the persistence, oxygen dependency, and ameliorate the outcomes, or infants born with this condition. I thought this was an interesting study, and nice, and I want to maybe to get that discussion going with you. Because I think there's a lot of, of stigma around the second dose, some people shy away from it, because they're like, well, it doesn't work. Some people may look at this data and say, well, the kids who do get the second dose actually do worse. But in my opinion, even looking at this data, I think, yes, some sicker infants are going to require more dosing. But I think we have yet in the literature, to see any. Any robust study, that actually helps us figure out that there's maybe causality between the second dose of surfactant and worse outcome, which I think is not, is not something that can be seen, my impression is that surfactants either work or doesn't work. And if it doesn't work, it usually doesn't lead to too much complication. It feels like almost like a shot in the dark. And, and so I'm very liberal with giving multiple doses of surfactant, especially as a baby is going through episodes that are known to be associated with surfactant, the activation, like episodes of pneumonia, sepsis, something like that. And so I'm curious what you make of, of this kind of data. does, is this something that that encourages you to say, well, now I can even target more specific group of babies that that I might consider a second dose or I mean, what are your thoughts on that?

Daphna 13:32

Yeah, no, I agree with you. I think that I mean, in this study, it's obvious that this was the babies who got two doses were a sicker cohort. Right? That's obvious. So it's, you had to take all of it with that in mind. But, you know, there's definitely a group of babies that seems to need and respond to multiple doses. And I think that's where maybe, you know, we think about clinical practice, there are some people who say like, wow, if the baby's oxygen is still high, again, they didn't they quote, unquote, didn't respond to the first dose, when maybe they just need more, you know, and I don't think anybody's really, I think we're looking at that enough that where they matter responders, they just need more,

Ben 14:18

which is super interesting, because in the study, because of this thing, where they actually had a cohort of kids who got like lower doses, they see that like, when the dose is too low, they need more like, like this concept that you're bringing up is not futile and saying like, well, maybe they need more it's like it is being shown that like lower doses leading to baby need, getting even more surfactant. So

Daphna 14:38

yeah, and obviously there are certain babies like you said if there's a process which was not this cohort, really but a process of surface surfactant deactivation, yeah, yeah, they're gonna need more than you know, I we will like to give surfactin in those non RDS situations where we know there's surfactant, deactivation, and then in those babies with truth surfactant deficiency, especially based on gestational age, like they're just not making it so it's gonna run. So, yeah, no, it's interesting. Yeah. All right. Um, okay, I had a paper that caught my eye. You know, I like to review papers when we, when they're timely for our team. And we have had a number of let's just say surgical babies in the unit. So I thought I thought this was interesting prophylactic acid suppression medication to prevent an anastomotic strictures after esophageal atresia surgery, a systematic review and meta analysis. This is actually from the Journal of Pediatric Surgery.

Ben 15:44

That was surprised when you sent me that paper. I was like, man, what are you doing browsing the journal pediatric surgery?

Daphna 15:50

Well, you see, it came across through one of our Twitter friends who's not a neonatologist, you know, so that is the benefit

Ben 15:58

of crass. Want to give a shout out to that social media, Twitter friend? Oh,

Unknown Speaker 16:02

yeah. Well,

Ben 16:03

I don't know who was fine. We'll give you credit, it was the surgeon. Fair enough. When we repost some of the highlights of that paper will will will tag you

Daphna 16:12

for sure for sure. So they aim to investigate whether patients who are treated prophylactically with acid suppression medication had a reduce incidence of strictures compared to those who did not receive it because the leading thought is that GERD increases stricture formation. And so that's why babies well with a number of surgical post surgical care, but specifically with T fistula repair, or esophageal atresia repair are on acid suppressing medications. So of No, this is this is a systematic review. It's a meta analysis of a number of papers. And the primary outcome was the incidence of Anna anastomotic strictures, at least up to one year of age. And the secondary outcomes were threefold. They looked at the incidence of gastro esophageal reflux, the incidence of anastomotic leak, and the incidence of esophagus itis or esophageal erosion. So, they found 142 studies, which were screened for eligibility, they use full text papers from 22 studies. And then eventually 12 studies were included in the final analysis. Obviously, they provide details about their search criteria, and, and why they didn't include some of those papers. But all of the studies they ended up with were actually observational and design, which I think is obviously a limitation of the study. So they had no randomized control studies identified in the search in 1395 patients evaluated for the primary outcome, which as a reminder, again, is the development of strictures and of the 13th of the 1395 patients 753 received acid suppression medication, and in general, the team does rate a high risk of bias. Specifically for the primary outcome, the assessment of esophageal stricture, due to a quote unquote non objective measures of assessment. So all those things are limitations of the study. So the real punchline is that for the primary outcome, there was no statistically significant difference in the rate of esophageal stricture in the group of infants who receive prophylactic acid suppression compared to infants who did not receive prophylactic acid suppression. There are more strictures though observed in the prophylactic acid suppression group, the pool dad raised odds ratio was increased to 1.33. But this did not reach statistical significance. And due to this concern for higher risk of bias in each of the studies, a sensitivity analysis was conducted by excluding them, and the pooled results from the two remaining studies were similar to the overall analysis and odds ratio of 1.27. That there were actually more strictures in the prophylactic acid suppression. For the secondary outcomes, there was no statistically significant differences noticed, noted in the incidence of GERD, there were no differences in an anastomotic leak, and there were no difference in esophagus, itis or esophageal erosion. So I thought this was interesting because it actually showed a trend to the opposite of the original hypothesis, which is that the prophylactic the group that got prophylactic acid suppression seemed to have more strictures, the only other limitation of the paper and again, as I mentioned, there were many were that there there appear to be it's not well delineated, but there appear to be a group who got some quote unquote, symptomatic treatment, with acid suppression met occasion, which is a different group than the babies who got prophylactic just straight out of the gate acid suppression. And I'm not sure how that swayed, you know, the other group, I would have liked to have seen as a subgroup analysis of those kids. But I thought it was interesting, and a reminder that not all of our practices are totally basted. Solid.

Ben 20:24

So let me let me ask you, then the absence of evidence is not the evidence of absence, right. So I am going to tell you what I think in a second, but I'm just here. So like, now you have a kid with a with a virtual latricia post repair? are you what are you doing?

Daphna 20:43

Yeah, I mean, it's tough, right? Because is this was this paper enough evidence to say not to do it? I'm not sure. I don't think so. I think there are a number of limitations in the study. I think these kids, and I'm saying this with hesitation, these kids definitely seem to have symptomatic reflux. But we're not very good at judging what is symptomatic reflex. That's part of the problem.

Ben 21:07

But beyond the reflux, I think, to me that the dreaded complication is the stricture. Correct. The stricture at the anastomosis site is what is what you like, if that happens,

Daphna 21:19

I mean, that kid has to go back for surgery, right? It's, it's a major complication.

Ben 21:23

And, and we've seen patients in those scenarios, unfortunately, where you're like, you're making progress, you're back on feeds, and you're on minimal respiratory support. And then over the course of a week, you're like, you're seeing that strictures shut, closed, and then all the secretions on your back end. So you're back to having to put back or re POGIL to suction to get those secretions. It's a mess. And it's like,

Daphna 21:44

yeah, or some of these kids go home. We think they're doing great and come back. Yeah.

Ben 21:51

Yeah. And so I think to me, I still would I don't know about the duration, you know, I mean, I will basically, I'm a NICU doc, which is kind of nice. I'll let somebody else decide with the other stuff. But I'm, I'm I would say, I mean, obviously in accordance with our surgical team, I would say just keep it on. Yeah,

Daphna 22:15

I think the only concerning thing is that there was a trend to more structure formation in the group that got prophylactic acid suppression. It wasn't statistically significant, but I'm just I'm just throwing it out there. Yeah,

Ben 22:28

but that goes against, right. I mean, we're thinking theoretically, maybe

Daphna 22:32

it's not the GERD, maybe it's not the Gert that causes the stricture formation. Right.

Ben 22:37

Right. And we know that there's not a lot of acidity in the in that kit in the stomach. And, and to be honest, I am far removed from my, my days as a chemical chemistry major to figure out whether whether the pH of these secretions how does that affect

Daphna 22:53

and me maybe, maybe that's exactly right, maybe it's the same thing. We're always saying about girt reflux, reflux in neonates, maybe it's not the acid, maybe it's just the irritation by the bolus, in which case, the antacid is not the right. medication. Maybe it's a pro, a pro kinetic agent.

Ben 23:18

You like profit, by the way?

Unknown Speaker 23:22

Should we make I don't have that, quote, poised to answer this.

Ben 23:26

We shouldn't make that disclosure. Yeah, no, I think I don't know. i You're right. It I think I think there's a lot of ambivalence. But,

Daphna 23:37

but we do that, right? Like, I'm not sure if it's gonna help or hurt, but the consequences bigs I'm gonna keep doing it, but people are studying it, because what if it's, what if it's worse?

Ben 23:49

And if you are interested in this dilemma, not this dilemma specifically about assets of presence and, and surgical repairs, we'll talk about clinical equipoise with Fe Felco fashio about PDN stuff in a week or two. So stay tuned for that. Anyway, at the end of the day, I guess you really would be well within your rights to do either, if you if you decided to keep them on or not. Anyway. Okay. Okay. And

Speaker 1 24:18

you will have to tackle that question alongside your surgical colleagues

Ben 24:21

and with the family. That's right. Yeah, I agree. All right. My next paper is my highlight of the week. So it's called. It's published in JAMA Network open. It's by Eric Jensen and the NI CHD NRN group. And it's called the assessment of corticosteroid therapy, and death or disability according to pretreatment risk of death or BPD in extremely preterm infants. The background of the section is actually quite interesting, right. I mean, they actually, they, they start, they start by saying something I'm going to quote the first sentence of the paper, the use of post natal corticosteroids to prevent bronchopulmonary dysplasia is among the most controversial topics in neonatal medicine. To which Eric is listening as like, I was gonna think, Eric, the PDA people want to have a word?

Daphna 25:13

Well, I think I think, you know, we spend a lot of time on social media, obviously. And maybe there we have a maybe we have more PDA people on social media than we do have BPD

Ben 25:26

selection bias. Yeah. So okay, so that's just me being anyway, so the background actually goes into the history of like steroid administration for the DEA. And it's quite interesting because it goes over like, the high doses and the long term side effects and mentions Lex Doyle's work that showed how basically the use of steroids in infants was associated with decreased rates of CP, in babies who were developing BPD you're gonna see some ISIS, you

Daphna 25:55

know, yeah. This is so wonderfully typical of every Dr. Jensen paper where you get like you you can you can catch up by just reading the latest paper, which

Ben 26:06

is I read, I read this paper yesterday at the airport, I was tired, not not like so tired that I couldn't read the paper. But what I'm saying is that when a paper is so well written, like, yeah, it's not like it doesn't mean it's easy. Yeah. And so basically, this led to the pediatric society's revising the recommendation, saying that it should be okay to use steroids in very preterm infants who are receiving like mechanical, mechanical ventilation, after maybe one to two weeks of life due to the increased risk of BPD in that specific population. Now, what Eric Jensen is and the group are mentioning is that most trial that at most trials that informed this revised guideline initiated corticosteroids in the first week after birth, or prescribed higher cumulative doses than the current recommendation. And so, what he's saying is that as a result, this these trial data may not accurately characterize the risk and benefit of postnatal corticosteroid treatment strategies used in in to prevent BPD in contemporary, extremely determined, so whether you're trying to do is that they're asking the question, does the pre treatment risk of death or grade two or three BPD at 36 weeks modifies the association between postnatal corticosteroid therapy and death or disability at two years correct age and extremely preterm. And so I'll go into that in a bit with the study design. So this is a retrospective propensity score matched cohort study using the neonatal research network data. The infants who were eligible were born before 27 weeks of gestation between 2011 and 2017. They survived the first postnatal the first seven postnatal days, and they had two year death or developmental follow up data. So it sort of matches the cohort rate mashes the cohort, even it's a bit more restrictive, but of the BPD outcome estimator that was recently updated. The infants who were enrolled in the neonatal Research Network hydrocortisone, for BB trial treated with systemic corticosteroids for BPD, beginning prior to postnatal day eight, or after day 42 kids who had severe congenital disease or who had missing data for key variables were excluded. The primary exposure was systemic steroids, right? We're not talking about inhaled we're talking about systemic steroids. For BPD prevention that's initiated between day eight and day 42 afterbirth. This range is specifically selected to exclude basically, the kids who get steroids in the first week, and infants were treated at ages when serial respiratory support data were no longer recorded. The primary outcome of the study is a composite of death between corticosteroid initiation and the two year follow up, or moderate to severe neurodevelopmental impairment, which was defined as a barely three score lower than 85 GMFCS level two or higher, moderate to severe CP and or visual or hearing impairment. The secondary outcome was the composite of death or moderate to severe CP, which was defined as GMFCS level two or higher and the clinical diagnosis of CPI to to power the estimated and so that's the key. They estimated the pretreatment probability of death or grade two or three BPD at 36 weeks for all eligible untreated controls using a logistic regression model, which is probably just the BPD outcome estimator that was fitted with 39 fixed and repeatedly measured variable that characterize respiratory state or are known or believed to be associated with the study outcomes. And then they performed this propensity score matching that were based on the probability that infants will receive corticosteroids to prevent BPD. And that was used to match treated infants to untreated controls to what does that look like in terms of the cohort, the cohort that includes 482 matched pair of infants. The gestational age, the mean gestational age was 24.1 weeks, and 44% were female 36% Male. And what was interesting is that the estimated mean pretreatment probability of death or grade two or three up at 36 weeks generally was zero point 53%. In both matched treated and untreated infants. The mean age at the corticosteroids initiation was 25.2 days, which for some maybe considered to be quite late, I mean, I think, but anyway, so it's another topic of discussion. I'm not going to get into that. Of the treated infants. 75% were recipients of dexamethasone. 24% received hydrocortisone and 0.6% received alternative corticosteroid. So there were no differences in the adjusted odds of death, or moderate to severe neurodevelopmental impairment, or death, or moderate to severe Cp at two years corrected age associated with corticosteroids therapy. And that's like, the big finding of this paper today. No difference, no difference, you say? Well, that's where Dr. Jensen is so good. But let's, let's get into some of the, let's get into some of the other stuff because that's what that's what it gets exciting. The adjusted odds of death or grade two, three vs 36 weeks, were also not significant between the two groups with an adjusted or of 1.35 and a confidence interval that passes one. Okay, so where's where do we get to the good part? There's an inverse association between the pretreatment probability of death or grade two or three BPD at 36 weeks, and the risk differences or death or disability associated with corticosteroid therapy? What does that mean, for each 10% increase in the probability of death or grade two or three BPD. The risk difference for death or moderate to severe NDI associated with corticosteroids decreased by 2.7%. Defeated defeated regression line cross the x axis at a probability of death, or grade two or three BPD of 53%. So is that mean is that when you're going to initiate corticosteroids, if the risk of death, or moderate to severe BPD are greater 3d video, I'm sorry, this is using the NRA definition is above a certain threshold, then you're then you're it's benefiting the patient, and you have less of the primary outcome. If you're below that number, then you have more of that primary outcome. The corresponding analysis for death or moderate to severe CP also found an inverse association. So the same thing and for each 10% increase in the pretreatment probability of death, or grade two or three BPD, the risk difference for death or CP, associated with steroid therapy decreased by 3.6%. And so what was the cutoff for that the fitted regression line crossed the exact set of probability of death or grade two or three BPD of 40%. And so to me, they have these beautiful graphs in the they have these beautiful graphs in the paper, which I think are the basis for how we should teach medicine and medical school, which is, if an intervention is not given to a patient that is at risk, it's not, it's not only not helping, but it is actually because it can actually cause harm. And if it's given in a patient who has a high risk of the disease you're trying to prevent, then then it will have a benefit. So we'll post that graph because there was another audit. I mean, this there's other this has been shown in other contexts as well, especially in the context of cognition and meta analysis of certain papers. But I think that's fascinating. There was no evidence, however, of a drug specific treatment effect for the primary outcome, meaning it didn't really matter which one they were using in terms of hydrocortisone dexamethasone, and they're mentioning that there was possibly a treatment advantage associated with extra medicine or death, or the outcome of death and moderate to severe CPE. But the conclusion of the paper is that the I'm going to read this because obviously, I think it's very impactful. In this propensity score matched cohort study the pretreatment probability of death or grade two or three GPA 36 weeks modified the association between postnatal systemic steroid therapy to prevent BPD and the risk of death or disability or two years grade age. These findings are consistent with prior meta analysis of randomized control trial and provide important evidence that contemporary dosing strategies for systemic steroid therapy may be associated with a decreased risk of adverse neonatal outcomes. When restricted to preterm infants at moderate to high risk of death, or BPD. The possible treatment advantage with dexamethasone funding the present study supports further unbiased evaluation of this medication to prevent the begin and improve neurodevelopment. And so to me, what that means is that you gotta use the outcome estimator before you initiate the PDE. And if the risk is not above that certain threshold, just back off.

Daphna 34:55

Yeah, I mean, it's the what is your positive predictive value, right? Like, and it's I mean, it's just another nod to the importance of individualized medicine. And why maybe for a number of therapies, we, when we, when we pool so many babies like we, we don't see a difference, because it's not help. It may not help everybody. But we have to find the babies that it will help. It's it's was a brilliant way to look at the problem. Yeah, my only my only problem my only, I guess disclaimer concern is that babies who are at risk for BPD are also at risk for like so many other things, right? So sometimes when we pick the therapeutics we're using, we have to weigh like, which one, are they more at risk for based on their like, brief postnatal, or even pre natal phenotypes? You know,

Ben 35:53

what I think is interesting about how the study was designed, right? Is that Eric Jensen always has this concern about what matters is what happens at two years, right? So it's interesting to link up with the risk of reaching 36 weeks with with the great two or three gpdr death rate to then the northern mental outcome, right? So it's almost like you're at time point zero, you're looking at time point one, which is 36 weeks to then find out what may happen when you're at time point 24 months. And I think that's interesting, right? Because in with that design, you're able to look at things in a very perspective, like in a very continuous manner, from from very early on to very far down the road when it's not just like, oh, this what does this time point yield at two years, but it's like, Hey, what is the risk? What is your risk? Your baseline risk at time point? 04. Time point one effects time point two. I think that's very interesting.

Daphna 36:50

Yeah, and I think, you know, they're not these variables are not in isolation, right? So there's always been this concern about steroids and neurodevelopmental outcomes, that period, about steroids, being modulated by what the nutrition looks like post steroids and neurodevelopmental outcomes. But there's this other huge variable that like chronic disease affects neurodevelopmental outcomes, right? So taking the risk of one to prevent the risk of the others is an interesting way to look at the problem.

Ben 37:27

This episode is proudly sponsored by rocket me Johnson. Recommend Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive Enfamil portfolio for premature and low birth weight infants learn more at HCP dot meat Europe?

Daphna 37:47

Oh, well, it's my turn, obviously. Okay. So I have another study, which I think I can say, I'm not sure equipoise to review this. Because it's just so funny, because we were just talking about it. I know what you like the word it seems. I do like the word. Yeah, I do like the word. I also really appreciate these topics. So I mean, you okay, I'll just say this. This is entitled a randomized controlled trial or Franjo therapy with mother's own milk for premature infants. And lead author Nancy Rodriguez. And this is in the Journal of Periodontology. So the question really what the objective was to determine if oral pharyngeal therapy with mother's own milk reduces late onset sepsis, which is the primary outcome, and then secondary outcomes of neck death, length of stay time to full enteral nutrition and full oral feeds in preterm infants. So this was a prospective multicenter, double blind, randomized controlled trial. The inclusion criteria included infants that met the following criteria of birth weight less than 12 150 grams, a mother that plan to express and provide milk for at least two months. So that was interesting inclusion criteria, the absence of severe congenital anomalies, admission to the NICU within 24 hours of life, and the ability to begin the treatment protocol before 96 hours of life, which meant that they had to have some milk available before that time. exclusion criteria included birth asphyxia, delineated by arterial pH less than seven on initial blood gas upon NICU admission, maternal positive HIV status, maternal drug or substance use that precluded breastfeeding and presence of a T fistula. So the team used a one to one blocked randomization scheme which they then stratified by birth weight and the groups were is falling less than 500 grams 501 to 749 grams 715 to 999 grams, and then 1000 to 1200 50 grams. They also random are they also stratified by sex and And then the babies were either and placed in one of two arms, point one and mils of placebo, or point one mL of moms Oh milk to each bugle mucosa. So a total point two and mils of study product. This procedure was repeated every two hours for 48 consecutive hours during the initial treatment period. And then every three hours during the quote unquote extended treatment period, which lasted until the infant reached 30 to 32 weeks postmenstrual age. They also studied, it did a nother analysis, they looked at the milk and infants urine, saliva and stool at a number of four time points to evaluate that, but that's a different discussion. Of note donor human milk was used when mom's own milk was unavailable. And I think that's an important point. So the primary outcome, the length of stay sorry, late onset sepsis was the primary outcome was defined as the new onset of at least two clinical symptoms with a positive blood culture noted after day of life three, and and was an identification of an organism known to be cause a cause of bacteremia. In the secondary outcomes, NAC was defined according to modified Bell's criteria stage greater than or equal to two, with clinical signs of X ray evidence of new Matosinhos portal venous gas with or without pneumoperitoneum. So the baseline results, I think it's important to have this discussion about enrollment. So they had an initial target sample of close to 500 infants. But they did an interim analysis at about 50% enrollment. And that was done by their, you know, safety monitoring board. And they, in in inferred that they were not likely to find a statistically significant difference that would be robust. And then they extrapolated that to enrolling the additional 239 infants, and they still felt that it was unlikely to give a statistically significant result in the primary outcome of late onset sepsis. So the study was stopped, because not because of anything negative per se, but that they felt they were unlikely to reach statistically statistical significance. So a total of 259 infants were enrolled. There were 39 screen failures, which meant that there was antenatal enrollment and then the parents were unable to sustain milk, or that there was antenatal enrollment and then the mother's pregnancy went too long, so then they were not able to enroll the baby any longer. Other screen failures, I told you not able to provide enough milk by 96 hours post delivery, there were seven withdrawals. In the sorry, there were 10 withdrawals by parents and because of transferred to another hospital a loss to follow up or in some cases parents withdrawing consent. There were 11 total deaths seven and Group A, which is the moms own milk, and foreign Group B which is placebo. The deaths were not unexpected, and a result of extreme prematurity and associated morbidity morbidities Group A deaths were more likely due to severe RDS and pulmonary hypoplasia MSSA sepsis, twin to twin transfusion, extreme prematurity with pulmonary hemorrhage, kidney failure, late onset sepsis and neck Groupby deaths were due to early onset sepsis, extreme prematurity with pulmonary hemorrhage, late onset sepsis, neck and intestinal perforation. So their final sample size was 220. And they did use an intention to treat analysis, the majority of subjects received greater than 90% of the planned treatments which, given how many treatments are a part of this study? I think that's pretty good. Group A infants, this group that received mom's own milk was 113, on average weighed 882 plus or minus 214 grams compared to Group B infants, the placebo group 107 infants which weighed 886 plus or minus 193 grams. So they're about similar the two groups were also similar in terms of gestational age. The average gestational age of Group A was 26.7 versus 26.8 and group B, and all other demographic variables, including the snap score is a measure of kind of illness severity. There was however, a statistically significant difference in sex. There were many more males in Group A the treatment group than in Group B, the placebo group And the overall results is that there were no significant difference differences in late onset sepsis, or neck or mortality. In addition, there were no statistically significant differences in length of hospital stay, and 80 days versus 88 days in the placebo group time to reach full enteral feeds 24 days versus 31 point 60s in the placebo group, time to reach full oral feeds 68 days versus 75 days, though there were a trend towards improvement in all of those factors in the group A are the treatment group. And there was no significant differences between the two groups and entrail exposure via device feed to mother's own milk. So, while there wasn't statistically statistical significance, I think there's potentially clinical significance in family really rated significance in some of these outcomes, particularly length of stay time to reach full enteral feedings and time to reach full oral feeds. The other things I wanted to talk about is in both groups, both a mom's own milk group and the placebo group, there was this stimulation of the oral mucosa and oral enzymes. So my question to the group is, it would have been nice to have a third arm that didn't get any oropharyngeal feedings as a as another group to look at. I'm gonna ask you your thoughts,

Ben 46:40

you're saying, you're saying a group that received the medical group that received the plus the placebo was water, right? sterile water? And then you would have liked the third group with nothing? Can you explain again, why why you wanted that third group,

Daphna 46:56

I wonder if there's just something about the activation of the oral mucosa, they were looking for late onset sepsis specifically. And that's, that's what they were looking for. Were the antimicrobial properties of mother's own milk, superior to placebo in protecting against infection. So that that's why they picked those two groups. But in terms of all of the outcomes they studied, I still wonder if there's a benefit to this oral stimulation. In, so I would have just liked to have seen that arm. That's all interesting. I also, the other thing I want to say is they didn't they, in both of these groups, they had similar amounts of moms own milk. But the moms didn't know if the babies were getting placebo, or they were getting their own milk. And I think we underestimate how powerful it is for a parent to see their baby be orally fed this product that they have been working tirelessly, you know, tirelessly on so. So I think that's why the third arm of no oral pharyngeal feeding would have been interesting as well. Because I wonder if we would, if we if we see more milk in those families whose babies are getting oropharyngeal feeding.

Ben 48:25

That's all. Yeah, and I think, I mean, once you put the once you, you, you provide the sample, like, you can probably tell what the kid I mean, if anything just makes its way back to the orifice like you can you can you can? Is it really truly blinded at that point? So yeah, you're probably right. My question to you is, do you think that we were, we were asking too much from this 0.2 ml?

Daphna 48:55

Of Yes. And that was your like, do you say that, like, sufficient enough? Or,

Ben 49:00

but I'm saying even Yeah, is it the dose, but like, even if you bring it up, it's like, Hey, we're gonna give these babies like metal, no point two ml, one mL, and it's gonna reduce neck length of stay sepsis. It's like, how much I mean, because I see this as part of a bundle. And I'm like, Yeah, this in combination with other things could have very beneficial effects. But I mean, when you're looking when you're reading through the paper, you're like, oh, there's a lot of work for these points to solve all our problems. Or problems.

Daphna 49:29

Yeah, no, I agree. I mean, there's this thought obviously, that the you know, we can get some good antibody response. And the thought is you don't need a big you don't need a large dose for that. And what can these babies tolerate? Obviously. But you're not wrong. It was a big ask. So my point in the possible benefits, and that's exactly my, what you said is exactly my point. I think the possible benefits of this interview intervention is that it may encourage families to bring in more milk. Right? Which that could could pay off in the no it would we know that babies who get more moms on milk have less of these outcomes.

Ben 50:15

And some of these tables again, I know that this analysis and they stopped the trial, but like you wonder if some of that signal or noise would would change if the numbers were dramatically daycare, right? Because I mean, I think they had they had, they had an aim of like, 500 kids, but what if it was 2000? Kids? What would we see? Right? I don't know. I mean, it's hard. I'm just It's easy. It's easy from my from my living room to say like, what just hundreds and

Daphna 50:36

just get more people? Yeah, but I mean, I think these these trends in length of stay, you know, eight, eight shorter days in the NICU, feeding full enteral feeds by a week earlier, full oral feeds by a week earlier. I think those are not small,

Ben 50:58

small things. Right. Okay, Daphna. So, I think we're gonna go to next is our EB Neo Article of the month segment, which you actually went out and interviewed our friend Shauvik Mitra, who is the author of today's commentary, so check your jingle? Let's do it. Let's do the jingle

Speaker 3 51:22

Article of the month commentary brought to you by the evidence based neonatology team. Make sure to follow EB Neil on Twitter at EB Neil or on the web at EB

Daphna 51:40

Today, we're joined for our EB Neo article the month segment by a good friend of the podcast Dr. Show Vic Mitra, Associate Professor at Dalhousie University, and IW K health Halifax, Canada. Show Vic today you'll be presenting your commentary in the article precision management at the patent ductus arteriosus and micro premium. For those that are interested we did a more brief review the article and episode 120 in the podcast. But we are so honored to have you on today to discuss this important work further.

Speaker 4 52:09

Thanks Daphna. Happy to be back on the incubator podcast to discuss my favorite topic. And what makes it really special is that I get the absolute honor and privilege to discuss Reagan's work was left such a lasting legacy in the field of neonatal hemodynamics and in otology. In general. This paper similar to many other recent work of hers, I think will inspire decades of hemodynamic research, especially in a population that is so conveniently excluded from clinical trials. So what this paper essentially asks is, in preterm infants spawned between 22 and 24 weeks of gestation, does management have a hemodynamically significant PDA? Based on early hemodynamic screening uses using targeted neonatal echocardiography versus echo screening when clinically symptomatic, improve the composite outcome of dead before 36 weeks, or severe BPD. Now, this was a single center retrospective cohort study, where they looked at two cohorts, one historical control between 2010 and 2017. And then a more recent hemodynamic screening cohort, after they introduced a comprehensive hemodynamic screening program, between 2018 and 2022. The results were really impressive. They included 189 infants in total. And they showed that with implementation of this early hemodynamic screening, they had a 23% absolute increase in survival without severe morbidity, a 20%, absolute reduction and severe ivh, a 26%, absolute reduction and severe BPD and a 14%, absolute reduction and interventional PDA closure. Now these results, obviously had all of us sit back and take note of, of this paper, and it has created some strong positive and negative reactions in the near Twitter world as we've seen, that's fair. So it's great that we are we are discussing this on the podcast. Now, just to kind of get into the critique of this paper a little bit. Yes, this was a retrospective cohort study with historical controls. And yes, they had impressive effect sizes in In terms of reduction of deaths over BPD, severe ivh, etc. So obviously people will definitely raise questions. Did early targeted period treatment actually result in such significant improvements? Now for me can causality be established? Definitely. No, not even with advanced interrupted time series analysis, unless you do a crossover study and reintroduce the hemodynamic management practices of the historical cohort for a period of time, which I don't think they will do. But no one can deny that at the end of the day, they did achieve these outcomes. So my question is, could a comprehensive hemodynamic screening program play the role in in achieving these outcomes? Well, quite likely. And there are a few reasons why I say this. First, I feel that though they reduced the median duration of the PDS tion by 13 days, still will have to acknowledge that Tylenol, which was their primary therapy of choice was only 50% effective in this population, which goes along with the existing literature on IV Tylenol in very preterm infants, as we showed in our last Cochrane review was bad. So questions remain on this truck. Is it the wrong drug for this population, or the right drug in the wrong dose? Only future research will tell. So maybe it was not just a PDA treatment. One can argue that it was rather their appreciation for the dynamic nature of the cardiovascular physiology early on in these tiny babies, and then reacting appropriately to it. And by saying keeping a close eye on the physiology, and not necessarily mean overtreating babies. In fact, what they showed was that potentially harmful drugs and therapies that we often use symptomatically in these small babies like nitric oxide, like vasopressors, like dopamine, were actually used much less with hemodynamic screening. So that didn't manage to show us that there is a difference between watchful waiting, and willful ignorance. And that may actually translate into meaningful benefit. So what we really need now is, we need to replicate this approach in larger, cleaner, unbiased studies to see if there is still a benefit. And how big is it?

Daphna 57:55

I loved your your quote on watchful waiting, you know, versus just ignorance. And, you know, certainly I what I found interesting is, you know, they use the historical cohort, but this is in a unit where echo cardio echo targeted Echo has been go happening for decades. So, you know, it's, it's not like a unit where there was no echo targeted screening, and now they've introduced the program. So I found that to be even more impressive for for the results kind of in their favor. I guess my one question is for people who, you know, see this and they want to replicate it, you know, the, the intervention was the hemodynamic screening. But it's not just a screening. It's how they reacted to what they found in the screening. And so I think, for people in the community who aren't doing a lot of targeted echo, they don't know what that means. Maybe you can speak a little bit to that.

Speaker 4 58:56

Yes. So thank you for bringing up the topic of replication because we talk about replication loosely. But if you think about it, what they did was very, very impressive. They managed to do a comprehensive echo and a micro preemie in less than 20 minutes with good quality images without causing problems essentially, that takes a lot of training and expertise. So without expertise, one trying to implement such a comprehensive program, where they do a targeted screening in all micro preemies within the first 12 to 18 hours. And then based on the physiology, either provide adequate management, be it treatment of the PDA or if they There is evidence of PPHN, treating the PPHN with nitric oxide with a follow up echo. Or if there is marcado dysfunction treating that appropriately. So that that takes a lot of training and expertise. And without the expertise trying to replicate that may actually cause more harm than good. So that is something that units who are just starting off should keep in mind. And they may have to tailor what their approach based on available expertise.

Daphna 1:00:38

And you've alluded to this a little bit, and we've been talking about it nonstop on the show, but that it's really about understanding kind of the underlying physiology and all of the other things happening to the baby, the ventilation, the cardiac output, the fluid management, and it's not that they're just looking at the PDA in this evaluation.

Speaker 4 1:01:02

Absolutely. And that was my big takeaway from this paper. That yes, this paper talks about precision management of the BDA. What I feel is that it was more than just precision management of the PDA. It was precision hemodynamic management of the micro preemie that may have resulted. And I say May because again, of the inherent nature of retrospective studies, and all the biases that come with it, that may have resulted in such significant improvements. Or it could have been just an addition to hemodynamic management, natural improvement over time, which they tried to account for other practice changes, which was not that different. So I feel it could largely be a function of precision hemodynamic management. But we do need to establish that now, as I said, through larger, unbiased studies, such as randomized trials.

Daphna 1:02:10

I had one question that's loosely related to the article, especially when you talked about kind of the incomplete closure rates. And this theory that maybe we don't even even if you're interested in closing the PDF, maybe we don't have to close it, we can make the shunt smaller thoughts?

Speaker 4 1:02:30

Yes, you're right. At the end of the day, what matters is how much blood is dumped into the lungs and how much blood is stolen away from the systemic circulation. And you do not need an absolutely closed PDA for that. And this paper also looked at presence of a hemodynamically significant shunt at seven days. And even that was 50%. So in half of the babies, Tylenol did not even manage to achieve lack of hemodynamic significance, even though the PDF was open. So that kind of highlights that we need to go beyond the empirical dosage of 15 per kilo and every six hours and put a bit more work in trying to find out what is the right dose in this population. I know there is a lot of interesting work going on right now especially in Europe, with the TREO, kappa trial of prophylactic staminas, and therapy, so I'm really looking forward some of their work. And hopefully, in the next few years, we'll get a bit more data on ideal dosage of of Tylenol in these babies.

Daphna 1:03:48

Yeah, and that brings me to my next question. So you mentioned dose. And also in your commentary, you mentioned how some people are wanting to us to just stop talking about the PDA altogether. But what do you think this paper adds to the PDA conversation? And what, you know, what does the future of research on the PDA look like?

Speaker 4 1:04:09

I think this this paper asks a lot of important questions. We cannot ignore the the significant benefits that this paper has demonstrated which could largely be related to precision management of the PDA. And therefore, rather than abandoning PDA research and PDA trials, I think what we really need to do is focus on the highly vulnerable population, which has been so far excluded from randomized trials, these micro preemies less than 26 weeks, and focus all our effort if we have to do a clinical trial. We should be focusing all our effort in this population and In finding out which PDS need to be closed, and then use the most effective therapy in the safest manner possible to eliminate the shunt, and see if that makes a difference in clinical outcomes. I think that is the direction of PD research.

Daphna 1:05:20

My last question to you and especially because we've talked about this in the past, and is it's hard to enroll parents of micro preemies are nano premies, the smallest and babies, and any tips about people who are trying to do research in this population.

Speaker 4 1:05:42

For me, we are running a trial right now, as you know, the smart period trial, which exclusively enrolls less than 26 weekers. Right, we've just hit our 50% Target enrollment. We have had a very good compliance rate so far, with more than 90% eligible patients being enrolled. And the reason for that is, you're being honest with parents saying that if if your baby's not enrolled in the trial, given the lay of the land, there is a 50% chance that your baby might get treated early, because some physicians would like to do that, or your baby may not get treated, because other half of the physicians would like to do the latter. So so it's actually not been that much of a problem enrolling patients because there is a truly there is an equipoise across the board. To the point, interestingly, that there was one senator who refused to participate in the trial, because they are convinced that treating a PDA does not help. And therefore they don't want to expose their babies to early treatment. There was another senator who did not want to participate, because they're convinced that these babies need to be treated early. And therefore they really want to randomize their babies to no treatment. But most of the senators who are in the trial are right in the middle with a lot of intra institution variability, and that has made enrollment easy. So I would see can read that convey that uncertainty to parents. And we've seen that most parents have have agreed to find out to help us find out an answer to this problem.

Daphna 1:07:36

Words To Live By. As we close this segment, I was just hoping to read this beautiful acknowledgement, and that you included in your commentary. And this commentary is a tribute to the late Dr. Reagan Kissinger's unwavering devotion towards improving the outcomes of the small since the kiss babies in a relatively short career, she advanced the field of neonatal hemodynamics in a manner that has not only touched the lives of hundreds of babies, but has also opened several avenues for future hemodynamic research. She will be dearly missed by the neonatal community show. Vic, thank you so much for joining us again today.

Unknown Speaker 1:08:13

Thank you so much for having me. Always a pleasure.

Ben 1:08:17

Thank you for that Daphna. Sometimes, it's nice to for you to have my back because I was not able to actually meet up with Shauvik on this one. So thank you for we missed I know I always enjoyed talking to Shauvik. So thank you for doing that. Okay, I have one more paper to review. I'm going to the journal. We were in the Journal of parasitology. We were in the genomic Perinatology with your paper so we're staying in the Journal of allergy. It is a paper called effects of prophylactic probiotics, supplementation and infants born very preterm or very low birth weight. first author is our kita Schererville. I hope I pronounced is correct. My volume. The Background section is what you would expect of a paper on probiotics, right? Probiotics are alive micro organisms. And when administered in adequate amount, they confer some form of health benefit to the host. That's the definition. Now what we know is that the intestinal flora of patients with neck has a predominance of Proteobacteria and significant reduction in the diversity of species. nematocysts. The pattern of monic sign for neck is due to abnormal bacterial fermentation. And so the theoretical thing is that they're optimizing the preterm gut microbiome with probiotic is a favorable strategy to prevent things. We're not really going to go into all the different meta analyses, all the different things about the evidence behind probiotics, I think, I think there's a lot of strong evidence to support the use of probiotics. It's still a subject of contention. So I'm staying staying far away from this for now. What is the goal of the study? Though the goal of this study is something that I think, or any unit, who is currently on the fence doesn't know what to do. I mean, this is the kind of study that's interesting. This is a group that basically decided to report a pre and post implementation of probiotic on their cohort to evaluate the effects of routine, prophylactic administration of a multi strain NICU specific probiotic product in infants who were born preterm in basically your unit in North Texas. So I think what's interesting, for example, is that we are just probiotics. We don't use the same probiotics that was used in this in this trial. However, we have colleagues from institutions from our neighboring institutions who are not using it, and they what did they do? They reached out to us and like, Hey, what are your experiences like? So I think people reporting it in these in this fashion is actually very helpful, because your account, let me see, let me see what this unit in North Texas who has started a process, what was their number? What how did they do it? So I think this is not a paper to really shatter the current body of evidence on probiotics, but it does, it does provide a lot of interesting information. So this is done in a unit that admits about 150, very preterm infants in here each year. Basically, it's a prospective and retrospective study. So it's prospective for the cohort that received the probiotic, but then they retrospectively used data for the, for the so it's the historical cohort for the control. And they compared basically, their experience after one year of using the probiotic and to basically a one year duration of infants who did not receive the probiotic. In the past, they excluded infants who death or discharge prior to the first dose death within 48 hours after birth or complex congenital anomalies. So, what is it that they use, so they implemented the routine use of a multi strain probiotic provided by the company Similac. And basically, for people who are interested this actually, probiotic provides 1 billion colony forming units 4.5 grams of the of the sample and it has by Phaedo, bacterium lactis Bifidobacterium infantis and Streptococcus thermophilus. What I think is very interesting is that the outlined their whole protocol for giving the probiotic and I think that's something that people Yeah, so I'm gonna go through it. So the probiotic packet is mixed in three ml of sterile water in a dedicated place by the nurse, there's a lot of concerns about probiotic contamination. So they did that in a separate space. The first dose was given within 48 hours after birth. After the first feed of mother's colostrum, or donor breast milk didn't have colostrum. It was administered through the DeVos tube, replacing a feed equivalent to the feeding volume if the infant was receiving less than three miles of feed, and if the feeds were three ml or more than the three ml of probiotics was given in addition to the feed, the probiotic was followed by a flush of 0.5 ml of sterile water, and subsequently, the probiotic was dosed once a day until the infant reached 35 weeks postmenstrual age or discharge, whichever was earlier. The contraindication for the administration of the probiotic in their unit was any breach in the gut integrity from conditions such as SIP or neck stage two or more. The primary outcome of the study was neck neck was described by the group as clinical radiographic criteria. Basically, infants must have at least one of the following signs either a bilious gastric aspirate or emesis, abdominal distension or a CT slash gross blood in the stools in the stool, no fissure. And at least one of the following radiographic findings dermatosis, or venous gas nimo, peritoneum, neck needing surgery was specifically differentiated from sips. The other outcome of interest were deaf and late onset sepsis. Other major neonatal outcomes included BPD or a P, and ivh. So basically, their prospective group included 125 infants, so they basically took a cohort of 126 infants, and there was no significant differences in the maternal characteristics between the group. The median gestational age at birth was 29 weeks, and the median birth weight of 100 grams. Although there was no significant differences in the incidence of late onset sepsis, the median evaluation for suspected late onset sepsis were significantly lower in the probiotic group compared to the no probiotic. I think that was an interesting finding. The incidence of neck decreased from 6.3 to 1.6%. In the probiotic, however, this was not statistically significant. But it's an impressive decrease Hmm, the other characteristics and outcomes, including the incidence of death were similar between both groups. The median age at which they started the probiotic was 33 hours of life. And they were given until 35 weeks, PMA, the growth velocity was significantly higher in the probiotic group compared to the no probiotic. 14 versus 13 grams per kilo per day. And so you may wonder you miss, I mean, when you read this, the results so far, you say, well, then I don't have issues with 29 weekers. Getting neck, like, this is not my problem. My problems are the smaller ones, right, the very mature ones. I don't know if that really applies. So I think the team realized that and they did a subgroup analysis only, including the ERP W's. And so that reduced the cohort to about 76 infants 34 in the probiotic group 42 in the historical cohort. And there, what they found was that the there were no cases of NEC in the probiotics group, compared to an incidence of 14.3% historical code. Yeah. And that was statistically significant. There were no significant differences in the other outcomes of interest between both groups. I think that's very interesting. Your conclusion was that the author's found that routine prophylactic supplementation of a of a NICU specific probiotic in infants born very preterm or very low birth weight was associated with a reduction of neck that is consistent with the literature reported effect size with no adverse effects, such as probiotic sepsis. This study adds to the evidence supporting the routine supplementation of prebiotics in infants born very preterm or very low birth weight further studies need to focus on the optimal length of therapy additional NICU populations that may benefit and other effective probiotic, and symbiotic combinations. IE, should we start using this more routinely in the kids who are getting 40 hours of antibiotics? All that stuff? I guess that's what you're, you're hinting at?

Daphna 1:16:52

Very interesting.

Ben 1:16:53

Yeah, I think so. I thought it was

Daphna 1:16:55

very interesting. Ya know, I It's always important, right? When we get we got some big papers, we start implementing it in real life. Right? What does that look like?

Ben 1:17:07

Yeah, cuz I think many people are like, Well, do you mix it in the milk room? Do you have a separate space? Do you do you flush the tube afterwards? Because it sort of sticks to the tubing. Like these are? These are things that sometimes you can get lost in those big mid analyses or sometimes trials? So I think, yeah, and

Daphna 1:17:24

I especially, you know, like, in our unit will say, like, the docs will get together. And so we were willing, we're gonna roll this out, we're gonna start nurses are like, and they're like, what about this and this and this, and this, and you're like, I didn't not think about any of

Ben 1:17:40

that. It's like, meet me in the kitchen. Say you mix the ingredients together, you bring it to the table. And it's great, right? And I was like, yeah, that's not how it works. But But I think what's interesting also is that it's nice, because you may think, you know, like, maybe you are a relatively smaller you. Maybe you are not like the nationwide Boston Children's of their world with hundreds and hundreds of babies each day. And then I cry. So like, I'm a smaller unit. How do I do this? That experience from this unit in North Texas is extremely valuable. Extremely valuable.

Daphna 1:18:13

Yeah. And sharing our protocols, right, which he knows there's like, the like state secret, like heavy heavily guarded when, you know, the goal for all of us, right? It's just to help more babies. So yeah, yeah. Great. Well, I think that's all we have time for today.

Ben 1:18:29

I think I think that's it.

Speaker 1 1:18:32

Thanks for anybody who's okay. All the way to the end with us today.

Ben 1:18:35

That's a long one. But it was an interesting series of papers. And we are are very happy to tease next week's episode. Which, if I'm not mistaken, man, our making mistake, but we have we were talking a lot about nutrition today. So it's quite exciting. That next week on the podcast, we'll have Amy hair. And Misty, good. Dr. Amy hair and Dr. Misty, good. So they're rock stars. Phenomenal.

Daphna 1:19:04

Yeah, and the only the only regret I have is that we needed like three hours to do this interview

Ben 1:19:10

we needed. We needed to do like a three hour interview that is Trey. That'd be a part two. But I mean, for people like me who are not deeply versed into nutrition, like they almost converted me. So.

Daphna 1:19:23

Yeah, I mean, they were a real pleasure to speak with obviously, and they have such a nice collaboration. And I think we got a lot done. I think people are really going to enjoy this episode. Yeah,

Ben 1:19:37

I think so too. Thanks. All right, definitely. I will see you later. Sounds good. Bye. 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 podcasts, Spotify, Google podcasts. Are 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 v dash incubator debt report. 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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