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#125 - 📑 Journal Club 48

Hello Friends 👋

For those of you attending PAS, we hope you are enjoying your time there. Please make sure to find us to grab some incubator swag. This week's episode of Journal Club reviews a few major articles published in NEJM and which deal with cerebral oximetry and the use of maternal RSV immunization to prevent neonatal RSV. Fascinating work all around. We also have the pleasure of discussing the long term effects of neonatal platelet transfusions for our monthly segment with EBNEO for their article of the month commentary.

We hope you enjoy this episode. Happy Sunday!


This week we had the pleasure of having Dr. Martha Sola Visner, Dr. Patricia Davenport, and Dr. Cassidy Delaney, who reviewed with us the long-term outcomes from the PlaNet2 trial.

Two-year outcomes following a randomised platelet transfusion trial in preterm infants.

Moore CM, D'Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Santamaria BL, Deary A, Hodge R, Hopkins V, Mora A, Llewelyn C, Venkatesh V, Khan R, Willoughby K, Onland W, Fijnvandraat K, New HV, Clarke P, Lopriore E, Watts T, Stanworth S, Curley A; PlaNeT2 MATISSE.Arch Dis Child Fetal Neonatal Ed. 2023 Sep;108(5):452-457. doi: 10.1136/archdischild-2022-324915. Epub 2023 Feb 21.PMID: 36810309 Free PMC article.

They discussed their nice commentary published for EBNEO in ACTA PEDIATRICA:

EBNEO commentary: Platelet transfusions in neonates and brain development: The new frontier.

Sola-Visner M, Delaney C, Davenport P.Acta Paediatr. 2023 Aug;112(8):1826-1827. doi: 10.1111/apa.16801. Epub 2023 May 1.PMID: 37128679 No abstract available.


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

Cerebral Oximetry Monitoring in Extremely Preterm Infants.

Hansen ML, Pellicer A, Hyttel-Sørensen S, Ergenekon E, Szczapa T, Hagmann C, Naulaers G, Mintzer J, Fumagalli M, Dimitriou G, Dempsey E, Tkaczyk J, Cheng G, Fredly S, Heuchan AM, Pichler G, Fuchs H, Nesargi S, Hahn GH, Piris-Borregas S, Širc J, Alsina-Casanova M, Stocker M, Ozkan H, Sarafidis K, Hopper AO, Karen T, Rzepecka-Weglarz B, Oguz SS, Arruza L, Memisoglu AC, Del Rio Florentino R, Baserga M, Maton P, Truttmann AC, de Las Cuevas I, Agergaard P, Zafra P, Bender L, Lauterbach R, Lecart C, de Buyst J, El-Khuffash A, Curley A, Vaccarello OO, Miletin J, Papathoma E, Vesoulis Z, Vento G, Cornette L, Lopez LS, Yasa B, Klamer A, Agosti M, Baud O, Mastretta E, Cetinkaya M, McCall K, Zeng S, Hatzidaki E, Bargiel A, Marciniak S, Gao X, Huijia L, Chalak L, Yang L, Rao SA, Xu X, Gonzalez BL, Wilinska M, Yin Z, Sadowska-Krawczenko I, Serrano-Viñuales I, Krolak-Olejnik B, Ybarra MM, Morales-Betancourt C, Korček P, Teresa-Palacio M, Mosca F, Hergenhan A, Koksal N, Tsoni K, Kadri MM, Knöpfli C, Rafinska-Wazny E, Akin MS, Nordvik T, Peng Z, Kersin SG, Thewissen L, Alarcon A, Healy D, Urlesberger B, Baş M, Baumgartner J, Skylogianni E, Karadyova V, Valverde E, Bergon-Sendin E, Kucera J, Pison…See abstract for full author list ➔N Engl J Med. 2023 Apr 20;388(16):1501-1511. doi: 10.1056/NEJMoa2207554.PMID: 37075142 Clinical Trial.

Impact of work schedules of senior resident physicians on patient and resident physician safety: nationwide, prospective cohort study.

Barger LK, Weaver MD, Sullivan JP, Qadri S, Landrigan CP, Czeisler CA.BMJ Med. 2023 Mar 30;2(1):e000320. doi: 10.1136/bmjmed-2022-000320. eCollection 2023.PMID: 37303489 Free PMC article.

Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

Kampmann B, Madhi SA, Munjal I, Simões EAF, Pahud BA, Llapur C, Baker J, Pérez Marc G, Radley D, Shittu E, Glanternik J, Snaggs H, Baber J, Zachariah P, Barnabas SL, Fausett M, Adam T, Perreras N, Van Houten MA, Kantele A, Huang LM, Bont LJ, Otsuki T, Vargas SL, Gullam J, Tapiero B, Stein RT, Polack FP, Zar HJ, Staerke NB, Duron Padilla M, Richmond PC, Koury K, Schneider K, Kalinina EV, Cooper D, Jansen KU, Anderson AS, Swanson KA, Gruber WC, Gurtman A; MATISSE Study Group.N Engl J Med. 2023 Apr 20;388(16):1451-1464. doi: 10.1056/NEJMoa2216480. Epub 2023 Apr 5.PMID: 37018474 Clinical Trial.

Intraventricular Hemorrhage in Very Preterm Children: Mortality and Neurodevelopment at Age 5.

Tréluyer L, Chevallier M, Jarreau PH, Baud O, Benhammou V, Gire C, Marchand-Martin L, Marret S, Pierrat V, Ancel PY, Torchin H.Pediatrics. 2023 Apr 1;151(4):e2022059138. doi: 10.1542/peds.2022-059138.PMID: 36919442

Interventions to Reduce Severe Brain Injury Risk in Preterm Neonates: A Systematic Review and Meta-analysis.

Razak A, Patel W, Durrani NUR, Pullattayil AK.JAMA Netw Open. 2023 Apr 3;6(4):e237473. doi: 10.1001/jamanetworkopen.2023.7473.PMID: 37052920 Free PMC article.

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Find some of our notes here 👇

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

Hello, buddy. Welcome back to the incubator podcast. It is Sunday Daphna, how are you?

Daphna 1:05

It's good. If it's Sunday, then we are in DC.

Ben 1:08

That's right. So if you are, but that's cool, though, because if you are listening to this, and you RFPs just reminding you, I'm not sure if it's Sunday, by by Sunday, I'm not sure how much swag we have left. We don't really have a booth. We do. I mean, if you're listening, we had a workshop on Friday. So you you missed it.

Unknown Speaker 1:28

Maybe have caught our live.

Ben 1:32

But you but we are going to be in the convention center for some time on Sunday. And so if you find us, please do not be shy. And it's not like I want to sign autographs, but like I have stuff to give. So we have stuff to give. So come say hi. We'd love to meet incubator members, audience members and stuff. It's always cool. Tell us what your thoughts are. Where

Daphna 1:58

are we? Well, where are we saying incubators?

Ben 2:00

incubators? Yeah, we love. We love to meet incubators. And so yeah, so just Yeah. It is Journal Club. We have a bunch of articles. There's a bunch of big articles, obviously, that have been published. Twitter has been this lazing. But that's it I've been talking for now. Two minutes. Yeah. What's new with you? Definitely.

Daphna 2:27

No, I think you've covered all the big things. You know,

Ben 2:32

if you're listening right now, and you didn't get to get free swag at the PS stuff, I think I think I should know, the merch store on our website should be up and running. So check it out.

Daphna 2:44

That is very exciting. We have been looking forward to that for some time.

Ben 2:47

Yeah. And we're gonna keep adding stuff to the store. Maybe it's take stuff down as we put more stuff on the store. The one thing I'm very proud of is, so we're putting on their store one of the first few items we're putting on so there's like some mugs and some shirts and stuff. But we do have the white cloud and black cloud T shirts. So for your favorite fellows and attendings, you may want to even want to grab

Daphna 3:10

I think it's just in time for like end end of the year gifts, right?

Ben 3:14

That's right. I think what's funny about it is that if I had to be gifted this, this t shirt as a fellow I would have gotten the black cloud early on and white cloud later on.

Unknown Speaker 3:23

It does seem to change, doesn't it? Yeah,

Ben 3:26

my luck did turn around. Thankfully, thankfully. The funny story that I always say was that when a cool fellow of mine called me while I was off to ask me like about how to fill out the death certificates because like, hey, you've done so many. And I'm like, just I hung up on him. I hung up on I was like, No, I'm not that person. I eventually give them the information they need. I'm not that bad. But yeah, Josh, if you're listening, what's up, man? Should we go? Yeah, you're waiting for me out?

Speaker 1 3:58

i Yeah, that's exactly right. What do you what do you snack in on their chocolate? Chocolate? Okay, that's a good choice.

Ben 4:06

Yeah. All right. So let's start with the big one. The big one is the article that came out in the New England this past week, called cerebral oximetry monitoring in extremely preterm infants. There's a lot of authors first author is Dr. Henson and already have the first name. It's a very international group. And it's published the New England Journal of Medicine. It's one of these big articles where, you know, it's a big article when the New England also adds like a research summary with it. So making my life easier, but I still reviewed the entire paper so I'm not going to just read the research summary from the New England. So let's go over some of the background stuff. We know that for LBW infants monitoring of cerebral oxygenation has been something that has been talked about as a means of alerting us to issues going on with cerebral blood flow and risk of cerebral ischemia. And so there's this idea that if we had this information, maybe we could intervene very early on in the process of cerebral pathologies, and not have to wait until you get the result of an ultrasound where things have really deteriorated. Now the safe boost to trial, which was published some time ago, and we'll put that as well on the on the on the episode page looked at 166 Extremely preterm infants who underwent randomization to receive treatment guided by cerebral oximetry during the first 72 hours after birth, or they were randomized to a blinded intervention, which was interesting, meaning they were in safe booths to both the control and the intervention group were hooked up to nears to near infrared spectroscopy, but the control the clinicians were blinded to the number. Now in that trial, the occurrence of what was defined as the primary outcome which was cerebral hypoxia, and hyperoxia, was reduced by a staggering 58% in the cerebral oximetry group primarily owing to a reduction Not really hyperoxia, but mostly hypoxia. So you can review the you can review that study, and that obviously was a paper that gave a lot of promise and optimism for the utilization of nears. Now, the question that the safe busque three trial is asking is, Can treatment guided by cerebral oximetry, in the first 72 hours after birth, resulted in lower incidence of death or survival with severe brain injury at 36 weeks postmenstrual age compared to routine care? So I think this is where we see the evolution of the research methodology, right? Where you're looking at cerebral hypoxia, cerebral hyperoxia, and safe busque to but now you're sort of asking like, I like things, how does that really translates into mortality, or severe brain injury? So the study design, obviously, as you can imagine, since it was published in the New England, it's a very robust study was pragmatic, it was a superiority, open labor multinational, phase three randomized clinical trial. Babies who were considered to be eligible were infants who were born before 28 weeks of gestation, who obviously were foreclosed where resuscitation was attempted, and on whom near infrared spectroscopy could be implemented within six hours of life, the infants were randomly assigned in a one to one ratio to either receive cerebral oximetry or usual care. The intervention and I think that's important is obviously being connected to cerebral oximetry monitoring for the first 72 hours after birth, that will be a big subject of discussion, obviously, because anytime you assign a time point to an intervention, people will say, well, but if you did it longer with you longer, so there'll be something that we can discuss afterwards. Now, what was very interesting is that, I think, always dig through the supplemental material, I'm gonna put this on Twitter, but like, they had a whole intervention, right? The thing that you wonder is, oh, how, how do we use cerebral oximetry? And in the methods, they say, Well, if an infant's cerebral oxygenation level dropped below the threshold for hypoxia, then treatment was considered, and intervention. Were based on the safe busque. Two, three treatment guideline, which usually include potential clinical intervention for the purpose of normalizing cerebral oxygenation. So now, if you do go into in the supplemental material, I think, first of all, that what was that threshold? That threshold was 55%. But then you say, okay, so what was that? So there's like a whole algorithm on how to approach babies who are having their threshold go below 55%. And so then, I'm gonna go through this because it's very valuable. They had three, three items in the city, either there's an issue with cardiovascular status, oxygen transport, or respiratory status. Cardiovascular status was then divided into either an ethnographic assessment, where you would look at cardiac output SVC flow, and you would consider maybe volume expansion and maybe I inotropes, maybe decreasing the map or you will found a significant PDA and you will consider treatment. In terms of clinical assessment, they will look at blood pressures, they will look at lactate, urine output and so on, and they would then consider potentially volume expansion, maybe vasopressors, et cetera. What if it was an issue of oxygen transport, they will look at hemoglobin and consider transfusion. What if it was a respiratory status issue, then they would look at maybe increasing the amount of oxygen increasing fire to increasing the map. And if the P co2 was low, then maybe decrease intermitted ventilation. So, if you're trying like we are right now to implement nears in your unit and you're looking at how to approach abnormal values figure s one in the supplemental material. The outcomes were assessed at 36 weeks postmenstrual age or the time of death or discharge to home whichever came first severe brain injury was assessed by means of review of all cerebral ultrasound scans and imaging reports available in the infant's clinical record. The primary outcome was a composite of death or survival with severe brain injury and severe brain injury was defined as either severe ivh cystic PVL, post hemorrhagic ventricular dilation, cerebellar, hemorrhage or cerebral atrophy. They also had some expiratory outcomes which were death at any time, up to 36 weeks or BPD. And the following outcomes that occurred at any time up to 36 weeks which were death or severe ROP, death or late onset sepsis, death or neck stage to slash maybe intestinal perforation. They also looked at some some adverse reactions to the use of nears, which included skin damage, physical injury, and so on and so forth. Now, interestingly enough, you can obviously review the statistical analysis. But the power of this the power calculation of the study was done in order to achieve a 20 to detect a 22% relative risk reduction, which I thought was very ambitious obviously. And the analysis was done in the r&d on an intention to treat principle. So the results are unfortunately a bit disappointing if you were hopeful that nears was the next big thing. A total of 1601 infants underwent randomization between June 2019 and December 2021 785. were assigned to the oximetry group 816, to the usual care group across 70 sites in Asia, Europe, and North America. Now, the key result is that 36 weeks postmenstrual Age 35% in the oximetry group and 34% in the Euro care group had died or survived with a severe brain injury. And that obviously was not statistically significant. We can look at table two in the in the results section, right, and we can look interestingly enough at the components of the primary outcome, they were also not very different. So when you're looking at death alone, it was 21% in the cerebral oximetry group versus 19.8%, in the usual care group, looking at severe brain injury alone, also 24.2% versus 23.6%. So it wasn't like the composite outcome really favored one or the other. Both of them were actually quite similar. The incidences of expiratory outcome events did not materially differ between the oximetry and usual care group. So looking at death, or BPD, that was also similar 66 versus 68% death or ROP, 30% versus 28% death or late onset sepsis, 73% versus 74% death or necrotizing, enterocolitis 30% versus 25.9%. Now, in terms of the adverse events in the oximetry group, one or more serious events, adverse events occurred in about 85% of infants as compared with 86%. In the usual care group, there were no appreciable differences between the oximetry, unusual care groups in the incidence of serious adverse events. The conclusion to the conclusion sorry, of the trial are that in extremely preterm infants, treatment, guided by cerebral oximetry monitoring in the first 72 hours after birth did not lead to a lower incidence of death or severe brain injury at 36 weeks, compared to usual care.

There's definitely a lot of disappointment, especially considering the promising results of the safe boost to trial, there are still some lingering questions that are left to be answered, for example, is 72 hours enough time to actually have a meaningful effect? Could you say that mean, that's something that in our division, right, one of our colleagues was mentioning, maybe, maybe longer periods of time, could be, could be more valuable? Also, the idea that the nurse because the nurse oximetry was being hooked up within six hours, and that could that leave enough time for event for things to happen without you intervening on them? That's also possible. And then obviously, the idea that the imaging imaging reviewed was obviously dependent on whatever the units were doing. So there were no, there were no consistent recommendations as to when to image The brain and there were no consistent recommendations on the use of ultrasound versus MRI. They basically reviewed every image that they possibly could that were gathered during the hospitalization. I'm not saying these are limitations, I'm saying these are questions that I think in the future, I can foresee other groups maybe tweaking and trying to study this. But other than that, yeah, an interesting paper that that's going to lead to a lot of conversation, especially as I think a lot of our people in our community, we're very hopeful about nears.

Daphna 15:30

Yeah, I totally agree. I think they gave us as much information as they could, I think the algorithm was very useful, because I think that's something we're all saying like, Okay, we have these values that we think are the threshold values, we're not even sure they're the threshold values, right. But we're starting to get more and more data with larger and larger cohorts looking at what is the what are the typical values? And then you say, but like, so then what do we do? But potentially, you know, I think, potentially, you know, if you haven't seen those found those findings on your other lab, you know, data or clinical data that potentially, you know, the new year's data will give you some information sooner. You know, I think one of the, one of the strengths of the study was how, you know, a ton of international sites. And I think that makes it harder to do oversight, right, at any, you know, at any site, like, what was the compliance to the algorithm? I don't know, who knows.

Ben 16:35

But I think the, the algorithm does, I think answer. So that's the other thing was that the compliance was a big deal. And the other component that I left out was that they did provide training. So they did try their best to give people as much education as possible on the device on the algorithm so that people would say, Well, you know, they're doing this trial in my unit, and I don't know what they want from me now. They were able to actually provide as much information, which was a big deal. Yeah.

Daphna 16:59

Yeah. The only thing I think about with with NIRS, in general, and our reactivity to nears is, you know, once you see those changes, once you've met the threshold, right, potentially, damage is already done. It's already happening, right, like, say what we see with like, ischemia and HIV. Right. So then, then, I mean, we're potentially preventing more damage, maybe I don't know. But I wonder if instead of using absolute thresholds they were using, you know, the trend, right change from baseline or how we know the it's the it's not even the absolute of fluctuations, but potentially how quickly you do these swings. So I don't know. I think there's still I think there's still hope. I'm still hopeful. I'm disappointed by that outcomes. But I'm, I hope that people won't just give up on studying it all together. Absolutely. It's just a jumping off point.

Ben 17:55

Absolutely. And then like we said, could the cut off have been the wrong one is 55%, not the right cut off? Maybe this was too low, right. And all these, like I said, I'm not here to disparage the study by any stretch. This is a phenomenally well crafted study. It's just, I think these are the things you're going to start seeing when people are going to re explore this idea and trying to see if there's really nothing to be gained there. I think that's going to be the interesting part. So yeah,

Daphna 18:23

very cool. Very cool. Well, that was a that was a big one. I think people have a lot to think about. So I'm going to take a little I got I'm calling it a lighter study, but it's actually not a lighter study. So I am doing this article from the BMJ medicine, the impact of work schedules of senior resident physicians on patient and resident physician safety. A nationwide prospective cohort study. Lead author Laura Barger trailing author, Charles Caesar.

Ben 18:56

You didn't wait, you see, you see the first thought that was easy to pronounce. And then yet, you you? You do this to yourself at this point?

Speaker 1 19:04

I know I shouldn't I could have just gone off. And that's what I do. Anyway, try to give everybody their credit.

Daphna 19:12

What's the question? So they wanted to look at whether long weekly work hours in shifts of extended duration so they're using greater than or equal to 24 hours are associated with adverse patient and physician safety outcomes. And they were looking for a quote unquote, more senior resident physician, so they were at least they weren't interns, PGY twos, or PGY threes. And as a reminder, our current duty our limits our 80 to 88 Hour Work Week limit 28 to 30 consecutive work hour limit, including these time for transitions and a minimum of four days off per month. And so their study design was a nationwide prospective cohort study of resident physicians in the US, and they use they collected data from 2002 to do that. wasn't seven, and again from 2014 to 2017. But the duty hours were the same. So they were able to combine.

Ben 20:08

And so just for clarification, right, we're not talking pediatrics like it's not just pediatric, residents, all residents,

Daphna 20:15

all residents. So they use a variety of ways to invite these. These residents, they found, you know, US medical school graduates, and individuals who've matched in a US residency program, we're, you know, invited by email to participate in this online study. And then in the second cohort, all medical school graduates who completed an application to the E RAs, which is for those who don't know, the electronic residency application service, it's like,

Ben 20:43

good luck explaining us to our international colleagues right now, there's no good way to

Daphna 20:48

anyways, because we didn't even like saying it. But they were invited by email to participate in the study. And this study was actually like pretty comprehensive. They sent out like, very frequent questionnaires that talked about like their lifestyle in and outside of the hospital. And so they collected a lot of data. But they wanted to look at, like the stratification of work hours. And the other thing they used was basically the, when you see the strategist stratification, they use the European work direction, guidelines for the stratification. So I'll tell you about that in a minute. So basically, what they were trying to look at is they wanted to look at medical errors. They wanted to look at motor vehicle crashes, and kind of these symptoms of inattention. So

Ben 21:49

motor vehicle crashes, you mean like Resident crashing their cars on the way? That's exactly right.

Daphna 21:53

That's exactly right. So the exclusion criteria, so they excluded so again, on these monthly questionnaires, they excluded months where participate participants reported greater than or equal to 14 work free days, ie vacation month. And when work our information was missing, or was reported to exceed 168 hours of work per week, so they threw those out. Oops, so the baseline characteristics they collected and 114 1173 responses from 1747 PGY, two plus, so PGY, two or three resident positions, from 2002 to 2007, and 24,529 responses from three just over 3000 PGY, two plus residents in the second epoch 2015 to 2017. More than 54 Sorry, 54% were female and the mean age was 29.7. resident physicians, like you asked were from our array of specialties in the study, the most prevalent specialty was internal medicine 24%. And that's consistent with like, the total number of residents in the in the country. So they had an average of 324 reports per month, and each resident completed an average of eight reports. The mean weekly work hours were 60. And overall 76.4% weeks exceeded 48 hours. So again, the 48 hours is actually from the European guidelines, and 46.7 exceeded 60 hours, and 10% exceeded 80 hours. And beyond those hours 21% of resident physicians reported moonlighting and among those who did moonlight the overall mean hours spent moonlighting were point six, so that's not 2.6 per week. Resident but I definitely wasn't doing any Moonlighting. Did you moonlight? You probably did. I'm sure you did.

Ben 23:52

Yeah, yes, I did. My financial constraints were significant. Actually, you know what, I'm going to interrupt you for one second, because it was a very valuable lesson. My wife actually went into being an attending for a year for two years, and then went back to fellowship. And we found like, I think if you haven't finished pursuing your fellowships, Do not raise your lifestyle. That's great. Because when my wife went back to fellowship, then I had, like, I had someone like, like crazy. But I was very happy that I was able to moonlight because I paid the bills.

Daphna 24:24

That's true. That's true. And certainly we certainly have people who need the moonlight just to make just to make it right. Okay, let's get in to the data. Then they talked about sleep, okay. Especially they said daily sleep duration, average 6.9 hours, which I thought that was pretty good. But resident physicians on shifts of extended duration, so those are those greater than 24 to 28 hour shifts, reported obtaining a mean of only 2.5 hours of sleep on those shifts and resident physicians reported obtaining no sleep on 14% of shifts of extended duration. Hold

Ben 25:04

on, hold on, you said oh, 2.5 hours of of mean sleep during shifts.

Daphna 25:09

So like if they were doing the 24 to 28 hour shifts, the mean average of duration of sleep was 2.5 hours.

Speaker 1 25:16

I don't think that's that bad. No, that's the point. That's. That's exactly right. You're like, Oh, I got a little bit of sleep sweet.

Ben 25:26

I mean, when I come home, if I have 2.5 hours, I consider myself to have slept. I know.

Daphna 25:30

That's the problem. That's exactly the problem. Sorry. And like I said, 14% of shifts of extended duration residents reported obtaining no sleep. That's exactly right. If you said that to a layperson, they'd be like, That's absurd. Everybody needs sleep. And us and medicine are like oh, and sweet. I can get I could get through the whole day after that.

Ben 25:55

It happened to me at the gym, I came, I went to the gym for like a session with a with my trainer POST call. And he's like, didn't you work last night? And I was like, Yeah, but I'm like, I got like two hours of sleep like I'm fine. And they're like, Are you like, that's not and then looking at him was like, Oh, that's not normal. Two hours, right? People don't just go on two hours, and I was having like, meetings lined up and everything. Yeah. Anyway.

Daphna 26:17

Okay. So let's get into the medical errors. 30.5% of the resident physicians reported at least one medical error 8.3% reported at least one preventable adverse event and 1.8% reported at least one fatal preventable adverse event. medical errors and preventable adverse events increased significantly in a linear manner, when weekly work hours exceeded 48 hours. fatal event adverse events also increased significantly, when weekly work exceeded 60 hours. Working between 60 and 70 hours per week was associated with more than twice the risk of reporting a medical error, and almost three times the risk of preventable adverse events. And, and it increased in in a significant statistically significant fashion, the fatal preventable adverse events. And so they have this really cool graph. It's not cool, it's but it's a telling graph that really shows like basically, by average weekly work hours, greater than 40, what are the odds ratios of like, all of these things, and it is like, totally linear. It's terrifying actually. When comparing categories of weekly work hours, the odds of reporting a medical error, a preventable adverse event, and a fatal adverse event increased roughly four fold, when weekly work hours exceeded 80, working one shift of extended duration in a month while averaging no more than 80 weekly work hours. So you weren't really breaking duty, our restrictions was associated still with an increased risk of reporting medical errors, an odds ratio of 1.8 for an increase preventable adverse events and odds ratio of 1.5 and an increase in fatal preventable adverse events 1.85 compared with working no shifts of extended duration, so by somehow working one of those, you know, over 24 hour shifts in a month where you weren't kind of over hours, and it it's still increased medical errors. When I was telling you about motor vehicle crashes, so residents reported 580 motor vehicle crashes 36.7% occurred on the commute from work. Compared with working fewer than 80 hours per week, when resident physicians worked 80 hours or more, there was an 86% increase in the risk of a crash on the commute from work and the 99% increase in the incidence of near miss crashes and working a shift of extended duration and 80 hours per week further increase the risk of any crash and a crash on the commute from work an odds ratio of 1.44 so of any crash and an odds ratio of 2.67 for a crash on the commute from work. And there was a dose dependent increase in reported near miss crashes as weekly work hours increased above 48 hours, the incidents more than doubled with 70 or more weekly work hours, working one or more shifts of extended duration while averaging no more than 80 hours per week in a month significantly increased the Near Miss crap the Near Miss crash risk. Tau 1.3 to the combination of more weekly workout was greater than 80 and shifts of extended duration further increase the risk of a near miss crash. They also looked at these percutaneous injuries and these What did they call them?

Ben 29:46

needle sticks,

Daphna 29:47

no needle sticks. Yes, percutaneous injuries, they showed the exact same thing. So basically, I won't even get into that. They also have a category called intent attentional failures, which I'm not even sure how you categorize those But I know what they're saying when you have the inability to pay attention to something happening, and those I mean, increased in the exact same fashion. That's true, I definitely think it's something for us to look at. Some people might say, Oh, well, that's residents, it doesn't happen to experienced physicians. And I think we have to disagree. And other studies definitely mirror this. But the point is, you know, there's a lot of concern about us, you know, having duty our restrictions. But in Europe, the physicians have even stricter duty, our restrictions, and some of our colleagues in New Zealand and the US and Canada have stricter duty hours. And you can see that the bit errors increased significantly.

Ben 30:51

Yeah, I think I would, I would moderate that by saying that whenever you leave the US, I think it's, it's not a uniform approach to that as well. I think you can, you can go, Rooney and I were talking about our friend from Switzerland, who was baffled that only one neonatologist covers our unit. So like, for him, this was unfathomable. But for some, it's like, you have a nurse practitioner with you. And it's like, you would cover this one. So there's a lot of variability. But there's no. But I also think that in the case of residents, What's always interesting to me is that we are, they are following what we're telling them to do. So we're putting them in these positions

Unknown Speaker 31:34

as if it's a safe thing. That's right. Because

Ben 31:37

many times as attendings, you can take on more than you can chew and that's your responsibility. You shouldn't do that. Like how many times have I done a reverse 2436 hours and and I regret it, but it's like, okay, I signed up for this. This was I chose this that's a problem but for residents, man, they're supposed to be learning this is not setting up a great example.

Daphna 31:56

Yeah, I totally agree with you. And even us attending physicians, we have a responsibility to our patients, right and right to 100 make it home. So, you know, I think it's definitely something we had to think about what I thought was especially interesting in you know, I hate 20 fours. But even if all things were the same, but you had one additional like extended shift, the risks were like exponentially greater.

Ben 32:21

Oh, and we all know this. We all know this. I mean, you wake your wake up 24 hours after your postcard day and you realize you're exhausted even though this episode is so proudly sponsored by Wreckit Matt Johnson recognized Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive and familiar portfolio for premature and low birth weight infants learn more at HCP dot meet

Speaker 3 32:49

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

Ben 33:06

So this month for the EB Neo commentary, we have the pleasure of having on with us, Dr. Cassidy Delaney, Dr. Martha sola listener and Dr. Patricia Devonport. Cassidy is an associate professor in pediatrics in the Division of Neurology at University of Colorado. Patricia Davenport is a physician scientist, who is a practicing psychologist at Boston Children's Hospital, where she works alongside Dr. Martha Silvaner, who is the director of newborn medicine, clinical research program programs at Boston Children's guys, thank you so much for being on the show with us today. So, of course, of course. And so I guess the paper that we are reviewing today are some of the long term outcomes of the planet to clinical trial. I am on even though I think we reviewed this paper on the podcast before if for some reason someone has not already listened to the podcast or read the paper can. Patricia, can you give us a brief review of what the paper did and what were some of the major results?

Speaker 4 34:10

Yeah, of course. So this was a much awaited paper that are the two year neurodevelopmental outcome follow up from the planet to trial. So I think most people practicing neonatology are familiar with the original planet to trial, which randomized neonates born less than 34 weeks to either a platelet transfusion threshold of 25,000 or 50,000. And that study strikingly found increased death, or major bleeding as the primary outcome within 28 days after randomization. And so then they followed these babies up to two years, and that's what the, this most recent paper found, and what they looked at was the incidence of death or severe neurodevelopmental impairment as a composite outcome. And what they found, strikingly again, is that there was an increased incidence of these outcomes in the neonates randomized to the more liberal transfusion. groups so that 50,000 compared to the 25,000. And I think the secondary analysis from both of those papers in the original planet two, they also looked at the incidence of BPD. And also found that that had a higher incidence as well in the liberally transfused group. And so again, in this follow up, they looked at two years and looked at, again, a composite of deaths, or the need for oxygen at two years. And they again found that the babies randomized to that liberal transfusion arm had a higher incidence of both. And actually, even when they looked at just the need for oxygen at two years, even removing the babies who had died, they still found a significant difference. And so really just suggesting that these liberal platelet transfusion practices not only have short term harmful effects, but also ones that persist out to two years.

Ben 35:50

Okay, so I mean, myself, I'm sorry, that thank you. So you guys wrote a very nice commentary for EB Neo. And I guess the the first question that everybody has, is, what do we make of these results? In terms of the way the studies were conducted? Is this is this data that we can take at face value, and really use to counsel families? Or are there any any things that we should take with a grain of salt with a grain of salt? I'm sorry, when it comes to that data?

Speaker 4 36:24

Yeah, that was that's always an important question, analyzing any study. And I think the most important thing that one of the most important messages that we would send across from both the original planet to trial and then also from this follow up is that by no stretch, are we saying don't transfuse platelets, platelet transfusions are still beneficial, and there are select populations of neonates, especially those who have bleeding, who platelet transfusions, of course, are life saving. But I think what both these trials do show is that there is really no reason to liberally transfuse prophylactically liberally transfused these, these these neonates and really in a non bleeding neonate, you should be following the evidence and really using a cutoff of 25,000 for again, non bleeding, prophylactic transfusion. I think with all study, there's always caveats, right? Nothing is perfect. And I think in this trial that we're just talking about the follow up, the biggest caveat is just that there's a pretty large heterogeneity in what the the assessment of a neurodevelopmental outcome was. So obviously, the Bailey's are the gold standard, and about 41%, I think of these babies did have a Bailey, and the rest was kind of a composite of another standardized test use more commonly in Europe. And then they also did use some parental scales of neurodevelopment neurodevelopmental outcomes. And they also do what sounds like a pretty comprehensive review of physician notes, hospital visits, really trying to get a sense for the babies who didn't have a formal vowel of really what their neurodevelopmental status was. And it was actually indicate that was their intention, from the beginning, knowing that it's hard to get neurodevelopmental assessment on all these babies. So it's, you know, they chose to look at all these different types hoping to get a high followup rate, which they did, they had a very, very good follow up rate. So I think that's the biggest caveat here. But I think one thing which we highlighted in our commentary is that even though there's this heterogeneity, they still found this substantial difference. And I think it just shows that there still is a signal there. But of course, further studies should try to use more rigorous all, you know, all Bailey's are all kind of a more unified approach to the, to the assessment. But I think still even with that heterogeneity, it's still a really strong signal. And it's an important message.

Ben 38:45

Martha, if I wanted to ask you the question specifically on this topic, because I think the holy grail for neurodevelopmental follow up data is that you will get a high retention rates 95% of babies followed up until two years with rigorous neurodevelopmental assessment tools used on all these babies. And that's maybe a naive view of how research can be done. And it's so hard to keep track of all these infants, especially years and years after they're discharged from the NICU. How as you What do you think, from the researchers standpoint, and from the reader standpoint, should we interpret either the kind of data we're seeing in this particular paper where the follow up rate is really, really high? But there's a lot of, as Patricia just mentioned, heterogeneity, in terms of the assessment tools that were used, versus potentially much lower follow up rates, but then a very rigorous assessment of neurodevelopment which one? What is your take on this?

Speaker 5 39:46

I don't think that is a question that can be easily answered. You know, because truly, ideally, in a well designed, powered study for neurodevelopmental long term outcome, you would try To achieve posts, you know, every researcher makes a trade off, they did theirs. If you only limit your assessment to that percentage of babies that had Bailey's, you probably wouldn't find a difference. But that is a very selected group of babies that may have had different variables that also made them made them different. And they, in order to be able to provide any data on follow up, they use this composite outcome of many different methods of evaluation, which a done allow us to look for more subtle, you know, and consistently assessed differences between the groups as we would have achieved with the Bailey's only. And second, they don't allow us to evaluate specific domains, like, you know, are the effects on language or the effects on motor development, fine motor motion, you know, like, it's only it's only a higher rate of neurodevelopmental impairment, to me most striking was actually the finding that there was a higher rate of oxygen requirement. And both respiratory support requiring at two years because while BPD is gone, and this population to still need oxygen, and still need respiratory support two years, that is relatively uncommon, and and that in isolation was statistically significant between the two, the two arms of the study, and very consistent with a higher rate of BPD. In the original study, and that it, you know, is severe BPD, almost by definition, if you're still needing oxygen at two years. So it was the most striking finding. And the second question is, are the difference in neurodevelopmental outcome mediated by the higher rates of IBH that they had in the original study, or by the higher rates of BPD? Because we know that severe BPD and ivh are related to higher incidence of neurodevelopmental impairment. So it could be that there is an indirect effect mediated by this two very strong findings from the original planet to trial, rather than a direct effect on playlets on on your development. So those those questions still still remain unanswered. But regardless, I agree with Patty, that it should lead us to apply the evidence and use in the great majority of babies, a more restrictive threshold, at least until we have more more evidence to answer some uncertainties that are lingering, and in some populations

Ben 42:36

that you're bringing up about the higher incidence of BPD is something that is very interesting. And I'm curious to get your thoughts. All of you, I guess, on on what does that say about? I mean, there's a lot of discussions about the etiology of BPD. And obviously, the inflammatory hit that babies are exposed to, what does that say about the pro inflammatory properties of platelet transfusion? Is that something that we we underestimated until now and that maybe we should take a closer look at in the future?

Speaker 4 43:07

That's a question that's near and dear to all of our hearts. I think it has to be I don't know if you want to go I'm happy to answer but you.

Unknown Speaker 43:16

Cassidy is the expert in in desperately and

Speaker 6 43:19

Yeah, well, both of you are the experts in thinking about how neonatal platelets may differ from adult platelets. But the focus of my work is really looking at how platelets mediate vascular inflammation and lung disease. And so I think there in the context of my work, we know that platelets contain a number of different basal activity eaters inflammatory molecules that are known to buy them selves promote inflammation, and then also through their interaction with other What are more classically thought of as immune cells and monocytes and neutrophils, the to prolonged inflammation. I think there's a lot of support in a number of different fields for this rationale, and that's what we're focusing on. And Martha and Patty have done a lot of work and looking at how neonatal platelets are unique compared to adult platelets and might have some gains of understanding and their work and how these transfusions of adult platelets may be promoting this inflammation and the acute and chronic setting. Yeah, and

Speaker 4 44:29

I think it's really, I mean, we all think it's super important question like, for a long time, people only thought platelets were hemostatic cells, they have no nucleus. They're just these little fragments. They're not that smart. And we all find that really offensive. They're super smart. They do a lot of other things, and they're really active immune cells, like Cassidy said, and really there's a lot of preclinical work going on and moving into the clinical arena as well from both both our lab and Cassidy's lab, trying to ask this question, so we use mouse models to look at inflammation for transfusion, and we're also looking at it in in humans. And so I think we're hoping, you know, there's gonna be new things coming down the pipeline in the next few years answering that exact question.

Ben 45:16

Martha, you're satisfied with it.

Speaker 5 45:23

think the key message for neonatologist should be that platelets have very important hemostatic function, and should be given when the level of thrombocytopenia or prior recent bleeding or active bleeding, really require this hemostatic activity. And there is evidence that if you transfuse at a person of 25,000, that's enough. But I think we as neonatologist, and everybody really in medicine, need to begin to understand that they also are very significant immune cells that interact with that immune cells of the baby. And that can really mediate immune responses that are different from what you would have desired and dysregulated. And there is important preclinical work that is just coming out from some of our laboratories and some other laboratories, showing, for example, that they promote monocyte migration into inflamed areas. So that might be one of the mechanisms that may contribute to, to this. So I think we need to begin to think about the platelets were given to babies and platelets in general, is living at the intersection of hemostasis and immunity and inflammation.

Ben 46:37

As we wrap up the planet to trial, the question that some clinicians may wonder is obviously, if if we have a certain degree of certainty that a baby is quote, unquote, clinically stable and has a platelet count of 26,000, then I will not transfuse, but there's always this gray area of what does a platelet count below 50,000, but yet still above 25,000? Is that maybe an early sign that there could be something going on some other form of inflammatory process, whether it is an infection, whether it is anything else? And what is your recommendation based on the data that is that we now have available for clinician to dissect between the approach to dissect, I would say between the Signal and the Noise when it comes to these infants who are in that area where it's like, am I am I looking at something here? Or is this just something I should let go for a second and keep watching you go ahead, Martha. Yeah.

Speaker 5 47:38

So then these are two completely completely different things, at what level a transfusion is justified and beneficial, is a completely different question of at what level is low platelet count indicating something at platelet count re below 100,000 is absolutely a sign that something is wrong. It doesn't mean we need to transfuse but it absolutely means we need to look into that. And and so these two things are not hand in hand, I think platelet count less than 50,000, and a baby that before wasn't thrombocytopenic. And where we don't have a clear explanation like severe preeclampsia should always always trigger concern and something is going on. And doesn't mean we need to transfuse but we need to evaluate. And the other thing to remember is that a low platelet count can be in frequently is the initial presenting sign of infection, sepsis or even necrotizing enterocolitis before the baby has other manifestations that are overt. So please take a look later can seriously referred you don't need to transfer.

Ben 48:52

I know how to trigger my hematology friends. Yeah. Sorry. Then I guess, as as we as we conclude this this review of the paper, my question is based on the data that we've reviewed, what doors do these papers do the study open for future questions that now need to be answered? I know we addressed some of this in terms of the content of of platelet transfusion and so on. But in terms of how we look at thrombocytopenia in the NICU, what are some of the questions now that come to the forefront of the of neonatology?

Speaker 6 49:31

I mean, I think for for me, and then I think Martha has a lot of thoughts on on where to go and how to answer these questions. But I think for me the questions that are still there and as we take care of smaller and smaller, more immature babies is are those thresholds similar, and our babies that the 22 to 24 week threshold, the majority of patients that were in that planet to trial for around 26 to 28 weeks So I still think we have questions in that regard. And I still think we have questions in the context of in the first several days of life, the babies in the planet to trial receive transfusions after a head ultrasound was performed, that was normal, and after the first several days of life, so I still think that there's a lot of studying sorry to move forward and addressing and studying that question.

Speaker 5 50:23

I could not agree more with Cassidy, I think planet to, you know, lift some uncertainty in those smallest, most fragile babies, particularly in the first week of life. Because 39% of the babies that were enrolled in Planet two had received one or more platelet transfusions before randomization, you know, and, and the median age at enrollment was seven to eight days. So I do think more data would be beneficial to clarify any remaining uncertainty, especially in that population that Cassidy was saying that 2324 weekers, in the very few first days of life, where it's the highest risk. And, you know, we're hoping to propose a trial to address specifically that population that time and that lingering uncertainty.

Speaker 4 51:18

And then I was just going to add from a more like developmental biology standpoint, I think the big unanswered question is, how is the unique platelet that we know neonates have that's different from adult platelets? How does it fit into the immune balance of a preterm neonate? Do they think we have a pretty good understanding of how it fits into the hemostatic balance of a preterm unit, but really how that plays out, like Martha said, that exists at the intersection of hemostasis and thrombosis, or sorry, of hemostasis and inflamed inflammation, how, how that platelet fits into the immune system of the neonate. And I think we really don't know that right now. It'll only add to those really important questions of why, why there's harm. So

Ben 52:00

and I'm assuming there's potential hope to see data from the planet to continuing to come in as these babies continue to grow, I guess, right, maybe hopefully did five years or something. If, if the investigators managed to, to get that done?

Speaker 5 52:17

I think that'd be wonderful. I don't know if that is planned. Or follow up? I hope so. You know, we don't know. We knew there was going to be a two year follow up. And as Patty said, this was long awaited. But we're done on life. Telesco. Reg,

Ben 52:31

when you do have a signal that is that is strong like this two years, you always wonder how does that continue? Does that continue to remain pronounced further? Does it does it taper off? And I think that could be a very interesting question, or maybe somebody else will, we'll take that off. Anyway. Guys, this was this was a phenomenal review. We really appreciate you sharing with us your commentary, and we'll obviously link the link to the video commentary on the episode page. And we look forward to chatting with you further on the incubator podcast on further episodes. Thank you all very much for making the time to be with us today. Thank you. Anyway, I have more to cover. So I have to. I have to keep the show moving if that's okay. So let's go. Let's go. So I'm going back to the New England again. And this was an this was a very interesting study. It's called by Vaillant. prefusion F vaccine and pregnancy to prevent RSV illness in infants. The first hold on one second.

Okay, I'm starting again. So this was called by villain profusion of vaccine in pregnancy. To prevent RSV illness in infants first author is cabman. And it's for the Matisse study group. It's in the New England Journal of Medicine, it is an international cohort. So the background is that we all know RSV is the most common cause of acute lower respiratory tract illness and a leading cause of death in infants younger than six months of age, particularly in low and middle income countries. Now, there's a recent European study that shows how approximately 50% of hospitalization for respiratory tract illness in children younger than a year of age, we're associated with RSV, and approximately 60% of these illnesses occurs in infants younger than three months of age. Now, in low income countries, it's actually thought to be even higher up to like 80%. Now there's this vaccine that we know potentially could lead to transplacental transfer of maternal antibodies to provide protection in infants immediately after birth. We know about the concept of transplacental transfer because of strategies like this being used for the tetanus and pertussis vaccine for the Coronavirus and influenza. And so the question that the group is asking is, what is the safety and efficacy of this, of maternal RSV pre F right which is the name of the RSV vaccine, in preventing RSV associated lower respiratory tract illness in infants. And so the idea is if we vaccinate the mothers, could we reduce the incidence of RSV in children less than three months of age? This to me is like, theoretically, everything makes sense. I am aware of transplacental transfer of antibodies, but this

Unknown Speaker 55:17

is still it's fairly and we do it for other things.

Ben 55:20

I know but it feels like science fiction.

Unknown Speaker 55:23

But we do it for purchases.

Ben 55:24

I know. I know. But

Unknown Speaker 55:26

it is cool that we are able to do it. I'm gonna tell

Ben 55:29

you why it looks like it feels like science fiction to me is because we I entered residency with pertussis being vaccinated in pregnancy. And so that's something so to me, I've saw very few cases of pertussis. I saw a few, but to imagine that this could potentially solve RSV in the first three months of life is mind blowing to share, right? Yes, as a resident, I feel like what else am I going to take care of them. So this is a phase three double blind randomized placebo controlled trial that was conducted in 18 countries over for RSV Season Two in the northern hemisphere to in the southern hemisphere. And it evaluated the efficacy and safety of maternal RSV pre F immunization against medically attended RSV associated lower respiratory tract illness in infants followed for one to two years so obviously, they tried to track RSV and all that stuff, but we really looking at some medically attended RSV infection. The patients who were eligible were mothers who were healthy 49 years of age or younger, who were pregnant between 24 and 36 weeks of gestation on the day of the planned injection. They had to have an uncomplicated singleton pregnancy, no known increased risk of pregnancy complications. The intervention was that eligible women were randomly assigned in a one to one ratio to receive either a single im injection of 120 microgram of the RSV pre vaccine. It included half and half antigens of RSV and RSPB in that 120 microgram, or a placebo. Now, they had two primary efficacy endpoints, and that was medically attended severe RSV associated lower respiratory tract illness, and medically attended RSV associated lower respiratory tract illness in infants 90 120 150 and 180 days after birth. So I think as you read the paper, it can get super confusing because you have to pay attention when they're talking about severe RSV or associated lower respiratory tract illness or just regularly regular medically attended RSV. So like they had some regular and severe. And I had when I was reading the paper, I had to go back several times it was that severe was that not severe because it's yeah, anyway, the secondary endpoints included medically attended RSV associated lower respiratory tract illness, RSV associated hospitalization, and medically attended lower respiratory tract illness of any cause occurring in the first under 360 days after birth. Like I said, they did try to track for RSV, so they had surveillance for respiratory tract illness, an infant started at 72 hours after birth, and that continued for up to 12 to 24 months depending on when you really were enrolled in this study. They basically did nasal swab with reverse transcriptase PCR, during any at any medically attended visit for respiratory infection. So they construct the conducted surveillance for medically attended respiratory tract illness in infants who were six months of age or younger through weekly contact with the infant's parents or legal guardians. Now in terms of so that was the efficacy endpoints that talked about safety endpoints, so they looked at reactogenicity and adverse events in the maternal participant and adverse events and newly diagnosed chronic medical conditions in the infants. The safety endpoints for kids were adverse events from birth to one month of age, serious adverse events and newly diagnosed chronic medical conditions from birth through 12 months of age. The adverse events of special interest obviously were preterm birth or delivery, developmental delay, a positive reverse transcriptase PCR based or antigen based SARS, cov to test extremely preterm birth, extremely low birth weight and congenital anomalies all were considered serious adverse event. Okay, so what are some of the results so they ended up randomizing about 7400 Women 7000 7358 received either the RSV pre F vaccine, I'm sorry, not 7000 3682 PARTICIPANT received the vaccine 3676 received a placebo. Obviously, the demographic characteristics were broadly similar across the Trial Group. A large proportion of the study participants were enrolled in the US that was about 45% Among the maternal participants 64% were white 20% Black 12% Asian 29% were Hispanic or Latinx. I think it's important to mention especially as we're doing these phase three trials, I think it's important to see who who and where were the people who were tested. At the time of injection, the median age of the woman was 29 years with a range of 14 to 47. I mean, terrifying 14 years old, and the median gestation was 31.1 31.3 weeks with a range of 24 to 36.9 weeks. Okay, so let's talk about some of the efficacy so they had like a pre specified date for the interim analysis. And the RSV pre F vaccine was effective against medically attended severe RSV associated lower respiratory tract illness within 90 days after birth, and protection was maintained through 180 days. The statistical success criterion for vaccine efficacy was not met for medically attended RSV lower respiratory tract illness. So they basically ended up stopping the trial early because for severe RSV, they had met the criteria now for regular medically attended RSV, they had not reached that point where they had to stop the trial, but the results were were were proven. So let me give you some of these efficacy data. So within 90 days after birth, six infants of mothers in the vaccine group compared to 33 infants in the placebo group had medically attended severe RSV. Within 180 days, there were 19 cases in the cases of vaccinated mothers compared to 62 cases in the control. When we're looking at 90 days 24 infants of mothers in the vaccine group, and 56 infants in the placebo group had medically attended RSV, so that's not severe, just straight up RSV that needed to be medically attended. And within 180 days, it was 57 infants in the vaccine group compared to 117 in the placebo group for RSV associated lower respiratory tract illness. So these are quite impressive, the vaccine efficacy was reported to be 67.7%. With respect to RSV associated hospitalization, within 90 days after birth, I mean, to me severe RSV, within three months when you can reduce it from 33 to six, and then within 180 days from 62 to 19 cases is insane. And even the regular RSV going down from 56 to 24. From 117 to 57. At six months is crazy. In terms of safety, there were no safety signals were detected in maternal participant or in infants and toddlers up to 24 months of age, the incidences of adverse events reported within one month after injection or within one month after birth, were similar between the two group and our usual culprit have like some some tenderness at the site and so on. The conclusion is that when administered to women, late in pregnancy, RSV pre vaccine was effective against medically attended severe RSV associated lower respiratory tract illness in infants. I'll post that graph. Did you see the graph? Yeah, it's beautiful. It's insane. I mean, what a paper.

Daphna 1:03:14

I mean, this is really exciting. It's really exciting. Especially, you know, even in our area, we have such a hard time with compliance with the RSV with the synergis, you know, schedule. And so I mean, I don't know that this would avoid that altogether,

Ben 1:03:31

we're gonna be, we're gonna be the last. We've our biggest thing six months in the NICU, we're still gonna have to, to vaccinate them before they go. But that's that's

Daphna 1:03:39

true. But, but even for, for for infants that are you know, not preemie are not high risk. I mean, RSV is such a significant cause of morbidity, mortality, it's just

Ben 1:03:51

I'm just curious to see how the circulation of the virus is going to be impacted by that as well on an epidemiological level. That's going to be interesting, too. But I mean, you reading the paper, and if you guys are reading it, just you read through it, and you're like, man, is this just going to solve the kids will get to the PICU. And this is exciting.

Daphna 1:04:08

Yeah, that would be great news. Okay, I have a paper. It's called intraventricular hemorrhage and very preterm children mortality, and neurodevelopmental at age five. This is in a journal Pediatrics. coming to us from France. You hear you'll help me with the names lead author, Ludovic train, New Year, your

Ben 1:04:32

tail, yeah. Sorry. That's okay.

Speaker 1 1:04:37

Okay. And then trailing author. Eloise,

Ben 1:04:42

Eloise, yeah Torshin Yeah, the wider paper doesn't want to open on my on my computer. I see the first author Hold on, actually, oh, it's Daksha but

Speaker 1 1:04:51

sorry, one of these days I get the French names.

Ben 1:04:55

I can do all of them for this one. That's second to last author is Pierre he won't sell. They will need PR Ah, Stefan money. I know how to pronounce all of these. Look at me. That's right.

Daphna 1:05:03

Very nice. Very nice. And of course the the study cohort importantly is coming from epi posh.

Ben 1:05:10

Yeah, that's right. You got that one down. Right.

Daphna 1:05:14

So the objectives of this study were to describe the mortality and cause of death and preterm children born before 32 weeks gestation, with ivh or intrapreneur intraparenchymal hemorrhage, and a steady neurodevelopmental outcomes in surviving children with low or high grade ivh. In this epi pouch to cohort, and specifically, they wanted to pay attention to the cause of death, and see if in particular, the cause of death in the high grade ivh grades three and four, were because of withdrawal of intensive care or withholding of intensive care. So I thought that was an interesting perspective. This is a secondary analysis of the French national population based in prospective cohort, epi posh to a team identified infants by grade of ivh and then excluded long term evaluated sorry, long term neurodevelopmental outcomes were available. So the inclusion criteria were children born before 32 weeks gestation, without cerebral congenital malformation or chromosomal abnormality and they were first admitted to NICUs. I told you that chromosomal abnormality children with missing ivh status stick PVOH were all excluded. Of note, they assigned ivh classification according to the peel classification. So it's different from the Volpe classification. Just something to keep in mind. For most children, at least one had ultrasound was performed in the first eight days of life than another before 2021 days of life. And at about 36 weeks postmenstrual age, the team use the highest IV age grade across the admission to classify infants. And importantly, in case of bilateral hemorrhage, the greater the most severely injured side was retained. I think this is important too, because we actually have quite a few papers in the last handful of years that looked at bilaterally of ivh. And it does change outcomes significantly. So I think that's just something to note, and if you're not familiar with that data, I recommend you take a look. neurodevelopmental measure measures of between age five and six children had a standard assessment by train pediatricians and neuro psychologists using a number of evaluation so they use the movement as Asri battery for children, the Wechsler Preschool and Primary skill of intelligence and of course hearing imaging screening. Parents also completed the strengths and difficulties questionnaire, and they mailed the questionnaires if the parents were not able to come to the center based assessment, okay. The primary outcomes were in hospital mortality, neurodevelopmental disabilities at age five and surviving children, and they lifted disability free survival. The eligible population consisted of 3646 children 2.6 were excluded for missing ivh 2.3% for cystic PVOH. Of the 3468 children 16.7 had grade one ivh 12.2 had grade two ivh 3.3% had grade three ivh and 4.1 had interpret trig intraparenchymal hemorrhage, the mean gestational age, per group 28.7, and grade one ivh 27.8 and grade 220 7.4 and grade three, and 26.6. Infants with grade four IBH for children with no ivh. The mean gestational age was 29 weeks. That's important to note also because that is a big difference in gestational age when you're talking about neurodevelopmental outcomes. mortality in the absence of ivh was 4% and increased to 6.7% in children with grade one ivh to 74.4%. For those children within truprint intraparenchymal hemorrhage, I'm going to call that IPH. death occurred mostly during the neonatal stay and was secondary to with what they say WW LS T withholding and withdrawal of life sustaining treatment. And so that occurred in 67.6% of children with grade three and an 88.7 of those with interpreted intraparenchymal hemorrhage. So that's the overall death 67 in grade three ADH in IPH. None of the children with Grade One and Two ivh died of central nervous system injury conversely, central nervous system injury was the main cause of death and 42% of children with grade three and seven to 3.5% in those with IPH and children with high grade ivh in hospital death secondary to withholding and withdrawal of life sustaining treatment was associated with low gestational age absence of antenatal steroid therapy, early hemodynamic disorders and central nervous system injury identified as the main cause of death in survivors. severe nerve event, your demand to disabilities and CP rates increased with ivh. severity. That's not surprising. But in a reference group of children without ivh, low grade ivh was actually not associated with any measured nerdy, nerdy, felt mental disability. Sorry. They also looked at a subgroup of babies born before 28 weeks gestation, and they were in line with this result that they did not they were not associated with measured neurodevelopmental disability. This in other studies have shown this and the converse, so there's still some debate about whether grades one and two predict neurodevelopmental outcomes. High Grade ivh was associated with moderate neurodevelopmental disabilities and odds ratio of 2.35 and severe neurodevelopmental disabilities and odds ratio of 2.28. It also was associated with reduced full scale IQ and cerebral palsy overall, with an odds ratio of 3.45. Disability free survival decreased with ivh severity, and those infants with no ivh the disability free survival is 45% in those with grade one ivh 41%, grade to ivh 40% grade 320 5%, disability free survival and in intraparenchymal, hemorrhage 11.6%. So the study takeaways are that children with low grade ivh had high with had higher mortality rates than those without ivh. But deaths were caused by other organ failures than to central nervous system injuries. Furthermore, low IQ low grade ivh was not associated with an increase in any neurodevelopmental disabilities at age five in this cohort. Among children with high grade ivh, mortality rate was high 50%. And having withdrawal or withholding of life sustaining treatment was very frequent. At age five, high grade IBH was strongly associated with overall neurodevelopmental disabilities reduce failed scale IQ and cerebral palsy. And it's correlated inversely with disability free survival. But I think this sheds a lot of light on to what are counseling looks like, you know, what, what we don't know what the outcomes of all of those babies would have been? Right? The ones then in which we, you know, they have this withdrawal of intensive care, or withholding of life sustaining therapies. And, you know, I just listened to a great lecture by Dr. Henner, Dr. Hunter, and about Trisomy 13, and 18. And that's different, obviously, I mean, they're just different cohorts. But, you know, we have biases in the medical system about what we think is quality of life compared to what parents think is quality of life. So I think this study sheds light on how much of those deaths are associated? Because of, you know, rerouting care?

Ben 1:13:18

Yeah, yeah, absolutely. I think it's, it's a good reminder of how bad those those severe severe cases can be, especially when you're looking at grade three, grade four and intraparenchymal hemorrhage, however you want to categorize that. But it also shows that for the milder forms, it's very variable, right? Because it does it feel like you, you could go through the literature and find papers that do show some impact, some that don't show an association. Is that your dog, we hear in the background,

Unknown Speaker 1:13:47

that mine the neighbor's dog,

Ben 1:13:48

the neighbors, fine will tolerate that.

Unknown Speaker 1:13:52

There's nothing I can do about that.

Ben 1:13:53

There's nothing you can do. What technically, if you won't go that far, we won't make you a criminal. But yeah, so when it comes to the lower grade ivh I think it's it's really, it's exciting for me that you can potentially tell the parents that it's variable, like, it could be some impact could be also no noticeable change. If therapies are implemented, and if everything else is done correctly, so that Yeah, yeah, I mean, yeah, we'll see. I mean, this is I'm not sure how many more papers they'll be able to pull out from the cuts,

Speaker 1 1:14:28

right. refute they've done I don't know least a dozen of them.

Ben 1:14:31

Yeah, they're gonna I'm curious to see what comes out next from this group. Okay, maybe I have time for one last one. What do you think? Well, yeah, since we're talking about ivh, I guess let's take let's stick to AVH. This is a paper that is published by our good friend Abdul Razak, in JAMA Network open, and it's called interventions to reduce severe brain injury risk in preterm neonates a systematic review and meta analysis mostly As we're talking about ivh, I thought this was an interesting paper. It talks about obviously how there are many perinatal interventions that have been tested in clinical trials to reduce the risk of severe brain injury in preterm neonates. But the authors say that to their knowledge, there has been no published systematic review of interventions, or a network meta analysis of the role that the interventions evaluated in clinical trials play in reducing the risk of severe brain injury in preterm neonates. So basically, they use an intervention review format to evaluate multiple perinatal interventions for reducing the risk of severe ivh and cystic PVL. In preterm neonates across clinical settings. So this was a systematic review and meta analysis following the Prisma reporting guidelines. They included in the review randomized control trials that had reported one or more pre specified outcomes, whether it is severe ivh, cystic PVL, and severe brain injury. They include a trial that reported outcomes in preterm neonates that were born before 37 weeks of gestation or in term and preterm neonates for whom data could be extracted. What was interesting is that if you're studying for the boards, it's a great review, they were able to identify 44 possible interventions that that they that they identified as having potentially a reported effect on brain injury. And the three pre specified outcomes were severe ivh cystic PVL, or severe brain injury defined as the presence of either severe ivh or cystic PVL. I'm going to go through some of these interventions. Basically, they divided these 44 interventions into either whether they were antenatal, and that included antenatal steroids beta versus dexamethasone for long maturity. The the repeat antenatal steroids versus a single course. Magnesium sulfate, the use of antibiotics and the decision to proceed with a C section versus vaginal delivery for preterm birth. They then identified a bunch of delivery room intervention which were vfio to use during resuscitation, the use of sustained inflation versus standard resuscitation delayed versus early cord clamping, cord milking versus early cord clamping cord milking versus delayed cord clamping, delayed cord clamping with respiratory support versus delayed cord clamping without respiratory support. And then 32 postnatal intervention that includes a lot of stuff, and we'll get into that I'm not going to go through the list of 32. But I thought it was a very nice little review. Now, in total 221 RCTs were included in the final sample these trials evaluated these 44 intervention. And as I said, there were six prenatal six in the delivery room and 32 new and neonatal interventions. So let's look at severe what how much time is it okay, I don't have much time, but I'm gonna go through the results section this way. So the minute analysis showed with moderate certainty, that antenatal corticosteroids were associated with a small reduction in severe ivh risk, the risk ratio of point five for the number needed to treat the number needed to treat of 80 whereas indomethacin prophylaxis was associated with moderate ridic reduction in severe ivh with a number needed to treat of 20. Similarly, the meta analysis showed with low certainty that volume targeted ventilation was associated with a large reduction in the risk of severe ivh with a number needed to treat a v 11. I was not expecting of all the things that they reviewed that this one was going to come back so prominently, another one that they intervention that they identified was the use of erythropoiesis. Stimulating agents the ESA is like EPO, and RB, Bo and so on with the number needed to treat of 34 and the relative risk of point six eight. Another intervention was prophylactic use of FM isolate, which I was not super familiar with, with a number needed to treat of 26. And they were associated with a moderate reduction in severe ivh risk with low certainty. The main analysis also showed with low certainty that compared with delayed cord clamping umbilical cord milking was associated with a moderate increase in severe ivh risk with a relative risk of 1.82. And so the conclusions of this study are that there are very few interventions including antenatal steroids interim indomethacin that were associated with a reduction in severe ivh risk and volume targeted ventilation early ESS prophylactic FM selects were associated with a reduction in severe ivh risk with low certainty in preterm neonates. Now clinicians they say should carefully consider all of the critical factors that may affect applicability in these interventions, including certainty of the evidence before applying them to clinical practice. And so it's it. I don't I mean, I don't know what to make of it. But it's a good reminder that has things come out when you actually do these. I mean, by the way, you read the paper and you you see how the work that was done by Abdullah and his colleagues. I mean, it's a massive undertaking. And and that's just the type of guy he is and the type of people he works with as well. But the, the impact of these interventions are not always so clear cut, then it goes back to the article that we reviewed by Shauvik, Mitra on on some of these interventions and what really is the effect? So? Yeah, I mean, not very much. I mean, looking at not very much. I mean, there was some things that were interesting, like maybe the the use of high frequency oscillation right off the bat, and severe and severe in the extreme low birth weight infant was kind of associated with worse ivh outcomes. So there were a lot of things that you can you can tease apart within the paper that were very interesting. I suggest you, you read it. And yeah, I mean,

Daphna 1:20:46

well, I think that's why, you know, in the hospitals that have shown decreased ivh. Over time, it's really these bundles. And I think it's just this attention to the fragility of these babies, because not one single intervention, like is the golden ticket, I think is the point. I think it's also a good reminder that like some babies are going to do well, no matter what, and some babies are, unfortunately, going to do poorly no matter what we do, but we should still be working to prevent every ivh possible.

Ben 1:21:19

Right. Right. Right. I agree. And then and then. But it's, it's interesting, it's interesting, because I think it goes back to some of the cognitive biases that we have, where, unless somebody does this work, you do not have the cognitive capability of grasping these large numbers. So when you're looking at 220, RCTs, like, just that alone is just makes my head hurt, right? It's like, how do you process that? And then when you look at all the different the different meta analysis that they did, based on the outcome, and based on what was tested. So for example, for for, let me see which one I'm looking at right now. Volume, targeted ventilation, 13 trials, 900 participants, like it's like, how do you put that into context, and it requires the work of people like Abdul to do this. In order to get a sense of like, wow, like we we have that many patients right? In the medicine 2584 participants 15 trials. That's, that's hard. That's hard to get a to just wrap your head around. So a very interesting paper. Definitely something I want to save in my my library of articles and something that I wanted to mention on the podcast today.

Daphna 1:22:31

Yes, sometimes you can learn as much from the Background section as you can from the work done on the paper. You know, they did such a nice job putting that together?

Ben 1:22:39

Absolutely. Absolutely.

Daphna 1:22:41

I only as we're wrapping up, I wanted to just bring people's attention. Maybe a lot of our listeners are not subscribers to the Lancet. But they did this. They call it the 20, the 2023 Lancet series on breastfeeding, they started doing these series on breastfeeding some time ago. And it's really basically a call to action. And I think that are

Ben 1:23:03

out of action. I'll tell you,

Daphna 1:23:04

I'll tell you what the I'll tell you what the articles are in this series. Breastfeeding crucially important, but increasingly challenged in a market driven world. That's one marketing of a commercial milk formula a system to capture parents community science and policy. The third is the political economy of infant and young child feeding, confronting corporate power, overcoming structural barriers, and accelerating progress. For stemming commercial milk formula marketing, now's the time for radical transformation to build resilience for breastfeeding, and five, unveiling the predatory tactics of the formula milk industry. Oh, so I mean, they, I think they anybody who's breastfed before or supported anybody who's breastfeeding, you know, they identified these creat key structural factors that, you know, are an obstacle or a barrier to breastfeeding. They list gender inequalities, misleading advertising, commercial milk formula industry, the government policies, economic interests, and of course, socio economic inequality and Neo colonial wealth extraction. So basically, the quote, breastfeeding is not the sole responsibility of women, but society's collective responsibility should be protected, promoted and supported by both governments and health organizations and healthcare systems and education. And they list

Ben 1:24:23

again, yeah, I love I love the beginning, that

Daphna 1:24:26

breastfeeding is not the sole responsibility of women, but society's collective responsibility. It should be protected, promoted and supported.

Ben 1:24:33

I love that man. That's really good.

Speaker 1 1:24:35

Oh, some some interesting food for thought articles to get into.

Ben 1:24:40

Should we should we then should we then give a plug to our to our series that was just passed that just aired last last week?

Unknown Speaker 1:24:50

Yes, sure.

Ben 1:24:52

Because we did. So I mean, this is a topic that obviously came up during our discussion on advocacy. So I give you the opportunity to mention it, you say go in and I know you go go, you go. So we had the we had the privilege of having on with us, Alison, rose and Emily Miller, who we spoke to about the provision of donor human milk in preterm infants, which again, is related to breastfeeding. But just goes to show that what seems to be something natural something that everybody has access to is not so straightforward and does need advocacy and needs needs, champions and so on. So yeah, go check them out. It was it was a great episode. I think this is the episode that aired on Tuesday. Okay, buddy. So thank you. Thank you for reviewing all these papers, and then do let's teases what's happening next week, we should have this week. More episodes of board review, we will have an episode of Tech Tuesday where we talk about a revolutionary device to actually keep babies warm in low and middle income countries. And then on Sunday, we have the pleasure of having on the show Jen canvasser from the next society. This is an interview that many of you have requested. So super excited to have her on and to talk to her. So yeah, I'm happy that despite PS despite all these things, we're able to continue churning out interviews and content for you guys. Yeah,

Daphna 1:26:32

for sure. For sure. And it's taken us such a long time to connect with Jen. We've been connecting with her, but we haven't yet been able to get to schedule and we finally got it on the books. So we're really looking forward to that. And you guys that article. yourself totally accessible.

Ben 1:26:50

Absolutely. Absolutely. But anyway, alright, buddy. See you later. All right. Bye. Thank you for listening to the incubator podcast. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address NICU You can also message the show on Instagram or Twitter, at NICU podcast or through our website at WWW dot v dash This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns. Please see your primary care professionals. Thank you

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