Hello Friends 👋

This week we have a special episode of journal club lined up for you. We have the pleasure of welcoming to the show the great folks from EBNEO (https://twitter.com/EBNEO) to discuss the eight articles competing in this year's article of the year campaign. We had the chance to review each paper and vote for the one we each liked. We encourage you to do the same by following EBNEO on twitter or checking our twitter feed where we will make sure to re-post some of the content published by the EBNEO team. Enjoy!

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

Immediate "Kangaroo Mother Care" and Survival of Infants with Low Birth Weight. WHO Immediate KMC Study Group; Arya S, Naburi H, Kawaza K, Newton S, Anyabolu CH, Bergman N, Rao SPN, Mittal P, Assenga E, Gadama L, Larsen-Reindorf R, Kuti O, Linnér A, Yoshida S, Chopra N, Ngarina M, Msusa AT, Boakye-Yiadom A, Kuti BP, Morgan B, Minckas N, Suri J, Moshiro R, Samuel V, Wireko-Brobby N, Rettedal S, Jaiswal HV, Sankar MJ, Nyanor I, Tiwary H, Anand P, Manu AA, Nagpal K, Ansong D, Saini I, Aggarwal KC, Wadhwa N, Bahl R, Westrup B, Adejuyigbe EA, Plange-Rhule G, Dube Q, Chellani H, Massawe A.N Engl J Med. 2021 May 27;384(21):2028-2038. doi: 10.1056/NEJMoa2026486.

Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P, Bassett P, Swamy R, Mendoza J, Moreno-Morales M, Lally PJ, Benakappa N, Bandiya P, Shivarudhrappa I, Somanna J, Kantharajanna UB, Rajvanshi A, Krishnappa S, Joby PK, Jayaraman K, Chandramohan R, Kamalarathnam CN, Sebastian M, Tamilselvam IA, Rajendran UD, Soundrarajan R, Kumar V, Sudarsanan H, Vadakepat P, Gopalan K, Sundaram M, Seeralar A, Vinayagam P, Sajjid M, Baburaj M, Murugan KD, Sathyanathan BP, Kumaran ES, Mondkar J, Manerkar S, Joshi AR, Dewang K, Bhisikar SM, Kalamdani P, Bichkar V, Patra S, Jiwnani K, Shahidullah M, Moni SC, Jahan I, Mannan MA, Dey SK, Nahar MN, Islam MN, Shabuj KH, Rodrigo R, Sumanasena S, Abayabandara-Herath T, Chathurangika GK, Wanigasinghe J, Sujatha R, Saraswathy S, Rahul A, Radha SJ, Sarojam MK, Krishnan V, Nair MK, Devadas S, Chandriah S, Venkateswaran H, Burgod C, Chandrasekaran M, Atreja G, Muraleedharan P, Herberg JA, Kling Chong WK, Sebire NJ, Pressler R, Ramji S, Shankaran S; HELIX consortium.Lancet Glob Health. 2021 Sep;9(9):e1273-e1285. doi: 10.1016/S2214-109X(21)00264-3. Epub 2021 Aug 3.

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia. Deprest JA, Nicolaides KH, Benachi A, Gratacos E, Ryan G, Persico N, Sago H, Johnson A, Wielgoś M, Berg C, Van Calster B, Russo FM; TOTAL Trial for Severe Hypoplasia Investigators.N Engl J Med. 2021 Jul 8;385(2):107-118. doi: 10.1056/NEJMoa2027030. Epub 2021 Jun 8.

Real-time continuous glucose monitoring in preterm infants (REACT): an international, open-label, randomised controlled trial.Beardsall K, Thomson L, Guy C, Iglesias-Platas I, van Weissenbruch MM, Bond S, Allison A, Kim S, Petrou S, Pantaleo B, Hovorka R, Dunger D; REACT collaborative.Lancet Child Adolesc Health. 2021 Apr;5(4):265-273. doi: 10.1016/S2352-4642(20)30367-9. Epub 2021 Feb 10.

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.Blakely ML, Tyson JE, Lally KP, Hintz SR, Eggleston B, Stevenson DK, Besner GE, Das A, Ohls RK, Truog WE, Nelin LD, Poindexter BB, Pedroza C, Walsh MC, Stoll BJ, Geller R, Kennedy KA, Dimmitt RA, Carlo WA, Cotten CM, Laptook AR, Van Meurs KP, Calkins KL, Sokol GM, Sanchez PJ, Wyckoff MH, Patel RM, Frantz ID 3rd, Shankaran S, D'Angio CT, Yoder BA, Bell EF, Watterberg KL, Martin CA, Harmon CM, Rice H, Kurkchubasche AG, Sylvester K, Dunn JCY, Markel TA, Diesen DL, Bhatia AM, Flake A, Chwals WJ, Brown R, Bass KD, St Peter SD, Shanti CM, Pegoli W Jr, Skarda D, Shilyansky J, Lemon DG, Mosquera RA, Peralta-Carcelen M, Goldstein RF, Vohr BR, Purdy IB, Hines AC, Maitre NL, Heyne RJ, DeMauro SB, McGowan EC, Yolton K, Kilbride HW, Natarajan G, Yost K, Winter S, Colaizy TT, Laughon MM, Lakshminrusimha S, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health, Human Development Neonatal Research Network.Ann Surg. 2021 Oct 1;274(4):e370-e380. doi: 10.1097/SLA.0000000000005099.

Effect of Treating Parents Colonized With Staphylococcus aureus on Transmission to Neonates in the Intensive Care Unit: A Randomized Clinical Trial. Milstone AM, Voskertchian A, Koontz DW, Khamash DF, Ross T, Aucott SW, Gilmore MM, Cosgrove SE, Carroll KC, Colantuoni E.JAMA. 2020 Jan 28;323(4):319-328. doi: 10.1001/jama.2019.20785.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, Cetinkaya M, Kornhauser-Cerar L, Derrick M, Özkan H, Hulzebos CV, Schmölzer GM, Aiyappan A, Lemyre B, Kuo S, Rajadurai VS, O'Shea J, Biniwale M, Ramanathan R, Kushnir A, Bader D, Thomas MR, Chakraborty M, Buksh MJ, Bhatia R, Sullivan CL, Shinwell ES, Dyson A, Barker DP, Kugelman A, Donovan TJ, Tauscher MK, Murthy V, Ali SKM, Yossuck P, Clark HW, Soll RF, Carlin JB, Davis PG; OPTIMIST-A Trial Investigators.JAMA. 2021 Dec 28;326(24):2478-2487. doi: 10.1001/jama.2021.21892.

Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial. Hunt RW, Liley HG, Wagh D, Schembri R, Lee KJ, Shearman AD, Francis-Pester S, deWaal K, Cheong JYL, Olischar M, Badawi N, Wong FY, Osborn DA, Rajadurai VS, Dargaville PA, Headley B, Wright I, Colditz PB; Newborn Electrographic Seizure Trial Investigators.JAMA Netw Open. 2021 Dec 1;4(12):e2139604. doi: 10.1001/jamanetworkopen.2021.39604.

Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants.Kirpalani H, Bell EF, Hintz SR, Tan S, Schmidt B, Chaudhary AS, Johnson KJ, Crawford MM, Newman JE, Vohr BR, Carlo WA, D'Angio CT, Kennedy KA, Ohls RK, Poindexter BB, Schibler K, Whyte RK, Widness JA, Zupancic JAF, Wyckoff MH, Truog WE, Walsh MC, Chock VY, Laptook AR, Sokol GM, Yoder BA, Patel RM, Cotten CM, Carmen MF, Devaskar U, Chawla S, Seabrook R, Higgins RD, Das A; Eunice Kennedy Shriver NICHD Neonatal Research Network.N Engl J Med. 2020 Dec 31;383(27):2639-2651. doi: 10.1056/NEJMoa2020248.

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

Ben 0:54

Welcome Hello, everybody. Welcome back to another episode of the incubator. It is Sunday, we have a very special episode for you guys. Today. Daphna. How are you?

Daphna 1:06

I'm doing well. I have jetlag from a recent travel but I was able to rally because we're so excited to have the EB Neo group on today.

Ben 1:19

I know we're very excited to have with us. Three of the members of the EB Neo team, we have Dr. Rasheeda Vereen Rashida, how's it going?

Speaker 3 1:27

Good, super honored to be here. I'm fanning out right now. Podcast.

Ben 1:33

first time caller longtime listener? Yes. Well, it's great to have you on. We also have Dr. Atul Malhotra a tour. How's it going? I feel like I was saying before, I feel like we know each other. We've been interacting on Twitter for so long. And we finally get to meet in virtually.

Speaker 4 1:50

Anyway, greetings. Thank you so much, Ben, in different great greetings from Melbourne, Australia. And it's really good to be able to connect from so far away. And I'm really privileged, like, like Rashida to be joining you guys.

Ben 2:01

Yeah, same here. And then last but not least, we have Dr. Brian kin director, Brian King. I'm sorry. How's it going? Brian?

Unknown Speaker 2:09

SPIE here as well.

Ben 2:11

Yeah, yeah. So we're very excited to have you guys on and for the people who haven't really followed us on Twitter in the past few weeks. And who aren't. We're just like, you know, how we, we get off Twitter when we're on service and things like that. We are together today to to go through the articles that I've been nominated for the article of the year campaign that EB Neo really runs every year. And we're very excited to partner with you guys. I think, using the podcast and its platform, to go over the articles and go over the bracket that you guys have set up, we'll make it a lot of fun for everybody listening to vote. Because I'm going to be transparent here. There's there are years where you ran the campaign. And there were some articles that had not yet gone through. So I was like, I can't vote because I haven't haven't read this article yet. And so we're hoping that maybe now people will have no excuse. And they will they'll definitely share with us what their thoughts are on these articles, which one has had the most impact in their day to day practice. And so that that promises to be a lot of fun. Now, the way you've organized, this, this voting system is that it's basically March Madness, right? You have you have brackets, you have articles competing, and we get to sort of a final, we have a Final Four, and then we get the semi finals, and then we get the finals. And the voting is split. Starting this week, basically. And, and and every specific days, you're going to be able to vote for a specific matchup. And so we'll go through each one of them. I have my bracket in front of me. And I've reviewed all the articles and we can't wait to get through some of these articles and start chatting about them. So Brian, do you want to do you want to lead the way?

Unknown Speaker 3:57

Yeah, sure. Do you want to start with a you want to start top left then? Oh,

Ben 4:05

yeah, that sounds that sounds great. So on the top left, which is going to be the article by big Blakely and colleagues versus the article by Dargaville and colleagues. So the article by Dargaville and colleagues is the it's the optimist study the effect of minimally invasive surfactin therapy versus sham treatment on death, or BPD. In preterm infants with RDS This was published in JAMA. This is a paper that we did review on the podcast before and the the article by Blakely is another article that we reviewed in the podcast that's published in the Annals of surgery called initial laparotomy versus peritoneal drainage in extremely low birth weight infants with surgical necrotizing enterocolitis or isolated intestinal perforation, a multicenter randomized clinical trial. So I think Brian, you're going to present to us the article about neck versus sip and the excellent versus drainage and and Rashida you're going to you're going to take care of the, the optimist trial. So I'm gonna I'm going to step away and let you guys let you guys present these two articles.

Speaker 5 5:11

Yes, I'll start so the the Dutch Blake these trials are called the nest trial which is a bit confusing because we got to nest trials on the in the brackets here but this nest trial of drainage and laparotomy was an NRN trial published that year. Looking, as you said at infants both with suspected neck or spontaneous intestinal perforation, and whether initial drainage or laparotomy was preferred with a primary outcome of death or neural disability at 18 to 22 months. They ended up getting enrolling three injured 10 infants that were less than one kilo in the first eight weeks of life across the 20 centers in the NRN. And they stratified them via pretreatment risk of neurodevelopmental impairment. And then in addition to looking at overall benefit of initial drainage and poor laparotomy. I think most importantly, they pre specified that they're also going to look at the interaction between that treatment arm and the preoperative diagnosis, whether the patients preoperatively were felt to have neck or sip, which I think is important for them. You know, they found no difference overall in death or neurodevelopmental disability for their primary outcome. So when you took the whole group together, there was no difference. But in that pre specified analysis plan, where they separated out the preoperative diagnosis of neck, or the preoperative diagnosis of sip, they did find that when essentially when the team felt it was neck, initial laparotomy was associated with reduction in death neurodevelopmental impairment, it wasn't significant in a typical frequentist analysis. So the confidence intervals crossed one slightly, but they also pre specified a Bayesian analysis that predicted a lower rate of death or neurodevelopmental impairment with a 97% probability as opposed to s IP, where if you preoperatively diagnosed s IP, there was less clear of a benefit in either arm and the Bayesian probability of a benefit from initial lap was only 20%. So there's certainly more uncertainty in the pre operative diagnosis of sip. There are a couple of big limitations of this trial that were discussed after it was published. They only they only randomized 34% of eligible infants. So there has been a lot of discussion about, you know, the population of patients that weren't chosen to be included in the trial, whether that was from physician discretion or or parental choice. Many of those were enrolled in an observational study alongside the trial. So kind of we'll see that in the future if we don't when that gets published. And then there's, you know, they also looked at correlation between the preoperative diagnosis and intraoperative diagnosis, which wasn't that great. So overall, in the lab group, when they when they did go to surgery, the preoperative diagnosis matched the operative one only 64% of the time. So that also kind of makes it difficult to interpret it, especially with the preoperative diagnosis of SI P, where it was even less of a evenness of an agreement with interruptive diagnosis, but still, you know, really challenging trial to conduct, you know, in surgical patients are rare. It's a rare disease, a rare population, the largest trial in this sort of population that we've that we've seen. So still, you know, with really excellent,

Ben 8:43

with excellent retention retention rate, also at 18 to 20 months, I think, was like 97%. Yeah, yeah, yeah, something like that. Why do you think this article deserves to? If you had to advocate for this article, since you're presenting it, why do you think this article should go through when? Because at the end of the day, it seems that it pushes us towards a question that we don't really have the answer to, which is when a baby has signs of abdominal distension, or whatever. If you can't tell whether it's a SIP or neck, then then this paper is helpful. If you can't tell, then you're sort of back where you started. So Where's where's the so what what would you answer to that question?

Speaker 5 9:24

Yeah, so I think, you know, I've been I've been involved in Eb Neo the past few years. So I've gone through a series of these voting sessions. And to me, when I think of impact it, I very, I really think specifically it how many people is this going to change what they do, right? And that can be in either direction that can be used to do things that you weren't otherwise doing? Or it could be you stopped doing things that you were doing before? All of those things are are impactful. So like negative trials can be impactful too, because it can still change what we do, I think here You hit the nail on the head a bit, it all comes down to what you what you think you know beforehand. And I think particularly with with neck, if you if you think the baby has neck, I do think that this probably closes the book really on future studies comparing, you know, initial lap with with with a drain the Bayesian analysis a 97% probability of a benefit of a benefit, even small. With this size of trial in this population, I think it's just gonna be really hard for us to do another trial with this many babies looking at this question. And so I think it really should, you know, kind of close that book. I think with SI P, it's a bit more complicated because we were, you know, the preoperative diagnosis wasn't correct is often a tool. Yeah,

Ben 10:51

I totally is raising his hand.

Speaker 4 10:53

Thanks, Brian. I think I agree with you. My main question here is how do we differentiate NEC and si p because both NEC and SAP can happen in the early and late period. And one of our very esteemed colleague, Nick Ebel, Embleton, from, you know, the UK talks about this very eloquently in a couple of review articles and studies that it's sometimes very difficult. So as clinicians, Brian, how do I know that this is definitely neck or SAP, especially in the first couple of weeks of life, for example?

Speaker 5 11:24

I mean, I think that's, I think that's true given just then you see can see that in the trial where, you know, in the in the laugh group where they could confirm the diagnosis, right, when they went to surgery 64% were matched up with their preoperative diagnosis, that means that, you know, over a third, they thought it was neck and it wasn't neck or they thought it was sipper. And it wasn't sip. And it was particularly, you know, it was worse with the preoperative diagnosis of sip. So there were more more infants, almost 50%. It was like 55%. In the SIP arm, when they got randomized the lab, it wasn't sip. And so I think that's that's the challenge. Now, I would argue that the basic analysis is using the preoperative diagnosis, not the true diagnosis. So that I still think lends some validity because it is suggesting that even if we're wrong, you know, that's still the association. I think that probably explains why next showed a more clear cut benefit, because we were probably right, more often in the neck arm than we were in the SIP arm.

Ben 12:24

Yeah, I also think that oh, sorry.

Daphna 12:27

No, I was I mean, I think that's what I took away from this is that we have to get better at deciding which it is, because because it might change our management. Right. So, you know, but you know, at some point in time, we said, oh, well, the management's potentially the same. But but it's not potentially so right.

Ben 12:47

And I also think it has to do with your level of certainty. And, and I think there's always going to be where you can tune the presentation either to the extreme. So if you have a very low birth weight infant that has that has free air on day one of life, your level of certainty for the spontaneous perforation may be much higher than it is for NEC. And then if you have a much older baby much further downstream, you can say my certainty is higher for for NEC, but then between there in between, you'll be a bit stuck. But at least for these cases, where your level of certainty is is quite elevated, this this data is very, very helpful. Okay. So anything else before we move on to the top trial? No. All right, Russia, Europe then. Tell us a little bit about?

Speaker 3 13:26

Yes. So I am going to talk a little bit about the Optimus trial. And the whole title for this trial is effective minimally invasive surfactant therapy versus sham treatment on death, or bronchopulmonary, dysplasia and preterm infants with respiratory distress syndrome. And this was published in JAMA in December of 2021. And the goal of this trial was to examine a minimally invasive way to deliver surfactant versus no surfactant at all, which I think is kind of interesting. And they randomized infants between 25 and 28 weeks gestational age, so not our younger babies below 25 weeks. So I think that's important to note for this trial, and eligibility. So between 25 and 28 weeks gestational age, and then all babies were actually on CPAP. So had never been intubated were eligible for randomization. This was this study was completed in 33, NICUs, actually, across the world, which I think is pretty amazing. So countries including Australia, Canada, Israel, New Zealand, Qatar, the list goes on. And I believe this trial, their goal was to originally enroll 600 infants, but I think it was stopped early because of the pandemic. That's, um, so their results. Yeah, so their results ended up including 485 infants, so about 240 in each group, but I still think the results are really interesting. So you have about 240 in each group, and they're out there. Emory outcome was looking at a composite outcome of death and BPD at 36 weeks. So in the midst group, you had 43.6% with the composite outcome versus in the control group of 49.6%. So lower composite outcome of death or BPD. In the Miss group, when you look at death by itself, you actually see slightly higher percentage in the Miss group versus control. So 10% versus 7.8%. But then when you separate out BPD, at 36 weeks, you see a lot lower amount of BPD in the mesh group. So, 37.3% versus 45.3%. So, when you take that all together, the conclusions for the authors were when you're looking at infants that are on CPAP. And you are looking at myths by itself versus nothing, there is not really a significant reduction in the composite outcome of death or BPD, even though they do note trending reduction of BPD by itself, but particularly, they really didn't see a difference in death. I think the important thing to note in this trial is because the comparison was no treatment at all is looking at how many infants were actually intubated, within the 72 hours, whether they received missed or no missed, and it's kind of interesting. So the babies that got the minimally invasive surfactant delivery 36% ended up intubated later, versus 76%. And some of those babies ended up getting surfactant. It's kind of interesting that you do have a lot higher percentage of babies that were intubated, obviously, in the control group. But the differences and BPD aren't much different death aren't much different. But you are starting to see trends. So one of the things that the authors note is, of course, because we're starting to see trends, if they would have made the goal number of of enrollment, they might have started to see a little bit more significance. But I think regardless of this was a beautifully done trial, and gives us a lot of information about ways to deliver surfactant and kind of how important surfactant is in terms of making a difference in our premies.

Ben 17:20

Yeah, I thought this was a phenomenal trial, I think their list of secondary outcomes was was staggering. I mean, all the different outcomes that they've looked at, and the effect of missed compared to controls. And even in the subgroup and exploratory analysis, I think everything was very insightful, especially when they're looking at death. And and how basically, for missed sort of loses out on the control when you're getting to lower gestational ages, which sort of correlates with a lot of things that have been published on non invasive or less invasive surfactant administration. So yeah, this was a phenomenal article. Yeah, Brian, go ahead.

Speaker 5 17:56

Yeah, one of the things I was gonna say is, what in favor of the article as well, I think this is a topic where if you would have asked many people, they would have said, it was gonna be not masked, not blinded, because you couldn't do it. Right? You'd be like, it's an intervention, like, you can't, this isn't a trial that you can blind, it's not feasible. And so I do think that just from the trial standpoint, even like outside of Lisa, just a, I think it's a huge success. And and I think potentially impactful, because it may look at how have future design of trials, maybe people will question like, Okay, well, maybe we can actually blind some of these interventions that would maybe seem to, to not be possible. So that on its own, I think is a huge success. Yeah, to

Speaker 4 18:38

and just adding to that, Brian, we were one of the centers. And what are the fantastic thing about this trial was that that Sham, that sham procedure, you know, when the baby was going to have the mist or optimist protocol being applied, there was a curtain or a screen applied to that, and you didn't know, the person who was doing it, what they were doing. So it was just amazing. I think it's a really well designed trial, and the team had no idea what we got. So it's, I think it's like you said, for future trials of these kinds of therapies. It's really, really important.

Ben 19:11

I think the other and I think I think it also impacts practice right away. No, I mean, I think this is data that that can be taken to the bedside pretty rapidly and change a little bit, or significantly, how we how we treat these babies, how early we administer surfactant and so on. I'm sorry, you were gonna say something. Right.

Speaker 5 19:28

Yeah. So I was just gonna add, I think, to that point is I think the second thing that this trial adds to the lease or missed literature specifically, is, is really comparing it to notes or facts. And I think a lot of the trials before all set the same threshold, but I think one of the potential benefits of Lisa should be it, you know, being able to administer surfactant comfortably earlier. Right, so maybe you're gonna give surfactant at 40% If you need to intubate the kid, but if you only have to do Lisa, if you don't have to do something less invasive, you're going to make To justify giving it sooner, and I think this is kind of what they were testing here. Whereas a lot of prior trials, were asking, you know, if you pick the same threshold is Lisa better than intubation. And so that I think also gives, you know, added added a lot to the topic of Lisa.

Ben 20:16

And personally, to me the consequence of articles that came out recently about the effects of attempts on intubation in those smaller babies and mortality. And like when you put all these things together, it really makes a case for if you can do this non invasively, and have these kinds of outcomes, maybe maybe it should be the way to go in that specific age range. So because we have more to go through this, the voting for this for this, for this matchup is on November 22. I'm going to I'm going with the missed the missed trial, the Dargaville. I'm putting this one down, what are you guys, what's your what's your pick?

Speaker 3 20:54

I agree with you, then I feel like this is something I can take immediately to the bedside. And unfortunately, or fortunately, I think I'm dealing with surfactant a little bit more in terms of my practice on a daily basis. So this is something that, you know, when I picked up this paper made a difference in terms of looking at some of the thresholds, delivery devices for surfactin. And even for trainees How am I training people in terms of what are the different ways of delivering surfactin? I think that that's really important as we're, you know, training the next generation.

Ben 21:27

Definitely which one you're picking? Yeah,

Daphna 21:29

I think I agree with you, if we're talking about impact in you know, getting getting, you know, into it at the bedside, I think this paper also, you know, this has been around, right? It's not new, but it really got people it really got the buzz going right and getting people excited about doing the procedure learning and if they hadn't yet. So I thought that was really neat.

Ben 21:52

All right at all.

Speaker 4 21:54

I'm going to go on a different limb. So we weren't part of the trial. But also we started implementing missed much before the trial finished. So for me, one of the things which I struggle with is the small baby, who has the SIP, why do we need to open them up, if we can get away with drainage, you know, so I think I'm going to go with the Blakely trial, just to kind of encourage more studies on it. And like Daphna said, sometimes a procedure comes and people are adopted immediately. I don't want that to happen, necessarily. But I want this trial to impact more thought on it. It's a very difficult trial to do. It's really, really hard to coordinate. So I'm gonna go for the blink literal. Right.

Speaker 5 22:34

Yeah. So before I vote, I'll say, very quickly that this is a friendly, competent competition, you know, in terms of I think all eight articles are very impactful, like to get to this point, right. So we're splitting hairs here. And I think I'm glad I went after tool, because I think maybe this reflects a bit of our differences in regional practice, because I'm going to go back to mist. Because while I think it has definitely taken over, you know, the service has taken over a lot and other places in the US, there's still a lot of work to go. There's a lot of places that haven't introduced it yet. So I think there's still a lot of growth. And I think it really adds to that growth. Versus I think it's interesting, you were talking about sip and the management approach. Because I would almost say, at least in centers that I've worked, we were kind of already taking the approach that the next trial did we were kind of already saying, Well, do you think it's neck? Okay, then we should do a lap? Or do you think it's just set? Okay, let's do a drain. I think that was kind of already happening during the trial. And so in my practice, I feel like it hasn't changed that that much versus versus

Speaker 4 23:34

I had a question if again, when do you think that was because many of these centers were part of the Blakely trial, or you think it was happening even before?

Ben 23:46

Well, I think I think it was, here's the thing, I think it's it's been happening before I agree with you that people I mean, we've been we've been doing Lisa and and and less invasive subtracting for some time, but I think providing the data to support and the indications where this might be very effective is really where we were missing information. Was it is Lisa better for older babies at what gestational ages? Do we see benefits? I think it was it's these kinds of trials that are gonna say, Well, I'm going to do research for this one and not that one. And, and, and that is why I think I think to me, that's why I'm picking this one,

Speaker 5 24:21

too. If you're talking about the net, the next trial, I at least in my personal experience, the centers that I'm talking about weren't in the trial. And then that was already our approach. Now, I think people talk, you know, people were talking and I think a lot of people knew that the trial was going on, and maybe that influenced people's practices. But definitely, you know, I think even before it was published if if you felt it was safe, the kid was getting a dream. And I'm talking I'm thinking of three senators I've worked at in the last five years.

Ben 24:52

Okay, so then let's go to the other matchup in this in this side of the bracket in the Eastern Conference of the bracket So the other two papers that are competing in this bracket are a paper by hunt and colleagues. And that's a paper that is published in JAMA, JAMA Network open. And it's called effective treatment of clinical seizures versus electrographic seizures in full term and near term neonates, a randomized clinical trial. And then we have another paper by Kier Palani, and colleagues in the New England Journal of Medicine that really made the rounds called higher or lower hemoglobin transfusion threshold for preterm infants. So, Brian, you you volunteer to present this, this JAMA paper about seizures. Tell us a little bit more about what this study you tried to do. And what did they find?

Speaker 5 25:44

Yeah, I think this is a really cool study. So they were they were looking at, you know, whether treatment of seizures in term or near term infants of greater than 35 weeks, whether treating seizures until the cessation of clinical seizures, or the cessation of electrographic seizures, was beneficial. So specifically asking the hypothesis, is it better to treat seizures until all electrographic seizures resolve? Or can you just stop at the resolution of clinical seizures, their primary outcome was death or disability at two years, which they found no difference in, though there was some in a secondary, sort of as US secondary analysis or a subgroup of disability, they found potentially better cognitive outcomes for the clinical seizure group. So treating just clinical seizures. This was a cross it was multicenter study across 13 sites in three countries. They enrolled a diverse population, which I think is is important for this. So a HIV was obviously a big, big sub component. But there were other causes, as well, and really is the largest study. Yeah, go ahead.

Ben 27:00

As I think 70 to 75% of the cohort ended up being paid babies with HIV.

Speaker 5 27:06

But it was the largest study, you know, specifically looking at this question of the approach to seizure management, they randomized two into 12 infants. Now, this is another trial that aims to enroll more and was stopped early. So their power analysis, they had aim to enroll 300 in each arm, and they stopped at the 212. They said that this was due to a loss of equipoise. So there was a separate study, a smaller study, but a separate study that had been published that while they were enrolling that suggested benefit from treating electrographic seizures, and that led to senators feeling like they, you know, they, they didn't feel as comfortable with randomization. So they ended up stopping early. I think the other the other potential small limitation is that that not all the infants actually even had electric traffic seizures. So even of that to 12, only 84% had electrographic seizures, which also, you know, kind of maybe minimizes the power that the study has. So even though they found a difference, you know, maybe that is because of a lack of power. Though the outcomes, interestingly, seem to trend towards at least for cognitive outcomes, some better outcomes for the clinical group.

Ben 28:24

Yeah, that was, that was really the interesting part. I thought the methodology was actually also interesting that they had one group where they have the they were using the one of the big things about the study also was that it was integrated integrated EEG that was used, and not and not continuous video EEG. But I think I think this is perfectly fine. I think they've, they're acknowledging that in their in their discussion, and it may be the more prevalent way that most units are monitoring procedures. But I thought it was cool that like, in one group, the Ag was covered, but it did have an artificial intelligence algorithm that would that would sort of let the conditions the investigators know whether what was happening exactly and alarm them. And, and it was interesting to see that that they did find lower cognitive scores, I think it was in in the, in the electrographic. Group. So did it change your your approach to management? How did that impact your your practice?

Speaker 5 29:22

It mostly impacted my practice in how I talked to neurology? I brought this up a lot on rounds for patients. I would say it hasn't actually really shifted our focus. So some, most of the time we ended up, we still seem to favor treatment of electric graphic seizures. But it certainly makes me think and I think and I think on the on the extreme end, I've brought it up mostly in situations where, you know, Despite attempts to treat electrographic seizures, you continue to have them and you're escalating multiple medications. And I think it is valid to bring up this question of look, even the medications that we're using aren't necessarily benign? And is is there a point at which you're not going to get added benefit? For what for what you're doing? is kind of how I've used it. Now, I don't always win that argument. But that's how I brought this paper up. I talk about it a lot.

Speaker 3 30:16

Now, Brian, yeah, I think you bring up a good point, because this paper really echoes some questions that many of us have had about the impact of anti epileptic medications. And there is obviously, the harm of seizures. But you know, the medications that we use are not benign. So I think this paper adds to that question of what is the balance? You know, maybe certain seizures are okay, if, depending on what anti epileptics you're using, or how many are on. So I think that this paper kind of adds to those kinds of questions.

Ben 30:54

This episode is proudly sponsored by Wreckit. Me Johnson recognized 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 meet johnson.com. Okay, Rashida. So you're next. Tell us about the yes, yeah, go ahead.

Speaker 3 31:19

Yeah, so I'm going to talk about the top trial. This was published in the New England Journal of Medicine, like the day before, it was 2021. So it came in this year, this year's impact Article of the year. But the top trial, the full title is higher or lower hemoglobin transfusion thresholds for preterm infants. And I think this study is super important, because it adds to the many number of studies that we're looking at when we're looking at transfusion thresholds. This primarily obviously focused on red blood cells. But there's been many recent studies to looking at platelets and things like that. But this study particularly looked at infants less than 28 weeks, so all the way up to 22 weeks and zero days, and less than 1000 grams. And the the primary outcome was to look at neuro impairment at 22 to 26 months as well as death. This included 41 NICUs. And the total number of babies they end up having was 1824. So a very large study, and what they found, and so, before I say what they found it, I think, if you haven't read this study, this is a really great study to pick up. Because in the supplementary supplementary materials actually has, what the transfusion thresholds are. And they're different based on your gestational, your postnatal age and your weight. And I think sometimes, many of us use transfusion three thresholds based on what we're familiar with based on our training, but not necessarily based on evidence. And I think that this paper really stuck to some strict transfusion thresholds based on evidence that was already published. So I would encourage people to really look at this trial even just for the supplementary materials, but what they found was so in the higher threshold group 50.1%, so the composite income outcome of 50.1% died or survived versus in the lower threshold group would 49.8%. So not much difference. And then when they looked at the two years in terms of the higher lower threshold, similar incidents, they also have similar incidences of death. So 16.2% versus 15%, and then neurodevelopment, in the higher threshold group, 39.6% versus 40.3%. So you can kind of hear that those percentages are very, very similar, so no differences in death and or neurodevelopmental outcomes. So the conclusion was, a higher hemoglobin threshold didn't improve survival, and or neuro developmental outcome, which I think goes back to the argument that lower transfusion thresholds could be safer, which is what I think many other randomized control trials are looking at that specific question. So I think it ties into those questions that we've been asking about. Hemoglobin threshold is higher, or is a lower unsafe, and this adds to the literature that says it may not be unsafe, we're not seeing higher incidences of death, we're not seeing higher incidences of neuro developmental impairment. And even in the secondary outcomes, when you start to look through those a little bit. They did talk about NEC and some other things and they're not seeing some major differences there either. So I think that again, this article adds to that body of literature about transfusion threshold. moulds for red cells.

Ben 35:02

Yeah, this is obviously a paper that that generated a lot of discussion, and it reinforced it a bit, some of the, of the evidence that was already published by other similar trials. But Brian, you wanted to say something.

Speaker 5 35:14

First of all, I just wanted to commend the authors and the and the trial for successfully achieving a difference in the groups because I think that's a huge challenge. In a trial like this, when you set thresholds, they kind of have, you know, essentially like Kaplan Meier curves almost of, of the hemoglobin levels in the two arms. And you can see there's a clear difference. I think that's the first big roadblock in a trial like this, if you set two thresholds, are you actually going to end up getting patients that are different enough to really test and I think they did well with that. And then for context, I think the other thing that's important for top is to look back and, and remember that the pike trial, which was published about maybe what like 10 years ago or so, which was a smaller transfusion threshold, a smaller trial of hemoglobin transfusion thresholds. While it also showed no difference, it had a post hoc analysis that suggested that there may have been a benefit in the higher threshold group. And that I think, was part of the justification of top was, you know, you had a 400 500 patient trial, which even even that by you know, neonatal trial standards is pretty decent sized, suggesting potential benefit of an arm. And so then they said, well, let's, let's make a trial three times bigger. And, and indeed, showing that, you know, by increasing your power, sometimes it does change your results. And they don't seem to find that same association with potential neurodevelopmental impairment, which kind of also is important to recognize how you know, the size and the power of a trial and secondary outcomes can change, you know, as you do more study, until

Speaker 4 36:52

in the last year of our impact of the year campaign, Brian, you might remember we had the Ethno trial from the European group, which is also similar. And I just wanted to bring up again, the geographical or Continental Divide, which we have, so that trial used hematocrit. Well, this one used hemoglobin. Do you guys have any thoughts on that? Because it's one of those confusing bits, especially for juniors when they start and in your ology, and they say, Why do you guys use different kind of terminologies and ways to look at the same thing?

Ben 37:21

I mean, I had, I had attendings who used to tell me that we use him adequate so that we could we could have a wider range to play with. Because, yeah, but I am going to reference this article again by Keith Barrington, in his blog, where, basically, I don't know if you guys have have seen this, I'm going to try to I'm going to try to share my window here. But he basically compiled Can you see this? So hold on. Yeah. So he basically compiled all the different the top, the Ethno, and the pine trial. And he had all the different thresholds for transfusion either with hemoglobin. And he also, I guess, was aware of what you were mentioning it also, he also did it for him adequate. And I think this table is super useful, I haven't saved on my phone. And

Speaker 4 38:06

and that's the other thing that we need to remind all our colleagues, and especially juniors, that the top trial, like Rashida said, was showing that there is no difference in the outcomes. But if you stick to the thresholds, it doesn't mean that you can go lower than these thresholds, because that's not been studied. So you run the risk of putting babies at harm, if you go beyond the top trial thresholds, so I think that's really important, because otherwise sometimes the message that lower hemoglobin is fine, can be really dangerous, you know, especially in that very controversial space of NEC associated with transfusion.

Ben 38:43

Agreed. And yeah, and we spoke to one of your colleagues, right, and our friend Ravi Patel about this subject and that's obviously something that needs to be considered. So alright, let's go around the room Daphna. Which Which one's your pick?

Daphna 38:58

Yeah, for me in terms of my practice, I really needed to see some more of the blood the you know, hemoglobin threshold papers because as a general pediatrician, where we all start out I still have this dogma about prolonged anemia and poor neurodevelopmental outcomes so this is you know, this goes against that so I really just needed to see more of these things it certainly did is changing my practice it's making our protocol much more confusing in our unit but

Ben 39:35

protocol God. Rashida, what what's your pick?

Speaker 3 39:42

Oh, man, this one's really hard for me because I both of these studies, I in fellowship, I think presented for journal clubs. So I both have such passion for both of these articles. Mmm hmm. I think I my answer, I think is similar to deafness though, because I think we're starting to see the, I think global kind of change in practice and the impact of transfusions and us really being methodical about us ordering them. So I think I would go with corporate money as well at all.

Speaker 4 40:24

I think I'm going to be a lone wolf in all these voting, because I'm going to go with my colleague, my boss, and very good friend, Rod Hunt, who had the courage to do this really, really hard trial against a lot of the world. So it was really hard for him and he he copped a lot of flack after the trial was published, as well. So So I just want to say that this is a really hard trial to do covering, you know, electrical seizures in babies. And when the world was starting to say, No, we need to really look at them. I think it's sometimes you need a lot of courage to do these studies. And I would vote for Rod, but I think I know who's going to be the winner already. Brian,

Speaker 5 41:03

I'm not sure I, you know, I I completely see where you're coming from. And honestly, from from just like the, as you said, the courage do the trial standpoint, I think, I think that it, it is it was a great trial. And I honestly probably talk about it more on rounds. But as I said, and the

Ben 41:22

front end is not good for you at all.

Speaker 5 41:25

You know, if I if I really think about if I really think about impact, while I talk about it a lot on rounds. The problem is, is I don't actually see it changing what we do yet, because it was underpowered. And because there's still questions about it. And so it gets brought up, but it's really interesting. But then we're like, okay, yeah, but still increase the verse that drip, you know, because they're still having seizures. So, I think in that sense, I'm gonna have to go with with top because I do think yeah, we're updating hemoglobin transfusion threshold as a result of that. And etc, no, as you said, came coming out, like, you know, six months earlier, but top is a big part of it huge trial to in neonatology, you know, just to get that many babies. So, still top,

Speaker 3 42:07

maybe to a tools point, as well, with the hunt trial, when we're thinking of seizures, we're also thinking of collaborating with our neurologist. And I think when we're thinking of our own impact, us being able to move change in practice, when we're treating seizures would have to involve our neurology colleagues. So maybe that is also a part of the process for this trial being so impactful, it would be great to get some collaboration from neurologists and their comments on it and say, What do you think about this, and that I think, would make the article even more impactful,

Ben 42:41

I mean, I'm gonna be with a two on this one, even though I appreciate the magnitude of the of the top trial, this paper, by hunting colleague really has has has been, in the past year, the approach to seizure has been flipped on its head. I remember as a fellow right, where you're being taught that like, a clinical seizure is not a seizure until you can prove it on EEG and like your your ability to clinically diagnose seizure is very low, and so on and so forth, that this paper comes out and then we have more recommendations coming out about the fact that we need to get EEG is on every single patient. So I It has given me more food for thought recently than then other papers. And so I think this one is the one I'm going with. So

Daphna 43:27

I think I love to this paper, he couldn't stop talking about it.

Speaker 4 43:31

I think there is a it brings up one interesting thing when when we talk about impact of articles and trials. And like Brian said, the top trial will definitely impact practice immediately. But there are sometimes articles which impact your thought process, your questioning dogma, your questioning, what am I doing? So you know, so I think the the enemy trials, we knew it was coming, we just wanted to show that it's definitely true. It happens in Europe, it happens in America, it happens everywhere, you know, but these kinds of trials by hunt, what they do is they make you think should I treat all these fits? Is it really good. And the problem with our season management in units is we don't have actually have a very good drug to treat them with. So, so we're not not doing any harm, but eating them. So I think yeah, I agree with you impact is a very difficult thing to sometimes discern.

Daphna 44:20

In order to I feel like a lot of the papers that we're discussing today have that impact, so to speak, is it we learned a lot, just from some of the other details that the study wasn't even trying to prove, right. So some of the observational things have I think been really useful.

Ben 44:42

Okay, so we're running short on time, so we have to move on to work so we have our I guess we have our to two papers for this final four. We have the Dargaville paper that our our consensus here has been voted to the next round and then we have the Care Planning paper about transfusion. Unfortunately, you and I were in the minority. Let's go on to the other side of the bracket. And we have two papers that we're going to talk about. The first one is by beard Saul and colleagues. And that's a paper that was published in The Lancet. And it's called Real Time continuous glucose monitoring in preterm infant, it's the React trial, an international open label randomized control trial. And Rashida is going to be presenting us this paper. And the other one is the paper that was also published in The Lancet. No, actually, no, it was not published in Lancet. I'm sorry, it was published in the New England, I apologize. And it's called immediate kangaroo mother care and survival of infants with low birth weight. And that was from the WH o immediate KMC study. And that will be presented to us vital. So at all we haven't heard from you want to start maybe and present to us the kangaroo mother care paper.

Speaker 4 45:52

Yeah, no, thank you so much. I think it's a fantastic paper, and I'm going to save time and vote for it already. I think this paper is going to win this round, so that we don't spend time on that later. So. So it's, it's an amazing paper, I think it's a strong candidate for Article of the year overall. And the reason for that is the impact it just got across the world is just mind blowing. So you know, kangaroo care, I wish the authors that call it kangaroo care into kangaroo mother care, because kangaroo care can be done by mothers or fathers, that's fine. But because they use mothers because it was culturally more acceptable. So the idea is, we know that kangaroo care is very helpful skin to skin contact is very helpful. It's very beneficial for a variety of reasons. We know that kangaroo care saves lives, we know that already. But what they did in this paradigm shifting trial was that they not only instituted kangaroo care, but they installed it early. So they instituted it soon after birth to such an extent that the mother was looked after in the maternal neonatal ICU set up so basically, he was not looked after in delivery switch, it wasn't looked after in recovery, he was moving with the baby to the nursery, it's just mind blowing. Now, it's not the the concept is not absolutely new, because the Swedish centers. And so

Ben 47:07

I was gonna say and it's important to know that these babies were very small, right? These were not like Altarum, right? These were like 1500 grams baby. So these are these are things that these are babies that I think in our in our units, we would we would automatically take to the NICU. And

Speaker 4 47:21

so I think you're absolutely right when that you know with with technology available and all those you know gadgets we have, we think oh, we I've got the best transport incubator, I've got the best incubator to put these babies in the best transport incubator is the mother or the father, I would say, but you know, it, this trial coming to the, you know, nuts and bolts of it, they looked at Babies between one and 1.8 kilos, because many of these countries, unfortunately do not have the resources to look after the baby smaller than them. But they also were worried that the less than one kilo baby might need a lot of interventions for them, which will mean that kangaroo care might not be feasible immediately after, but they may, they may stretch the boundary and go even lower. But five countries across Africa and India, one of the centers where I actually started my neural training, so I'm quite close to my heart. And what they did was basically, in the intervention arm kangaroo care was initiated for the baby soon after birth, while in the other arm only after stabilization. So that meant that in the intervention arm, the mother, the baby's got kangaroo care for much, much longer. So if you look at the median duration, around 17 hours with interquartile range of 13 to 20. While in the in the control group, it was 1.5 or so huge difference 10 times more kangaroo care in the intervention arm as compared to the control arm, they had planned to enroll 4200 babies to this trial for a 20% difference in mortality at 28 days, or in the first 28 days. But after 303,200 infants, they actually stopped the trial because they showed a clear benefit. So neonatal deaths occurred in the intervention in 12%, while in the control arm and 15.7% in the first 28 days. So that's a huge 25% reduction of death. You know, you can just multiply that by the number of babies who die in these kinds of setups. It's just amazing. Interestingly, the neonatal death in the first 72 hours of life wasn't statistically significant. But I think, obviously, they were not prepared for that. But if you look at it, it's 4.6 versus 5.8. So like this trial, Ben and Daphna I think there is no actually, you know, problems with it at all. It basically shows a simple natural intervention, almost like breast milk is the most important intervention for units providing kangaroo care for these babies. If you have the setup, nothing beats it. I think the challenge for this is how we implement it. And I know that Professor Jelani and colleagues and who group have been trying to implement the findings of this trial in the low and middle income setups. But I challenged my colleagues, you know, in America, in Australia, everywhere in the world to be able to implement it in the high income setting as well, because I think we could save not just lives, but actually improve the, you know, I guess, experience of these families and, you know, maybe so Yeah, amazing trial, I can keep speaking about it all day. But I think in the interest of time, I'm just going to stop there, because I think it's just a very, very paradigm shifting trial.

Ben 50:34

All right, where she that was made it very compelling. So

Speaker 3 50:38

yeah, I cannot follow that well, but I will attempt to talk about the React trial. So this was a trial that looked at the safety of continuous glucose monitoring and infants born less than 34 weeks, in comparison to kind of standard care. And they wanted to look at the proportion of time that was spent in 2.6 to 10 millimoles per liter, which, for a lot of us in the US, we're using milligrams per deciliter. That roughly translates to 45 to 180, in the first week of life, so randomized to 180 babies, so 85, and the continuous glucose monitoring group 95, and the standard group, and what they found that in the continuous glucose monitoring group 94% spent time in the goal range of versus 84%. In the standard group, when you look at interventions for those that were hypo or hyperglycaemic, you saw that the continuous glucose monitoring group received more insulin overall. So 61% versus 37%, in the standard group, and when you look at hypoglycemia, which was kind of interesting, so more, more time, for the continuous glucose monitoring group, were hypoglycemic, but less of it was severe hypoglycemic. So even though there was more times that they were hypoglycemic, you actually saw more severe hyperglycemia in the standard group. And when you're looking at kind of workload and things like that, which I was very curious about, they did see the ancillary staff in terms of recording and making sure that the device was in place. They did say that there was increased workload with the device, but there were no reported adverse effects. So the conclusion was that continuous glucose monitoring is safe, and it reduced the overall exposure to severe hypoglycemia or incidences of hyper glycaemia. In this trial was completed in the UK, Spain, another lens across 13 NICUs. I think. So definitely, I think when we're thinking about technology in the NICU, and looking more about how we can control certain parameters in our patients, this study, I think pushes us forward a little bit. Hypoglycemia, hyperglycemia are very common in all gestational ages in the NICU. So I think it gives us another tool in terms of monitoring very closely and making sure that we're staying on top of the hypo or hyperglycemia. The the authors do note that I know many of us don't like to use insulin and they do note that use the amount of insulin that was used in this study is not necessarily what many people do, and the safety profile around insulin is something to be note noted of the note that in that discussion, so I really

Ben 53:37

liked this paper, because we've had on the podcast some of the of the way, the series that we call the giants of neonatology, they tell you about these these times in neonatology where they didn't have pulse ox, and they're like, hey, we'll just we'll just like eyeball the saturation. And then suddenly, we were able to get the saturation in real time. And it was like, Ooh, is this like the equivalent of, of this evolution in our times, I was shocked to see that there was no adverse event that like this, because the the, the device is subcutaneous. So it's not like it's not a sticker, like a Pawsox that you put on. So that's something that initially put me off a little bit. But, but I mean, this, these, these findings were quite incredible. And I don't know if you if you mentioned this, but in the secondary outcomes, like the mention of the necrotizing enterocolitis rates, which were lower in the continuous glucose monitoring group by like, I think 13 versus like, 20% I wrote, so that I mean, that makes you wonder, like, what is the potential? But yeah, this was this was a nominal trial. So Brian, go ahead.

Speaker 5 54:39

Yeah, you know, I think people who know me well and talk to me know that I'm a bit of a what I consider a conservative in the ontology in terms of like, you know, new new interventions, new devices, new technology. So it first of all, yeah, I mean, I'll come in that we're looking at this as opposed to just, you know, places say, hey, it's new tech. Let's start using it without really knowing the implications, it always worries me when we start talking about things like increased workload, because I do think these things can add up. And if we don't show that there's a clear benefit to some of these things that we're adding into, you know, routine care, you know, more isn't always better. And, and so I'm always cautious about that. I think the other thing about this trial, and I was trying to look and maybe Rashida if anyone else, you know, kind of dug through the paper a bit more detail. You know, I immediately thought it was actually our Article of the Year winner from the year prior, which was the lower versus traditional glucose threshold trial. That was published in the New England Journal in 2020. That actually showed that there's potentially safety in going down to two millimoles per per liter, or 36 milligrams per deciliter. So, which, which obviously is lower than the threshold that this study used, probably there was, you know, they're probably running contemporaneously in some ways. But that also just makes me think, again, though, that like, you can set goals without actually knowing is that even the right goal that you you need to set? So if that's not a part that makes me think.

Ben 56:18

Okay, yeah, definitely. Yeah. So

Daphna 56:20

I think, definitely, we will end up with continuous glucose monitoring in the NICU, I have no doubt that that's the future of neonatology, especially when you think about when we talk about workload, really, and the trauma of repeated glucose measurements, like around the clock for some of these babies or accessing align around the clock, I think there are some risks that have not been accounted for in the way we routinely monitor glucose. But my vote is for the kangaroo care paper. I'm sure nobody's surprised by that.

Ben 56:53

I thought you might like the glucose paper, because I have to tell the audience, Daphna is the one who will make sure that these q3 orders are gone when

Daphna 57:01

next next No, q3, no way. The bad for babies are bad for parents anyways. But the kangaroo care, I think when we talk about we get so focused on our high intensity interventions in the NICU, especially here in the States. But when we talk about a global impact, and this is a this is a slam dunk. But I think a tool, you hit the nail on the head that kangaroo care is not like a nice thing to do, which is how it's sometimes described in the in the States. This is a, this is a medical intervention that changes outcomes. And I, in my experience, as someone who is obsessed with kangaroo care, in some of my previous academic centers, it's still not seen as as a rigorous intervention. And I think that's a mistake. And I hope it is the pendulum swing towards more couplet care. Coming back, if

Ben 57:59

I were basic, I'm gonna I'm gonna piggyback on your comments. And I'm going to I think this the impact of this paper on kangaroo, Medicare is significant. So that's, that's my voice as well.

Speaker 3 58:10

I agree, we don't do it enough. We don't do it enough. We don't do it enough, and that we shouldn't be doing it.

Unknown Speaker 58:18

Okay, Brian? Yeah,

Speaker 5 58:20

I mean, I'll say the same thing. I completely agree. You know, I think, I think a tool, you said it best when you're talking about the best form of transport is the mom or the dad. But I would even go a step further. And potentially, like, where I could see this trial going in the higher income countries, is saying maybe the best form of transport is no transplant at all. And whether these, you know, these babies should just be delivered, where they're cared for with the mom, they never leave. The care happens. They're on mom. And I know there are some new NICUs that have been built from the ground up to have that component. Which I think would be like the next step in this sort of care.

Ben 59:03

Yeah, and for I know, we didn't mention it, but obviously the the investigators were very, very careful. And they have these exclusion criterias for babies who had issues with breathing and stuff. So we're talking about TVs that are stable, obviously, there's no recklessness there. So I just wanted to mention that. Okay, so it looks like we have a clear winner for this one. The voting for this little matchup will be on November 18. So make sure you look out for that. And then we have our last matchup for today. And we have two articles. I'm sorry, I'm lagging behind now. But the first one is by title and colleagues. It's a paper that was published in Lancet. It's the helix trial, which many people talked about the hypothermia for moderate or severe neonatal encephalopathy in low and middle middle income countries. And then we have against this one the article by depressed and colleagues published in the New England Journal of Medicine called randomized trial of fetal surgery for fetal I'm sorry randomised trial of fetal surgery 14. Your left diaphragmatic hernia. So these are the two articles, a tool I think you have the paper by to on the helix trial and Rashida you have the depressed trial. So at all go ahead, tell us a little bit about the helix trial

Speaker 4 1:00:16

and other people by one of my very good friends so the entire and another paper where courage is required. One of the most polarizing papers, very, very controversial paper wanted published. So the NASA superstar he's taken all that flack very well. And I think one of the reasons was I'm going to start off by the conclusions of this trial, Ben, was that he said in the conclusion of the study that

Ben 1:00:39

I can have, yeah, we have the therapeutic hypothermia

Speaker 4 1:00:42

should not be offered as treatment for near Clinica floppity. In low income and middle income countries, even when tertiary Neonatal Intensive Care is a facility. I think that's what polarized the world. So we can keep talking about the controversy around this trial. But I think I want to talk about the positives, it is the largest therapeutic hypothermia trial conducted to date, the you know, the NI CHD trials, the Toby trials and the all the trials, the ice trial from Australia, all the trials, which were done in the early 2000s, were of smaller magnitude. So they basically enrolled 404 108 eligible infants 202, to the hypothermia group, and 206 to the control group. And primary data was available for 97% of them. So that is amazing out, you know, kind of follow up at 18 to 12. Very two months. And obviously, the primary outcome was the combined outcome of death, or moderate and severe disability like similar to the other previous hypothermia trials. Now, hypothermia is the standard of care in the high income settings, but they had equipoise in the low income or middle income settings, because of that reason.

Unknown Speaker 1:01:52

What they found was staggering. What they found was that in the hypothermia group, they had 50% infants who died or had moderate severe disability and in the control group 47%.

Speaker 4 1:02:14

Have a miss something. No, yeah, 50% in the hypothermia group and 47%, in infant in the control group died or had a moderate severe disability. So the overall outcome wasn't different. But when it when you look at the only the death outcome 42% in the hyperthermia group and 31% in the control group, so that was a difference of 42 versus 31%. died. And you know, if you look at the in the deaths in the hospitalization period, it was 36 versus 24%. So I hope the audience is able to understand that what they were showing was the hypothermia was leading to more death in the early neonatal period. By the time we looked at death, or moderate severe disability at 18 to 22 months, there was no difference. But this was in contrast to what we know of hypothermia in you know, HIV, or moderate to severe HIV from the high income trials. So very interesting outcomes. The reason they feel is that many of these women, or you know, babies, when they were cooled, were probably already in a later stage of their enca floppity as compared to the high income trials. So the subset, or you can say the characteristics of these babies was different. Interestingly, it is still a pragmatic trial, because end of the day, that's when you kill the babies whenever you see them. But like I said, previously, this instigated a lot of commentary. There's a lot of comments on it, there are last I counted, there were at least 10 Comment pieces, not just in the Lancet itself, the editorial which went with it, but in a lot of other journals, especially in the subcontinent, and so on. Because people feel who have good resource setups in those areas, they feel that they should be fine to continue cooling. I think a lot will need to come about this in the future. Now, whether this can be replicated, I'm not sure because it's a big trial, replicating such trials is very hard. And personally, I've lost equipoise I think hypothermia so far, or today, it is the only kind of intervention we have for these babies. So to not instigate it is really hard. So it was a very difficult, you know, exercise for me to go through, you know, reviewing this study because on one hand, I trust hyperthermia, but on the other hand, I do not work in those low and middle income countries where there is a lot of challenges. So I don't know, it's a hard one.

Ben 1:04:54

It's a hard one for sure. For sure. Yeah, I mean, the conclusion was so strongly war did and I think that really was created a big, big explosion in the neonatal field. So I'm curious to see what we ended up deciding on this on this on this particular much matchup, Rashida, you you're you're presenting to us some of these fetal interventions that are also quite impressive. Tell us a little bit more about

Speaker 3 1:05:22

this. Yeah. So the last paper that I'm going to talk about, was published in New England Journal of Medicine, the Phaedo trial. So it was a randomized randomized controlled trial that looked at fetal surgery for severe left diaphragmatic hernia. And what they were using was endoluminal tracheal. Ocular occlusion, I would encourage everybody to also to find this paper because there's some really nice links to videos of what this actually looks like. And so they randomized babies to this fetal surgery where they occlude the trachea at the around 27 to 29 weeks gestation, and then the balloon basically descends, the chest, which decreases the thought is that it will decrease respiratory morbidity allow the lungs to grow, and then they pull that balloon out or deflated at around 34 weeks. And the goal of the trial was to look at the outcome of survival at six months of age. So they enrolled 80 families, and it was stopped early because of the significant differences that they were seeing. So at six months, the babies that underwent this fetal surgery, their survival was 40% versus families that did not their survival was 15%. So huge difference there. So the relative risk was 2.61. thing to note, that's important in these outcomes was you did of course, have a significant increase in preterm labor and the families that underwent the surgery. So 75% of the families that went through the surgery went into preterm labor versus 30%. And you start to see a mean difference in the difference in terms of gestational Ages was about four weeks, and therefore you get a birth weight difference of about 500 grams. So that's just something important to note. But their overall conclusion is that this surgery was overall safe, greatly improved outcomes for babies with severe left diaphragmatic hernia, some of the previous trials have looked at even babies with right, the ratios were a little bit higher, some favorable ratio. So this study, I think I didn't mention, included ratio is below point eight, for the lung to head ratio. So really kind of impressive study. And I think it it adds to the literature about when we're looking at families and patients with really complex care siloing, that care being at an ECMO center, or potentially centers that can do the surgery for severe cases, I think is one of the really big things that the study adds because the survivability difference is huge. And so I think that that's something to that this study really adds to it.

Ben 1:08:20

Yeah. And I think the technique itself is something that's been described before, I think what's very novel about this paper is that I think there's there's been papers that show like, you could clip the trachea basically occluding the trachea in other ways, but this one was really impressive in the, in the in the way it was done, where this balloon is being inserted, and then and then retrieved later on. And in the article, as we said, in the title is for severe left diaphragmatic hernia, which showed the staggering differences. But there's also a companion article in the New England Journal of Medicine published around the same time by the same authors that look at not severe, but sort of moderate diaphragmatic hernia. And, and we don't see the same effects. So it was very interesting that this was a very thorough body of work that provides a lot of information on this topic. And it feels like science fiction really where where they can access the trachea during pregnancy and do all these things. Sorry, at all. You were gonna say something?

Speaker 4 1:09:17

No, no, I think I think you covered it mostly when what you said is absolutely right. It's science fiction, and you need to be careful about it. Because end of the day, you need to do it in high volume centers. You can't leave it in people who don't have experience, and it's a first world thing. It's not something which can have a global impact. So we need to really, really remember that because, you know, the resources of these setups in smaller is really hard. So in Australia, for example, we have only one center which offers this so even in high income settings, you need a lot of volume. So you saw I think you're depressed is a global superstar on this, you know, absolutely yeah. And the paper is the PA

Speaker 3 1:09:56

and a tool to your point. It's like the centers To even be a part of the study, they had to do at least 36, fetus copies a year, they had to have already done a minimum of the 15 of that specific procedure. So it was very, very controlled in terms of who was a part of the trial, just just like, it's very interesting,

Ben 1:10:15

because the paper is very thorough in describing all the possible things that could go wrong, where the building deflates, and all these different things. And I think once you go through all these adverse events that could potentially happen, you understand that experience is very important, because there's a lot of things that could go wrong during this procedure. And after the procedure is done, and so yes, experiences is tremendously important. And, yeah, the centralization of care on that front is important. Brian? Yeah,

Speaker 5 1:10:41

I mean, I was, I was I did my fellowship at one of the centers that was high volume and did a lot of these cases. In Texas, and and yeah, just to that point, in terms of everything that can go wrong, I mean, the neonatal teams we all got trained on, if a baby was delivered prior to deflation of the balloon, how to retrieve the balloon and the delivery room, which was a whole skill that we had to be prepared to do it. Because if they weren't born preterm, and the balloon hadn't been deflated. So I think there was, there's yeah, there's many levels to it. And then as Rashida said, you know, the infants were born a little bit smaller a little bit earlier. That being said, despite all of those challenges, you still see this significant benefit, and not only survival, but I mean, the use of ECMO was drastically reduced in the severe group as well. So huge benefits for the population. But I also get, what a tool saying is that, you know, it has to be the right patient in the right center. And, and that's going to favor certain groups of people who can, you know, pick up their life and go where they need to go to get the best care, and is that, you know, it's important to show that we can do this, but also to recognize that that it's not going to impact everyone equally.

Speaker 3 1:11:53

And families have to stay in the area, wherever the balloon is placed for that duration. So they like you said, Brian, they have to pick up their family and stay somewhere for at least six weeks. Tippett's was

Speaker 5 1:12:05

this challenge of like balancing, you know, getting the best care to all of our patients, which it does involve, you know, regionalization, a pyramid sort of level of care. But also recognizing that, you know, you can't you can't do it so much to the point where you have, like a tool set one center and all of Australia like is that that's massive. I mean, it's, it's, yeah, it's tough.

Daphna 1:12:32

Yeah, I had trouble, even considering my vote for this matchup, because I think it just shows how significant the disparities are, right? When we, we have a therapy that is well utilized shows good outcomes, you know, in in high resource countries, like therapeutic hypothermia, that's, that's not providing the same outcomes in these lower resource countries. And then we have this, you know, like you guys said, science fiction, I think this paper is really going to push the needle on more fetus scopic surgeries. But it's, it's for a very small proportion, what's your pick of our population? I may, I may abstain

Unknown Speaker 1:13:16

from from,

Ben 1:13:18

there's no such thing.

Daphna 1:13:19

I will say, the therapeutic hypothermia paper made me maybe sad, I was so disappointed by the the outcomes. I do know, though, that the hypothermia group was much sicker than the babies who didn't receive hypothermia. And if I remember correctly, is trying to re pull it up again. But I think those babies also got colder, too cold. And so that is obviously a risk when you have less resources to do temperature monitoring. But we know that predicted poor outcomes and in the original cooling trial, so I wonder if that has something to do with some of the findings, I think that this paper will have a larger global impact.

Ben 1:14:03

Killer Glenn.

Daphna 1:14:05

He looks for Murshida.

Speaker 3 1:14:08

Yeah, I'm gonna go with the helix trial for slightly different reasons. Because I agree, I think we were all really sad when we saw the outcomes. But I think if anything, it will encourage us to figure out how can we make these outcomes better? And that's the important part. So what works in high income countries shouldn't work necessarily for low income countries, but what can we do to make those outcomes better? And I think it exposes that, you know, not everything works for everybody. And so how can we figure out to make things better for our partners in low income countries? Yeah,

Ben 1:14:41

that's all I think we know.

Speaker 4 1:14:44

Yeah. No, no, I'm not actually going to go with 16. But I would want to make a call comment. The comment is that I think this is the first year Brian when we have to low income or middle income country focus papers in the impact Article of the year which is fantastic. Stick, which means that we are as a nice little community, you know, really doing great when it comes to studies coming from this. Obviously, we need a lot of sponsorship, we need a lot of funding to do good quality trials in those setups, but we are getting there. And I think who is supporting a lot of good work action trials have come out with a bit of medicine and all that. So I think it's really good to see that. But I'm actually going to go with Dr. depressed because what he is doing is just phenomenal. I know it's high income focused and all that, but it just kind of opens up, you know, our kind of thinking to what else is possible. And I work in cell therapies. And I also do a bit of science fiction. So I think it's just amazing to actually be able to offer these families who otherwise would have really, really poor outcomes. And I know in Australia, they have really poor outcomes, because Fito is not easily available at all. So I think it it helps us consider that what could we achieve when resource is not an issue, and I reiterate that when resources is not an issue.

Speaker 5 1:15:59

Ryan, I just want to say definitely, this particular matchup, it was not intentional that it is but I think your observation is very telling and you're right. But that's purely by chance that these two are matched up, but it doesn't make for a very interesting matchup. I'm pretty sure all four I voted the opposite way from a tool after he's given his opinion. But I'm gonna go with healings for the reasons that have all been stated. I also agree with everything you've said about you know, the, the Phaedo study and the intervention. And it does make us think about what else could we do? There's a lot of fetus scopic procedures that are doing that, you know, same with spina bifida and other conditions. So it's great. And I also think it may be the first time that neonatology has had two articles in doing the journal on the same day, because they were actually published at the same time, which is just crazy. But but the helix just because I think it's already made a huge impact, as you commented on all the editorials and the commentary, you know, positive and negative impact, right? That's still impact.

Ben 1:17:03

Yeah, I mean, I'm gonna go with the helix trial. And I feel very bad just because the Phaedo study was so impressive. However, the helix trial was one of these papers where it made you rethink something that that had taken for granted, where it's like, Oh, ha, we have a therapy for that. And it's like, well, how good is that? And how foolproof is your therapy? I think it's always good, like Rashida said that we can actually continue to think about the things that we have to offer and improve upon them. So yeah, so I think this is it for us. For this first part of the campaign, we have our final four. So just to summarize, in one on one side of the bracket, we have the paper from Dargaville. That, about about missed that, that made it through, and then on the that will be competing against the care planning paper at the top trial. And I'm just going back to the consensus of the group that we have here today. And on the other side, we'll have

Daphna 1:17:59

the people, the people get to vote, I know.

Ben 1:18:02

And so that's gonna be the fun part. So and then the other side, we have the kangaroo mother care versus the helix paper. So what we'll do that we'll leave it there, and then obviously, we'll have another episode, once the voting is done, and we'll announce the winners. And it will be interesting to have the discussion about who do we think should make it to the semis and to ultimately to the who should make it to the to the to the finals, and who should win, and then compare that to what the audience voted for. So we're going to post on the website or the articles that were reviewed today, we will also post the brackets, so the picture of the bracket. So you're going to vote right to Brian, it's going to be a poll that people can just click for the articles, that will be very easy. But if you want to share your bracket on Twitter, then let's let's do that. Let's let's start sharing that started commenting on each other's bracket, that could be fun. And we'll be back in a few weeks to go over the winners.

Speaker 3 1:18:56

And when people vote, we want to hear why you chose what you chose. I think the really important part of this campaign is what is impactful to you. And we want to hear from you.

Ben 1:19:08

That's exactly right. And I think that will make a great conversation on Twitter. So make sure you follow up, Neil. And we will repost some of these tweets as well so that you can access them. But yeah, this was a lot of fun, everybody, thank you for making the time to come on the show, and for giving us the opportunity to take part in this impact Article of the year campaign. This was a bit of happiness.

Daphna 1:19:31

Thanks, everybody. All right.

Unknown Speaker 1:19:33

Thank you.

Ben 1:19:34

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, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address NICU podcast@gmail.com. You can also message the show on Instagram or Twitter at At NICU podcast, or through our website at WWW dot v dash incubator, that org This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns, please see the primary care professional. Thank you

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