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#165 - 📑 Article of the Year Campaign - ft. the EBNEO Team



Hello friends 👋

In this special episode of the Incubator podcast, Ben and Daphna collaborate with the EBNEO team to review the candidates for Impact Article of the Year. This episode features an in-depth review of eight cutting-edge neonatology articles, sparking engaging discussions among team members Dr. Brian King, Dr. Rasheda Vereen, Dr. Abdul Razak, and Dr. Atul Malhotra. Highlighting groundbreaking research and thought-provoking findings, the team debates the impact and implications of each study. A special thank you to the EBNEO team for the opportunity to feature this campaign on our platform. Don’t forget to submit your bracket to participate in our giveaway!


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Make sure to fill out your bracket and enter our giveaway!


You can download a bracket in a word document if it makes it easier for you to fill out:

BRACKET_IAOY
.docx
Download DOCX • 567KB


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You can find the articles competing in the Impact Article of the Year Campaign here 👇


Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years. Bloomfield FH, Jiang Y, Harding JE, Crowther CA, Cormack BE; ProVIDe Trial Group.N Engl J Med. 2022 Nov 3;387(18):1661-1672. doi: 10.1056/NEJMoa2204886.PMID: 36322845 Clinical Trial.


Randomized Trial of Surfactant Therapy via Laryngeal Mask Airway Versus Brief Tracheal Intubation in Neonates Born Preterm.Gallup JA, Ndakor SM, Pezzano C, Pinheiro JMB.J Pediatr. 2023 Mar;254:17-24.e2. doi: 10.1016/j.jpeds.2022.10.009. Epub 2022 Oct 12.PMID: 36241051 Clinical Trial.


Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants.Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, Muller WJ, Zar HJ, Brooks D, Grenham A, Wählby Hamrén U, Mankad VS, Ren P, Takas T, Abram ME, Leach A, Griffin MP, Villafana T; MELODY Study Group.N Engl J Med. 2022 Mar 3;386(9):837-846. doi: 10.1056/NEJMoa2110275.PMID: 35235726 Clinical Trial.


Nasal High-Flow Therapy during Neonatal Endotracheal Intubation.Hodgson KA, Owen LS, Kamlin COF, Roberts CT, Newman SE, Francis KL, Donath SM, Davis PG, Manley BJ.N Engl J Med. 2022 Apr 28;386(17):1627-1637. doi: 10.1056/NEJMoa2116735.PMID: 35476651 Clinical Trial.


Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, de Vries WB, Dijkman KP, van Kaam AH, Villamor E, Kroon AA, Visser R, Mulder-de Tollenaer SM, De Bisschop B, Dijk PH, Avino D, Hocq C, Zecic A, Meeus M, de Baat T, Derriks F, Henriksen TB, Kyng KJ, Donders R, Nuytemans DHGM, Van Overmeire B, Mulder AL, de Boode WP; BeNeDuctus Trial Investigators.N Engl J Med. 2023 Mar 16;388(11):980-990. doi: 10.1056/NEJMoa2207418. Epub 2022 Dec 6.PMID: 36477458 Clinical Trial.


Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.Watterberg KL, Walsh MC, Li L, Chawla S, D'Angio CT, Goldberg RN, Hintz SR, Laughon MM, Yoder BA, Kennedy KA, McDavid GE, Backstrom-Lacy C, Das A, Crawford MM, Keszler M, Sokol GM, Poindexter BB, Ambalavanan N, Hibbs AM, Truog WE, Schmidt B, Wyckoff MH, Khan AM, Garg M, Chess PR, Reynolds AM, Moallem M, Bell EF, Meyer LR, Patel RM, Van Meurs KP, Cotten CM, McGowan EC, Hines AC, Merhar S, Peralta-Carcelen M, Wilson-Costello DE, Kilbride HW, DeMauro SB, Heyne RJ, Mosquera RA, Natarajan G, Purdy IB, Lowe JR, Maitre NL, Harmon HM, Hogden LA, Adams-Chapman I, Winter S, Malcolm WF, Higgins RD; Eunice Kennedy Shriver NICHD Neonatal Research Network.N Engl J Med. 2022 Mar 24;386(12):1121-1131. doi: 10.1056/NEJMoa2114897.PMID: 35320643 Free PMC article. Clinical Trial.


Antenatal dexamethasone for late preterm birth: A multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial.WHO ACTION Trials Collaborators.EClinicalMedicine. 2022 Feb 12;44:101285. doi: 10.1016/j.eclinm.2022.101285. eCollection 2022 Feb.PMID: 35198915 Free PMC article.


Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, Chang T, Van Meurs KP, Lampland AL, Bendel-Stenzel E, Mathur AM, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Poindexter BB, Rogers EE, Lowe JR, Kuban KCK, O'Shea TM, Wisnowski JL, McKinstry RC, Bluml S, Bonifacio S, Benninger KL, Rao R, Smyser CD, Sokol GM, Merhar S, Schreiber MD, Glass HC, Heagerty PJ, Juul SE; HEAL Consortium.N Engl J Med. 2022 Jul 14;387(2):148-159. doi: 10.1056/NEJMoa2119660.PMID: 35830641 Free PMC article. Clinical Trial.


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You can find the transcript for today's episode here 👇


Ben:1:06

Hello everybody, welcome back to the Incubator podcast. We are back with a special episode. Daphna and I are today joined by the EBE Neo team and we are going over contenders for the Article of the Year campaign. Daphna, how are you?

Daphna:1:22

I'm doing great. We had so much fun doing this last year and we're so grateful that the EBE Neo team is willing to collaborate with us again, so we can't wait to inform everybody of the finalists let's say that's right, that's right.

Ben:1:36

And so today we are joined by four of the EBE Neo team members. We have Dr Brian King, Dr Rashida Vereen, Dr Abdul Razak and Dr Atul Mahotra. Guys, welcome back to the show.

Rasheeda:1:51

Happy to be back, thank you.

Abdul:1:52

Thanks for having us.

Ben:1:54

Yeah, For people who are following along, we are recording this episode. The brackets will be released on social media and we're going to have a form of giveaway for people who are entering this campaign, submitting their votes for the Article of the Year, and there'll be special prizes for people who simply submit a bracket, but be more special prizes for people who actually get the bracket correct. So stay tuned for that. We're still debating on gifts and methodology, so that will come as this episode airs. So yeah, so please pay attention as we go through this bracket. So, without further ado, we're going to put Rashida on the spot and we are going to start with the bottom left of the bracket with a paper by Jacqueline Gallup, and it's called Randomized Trial of Surfactant Therapy via Laryngiol Mask Airway versus Brief Tracheal Intubation in Neonates Born Preterm. Rashida, can you tell us a little bit about this paper?

Rasheeda:3:04

Yeah, so this paper was published in Journal of Pediatrics. I love this paper because basically what they're trying to do is see is there another way for us to administer surfactant? So we all know about mist, we all know about insure, we've heard about the aerosolized, but what about laryngiol mask? And I think the great thing about this trial is it's a non-inferiority trial. So the results and the methodology give us another technique to administer surfactant. So all they unfortunately they only had 100 babies because this trial actually was done right, was done right before the COVID pandemic, so they had to stop. So they had 51 infants in the group that got surfactant via LMA, 42 in the group that got surfactant through an ETT tube and their outcome was to look at failure or need for mechanical ventilation after an hour and what they saw was failure rates were actually less in the LMA group and they looked at some secondary outcomes as well and there was no difference there. So the conclusion from the study was that surfactant therapy via LMA was non-inferior to the insure what they used. And I just wanted to point out some other really interesting thing in the methodology. They did do premedication that was standard for ETT excuse me, the insure method as well as LMA method, and then they also included learners in this trial. Most of the learners did LMA and did not do the insure, but I thought it was a really great study that I think gives us more evidence in terms of LMA being a viable method for administering surfactant, especially when we think about intubation opportunities going down and many babies are just needing intubation just for surfactant administration. So I thought this was a great trial and definitely a wonderful candidate for article of the year.

Ben:4:53

All right, she seems biased. Let's hear from the other. What do you guys think? I'm being facetious. I kind of agree with Rashida. I think this is also a great candidate for article of the year, especially considering how many people it can impact. When we're looking at the number of people who are intervening on babies at the time of delivery with various levels of grooming, I think the opportunity to use something other than a nitty tube, which is sometimes difficult to insert, really increases the possibilities for how many people can actually successfully manage babies with complex respiratory symptoms at the time of birth. So I kind of agree, but I'm just curious to hear a little bit from the group. What do other people think? But we'll go ahead.

Atul:5:38

I'm not in favor of this article. Actually, I don't think it should have been in the top eight. If you ask me, you can say I'm starting off controversial. The reason, I think, is that they put a non-infrauding margin of 20%, so they were happy to accept 20% failure. There are two aspects of the trial, which one was the non-infraurity which I was not happy with. The other thing is a lot of units around the world have gone on to minimally invasive surfactant therapy, or LISA as people know it. So insure is not done in many units, so it's not directly comparing what is even more minimally invasive versus something which is quite. I agree with Rashida on the front that it is another technique of surfactant administration, the supraglottic or the LMA. But, yeah, sorry, I'm not in favor of this trial.

Abdul:6:25

Okay, I think I partly agree with Atul as well, not just being in Australia, but I'm saying that this is this trial is a small trial. So we are basing the conclusions on the small number of babies that are recruited and saying that it is a non-inferior. But the major problem is the non-inferiority margin is very, very large. That is number one. Number two is, I mean, of course, when you take a non-inferiority margin which is very, very large, then you end up with sample size that is being very small and you conclude non-inferiority. But technically it might not be the case because it's the margin is so small and the babies included in the trial is very, very small. The other big problem, which Atul has rightly pointed out, is that the comparison seems to be balanced. So in one group you are administrating pre-medications, which is ETT because you have to. There's no other way. You don't want to put a tube in a baby without giving any medications. In another group you're not doing that, and I mean what really you're trying to understand here is whether we can reliably give surfactant to LMA. But here what the authors have shown is that I mean, I don't know whether the surfactant has gone really well, but what they have really shown is that there are adverse effects of the pre-medications, which is why they have shown there's no difference. But the problem is the comparisons are imbalanced. The pre-medications have administered in one group and it is not in another group and that is why you can see a bit of more failure rate. In fact they looked at 24 hours failure rate and they have said the failure rates are more in ETT surfactant group and that was surprising for me when the article came up. Why, when surfactant has gone right in you through the energy field to why should it fail? Then I realized that pre-medications was administered in another group and then it's not in another group. So the group are imbalanced and people have gone to miss. The ideal should have been give same pre-medications and give same missed and then ensure the non-inferiority and whether we can really give. I mean, I think this is going to be one of the future of surfactant therapy, but at this point it's a small trial. Non-inferior margin is very large. The groups are a bit imbalanced, so I'm a little bit not sure whether this is really going to make a difference. But it is one of the important article that many of us have talked about here.

Ben:8:53

So I think you guys have really, really took away the wind out of the cell of this article. But let's talk about the article.

Daphna:9:03

That's a good food for thought, you know.

Ben:9:04

Yeah. Yeah everybody can mull about on that.

Rasheeda:9:06

But Abdul did say it is the future of surfactant there.

Ben:9:09

Fair enough.

Rasheeda:9:10

Period so period.

Ben:9:13

Fair enough Now. I think that the article we're just competing with is a very important one, and it's a one by Laura Hammett in the New England Journal of Medicine, and it's near Civimab for the prevention of RSV and healthy late preterm and term infants. So let's hear about that one. Brian, do you want to tell us about this paper?

Brian:9:31

Yeah, yeah, this is a, as you said, a big one, particularly in the US right now as it is rolling out in practices. But this is a randomized trial of Nur-Civimab that was published in the New England Journal. This is in infants that were greater than 35 weeks. They were randomized to Nur-Civimab versus placebo in a two to one ratio and, importantly, this didn't include anybody that would have qualified for Pavalizumab or Cinegis as we call it, which is our typical standard of care for RSV prophylaxis for babies who qualify. So this is for term or close to term kids who don't qualify for Cinegis. In their first RSV season they were randomized to get Nur-Civimab or placebo. The primary outcome was medically attended RSV-associated lower respiratory tract infection. They had a few definitions that they looked at whether you had an RSV diagnosis with PCR, whether it was in what sort of clinical symptoms you had, but it was. The primary outcome was including a PCR diagnosis and that was out to 150 days from the dose of Nur-Civimab, and then a secondary I think pretty important outcome was hospitalization. So RSV or any respiratory hospitalization was what were important. Secondary outcomes 1490 babies were randomized, 994 in Nur-Civimab, 496 the placebo. Again because of that two to one ratio and the primary outcome the medically attended respiratory tract infections occurred in 1.2% of infants getting the Nur-Civimab, versus 5% in those receiving placebo, and hospitalizations also significantly reduced from 1.6% of those getting placebo to 0.6%. And I like they have a table that or a figure where they sort of display that in terms of number of cases averted. And so if you look at like the broadest definition of RSV infection that they used, nur-civimab was estimated to avert 84 cases of respiratory illness per 1000 infants treated and prevent 19 hospitalizations to RSV averted for 1000 infants treated. So yeah, this is a big one, particularly in the US. I don't know what's going on in Canada or Australia or other countries, but here it's been a pretty high impact study with many infants getting access to it now and I agree I think a synegist has always had these very restrictive criteria, in part because of concerns about cost effectiveness and so the opportunity to have a single dose given for the whole season and potentially produced at a lower cost the estimates for cost are substantially less than Pavilizimab per dose and you only have to give it once really opens it up to a wide population of infants that were going to be eligible for Pavilizimab before.

Ben:12:22

Yeah, and I think it's something that impacts us as neonatologists, for all of our babies, who are at a very high risk of developing RSV and more severe complications of RSV, but also an article that has tremendous impact for the pediatric field at large. So, yeah, I think that, despite my initial enthusiasm comparing this one to the surfactant administration, I think this paper probably wins the battle. I'm not even gonna bring in a tool and, abdul, we get it. Like you thought, the other one didn't even need to be in the brackets. I'm assuming your vote is there. But Daphna, brian, rashida, which one do you vote for? Near CIVIMAB or LMA versus ZT tube?

Daphna:13:05

For me, this is my top contender to go all the way.

Atul:13:08

So I think it wins.

Daphna:13:09

I think it wins this matchup.

Atul:13:12

Can I make a very quick comment about the problems of the study? I'm not saying it's not a good study, but my problem with the study was this is not in a high risk population, so obviously it's easier to do it in a low risk population. That's fair enough. But we all know that when we give vaccines to preterm infants they have side effects much more than term infants. And especially if you want to give it a time when they want to be protected from the RSV season, that needs to be tested and rolling it out before testing it in preterm. So I'm not sure, brian, if there is other trials going on. That was one point, and the other point I want to quickly make is maternal RSV immunization is also up on the cards, remember. So how does that work out? I would rather give it to mum, but obviously if you have mum delivering at 24 weeks for a preterm infant, if that antibodies are going to be there six months down the line when the patient gets out of the hospital is something. Just putting it out there.

Ben:14:03

Yeah, it's interesting that these articles came out around the same time where vaccination for the mother, protecting the infant, especially in the first, about three months of life. So yeah, there's some competing factors there, brian, yeah, you were going to say something.

Brian:14:16

Yeah, I agree with you. I think you have to be aware of what population this study applies to. And while I completely agree that the preterm population, which all of us here think a lot about, is a much higher risk population for RSV, that doesn't mean that RSV doesn't impact the older infants and the term infants and even if their individual risk is lower, there's so many more of them that to the health system. There are a ton of hospitalizations. That treatment that is lower cost, that can be effective for term infants at reducing these hospitalizations and these illnesses, is still hugely impactful. There has been CDC has online you can look up a cost effectiveness analysis done. I'm not seeing it published yet. It has been presented using data from this trial that suggests that within a reasonable cost range. It's like the cost affected in the US and there's also one in Canada that actually combined it with the maternal vaccine and, very interestingly, it used different models and approaches to vaccinating some women and then also vaccinating some babies to kind of find the most cost effective means of offering protection to as many infants as possible. Because, again, like you said and like I mentioned at the beginning, this study did not include anyone that was already qualifying for synergists.

Ben:15:29

All right, do we have a consensus rights? I think the RSV paper seems to be the winner of this matchup.

Rasheeda:15:35

I still my vote is actually still for Gallup only because I do think we need to acknowledge that, even though it's not a vaccine, vaccine uptake in the US has actually been stable and going down. So this is something that will be on the onus of the parents, on the onus for access, and so I do think that access for this is going to take a lot more time than we think. But even though the Gallup trial is very small, will require a lot more research, it does impact what we do as providers, and so I think for me it was the most impactful article of the year, at least in this matchup, because of the impact that we can immediately take to the bedside, where there's a lot of different factors with the RSV, availability of this and other factors that I think will also take some time. So that's my opinion.

Ben:16:27

Fair enough, fair enough, All right, for our next matchup. Abdul is gonna present both of these papers. The first one is a paper by Christy Waterberg and a colleague called Hydrochorazone to Improve Survival Without BPD, published in the New England Journal of Medicine, and the competing article is also published in the New England. That's called Early Amino Acids and Extremely Preterm Infants and Neurodisability at Two Years. First author is Frank Bloomfield. So, Tule, briefly, can you walk us through what each of these papers are about?

Abdul:16:57

Yeah, that's right. So the first trial by Christy Waterberg was on hydrochorazone to improve survival without BPD. I think steroids have been there going on for quite a while and BPD is on top of the list and we're trying to reduce BPD by giving different medications. We're trialing off and steroids have been on top of the list but we don't have a large trial that has proven that this is going to be beneficial. Yet we use steroids and this trial particularly looked at hydrochorazone in babies who have been ventilated. So what this trial did is looked at very small babies who are less than 30 weeks and who have been intubated for at least a week and the randomization occurred between two and four weeks, if a third and fourth week of age, and babies received hydrochorazone which was four milligrams per kilo over 10 days and I believe the cumulative dose somewhere comes to around 18 milligrams per kilo or the placebo, and the main outcome for this trial was survival without BPD at 36 weeks. They also looked at that was the efficacy outcome, but they also looked at the safety outcome, which was survival without moderate to severe neurodevelopmental disability at 22 to 26 months. So the trial endured almost 800 babies. So this is a very large trial, and we need to. This is the only large trial that we have on steroids and I don't think we have any larger than this. And the babies were quite small, 700 grams. And they're also small 24, 24.9 weeks that was a mean gestational age. The outcome that occurred in the hydrochorazone group, which was survival without moderate to severe BPD, was 16.6%. There was a small number of babies surviving without BPD, that is in hydrochorazone group. But in placebo group the EVA occurred in 13.2% and the adjusted risk ratio was 1.27, spanning from 0.93 to 1.74. So there was no difference. But you can see that the confidence interval is almost suggesting that there could be benefit with the hydrochorazone group. And the other outcome, which was survival without modern to severe neurodevelopmental disability, was that there was no difference. The outcome occurred in 36.9% in hydrocortisone group and 37.3%. So it's very evenly spread. And if you look at the confidence interval it's very evenly spread. So that was one of the win for hydrocortisone, because we are always worried when we give steroids to babies whether it's going to cause problems with their brain and development. So that was at least one trial so far. My knowledge that has powered for neurodevelopment. We don't have any major trial until this point that has powered for neurodevelopmental outcome. And even if you look at the Cochrane Metaanalysis, even combining all the dexamethicone trials, we still are not forward. And this is one of the big trial that has really shown that giving hydrocortisone will not affect babies. But again, there's not much benefit with that. But there were other secondary outcomes that the trial had looked into, which was extubation extubation, whether we can extubate babies, and the trial did show that babies were extubatable earlier. And if you see the difference in the extubation days, so babies who are given hydrocortisone, they're extubated three days earlier and that effect was spanning from as high as five days to as low as one day, so that there was benefit. So if you're really looking into extubating babies, I think hydrocortisone is one of the good choice of truck to give to these babies. But then we have to remember that the outcomes that is the main outcome, that survival without BPD is not going to make much difference overall. I think this article has. I would say, when I look at the evidence per say, this is one of the major trial that has shown that the outcomes might be better with hydrocortisone, particularly extubation. We can, we can extubate earlier, but you know, the other main outcomes have not been different.

Ben:21:09

So, abdul, then take us to the next article by Frank Bloomfield on the early amino acids, and let's see what hydrocortisone is competing against today.

Abdul:21:18

The other article was essentially whether we can give more freedom, more parental nutrition to babies. So this was an early amino acid in extremely preterm babies, at two years, and this is again a multi-center trial that I believe conducted across Australian and New Zealand centers and what they really looked at is in small babies whether giving extra protein is going to be beneficial, because the school of thought is giving more protein these babies are going to be, they're going to grow better and they're going to have less neurodevelopmental problems, and that was the hypothesis when they started with. So what they did is they randomized babies 434 babies, 217 in each group, the extra gram of protein in first five days of birth. So what they really did is whatever the parental nutrition was going on. So they just added a gram of protein extra to the randomized group, to one of the group, and the other group received the usual pre-tmpian and I think they they tried to maintain that difference and in the randomized group the overall the protein that intake the babies had, I think, was 3.6, 3.4 grams per kilo in the first week. That was the mean and whereas in the placebo group that was less, which is 2.6 grams per kilo per day. But surprising was that the babies who received extra protein didn't do better. So the main outcome was survival free of neurodevelopmental disability, which was not different. The the outcome occurred in 47.28%, that is, half of the babies had survived without any neurological problems. And it was nearly same in the placebo group, which was 49.8% and the risk ratio was 0.95, spanning from 0.79 to 1.14. So there was no difference. But there are many other secondary outcomes that they looked at, which is death per se and neuro develop, neurodevelopment, neurodisability per se, and that was of course no difference. But it was infrequent outcome and there was some wide confidence range to it. But if you look at the neurodise, what a big difference. And also the language delay. There was some concerns and also more delay 7% of babies had moderate to severe motor delay. There is only 2.5% babies had it. So giving extra protein was causing problems. So I think if you look back, new netology has changed. So aggressive is not always good. So this is one of the article that really brings up. So we need to be careful in what we are feeding to babies and we have to be very careful with that. And they have in fact supported the hypothesis to trial that when babies have given extra protein. They had more refeeding syndrome and more PDAs, and this is all linked with extra protein and that is why these babies have these outcomes. That, thinks the right time for us now to really think how we should give proteins to these babies. We should not be aggressive. We should be careful. We should be looking into all those tiny little things like phosphate, potassium and things like that and making sure that we don't give too much to these babies.

Ben:24:53

Okay, if you had to pick a winner, which one do you think, in your opinion, is the most impactful paper between these two?

Abdul:25:01

I think, both.

Ben:25:03

No, that's not an option. Come on, get out of here.

Abdul:25:06

No, I think they can have both articles which can influence practice. Sir, I'm DGV.

Ben:25:12

You got to pick one.

Abdul:25:13

Yeah, I'll go with bluefield.

Ben:25:18

Brian is giving you the thumbs up. Rashida is nodding as well. Atul has a comment. Yes, Atul.

Atul:25:25

I just take comment. So the water book trial Abdul is right is quite a large trial but I was not too fussed about it, even though the neurodevelopmental outcomes Abdul is right was the primary outcome. The PremiLoc study and the Stop BPD study from Europe had looked at hydrocortisone, albeit different protocols of administration, so that wasn't selling it for me. Bloomfield, I think, is really good because, like Abdul said, everybody thinks if we support these babies with more nutrition they do better. But actually less is more and KMI Martin put it so nicely in her editorial for this article. So I think Bloomfield is the winner, definitely for me Very good.

Ben:26:04

All right, we're going to Brian, sorry.

Brian:26:06

Well, I was going to say I gave an enthusiastic thumbs up because, in terms of all of these eight papers, which one actually has already changed practice? Where I'm at, and it's Bloomfield, we already, after publishing that, reviewed our protein administration in the first few days of life and cut back our standard TPN orders for the extremely preterm infants to give them less, because we were realizing we were giving close to four grams per kilo by day three or by day two or three, and we said, look, this looks like there might be harm. There's certainly no benefit, and we already cut back. So we absolutely changed our practice based on that, whereas Waterberg and maybe this is my bias I already use DEX. I kind of want at this point a DEX versus hydrocortisone trial, if anything, because if I'm going to want to get a baby extubated, I would use low dose DEX and methamethasone in this age group in this time period. So this one not showing that it reduces BPD, I'm like okay. Well, how does it compare to the thing I already do, which it didn't answer the question? So, fair enough, fair enough.

Ben:27:06

Okay then. So we are going next in the next bracket, this one will be. We'll have Brian and Atul present these two papers. Maybe, Atul, we haven't really heard you present, so maybe you can get us started. You're presenting a paper that is published in the lens that it hasn't like. It's the WHO action trials collaborator. It's called antenatal dexamethasone for late preterm birth, a multi center to arm parallel double blind placebo controlled randomized trial. Tell us a little bit about this paper and then Brian will follow that with the article this is competing against.

Atul:27:40

Yeah, so this is an important paper. So the WHO action group is a very active group, obviously sponsored by the WHO, on doing these low middle income country trials on dexamethasone or beta methasone, the steroids, antenatal steroids in women who are pregnant with premature babies. This particular one is the largest late preterm trial. So these are babies who are between 34 weeks and 36 weeks of mothers who have imminent preterm birth between 34 weeks and 36 weeks of gestation and, as you know, we all give steroids to women less than 34 weeks in high income countries. But you know, the biggest killer or the biggest impact of premature death happens in low middle income settings and they happen in the 34 weeks to 36 weeks because obviously most preterm babies are born in late prematureties. I think it's a really important trial. So they randomized 780 women to either getting the steroid before imminent birth, preterm birth or placebo. So the steroid they use was dexamethasone in this case. Unfortunately, the antenatal dexamethasone did not show a reduction in neonatal death, stillbirth or severe neonatal stress in this trial. The problem is it was not powered for those things because unfortunately what happens is in these late premature babies. The incidence of any of these problems is not very high. So you need a very big trial and I think they mentioned it that they needed trial of more than 3000 women to be able to power that outcome. So I was a bit disappointed overall with the study because they could have done a bigger trial, because there's no death of babies, so but unfortunately they had planned for a smaller trial. So although the trial is very important, it adds, it doesn't actually conclude much. So we need more trials and that was the conclusion from this trial.

Ben:29:37

Very enough, brian. You're reviewing for us then the competing article, which is an article by Huntfield, and that is the expected measurement of early IB proven for pain ducts or karyosis, depending on the trial.

Brian:29:53

Yeah, yeah. So this is the Beneductose Trial. This is the hot topic of Neonatology Forevermore, the PDA. This is a multi-center and non-inferiority trial of selective, what they call selective PDA treatment. This is selecting PDAs that were above a certain size, greater than 1.5 millimeters, with left to right shunting, among infants who were extremely preterm, defined as less than 28 weeks, to either expected management, which is no treatment, or early hyperpropan therapy given within the first 72 hours. Their primary outcome was a composite of moderate to severe BPD or death at 36 weeks PMA, or they also included in the composite a stage 2A neck or greater. So the typical what we normally see is the death of the moderate to severe BPD, but they also added a neck, 2a or greater to that composite outcome. They randomized 273 babies with a mean gestational age of 26 weeks and 845 grams. And I think, most importantly, one of the big topics in PDA trials is sort of off-label or off-trial treatment of the PDA and they managed to not only successfully randomize those babies to expected management or early hyperpropan, but the rate of PDA treatment in the expected management group was exceedingly low. I think either none or maybe one baby, if I remember correctly. So they really very successfully performed this trial. The primary outcome was 64% in the treatment group versus 46%. So higher incidence of the composite outcome of neck 2A or greater, moderate to severe BPD or death at 36 weeks, and this was primarily due to increases. If you break up the composite outcome, primarily due to increases in BPD from 33% in the expected management group to 51%, and death, which increased from 14% to 18%, the neck 2A outcome was their event rates were very similar. Yeah, so this is, you know, I think, adds to the PDA literature, particularly, I think, because it does address one of the primary concerns about a lot of PDA trials and that many, many times a lot of infants get treated, even when they get randomized to no treatment, which the Benaducta trial was able to successfully solve that issue. For me personally, I don't think it's going to necessarily hugely shift the needle on PDA treatment, mostly because I think people are just so entrenched regardless, but I do think it was a very well designed trial. I think it solved some of it. It kind of addressed some of the big concerns about prior trials. I think one concern that still remains is whether we're selecting the right PDAs to be treated. They just went on this size measurement which some people say you know is maybe not the best measurement, and there were no clinical criteria that you had to qualify for.

Daphna:32:41

So I think that's.

Brian:32:42

that's a limitation to me, like it wasn't babies who are mechanically ventilated with big PDAs. It was just based on that size.

Ben:32:49

And okay, I agree. I agree with that, brian. What do you think, then, would be your pick between these two articles to move on to the next round?

Brian:32:57

I think it's. For me it's tricky because I don't. I don't think either for me personally, is changing my treatment and I think, as a tool mentioned because the WHO trial, you know, wasn't powered appropriately, I don't know if it's going to maybe get defeated in the next round, big deal.

Ben:33:14

But still just so I probably still.

Brian:33:17

Yeah, I probably still pick the Benaducta trial. I do think. At the very least, one of the things that it highlights for me is, while there certainly may be certain babies with certain types of PDAs that still warrant treatment, if you actually, there was a good editorial by Jonathan Slaughter and Carl Backus, who are doing the trial of percutaneous closure, that commented that this was designed as a non-affiriority trial. But when you have a non-affiriority trial that has event rates like this, you can test for superiority, and when you do so, actually expected management was better than ibuprofen therapy in this trial, and so I do think that's just not to say that. You know, not treating the PDA is always better, but I think it highlights that there are certain babies that the treatment can cause more harm than good, and so that we should think cautiously about using drugs, because, even if you're doing with the best intention, you might also worse outcomes for some babies.

Ben:34:12

Atul, would you agree with that? Do you think the Benaducta trial is probably informing us more on what to do?

Atul:34:19

Yeah, like Pan said, both of these trials, you know, made us want more. They were not great, unfortunately. I agree the Benaducta trial should probably go ahead, although I work in the low-middle income setting as well and I would have liked a low-middle income trial to move to the next round. But I think the Benaducta is going to be the winner. Okay.

Abdul:34:41

I think we must say that many people still treat PDA aggressively and for them this is still a win. They have to really think about what we did and we should probably start not giving treatment for babies just based on that size. The important findings I would pick up from this trial is that if you see the ibuprofen exposure group the exposure group they had more severe outcomes, more BP days. That was surprising, I mean. At least if there was no difference that was okay. But giving ibuprofen is worsening BP day and that was something concerning, so that people have to realize that it's not a simple treatment. It just doesn't cause GI or renalysis, but it also can increase BP. It can affect the vasculature. That can something come up. And it's similar to like pre-mod. This was in fact was prematurely terminated because the outcomes were more in the exposure group and people are concerned that I don't think we have to randomize more babies because randomizing more babies is causing harms. So this article I mean even though we picked up now, it might not change the practice, but we have to realize that there might be some concerns with ibuprofen. So we have to be really careful how we choose to treat babies.

Ben:36:05

Arvishita, you're up next. You're doing our last matchup. Two articles, I think, two very good articles. Actually I'm not. Yeah, this is. It's interesting. We had some, some, some matchup of, I would say, weaker articles that we thought were not as impactful as we would have hoped. And then we have this bracket where we have a two articles published in the New England. The first one is by Wu and colleague, called trial of erythropoietin for hypoxic ischemic encephalopathy in newborns and the result of the hill trial. And then you're going to tell us about another article by Kate Hodgson and colleague about the use of nasal high-flow therapy during neonatal and retracial intubation. Which one do you want to start with?

Rasheeda:36:48

Yeah, I'll start with the heel trial, since you introduced that one first, and I like to think of this trial as sort of the heartbreak of neonatology for 2022. I think there was a lot of conversation and devastation, totally agree, totally agree, right, such high hopes, yeah. But I do think that there's a lot of important information to be gathered from this trial and actually I think that there's some even though it is the heartbreak, I think some really positive information that came out of it, and so the objective of the study was to look at erythropoietin in terms of its neuroprotective effects and hypoxic semic and cephalopathy, and that was also in the setting of babies that were receiving therapeutic hypothermia. And so the methods are important for this trial, because they used a hundred excuse me, a thousand units per kilogram given within 26 hours after birth, as well as days two, three, four and seven, and the primary outcome was death or neurodevelopment and neurodevelopmental impairment at 22 to 36 months, and unfortunately, the results show that the incidence of the outcome was higher in the EPO group, and you know that was a very unexpected result. But I think there's really important and the reason why this was unexpected, to give people a little background that may be unfamiliar with this. There are some smaller studies that do show some benefit with EPOGEN, as well as some many, many, many animal trials that show significant benefit. So this would benefit with EPO. So this was a very unexpected result, but I do think that there's some important things to be noted from it. The authors do talk about some upcoming trials that may give us that will add data. So the PAEN trial that will be coming out soon. There's questions about, you know, administration of the doses in terms of timing and the amount. And then, I think, most importantly, what are some other adjuncts that may be a part of this. So there are some smaller animal studies that are also looking at melatonin and other adjuncts that may be a part of sort of like a bundle of treating HIE. So we only right now have therapeutic hypothermia. We don't have another adjunct, but you know there may be more information with EPO. There may be other adjuncts like melatonin or other things. So I do think that this trial, even though it does give a negative result, actually is sort of, in the context of the literature, very important because A I don't think negative trials get as much press as they should, and so it really makes us go back and think about the methodology and our practice, but also think about maybe it's not working because we need a bundle. So I do think that this is really a great trial that has a lot of impact in terms of the context of literature.

Ben:39:50

I found it interesting that, as you said, some of these smaller studies that had shown promise for EPO were by the same authors, and so sometimes you were like man, these guys are giving us good stuff and hopefully they're going to want delivering this great news, and that's why I think I agree with you. It is the heartbreak of the year for Neuronatology, because you're like, oh no, but yeah, a great also to see, like you said, that negative studies are being published and are getting the attention that they now need, because it gives us challenges us to think differently about the problem. Okay then, so the HEAL trial is competing against the paper by Hodgson about using high-flow nasal cannula, high-flow therapy during intubation. Tell us about, I like that paper too.

Rasheeda:40:30

Yeah, this was a really interesting paper that I don't think got as much press as it should have. But I do think again, when we're talking about intubations right sort of as we started the conversation this hour we were talking about, you know, the intubation success rate is 50% and other than having more opportunities to intubate, what else can we do as an adjunct to help these babies that are going through a traumatic procedure? So of course we know about studies, about premedication and skills and all those things. But what this trial looks at is, if you have the baby on high-flow with intubation, can you sort of stabilize them through that intubation process? So this was an intention to treat and they had 202 infants for 251 intubations and they did look at two groups. So they looked at infants greater than 28 weeks, less than 28 weeks and what they saw is that the successful intubation of the first attempt without physiological instability. They had greater success in the group that was receiving high-flow and then also greater success overall. And I think when you sort of think about it, it makes sense because you know intubation is a time-sensitive procedure, right? You only have a certain amount of time to get the endotracheal tube in and maybe the baby. Receiving that high-flow gives you a little bit more time, and they I encourage people to read through the paper because it does talk about the physiology of why they think that happens. And so, again, I do think this paper is important because it's another adjunct that will allow you know the person who's intubating to maybe have a little bit more time. Take their time as they're going through this. So that is the study, oh, and the number needed to treat was six, so I thought that was actually pretty significant as well in terms of their results.

Ben:42:30

Yeah, I think. To me, the last paper by Hodgson about this, about using up high-flow, is something that had a dramatic impact and definitely something that changed our practice quite soon after the publication and addressed another big issue, obviously, which is not only improving success rate for intubation, but improving also the safety of intubation. As we have more trainees and we have less opportunities for people to practice, we intubate many, much less maybe. So I think you're absolutely right. I am wondering, before I let everybody comment, which one is your pick, rashida?

Brian:43:03

This is probably the hardest matchup for me, but in the set I think the Heels study. I agree with Rashida. I think we should give more attention to negative studies. I think it kind of fits a theme with the beneductous trial and the prior bracket and even with Bloomfield in the bracket before that, that treatments aren't always beneficial and you should really know that something is effective before you use it in practice. I don't have a great idea of how many centers were using EPO for HIE prior to this study being resulted, but I think if anyone was, they hopefully aren't now, I would say, and so that might be directly changing some people's practice. And I think HIE in general is just there's a lot of things that are creeping right, like not just EPO, but you even saw in the trial 20% of the babies who were eligible, who were being pooled, weren't eligible because they had mild HIE and they were being cooled. A whole. Nother intervention in this population that we don't know is beneficial. So if one of these things isn't beneficial, we have to really question everything else we're doing about this population and making sure that we really know that what we're doing helps. So I think I think highlighting that is super important. On the other hand, rashida ended with the number needed to treat from the Shine trial which, like we don't have that many things that have that rate of a number needed to treat. I think it's clearly an effective intervention that helps with innovation. I kind of wish it was a bit more pragmatic. By only negative to the trial, which I talked to the authors about, is that. What I almost wanted to know was, if you continued, whatever interface or whatever support you were giving, do you improve intubation success? Because what they had to do like 90% of the babies were on CPAP, so what they had to do was they had to take them off CPAP, put them on high flow for the five minutes to intubate them. And I do wonder, especially with Lisa lots of people are doing Lisa with CPAP already like there's a comfort with doing the laryngoscope and maintaining CPAP. Like, does CPAP when you're intubating already just help you with intubation in the same way? And I think that would be much more pragmatic, maybe more cost effective, instead of breaking open a whole new piece of equipment for five minutes. So that's the only thing that hasn't kept me from implementing in my practice. I've intubated a few kids with CPAP because of this because I've thought, hey, maybe if it helps with high flow, it'll help with CPAP.

Ben:45:16

But my vote was pretty significant as well.

Brian:45:19

Yeah, but my vote was for the Shine trial.

Ben:45:21

Anybody has any comments about this matchup?

Daphna:45:23

I agree with everybody says it. Actually both trials have changed practice in our NICU specifically. But I like that the Shine trial highlighted one success rate of intubation. Of course, huge win. But I think it is a move in the right direction of saying we got to do a lot of negative things to babies, like how can we make it better? So I think there are some intangibles that we're not even measured. That I think are wins for babies. So that's my vote too.

Ben:45:53

Yeah, you were going to say something.

Abdul:45:55

I completely echo with Brian what you were saying. The Shine trial should come up, definitely. No doubt on that. It really does give that extra 10 seconds. If you look into the NETGRED, the authors have presented that extra 10 seconds. The babies in the standard group they took almost 35 seconds to desaturate while babies were on high flow with some oxygen so they took almost 45 seconds to desaturate. So that extra 10 seconds, these 10 seconds might be very important for trainees and they can get the tube in and they have shown it and I think that really extra time which high flow does give is going to change it. If you have a lot of trainees in your unit, which we all have, so this is the right time to use that. But if you look into other things as well, they also looked at if you're an experience intubation, in that case it might not change because with an experience you can quickly go in without that time to desaturate. So there's no difference if you're an experience intubator but of course that was not powered for that particular group but in that subgroup that did show that if you're an experienced it might not be different. But if you're having a trainee and the unit is a lot of trainees, then definitely that's the thing to go. There's a little bit extra thing that you have to do. The client has slightly taken out of high flow and for some units it might be a bit of extra cost and things like that, but I think still it does add great benefit. So as long as we can get a tube without causing problems, that's something really going to change.

Ben:47:30

Well, I think we have our final four. Then I think we will publish that on social media and we will see if some people agree. People can actually disagree with our final four and see which one will take it all the way. I don't know if we, should we go all the way? Should we make a consensus of? I was thinking, we are going to Fine, let's do it then.

Abdul:47:55

I was very surprised to see what is going to come up.

Ben:47:57

Yeah, so we have two matchups. So then the first matchup will have the paper by Hodgson that we just presented, competing with the paper by Hunchid on the Benedictus trial. So, but which one is your pick?

Atul:48:12

So I think this year, as compared to last year, it's been more difficult. Last year at the IKMC study I'm going to put it out there again was such a clear winner from the start it was very easy. This year the competition is stiffer, but I'm going to go with the shine trial. All these are closely matched. I think the final four are all closely matched, but I think Hans Sheed because I would proof in is a practice which is used across the world, not just the high income world. I think people should really question it. The shine trial and the high flow it's not applicable to low and middle income settings. It's a lot of cost impact. So I would go with the Hans Sheed trial Okay.

Brian:48:52

Brian, I'm going to go with the shine trial. I agree with the tool. This is tricky but I completely see a tool's points. But I think I'm going to go with the trial that clearly showed a benefit. That is patient centered. Shine trial is for me no problem, taffana.

Daphna:49:12

Yeah, I mean it's the Taffana, it's shine for me. I think if we had shown a positive impact of something we could use a low and middle income countries that would be the biggest impact. But this was the opposite, which hopefully we can save cost in this and use it somewhere else, but shine for me in this matchup.

Ben:49:32

Rashida.

Rasheeda:49:33

Yeah, shine for me as well, because of just the immediate impact on babies and something that we really can do at the bedside. But I think a tool has really great points and the theme, too, of less is more. Looking at protein and benedictus, I think if we're looking at overall themes for the articles from last year, that should be a really important take home point for folks in terms of sometimes doing things is not always better.

Ben:50:06

What about you?

Abdul:50:07

Yeah, I would also go with shine trial, just because the way the trial has been done and the way the findings we can interpret With the handshield. I think the problem is that they just use deductible measurement and I'm sure that there's no difference. But they have really raised an important point that I wouldn't can be problem. So people have to be careful. But then I think some people have backed off, but there's still some of us questioning whether the trial really chose the right population. So, given that point in mind and given the shine trial showing clear benefits, I would go with shine as well.

Ben:50:48

Okay, our next matchup then sees competing the article about the provide trial grid, the group the early amino acids and extremely preterm infants, by Frank Bloomfield, against the near-sivamab paper published in New England by the Melody Study Group. The tool, which one is your pick?

Daphna:51:06

We see you not voting, by the way, ben.

Ben:51:09

I was agreeing. I agreed with everybody I would have voted the shine trial, and so at some point I actually started writing it because I was going to be in the majority. So, yes, you're right. All right, the tool. Tell us which one is your pick near-sivamab or early amino acid.

Atul:51:25

Yeah, no, I think we'll have to go with the Hammett trial. Like Brian said, it impacts a huge population. Obviously it doesn't impact our NICU population, but RSV is a big problem in babies as a whole and definitely this is game changing.

Ben:51:39

All right, brian. He sort of co-opted you a bit there, co-opted your vote. What do you think?

Brian:51:46

Yeah, no, I think Hammett for me as well.

Ben:51:50

Definitely that was your front runner, so you're still going with that, huh.

Daphna:51:53

Yeah, I agree. I mean, I do think the amino acid trial is a pendulum swing for us, but in terms of impact it's the near-sivamab.

Ben:52:05

Rashida.

Rasheeda:52:06

Yeah, I think very important trial. I still significantly worry about access issues with cost and things like that, but I do think this will have a great impact long-term and so I will cede to this trial and divert my vote.

Ben:52:22

I agree with that vote as well, abdul, just for the sake of completeness. Your vote almost doesn't matter at this point, but please.

Daphna:52:31

Oh, we want to hear it.

Abdul:52:33

I was thinking the bloom field will come up, yeah dissenter. Yeah, just because I'm an enotologist and this has definitely changed to practice, the Hammett one is more of a community pediatricians. I think the question is, how impact will? It will be in low-middle income countries as well, because we have a large population. Are we going to give every single baby RSV? And so that's the question. I will go for the bloom field, but anyways, consensus has come up with Hammett. That's fine, yeah.

Ben:53:06

You can submit your own brackets, sir at your own, I'll go bloom field. We will know the brackets coming back with bloom field all the way will know it's coming from there. Our finalist, then, would be the paper by Hammett on near-sivamab against the Shine trial. We have to take a vote, then, on which one wins for us, the article of the impact article of the year, but, abdul, which one for you is the winner?

Atul:53:29

I'll go with the Hammett. Obviously we were part of the Shine trial team so we are probably already implementing it for some of our babies. But the impact overall, I always look at a global perspective. I would think globally vaccines save lives and we should keep trying in neurologists to sell that. I think if any vaccine saves lives that's much more important than a small practice.

Ben:53:53

All right, brian.

Brian:53:56

This is kind of my pick from the beginning. I think that under-sivamab trial Hammett.

Ben:54:01

Definitely.

Daphna:54:02

You already know how I feel about that, and I mean to Rachida's point in terms of access. I mean in our community I mean our pre-trimed babies were not getting all of their RSV vaccines. I mean we were not able to get them in, and in Florida it's a year-round problem. So I'm hoping this will improve access.

Ben:54:22

I don't want to leave Abdul for last. Can we get? Let Abdul just not go last this time.

Abdul:54:28

That's fine, I can go with Hammett as well, that's okay.

Ben:54:31

We've converted him. Oh my God, what about you, Rachida?

Rasheeda:54:35

Yeah, and I think, like a tool said vaccine-saved lives, I do think you know, with this back to my access thing, I'm sorry to keep harping on this, Especially when you look at low and middle-income countries, because of budgets, they're having to prioritize which vaccines are available and I just I don't know if this one will actually be one that will be available. I'm sort of prioritizing rubella, mumps, measles I don't see this one being there for a while, and so I think that that is the part that's difficult for me, which, and so that makes me lean a little bit more towards the SHINE study as the most impactful for the year. But again, if I'm then thinking about low and middle-income countries, I don't even know if high-flow makes sense for that. So, yeah, I think that's the difficult part.

Ben:55:34

I want to hope that this is the first step to me to address your point, that obviously you're, I think you're absolutely right, but hopefully then this is the first step of identifying a solution. And then, how does the solution become so disseminated that then the cost eventually goes down? And hopefully, hopefully we'll get there not too late, but yeah, it is a definite concern. Okay, then I think we have one comment to make.

Abdul:55:59

The Hammett trial didn't show any difference in depth, so it didn't show the. There was reduction in that, but I think there might be. You know, if you reduce RSV in the community they might impact our preemie baby sign. Might, might we can see that effect. But just wanted to say that from the article perspective itself. It didn't show the difference in that but there was reduction in the access, medical access related to RSV.

Ben:56:27

Well, that does it for us. We have identified a consensus based on the group that we have here today. Please join us in submitting your brackets. Look out for our special giveaway in collaboration with the Ebenio team, and we're very much looking forward to hearing and reading everybody's opinion. I think this is always a great source of discussion, so thank you. Thank you all for participating and for making the time to be with us today.

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