Hello Friends 👋,

This week's journal club focuses on a few topics. We have three articles discussing sepsis-related topics. The first articles compared the sensitivity of the EOS calculator and the NICE/Dutch guidelines for the evalution of early onset sepsis. Daphna reviewed a paper from Pediatrics that looked out how many infants with low-risk for EOS were evaluated for sepsis, started on antibiotics and how long were they on antibiotics for (very interesting work from our friend Dustin Flannery). We also reviewed a paper proposing an interesting framework to approach "culture negative" sepsis. Other than sepsis, we reviewed two papers from both 🇫🇷 and 🇨🇳 looking at the effect of vitamin D levels on neonatal RDS. To close the show we discussed the latest report of the neonatal research network (https://neonatal.rti.org) that published its outcomes from 2013-2018, so much interesting data in that paper.

We hope you enjoy this episode. Thank you for listening and for your support.

As always, feel free to send us questions, comments or suggestions to our email: nicupodcast@gmail.com. You can also contact the show through instagram or twitter, @nicupodcast. Or contact Ben and Daphna directly via their twitter profiles: @drnicu and @doctordaphnamd. Papers discussed in today's episode are listed and timestamped below.

Enjoy!

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

Neonatal early-onset infections: Comparing the sensitivity of the neonatal early-onset sepsis calculator to the Dutch and the updated NICE guidelines in an observational cohort of culture-positive cases. Snoek L, van Kassel MN, Krommenhoek JF, Achten NB, Plötz FB, van Sorge NM, Brouwer MC, van de Beek D, Bijlsma MW; NOGBS study group.EClinicalMedicine. 2022 Jan 10;44:101270. doi: 10.1016/j.eclinm.2021.101270. eCollection 2022 Feb.

Delivery Characteristics and the Risk of Early-Onset Neonatal Sepsis. Flannery DD, Mukhopadhyay S, Morales KH, Dhudasia MB, Passarella M, Gerber JS, Puopolo KM.Pediatrics. 2022 Feb 1;149(2):e2021052900. doi: 10.1542/peds.2021-052900.

A Proposed Framework for the Clinical Management of Neonatal "Culture-Negative" Sepsis. Cantey JB, Prusakov P.J Pediatr. 2022 May;244:203-211. doi: 10.1016/j.jpeds.2022.01.006. Epub 2022 Jan 22.

Low Vitamin D Levels at Birth and Early Respiratory Outcome in Infants With Gestational Age Less Than 29 Weeks. Papalia H, Samonini A, Buffat C, Gras E, des Robert C, Landrier JF, Pauly V, Boubred F.Front Pediatr. 2022 Jan 21;9:790839. doi: 10.3389/fped.2021.790839. eCollection 2021.

Association between vitamin D level and respiratory distress syndrome: A systematic review and meta-analysis. Kim YJ, Lim G, Lee R, Chung S, Son JS, Park HW.PLoS One. 2023 Jan 26;18(1):e0279064. doi: 10.1371/journal.pone.0279064. eCollection 2023.

Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018. Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, DeMauro SB, Walsh MC, Vohr BR, Stoll BJ, Carlo WA, Van Meurs KP, Rysavy MA, Patel RM, Merhar SL, Sánchez PJ, Laptook AR, Hibbs AM, Cotten CM, D'Angio CT, Winter S, Fuller J, Das A; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. JAMA. 2022 Jan 18;327(3):248-263. doi: 10.1001/jama.2021.23580.

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

Daphna 0:49

I'm good. Full disclosure. Still in my jammies this morning. So that should tell you how the morning is. And yet here you are, you had a recent travel and you you're

Ben 1:03

ready to IMO recharged. I I just came back from what was it for five days in Utah. The family and I went skiing. It was a ton of fun. And I we took the flight yesterday from like it was it was not an overnight flight. It was like from 6pm to like midnight. And I did Journal Club Prep on the flight. So everyone was trying to sleep and like my life was on my computer was on tell. I could tell it was bothering some people, but I'm like, Listen. I was like, if people are looking, they're like, What is this guy doing? You know? Like, it's it's 10pm. You know, I'm assuming everybody did the same thing we did, which was they had like a busy day and then they were flying either back home to Miami or on vacation. But it was funny. I just I just couldn't care too much about other people's, you know? Yeah, I mean, had to get it done.

Daphna 1:58

You could have shared with them the articles.

Ben 2:03

I'm sure they would have been super excited. What else do we have this and that, that that giants of neonatology series was a tremendous success.

Daphna 2:14

Yeah, I'm happy people seem to seem to enjoy it. I learned a lot. So it was good.

Ben 2:22

Yeah, this was great. I mean, this episode was probably our most downloaded episode yet in the span of a week. Thank you to Dr. Wily Carlo for agreeing to come on. And what's funny is all these other greats who are now like jumping on saying, Yeah, sure. I'll do an interview. So I mean, it's

Daphna 2:39

super exciting. Audience. That's a good lineup. Such a good line. Oh, yeah.

Ben 2:42

Oh, yeah. So this is gonna be fun. You guys. We're gonna have a ton of good good interviews for the year. Yeah, thank you for everybody. Again, interacting with us and following us on Twitter.

Daphna 2:57

Via Twitter has been a buzz this week, huh?

Ben 3:00

My god. Yeah, everything is. Everything is my phone is buzzing off the hook. So anyway. Alright. Should we do some some journal club after? Yeah. Okay, so since we're talking about Twitter, I will start with this article that was published in Clinical Medicine. Right. Am I saying this correctly?

Daphna 3:25

Yeah, it's a it's an open access version of the Lancet.

Ben 3:31

That's right. That's exactly right. I knew it was nothing. Okay, fine. Thank you for that. And so the, the article is called early onset, neonatal early onset infection, comparing the sensitivity of the neonatal early onset sepsis calculator to the Dutch and the updated NIC guidelines in an observational cohort of culture positive cases. So this is a first author is Lindy Snoke. I think it's an M, and she, this is from a group out of the Netherlands specifically out of a hospital in Amsterdam. This was an interesting study, right? I mean, the goal was to compare the sensitivity of the early onset sepsis calculator compared to the Dutch versus and NICE guidelines. I'm going to call them nice guideline. Right. That's, I guess that's what they're referring to. Yeah. And so what did they do is that they used sample they used patient population from this other study called the no GBS study. And that's a that's a that's an observational study that looks at early onset GBS disease, bacterial virulence, and other protective Serologies. But the bottom line is, they were looking at babies from the age of 03 months. that had either GBS or E. coli back to blood culture or CSF culture that were positive. This is the no GBS study. This was done in the this is being done in the Netherlands. It's a multicenter prospective study. And so what they did is that they isolated from the population from this no GBS study, all babies who were born at 34 weeks or more, and who had in the first 72 hours of life, a positive blood or CSF culture. And they looked at data from January 2018 to January 2021. Now, what was interesting was that in the Netherlands, they have this thing which I was not aware of, called the Netherland reference lab for bacterial meningitis. And this lab basically gets all CSF isolates of patients with bacterial meningitis. And if you are less than a year old, then they also get all the positive blood culture. So they have like, this national lab that has all the positive results, and it's like it, you read through this and it's like, Oh, my God, this is like a goldmine for research. And, and so the early onset sepsis, again, as we, as we've said, in the title, they define it pretty standard Lee, which is you have a positive blood culture or a positive CSF culture in the first 72 hours of life. Now, what was interesting was that they're comparing the EUs the early onset sepsis calculator, they're not formally using the calculator that we all know from the Kaiser Permanente, but they basically use the paper to recreate a mathematical algorithm that so basically, it's the same, right. But they don't come out outright saying we're using that calculators, they're saying, we're we're creating the calculator based on the data that was published by these guys. However, what was interesting was that Dutch slash NICE guidelines. I mean, I never spent too much time, right. I mean, we're in the US. And so it was a good opportunity to review when these were and and so I was actually not super familiar with with how they how they work. And interestingly enough, you should, if you're interested, like I was, on how the Dutch guidelines and the nice guideline function, they have in the supplementary table one very good table that that explains that. And the way it works is that they have maternal risk factors. And then they have neonatal risk factors. And for both guidelines, some of them are identified as red flags, and some of them are identified as a risk factor, but not really a red flag. And then, depending on how many red flags versus no red flags you have, you recommend different approaches. And so antibiotics usually is recommended if you have two or more risk factors that are not red flags, or if you have one red flag or more. Now, there's something interesting about so and the red flags are not always the same, right? So for example, and again, we're going to talk about this for seconds. For example, in the nice guideline, apnea is considered a red flag when in the Dutch guideline, it's also a risk factor, but it's not really considered a red flag. So these, this is where these two types of guidelines differ. Obviously, I think it's important to also know that while they were conducting the study, the nice guideline were updated in 2021. And so the the eventually in the data, compared a little bit how that new updated version of the guideline would have changed the outcome. And so what they did is that they looked at the treatment advice that would have been recommended by the guidelines and the calculator at three times three time points, I'm sorry, at four hours, 12 hours and 24 hours. And then the dude sensitivity analysis. So, so far, so good. Okay, so they were able to identify 88 patients with early onset sepsis, and of which obviously, so 100% had a positive blood culture. And of these 88 11% also had a positive CSF culture. Interestingly enough, GBS was the most commonly responsible pathogen being present and being identified on culture in 81 out of 88 patients, which was 92% of cases. Interestingly enough, they mentioned that down downstream in the paper and, and they said that only 14% of the mother received GBS prophylaxis. So I thought that was interesting. Okay, so let's talk about symptoms. So symptoms 69% of babies develop symptoms within 12 hours 76% within 24 hours. What was interesting Was that when you compare that to the babies who were considered to be clinically ill at birth, that was only 36% of the court. So that's, that's, I mean, when you read that, the fact that the number will jump from 36% of symptoms at birth to 76 or 24 hours. I mean, it's pretty staggering, especially considering that we, we try to make decisions really soon after birth. Only 3% of babies in this cohort never develop symptoms. So, really 97% eventually developed symptoms throughout the course of their disease.

Daphna 10:31

And most of them in the first 24 hours, which that's fit with what we know about early onset sepsis. However, it's nice to know if you really have a well appearing baby, you know, 24 to 36 hours that you should be okay. Yeah, much lower of sepsis.

Ben 10:49

So let's look at the sensitivity analysis. And that was very interesting, obviously. So when it comes to the percentages of babies on whom antibiotics would have been recommended, looking at the first time point, which was at four hours, the early onset sepsis calculator recommended antibiotics in 36% of cases. So 36% of the babies who ended up having early onset sepsis. So yeah, the Dutch guideline did a bit better with 50%. And the nice guideline, which again, we had never, we didn't mention, but the nice guideline is from the UK. It was 55%. And that was a statistically significant difference. Obviously, routine care was also similarly divided. The early onset sepsis calculator was recommended routine care in 52% of cases at four hours, the Dutch guideline add, in 31% of cases, and the nice guideline in 30% of cases. When we're looking at antibiotic recommendation, what was very interesting to see and I suggest you look at the figure in the paper is that after four hours, the recommendations at 12 and 24 hours, the gap between the recommendation got significantly narrower. So at 12 hours, the brilliance of this calculator recommend antibiotics in 55% of cases, while the Dutch guideline recommended it in 69% of cases and the nice guideline in 68% of cases, again, statistically significant, at 24 hours. Still a bit of a gap, the early onset sepsis calculator recommend antibiotics in 61% of cases, the Dutch guidelines and nice Ghana and about 70 to 73%, that no longer was statistically significant. So that gap had pretty much closed. The, what was interesting is that the people mentioned which like in how many percent of babies did the recommendation really differ. And the recommendations differed for 17 kids in total when it came to antibiotic. And for 15, out of the 17. And the early onset sepsis calculator recommended no antibiotics, while the other guidelines recommended Direct, which means that for the other two, maybe they recommended cause follow up or routine. But I thought that was interesting. Going back to some of the of the sub analysis, 28% of the ADA, kids had severe diseases, and they had defined severe disease, I think pretty well, seeing that the baby's development and giantess seizures, any form of brain lesions, had any need for pressors mechanical ventilation or unfortunately passed away. Now, of these 28 Babies who had severe disease 40% of them so 10 Kids, the EOS calculator recommended antibiotics, compared to 44% for the Dutch guideline and 48% in the nice guideline. So again, a bit more inclusive when it comes to these other guidelines that they looked at how the new changes in the guidelines affected their results. And the sensitivity of the new nice guideline did affect the results. So the sensitivity increased at four hours of life by 1%. But the sensitivity then decreased at 12 and 24 hours by 2%. And so their interpretation is that the EOS calculator is less sensitive than the Dutch slash nice guideline, especially when you're looking at it directly after birth. They are moderating their statement by saying that the early onset sepsis calculator does rely heavily on clinical illness and less so on just plain risk factors. But still, I mean, in terms of sensitivity, deduction, the nice guideline definitely had had better sensitivity. So very, I mean, I'm not going to go into the discussion because Go ahead, I'm gonna give you the

Daphna 14:49

well I think if you if you really want a very input discussion, then then you gotta review the Twitter feed for for the last week, right So there's a whole bunch of opinions on on on the issue and you know, who's to say, who's right or wrong. But I think it's not to say that these calculators are not useful, right? They're, they're helpful, especially in identifying risk factors. And they've certainly reduced antibiotic use, which, which is a good thing, especially as we discuss the next paper. But that, that, you know, so much of medicine and the art of medicine still relies on your, you know, your clinical evaluation of the baby and serial monitoring. And that's, you know, I'm hopeful that our machine learning will continue to improve, but I'm, I'm hopeful that I will still be needed as a physician, and that my clinical acumen has has some utility.

Ben 15:49

But yeah, I mean, I think the way the paper is, is framed, makes you feel like, oh, like, if we could reach 100%, that would be the best, like the most sensitive, and you almost find yourself falling into this, like, first year med student mindset where it's like 100% sensitivity.

Daphna 16:07

Yeah, if it's not good, then it's not good enough, right.

Ben 16:10

And it's, and it's so untrue. I mean, rate sensitivity means that you would catch, if you had 100%, sensitivity, you would catch everybody with early onset sepsis, which would be great. But it would also mean, you're going to end up dying, working up and treating separating babies from their mothers in vast number of cases. And that would not be that would not be appropriate, that's where specificity would really be an important other variable. So I think that the paper concludes that the sensitivity of the doctrine, the nice guideline is superior to the US calculator. And I found that to be a bad thing. I mean, again, I'm on that side of the equation, when it comes to the Twitter discussion, which is, I would much rather have a tool that is less sensitive. And that relies more on your clinical argument than the tool that forces you to pushes you towards a direction that's invasive, with more interventions, more meant more treatment, right. And, and the reassuring thing in this whole paper is that if you follow up these kids at 20, for 12 hours, you should catch all of them, right? I mean, the, you see that as you follow these kids throughout the first, I would say 72 hours, they will all be developing symptoms. So it's up to you, like you said, the clinician to follow up with them, check on them, and rely on your clinical acumen. And what's interesting is that maybe the NICE guidelines are trying to aim at that because you see that the new updated guidelines reduce their sensitivity a little bit, especially at 12 and 24 hours. So I was not all doom and gloom on the Eos calculator after this, I was actually pretty happy. And it can, comforted me in the idea that if you are out there using the EOS calculator, this is not something you do after birth, and then put away like, must do the scenario evaluations, if the risk factors are there, but this is a journal club that's going to be all dedicated almost to sepsis. So there's more discussions to be had, I think,

Daphna 18:15

yeah, you know, it's complicated because of how medicine is changing, right. So more patient load more time spent on EMR, so really, less time at the bedside. And I think that's where we've reached this crossroads where, you know, this is where these, these babies may get messed, right, because you you if you're not able to do serial exams, or we're bringing way fewer kids into the NICU for monitoring, which is a good thing. But then they're out there in the world in the nursery, where they may only be seen by somebody once once a day. And

Ben 18:57

well, then that that's a good reminder that yes, don't spend so much time documenting good check on the babies.

Daphna 19:06

And that's our, that's our unit paradigm. Right? We will have better outcomes if we spend more time on the floor is then in our office.

Ben 19:14

But yeah, I want to mention to the audience that throughout my fellowship on every evaluation that I received from my program director was like, you could improve on your documentation. And I was like, I could not care less about my documentation. If my patient outcomes are good, if the staff is happy, and I think in our hospital, I'm sure like they have my picture in the medical records office because I have like hundreds of things to sign and, and I just don't prioritize it because to me, speaking with families, checking with your nurses teaching and checking on patients is what is paramount. So anyway.

Daphna 19:52

That's a loaded statement. Dr. Porsche, that patient doesn't matter. I think there's a there's probably a middle ground right where we My employer will

Ben 20:00

not be happy to hear that though. That's okay.

Daphna 20:04

Anyways, moving quickly Oh, wait. We have another another paper that focuses on sepsis. This is in pediatrics is entitled delivery characteristics and the risk of early onset neonatal sepsis. The lead author is Dustin Flannery, who is very active on Twitter.

Ben 20:27

And, you know, what I wanted to do is that we should mention their handles. You know, I was I think that's great. Yeah. So I think Dustin is a great follow if you're on Twitter and his handle is at D U. S. 10. Flan. So Dustin, finally, at the US 10 Flan follow him. He's great. And he's interested in early onset sepsis. So he'll post like, very valuable evidence. And I think I started writing those down.

Daphna 20:52

Yeah. And you know what I like about Dr. Flannery's, he doesn't like, what? He doesn't post and ghost, right. So he'll post and then we'll really have a, a discussion with whoever interacts. And I think that's one of the most valuable things about being on to Twitter. And then I'll just mention that the, the anchoring author is Dr. pueblos. So I've known for this. So this is a retrospective cohort study of babies born in Philadelphia hospitals, they looked at all infants born between January 2009, and December 2014, with at least one blood culture obtained at less than or equal to 72 hours of age with or without a CSF culture. So either a positive blood culture or a CSF culture that was positive or both. And what they really wanted to look at was were their characteristics of term and preterm infant deliveries, really, and that would modify their risk for early onset sepsis. So they don't talk about the sepsis calculator, except that some of the criteria are the same, but that they include a lot more delivery characteristics. And so they placed infants into risk categories for the development of sepsis based on a variety of criteria. So I guess we should talk about those a little bit. So I really hope people will take a look at their stratification because I think it will help. But they really wanted to identify really which babies had low, low risk, but really no risk, frankly, of developing early onset sepsis. And that's what they showed in the paper. So they looked at rupture of membranes, they looked at the presence or absence of labor, they looked at things like were you a VBAC, or a TOLAC? Did you have preterm labor or prolonged rupture of membranes? Were there other problems with delivery, like arrest of labor failure of dissent, and then non reassuring fetal heart tracings, they looked at chorioamnionitis. And then they hand reviewed all of the charts to make sure that there wasn't something that could still be in the documentation, see, documentation is valuable. That would bump babies into a knot, low risk criteria. You didn't like that?

Ben 23:47

Document. It's going to take more than that.

Daphna 23:52

All right. So

Ben 23:54

they couldn't say like high risk,

Daphna 23:56

not low risk. Yeah, that's fair. So the primary outcome they looked at was a culture positive infection. And the secondary outcome, which this was, I think, gold, initiate an initiation of antibiotics less than or equal to 72 hours after birth. And they looked at the duration of those antibiotics. They were particularly interested in the babies who had negative cultures. And when we talk about culture positive cultures growing cons or coagulase, negative staph or other known commensal, organisms were considered contaminants. Has anybody had any questions about that? So they had over 53,000 live births during the study period, and of those live births. 7549 infants are 14% had a blood culture drawn, which I thought was interesting, just of note.

Ben 24:54

And 1091 Did you think this was high or low?

Daphna 24:57

I actually thought it was low. or 14% to have our culture drawn based on places where I have worked, of which. But of course, this includes babies in the nursery, right who who not who never come to the NICU. So, so obviously, of which 1091 14% also had CSF obtained for culture. blood cultures were drawn into meaning time of one and a half hours after birth. 41 infants of those babies had a culture confirmed early onset sepsis. And then again, all early onset sepsis were defined by bacteremia, one of the babies had both bacteremia and meningitis with the same organisms. Of note, they had 26% of the of all cultures had a contaminant species, and so 15 additional babies. And then in no case was a pathogen isolated from the CSF culture when the blood culture was negative. So I thought that was also a valuable piece of information, especially as we're doing less C, we're doing less lumbar punctures at at some beginning sepsis. workups. The other thing that was interesting was, he talked about the they talked about the bacterial species. So E coli 39%. GBS 39%, followed by other streptococcal species. So I'll tell you a little bit more about the babies, the infants with early onset sepsis had a median gestational age of 35 weeks, a median birth weight of 2400 grams, and 68% were female. All 41 infants with early onset sepsis were administered empirical antibiotics. And of the 7508 infants without early onset sepsis, who had at least one blood culture obtained in the first 72 hours of life. And 90%. Were started on antibiotics with a mean duration of antibiotic therapy of 39 hours. So I was pleased that the average baby came off antibiotics at 40, before the 48 hours, but 90% of babies who didn't have early onset sepsis, who had blood cultures, were still started on antibiotics. So that's important to know.

Ben 27:27

Right, that dovetails so well, with the discussion we just had, right? If you're too sensitive, then this is what you end up

Daphna 27:33

a lot of bees. Yeah. And 25% of them, you know, had contaminants. So that is that, then then they are started on antibiotics, or they have read people and cultures, they're moved to the US. Right? It's like it's such a headache. Yeah. And you know, you know, a lot, a lot of invasiveness for the that group of babies. Okay, so let's get more into the groups. So out of the 7500 infants with a blood culture drawn 14.8% were born in the setting of the hypothesized low risk delivery criteria, and about 60 485% were not. So again, it's still the minority of babies who are truly in this low risk data set. But I think that's particularly valuable. And we'll talk about that in a second. So multiple clinical characteristics differed among these groups, but primarily because a larger proportion of infants with a low risk delivery criteria were born less than 37 weeks. So interestingly, more of the low risk infants tended to be younger and lower birth weight. And that's likely because they were delivered for potentially some maternal indication, that was not a high risk delivery criteria. So all 41 cases of early onset sepsis were among the 6400 infants without low risk delivery characteristics. So like you said, They're not, they're not labeled as high risk. They're disabled, labeled as not Low risk, low risk, but all the babies who had culture positive sepsis, were in the not low risk category. And in two or 41 cases, all of the low risk delivery characteristics were met except for the presence of unexplained non non resharing fetal heart rate, which I thought was really interesting, because sometimes you'll go to these deliveries where there aren't a lot of sepsis risk factors. There's non reassuring tracing the baby maybe need some resuscitation, and then they're potentially well, and you don't always know what to do with that group of babies. So I thought that was interesting. Of the 7500 infants, who, without early onset sepsis, who had blood cultures drawn, like I said, 90% were started on antibiotics in the low risk group, and 91% in the not low risk group. So it was obvious that people determined the babies were potentially lower risk, they got lower antibiotics. But still, even in the babies who were put into the low risk group, they had 80% in antibiotics, again, as compared to 91% in the not low risk group. So it's still a lot of antibiotic use. For babies who, in this cohort were at basically no risk of developing early onset sepsis, early onset sepsis. So the other antibiotic details, so low risk infants without early onset sepsis, who were started on antibiotics, were more likely to have prolonged antibiotic duration, so greater than 72 hours, then the non low risk infants without early onset sepsis. So I think this was especially salient. So the low risk infants had less antibiotic use, though it was still the majority of babies, but they had a prolonged duration of antibiotic therapy, even though the cultures were negative. And then low risk infants without early onset substance who were started on antibiotics. They did some adjustments for gestational age, sex, maternal race, and ethnicity, maternal age, the five minute Apgar. And these low risk infants did have lower odds of antibiotic initiation when they did the adjustments for all of these parameters. And then among uninfected, uninfected infants started on antibiotics, there was no difference in either the adjusted odds of prolonged antibiotic duration or antibiotic duration and hours by the presence or absence of low risk delivery characteristics. And finally, among infants outside of low risk delivery criteria, what they found was that 157 infants were started on antibiotics for every case of early onset sepsis. And they concluded that because no cases of early onset sepsis were identified in their low risk group, they obviously couldn't evaluate what was the antibiotic utilization because they didn't develop early onset sepsis. But that these low the low risk babies, were at basically no risk, like I said, for developing early onset sepsis. So I gave my thoughts along the way.

Ben 32:44

Right, but what's the duration and the antibiotic duration or prolonged antibiotic duration, then they say that at the end, there was no difference between the low risk and

Daphna 32:59

so after they adjusted, or this these parameters like gestational age, sex, maternal.

Ben 33:09

Okay, sorry, man. Yeah, I mean, this is this is a fascinating first of all, I want to say something when when somebody like Dustin puts out like a study like this, it's very valuable because it almost gives you incidence numbers, right? You have 2000 births. And so when a parent asks asks you in a delivery saying, like, Oh, you want to do a rollout tips for my baby, what are the chances, then you can say, the recent evidence from Pennsylvania shows that you do it on 14% of babies, you do this rollout sepsis, and point 5% will actually have early onset disease. And these are important numbers for us as neonatologist to know and obviously, these are dynamic numbers. We can't we need updated values. And we'll talk about that. I guess also for the previous when we talk about the the outcomes paper from the general research network. So from that standpoint, I think it's very valuable. And, and this is a very nice paper to discuss after the one we just we just reviewed where yeah, you you don't want to be oversensitive, right, this is the reason why you don't want to be oversensitive. Because then you do expose babies to more antibiotics, you do expose the babies to get a culture which is not a benign intervention because if you do get a quarter and it's positive then all these things ensue where I've seen babies get put on broader spectrum antibiotics for some time. CSF being done prolonged antibiotics, CSF doesn't, right. How many times have we seen this? blood cultures positive we don't have sensitivity you do a lumbar puncture, it's not successful you do another one like this baby is being put through this protracted thing when they may have nothing. So understanding the the importance of risk factors is critical. And I think I don't want to talk too much about this because then our next paper is talking about the other side of the coin and I thought I think maybe we should just go into that.

Daphna 34:53

Okay, sounds good. So

Ben 34:56

the other the other paper I enjoyed thoroughly It's not a study, it's a review. It's published in the Journal of Pediatrics. It's called a proposed framework for the clinical management of culture negative sepsis. It's by first author JB Canty, who is a Twitter friend of ours on you can find him at at infectious Neil. and his co author is none other than pebble Prusa cough, who is a pharmacist at nationwide and he is also on Twitter at kids farm, the JD is from the University of Texas. And so I had not seen the word culture negative citizens residency. This is how we call it when I was a med student resident. And, and the introduction is great. So right, so they said the term sepsis come from the Greek word to right. And then the definition of sepsis is that you have an infection, but you're not just back to remake or anything, you also have an associated organ dysfunction. Now, the clinical definition of sepsis is that you have some clinical plus minus laboratory signs of infection and some type of positive culture. And this clinical definition can often be guided by markers like CDC, CRP, procalcitonin, etc, etc. So what is culture negative sepsis. So, I think, I think the paper is extremely, extremely well written. So it's basically when you evaluate a baby for sepsis, and cultures are negative. But clinically, you are very suspicious of the baby having some symptoms, but some maybe other lab abnormalities. And you do believe, as the provider that this baby would benefit from antibiotics. So this is the paradigm where this is culture negative sepsis. Now, the data that's presented in the intro is kind of nice, because it says the diagnosis of culture negative sepsis is 16 times more prevalent than culture positive sepsis in the US. So we treat more culture negative sepsis than actually culture positive sepsis. And it is 50 times in the incidence of culture positive sepsis in low and middle income countries.

Daphna 37:04

That's what we saw on the in the last paper, right, we that's why those papers are so good, prolonged antibiotic courses, when they didn't have women didn't have sepsis, but somebody thought they needed to be on prolonged antibiotics.

Ben 37:17

And to follow that up the culture, negative sepsis contributes to 10 to 20%, antibiotic use in the slightest thing.

Daphna 37:26

Yeah, it's the big, big thing. So

Ben 37:28

it's a big thing. And obviously, in the introduction, then they conclude their introduction by saying that there's two important negative effects of portrait negative substance. Number one, you have the adverse events of antibiotics without proven infections. And then number two, and I think most importantly, you may be not treating the right pathology, like you may have missed a diagnosis. And then if you're treating something that's not really causing the problem, what else are you missing? So the whole goal of the paper is to provide a framework to think about these babies who could put you in this position where their culture is not positive, but you still have suspicions that something is going on. And the the framework is based on understanding what the differential diagnosis is. And I'm just going to give you the different categories for the differential. But the first is, is this physiologic meaning, is this normal, for example, for a preterm baby to be pre tournaments, so they have these unseen instabilities? And so is there really anything going on? Number two? Could it be a focal infection, meaning you don't have bacteremia, but you have something more localized? Other things are more fastidious, or non bacterial organism, like a viral infection, fungal parasites? What about if it's probable meaning, like, you do have sepsis or bacteremia? But you're you're didn't collect the data do the labs well? Or what if it's just non infectious? So then they go into the different categories, and I'm not going to go through the entire I'm gonna go through the entire paper, I'm sorry, but I'm gonna go through what I highlighted.

Daphna 38:55

It's so it's a read. It's a it's a very thorough paper.

Ben 39:00

It's, it has a paragraph which I will quote, because it's the best thing I've read in a long time. So the first question is, is it just prematurity that goes without saying, adrenal insufficiency, they have low blood pressures, like all these things, we understand. The second thing to think about is is it localized, they'd give the example of like pneumonia, pneumonia, super hard to diagnose and a preterm baby, but it's a but if it is pneumonia, then they don't need antibiotics for seven days, 14 days, 21 days, like four to five days is sufficient. Interesting data that they presented 34 to 69% of neonates with meningitis don't have bacteremia. And so I thought that was interesting considering what you just mentioned, in the Dustin paper, were in early onset sepsis. It's very rare, right? And I think this is important for us. It's very rare in early onset sepsis, that you would have meningitis without bacteremia. But late onset sepsis, doesn't function like that. You could have late onset meningitis and vectoring. Right, you shouldn't that's

Daphna 39:54

a that's a great good word review tip, just for any study.

Ben 39:59

So I thought that was interesting. Number three, they said, maybe it is sepsis, but you just have poor technique. And they talk about like the minimum one mL of blood required. I have seen so many, I have seen a lot of crap being done when blood cultures are collected in my career from low volumes from, I'm not putting anybody under the bus, but like people telling me as long as the bottle fluid turns red, you have enough blood. No, you don't need a full ml point five is fine. Well, they have a ton of good data, sensitivity of the blood culture for five Cfu sperm cells, when you get one mL of blood from the baby is 99% sensitive, actually secure more than 99% sensitive. And but there's many studies that have shown that the median blood volume collected from babies is less than point five ml. So we feel

Daphna 40:54

bad taking off so much blood however you don't want. That's what they say you don't want.

Ben 41:01

So that's what they say they say, oh, but what about the babies will have such low blood volume, they say well prioritize them, then prioritize your blood culture. And if you really think you need it, then get it. But then don't waste blood on like, a CRP, for example. Right. So that was very valuable advice.

Daphna 41:18

And, you know, in our unit we're taking, for example, for early onset sepsis, we're taking blood cultures from the cord. So

Ben 41:26

that's another that's another technique that was pioneered by Dr. Christensen that I think is very, very valuable too. And it works for you. Well, point number five was, Are you pretreated with antibiotic meaning, sometimes they go antibodies were really started by the time we got the culture, they make the point that's very valuable. Delaying antibiotics, and not pre emptive therapy is the issue. So don't be so eager to quickly, like get your culture first. But just don't delay. It's not the pre emptive that pre emptive therapy with, which is usually the issue. Also other thing, but culture may be positive at the time of collection, but then turn positive later on. So serial observation is sometimes very valuable. Maybe even start with serial observation and then delay a little bit your blood culture so that you can give yourself the best chance possible of getting something positive there. That's, I wrote there, I'm not so sure about that, because it's difficult, obviously, to recommend. But anyway, other point they're making point number six that I wrote is fastidious organisms, like ureaplasma, mycoplasma, super, super common cause of codium Unitus, super, super common cause of respiratory distress, especially in preterm babies doesn't grow on regular blood culture needs special testing. This is a perfect example of something that wouldn't grow on unregular, bacterial blood culture medium. Point six say it's not bacterial, something else like like viral is the most common. The next thing they mentioned was seven point number seven here I have is ultra low concentration, meaning if there's less than four Cfu per ml, then the blood culture sensitivity for one mL of blood goes below 98%. Now how common that is, they're mentioning that there's a ton of studies that are saying it's super common. Some of they're saying it's really rare. But that's something that had never really considered. And so then they said, we can so these are sort of the recommendations, the way you should think about it, obviously, they are then talking about an equation to estimate the risk probability that culture negative sepsis requires treatment for more than 24 to 36 hours. And I don't know how useful that is because it talks about the different parameters that would go into this equation, meaning the incidence of sets of sepsis based on the risk profile, the probability that it's due to bacteria, the probability that this bacteria is recoverable by blood culture, the probability that this bacteremia is in ultra low concentration. And the probability that this ultra low concentration of bacteria requires antibiotics. So they created this, this and that this, but then, and you're going to have fun this is this was my, this made my day yesterday, they talked about how this is similar to the so I'm going to read you the paragraph and you're just enjoying this. So at the end towards the end of the paper they rate how can we estimate the probability of cultural negative sepsis question? We propose borrowing a tool from astronomer, astronomers use the Drake equation to estimate the number of extraterrestrial civilizations that could make contact with Earth. First of all, you read this to like, where are we going? The Drake Equation uses several probabilities, such as the number of life supporting planets in our galaxy, the chance that such a planet develops intelligent life, and the probability that such life form broadcasts their existence into space. Individually, these probabilities are not high. And as a result, all of the estimated solution to the Drake equation that is the number of sentient races trying to communicate with us is extremely low, but not zero because of this nonzero part ability, the coordinated search for extraterrestrial life is now more than 60 years old.

Daphna 45:05

Well, I don't know what's I don't know what's, what's scarier culture negatives are extraterrestrial life.

Ben 45:12

I thought that was very funny to say that. Yeah, I thought that was very funny. And that was that was kind of cool. So, at the end of the paper, they talk about some practice considerations. And the practice considerations are summarized into, into three to four points. Point number one, consider non infectious causes. If you are suspecting late onset sepsis, do a complete evaluation before you starting to buy new blood urine NCSF. Before you begin antibiotics to avoid scenarios in which antibiotics already on board when you're getting the cultures with number to optimize your cultures, better volume, consider sending like consider prioritizing the blood culture over less essential blood values. Point number three consider like sending some more sophisticated studies like for that grow on different media, specifically like anaerobic culture for any type of abdominal pathogen, consider sending viral studies as well to look for other non bacterial or something that would not be picked up on a regular blood culture and for keep the duration of the antibiotics short if you don't have to keep them long. So I thought that was very interesting. The paper is beautifully written. It's long, I agree with that was a long paper. I kept scrolling. I was like, where's this going? And then when they got to the Drake Equation, I was like, Okay, that was worth it.

Daphna 46:32

Well, I think the other salient point was if, if you don't have bacteremia, culture, positive bacteria, what do you think is going on? Right, and they alluded to that in terms of, maybe it is pneumonia. Well, okay, do you have any features of pneumonia? You know, can you tailor your antibiotic course instead of having very prolonged broad spectrum antibiotics? Are you sure it's not intraabdominal? You know, is there something else going on? So great, great paper, it will take some time to read but Well, as you hypothesize, we've spent most of the time talking about sepsis. So we have some, we I don't know what we'll be able to get to, but you want to talk about vitamin D. Okay. So I'll start with this paper from frontiers in pediatrics, low vitamin D levels at birth and early respiratory outcome in infants with gestational age less than 29 weeks, and lead author on array pup Yulia.

Ben 47:35

pelea Okay. Lupita de la Concepcion, I must say, in France,

Daphna 47:40

it sounds much nicer.

Ben 47:42

I was born not too far away from there. And my dad worked in this hospital. So I know the place very well. I don't know the author's did I left too long ago. But yeah, that was cool to see them my hometown. Again. frontiers. Yeah, they're

Daphna 47:57

becoming a blossoming research. I think. We've had a few papers in the last few months. Anyways, we had to do that. Well, it's not that big of town, right.

Ben 48:10

And there's observer bias from the guy picking the paper from the hunter.

Daphna 48:15

So this is an observational retrospective study, including preterm infants born with a gestational age between 24 and zero weeks and 28 and six weeks, during the years of 2018 to 2020. Like you said, it's coming from Marseille, France. And this study was part of a larger QI project to optimize vitamin D in pre knees. So I thought this was interesting. They do have a post natal vitamin D supply protocol. And their preliminary measurements were of blood vitamin D concentrations, measured in the umbilical cord blood, which is another way that we can do evaluations of our babies without taking a large blood volume civilly. Yeah, I thought was was really neat. And sidestep, you know, in our unit, it may be some time before we evaluate vitamin D levels. So I thought this was a nice way to know what the babies were kind of coming in with. They collected a number of maternal and infant characteristics. So in the interest of time, I won't tell you all of them, but definitely pretty standard. Yeah, pretty standard. They looked at a primary outcome, which was the combined outcome of death in the first week of life or the need for mechanical ventilation on day of life seven, and then they looked at those outcomes separately. And they also performed some univariate and multivariate logistic regression analyses to look at the various factors that may be associated with those combined variables. Then they performed a classification regression tree analysis or a cart analysis to identify what could potentially be the threshold or a cutoff point of some of these variables. In particular, they were looking at vitamin D levels. The things they looked for. In the current analysis were, again, pretty standard gestational age, sex, multiple pregnancies, preterm premature rupture of membranes, choreo antenatal corticosteroid therapy, C section, placental transfusion, and the cord blood, vitamin D levels. So they had 112 babies, the mean gestational age and birth weight were 26 weeks, and 801 grams. The mean cord blood level of vitamin D was 53 nanomoles per liter. And a total of 81, or 74% of infants had what they considered a low cord blood level. And so their cut off was using less than or equal to 75 nanomoles per liter. And 56 or 51% of infants had cord blood levels less than 50. There were no major differences between the two groups in regards to the characteristics that I discussed. So they were pretty similar.

Ben 51:20

I was gonna say, when I read the paper, obviously 75 Like this, again, this is like Europe and the US like the unit's don't match. So I don't know how it is. For the listeners, whoever's listening, we measure it here. I mean, here in South Florida, we measure it in nanograms per ml, right? And so to convert back and forth, the factor is 2.5. So if you are measuring this nanograms per ml, then you should take the number divided by 2.5. So in our case, this would mean like a vitamin D of 30 or less. And that makes sense. So that was like, Oh, that's right, which that makes more sense. But I think this is always important, especially like the bilirubin, these ones to know the conversion factor. So this is 2.5. For

Daphna 52:03

sure, right? It's not a level for us in our unit of 75. It's a huge, it's a love, right? Right, because 70 out of 75 is pretty good. We're starting to wheat in the vitamin D. So the other things they looked at in terms of again, respiratory distress, was the timing, dose number and technique of surfactant. But they didn't find any major differences in how soon they got surfactant, how many loved doses of surfactant and whether the baby got lizer or unsure methods of surfactant administration. But they did find that the FY oh two levels at the time of the first surfactin administration were 25% higher in the low vitamin D. Infants as compared to the kind of normal vitamin D infants. So I thought that was an interesting point, especially given some of the recent articles we've reviewed were the height of oxygen requirement at the time a surfactant administration did predict some additional RDS outcomes. So just something to keep in mind. A day of life seven, the rate of combined outcome of death or mechanical ventilation requirement was higher, and the low vitamin D babies 36% versus 7%. And overall, these infants were more likely to have received mechanical ventilation during the first week of life 53% versus 32%. Again, as compared to the, what they call sufficient vitamin D status infants, they tended to need high frequency oscillation more often 46% versus 11%. And 90 a day of life 790 3% of infants who died or needed mechanical ventilation, were from the low vitamin D status group. And then I told you, they did a lot of multivariate analysis. And so after elimination, and adjustment for gestational age, infants with a low vitamin D status had higher odds of death are still being mechanically ventilated at Daylife seven. So it was an adjusted odds ratio of 10.6. When then they looked again, at the outcome, just a mechanical ventilation a day of life seven, with an adjusted odds ratio of 8.14. And then, really, what they found in the current analysis was that gestational age and and Cord Blood vitamin D levels were the kind of best predictors and so the threshold for gestational age was about 26 weeks, and the cord blood threshold was actually 70 for the animals per liter so pretty close to their cut offs that they use for sufficient vitamin D and low vitamin D. Groups. Thoughts I

Ben 55:00

think I mean this this vitamin D debate is becoming a hot hot topic.

Daphna 55:05

Yeah, I mean, every week we're every week we're looking at vitamin D papers. And it's very prevalent in the adult literature also at this time.

Ben 55:15

Right. And so there's this other paper in in frontiers from China, by Rena Zang, which is a systematic review slash meta analysis. And and it's not super interesting because it just looks at case control studies that look at babies with RDS and who are less than 37 weeks and looking at their vitamin D levels at birth, and basically found the same thing that low vitamin D levels at birth are associated with with more red, neonatal respiratory distress. But they were only able to find nine studies, five of which are out of our out of China, which, again, goes to show that that they're focusing on that issue more probably than other countries. The other countries, I think, included Egypt, and I think Turkey, not many not much know, from from Europe or the US. And Iran. That's correct. So it's an interesting, it's an interesting topic. The big question, in my opinion is, is this something that it seems that the data, what's interesting is that usually when something comes out in the literature, there's usually follow up papers that either disprove or confirm, and all the papers are pointing in the same direction. So there's not much it doesn't seem like it's a controversial topic. low vitamin D at birth, worse respiratory, worse respiratory outcomes. The question becomes, do we give these babies vitamin D? Or do we increase the mother's supplementation of vitamin D, during the pregnancy? Does that make any difference when it comes to the baby's vitamin D level at birth? To be honest with you? I haven't reviewed the literature. I don't know. But yeah, this is this is this is interesting.

Daphna 57:02

Yeah, I think certainly, there are probably maternal states that that predict lower vitamin D, you know, transmission to the baby. I'm not sure that we've elucidated all of those, but they're probably probably the same things that predict worse outcomes, like growth restriction like placental insufficiency, things like that. So I,

Ben 57:27

and if you're and if you're if you're pregnant, in Iceland in the winter, and your sunlight exposure is amounting to like three hours in a day, do the recommendations then would defer saying well, you do need maybe 1000 units per day? Because your baby is

Daphna 57:42

right. Yeah. And it's not even that far off for us here in Florida. So we have a lot of vitamin D deficient pregnant mothers because they stay indoors or when it's hot, or they wear a lot of sunscreen, because that's the recommendation. So So yeah, I think it's totally irrelevant.

Ben 57:59

I'm very interested to see what's going to come out. Because this is going to be a hot topic. If you're a young investigator hop on the vitamin D bandwagon. It's not hot. Yeah, please. Well, we acknowledge this in the in the discussion, if you don't mind.

Daphna 58:17

That podcast. I really wanted to get to this outcomes paper do we have? Oh, good. Yeah, a lot of data. It's a lot of data.

Ben 58:29

So the paper is called mortality in horse in hospital morbidity, care practices and two year outcome for extremely preterm infants in the US between 2013 and 2018. First author is Edward bale. And this is data from the neonatal Research Network. This is the papers that people usually wait on, right, the network publishes there, they're pretty much all their data in, in JAMA every, every, every couple of years. And so it's really, really valuable to take a look at what these incidents these numbers look like. I mean, technically, I don't really like to say this, but the neonatal Research Network is a collection of hospitals that that practice medicine at a very high level of excellence. And so their data is usually very robust. So I don't like to put people on a pedestal saying they are better than anybody else. But I think it's it's valuable data nonetheless.

Daphna 59:26

Yeah. And the collaboration, right of this many hospital practice solutions, and some very big name researchers, you know, I think is of note

Ben 59:37

and so why the methods of this paper are not very interesting is because if you've read their papers in the past, they're the same, right? So they they take babies from 400 grams to 1000 grams 22 to 28 and six weeks, they have 90 networks. The data goes from 2013 to 2018, as they mentioned in the title, however, for the long term outcomes the two year obviously that stopped at 20 16 Because then the babies had to reach two years old. They collect a ton of different variables. They follow the Jensen criteria for their BPD definition. Obviously, the Jensen paper from 2019 was published through the neonatal Research Network, so that makes sense. And then they look at neurodevelopmental impairment looking at cerebral palsy, hearing impairment, vision impairment, and then they do belly threes. A five plus is considered mild or no or no impairment 70 to 84 is moderate, less than 70 is called severe. So, so far, so good, correct. So let's take a look at some of their results and chat about them. So 10,877 infants, again, massive, massive amount of data considering 22 to 2010, six weeks. Interesting prenatal stuff. 88% of mothers received antenatal steroids 79.4% of mothers received magnesium 65% delivered by C section. However, only 3% by C section at 22 weeks, compared to 39% at 23 weeks, which kind of makes sense. You're assuming that if they're showing up at 22 weeks, they're probably laboring?

Daphna 1:01:20

Yeah, or the risk benefit ratio of doing seat reception at 22 weeks is still up for discussion.

Ben 1:01:30

Let's talk about survival. Because I think that's an important topic of discussion. And we did share that New England sort of case simulation on our Twitter account. But 78% survive to discharge or to one year if they were still hospitalized. And obviously, as you would expect that survival data increase with gestational age looking at specific gestational ages, because obviously what everybody wants to know is what about the 22 weaker, so 22 weeks had 11% survival. And that was comparing to their data that they published last time from 2008 to 2012. That had improved 22 week survival was 6.6 to 7%. And now it's 11% 23 weeks, the survival was 49.4%. Similarly had increased from 32%, the last time they published data. And then interestingly, you got to 28 weeks and survival is 94%. So the mean survival is not super, super helpful. You really have to look at it from the by the breakdown of gestational age. Now, the big question then is, did they did they actively resuscitate everybody, only 36% of the babies born at 22 weeks were actively resuscitated. That number really increased by gestational age. So at 23 weeks, 88.5% were actively resuscitated. 24 weeks 97.9 25 And above was 99%. So the big question is of the babies who were actively resuscitated, how many survived, and in the 22, weaker group, it was 30%. So that was, that's, that's pretty significant. When it comes to 23, weekers, it was about 56%. I'm going to start rounding up these numbers so that they're more easy to listen to. So in this case, right, the survival form, the activity treated group at 23. Weeks was 55.8. So 56% Makes sense. anything so far? Definitely.

Daphna 1:03:29

No. But I think this is important because as people use like the perinatal calculator, that you know, this is this is an update. Right? So the actually the perinatal calculator has changed not to reflect this data, I don't believe because this just came out, but it has already been updated once.

Ben 1:03:52

Right. And so when we're looking at specific outcomes that we can go one by one, and it's interesting. So delayed cord clamping, or umbilical cord milking was present in 40.6%. So when you feel good about the times where we don't we get to do delayed cord clamping. 84% of babies eventually went on the ventilator. 80% received surfactant. About 19% received steroids for BPD. And about 18% received vitamin A. So I thought I thought that was interesting, especially the fact that 84% of babies eventually went on a ventilator. This I mean, I think, if you are looking at the data, and this push to keep the small babies excavated, sometimes can can be counterintuitive. And you may you may want to believe that these babies can do it without the vent, but it's important to remember that still 84% of these 22 to 28 and six did eventually need to go on event. So it's not it's not the massive amount of failure. If you have to eventually intubate a baby like that. The PDA stuff was interesting 23% received medical medical treatment for PDA. 7% actually had to undergo some form of ligation with a surgical catheter and so on. So that was interesting. 23%, I thought was quite low. I was I was expecting in this very small population to be a bit higher.

Daphna 1:05:23

But again, there's such a heterogeneous group 22 to 28 weeks. And that's why this paper is so important. And I think, you know, we'll start to see studies that really are only looking at 22 to 24, weekers, or something in the future, because they're not a heterogeneous group.

Ben 1:05:42

I'm very curious about the I'm very curious about the next paper that's going to come out several years from now, just because we're reviewing more and more data that says 26 or less should really have that PDA closed. I'm curious. I'm curious. I'm not saying this is the way it should be. But I'm curious to see that number we'll we'll we'll just have an inflection point and jump, we'll see. We'll see the number of transfusions. 78% of all babies received a transfusion and 22 to 25 weeks more than 95% had to get a blood transfusion. They reported on probiotics, the the administration of probiotics was about 10%. But they were very cautious to say that this was very, very variable based on centers, enormous, enormous variation. Oh my god, we're running late, but TPN duration, the median TPN duration was 17 days, that was humbling 22 to 28 weeks that they stayed on TPN for me, 17 days, like that's something that we know at our institution, one of our colleagues is working hard to get us to come off TPS sooner. But 17 days in that very small population was something that I took note of. length of stay was not very impressive 9% rates of NEC 4% needing surgery. The rates of early onset sepsis were 2.4%. late onset sepsis. 20%. That's something that again, was was quite impressive. The degree of severe ivh was severe. IVF was 14%. And compared by gestational age, it was quite impressive. At 22 weeks, the rates were 38% and 28 weeks, it went down to 5%. So again, something that really really drops off when it comes to higher gestational ages. Cystic PVR incidence was 4.6% 55% rates of retinopathy of prematurity 13% of severe ROP, interestingly enough at 22 weeks 93% rates of ROP compared to 30%, when they reach 28 weeks BPD data, which is something that I was interested in 49.8% Yeah, this is this is huge. This is huge. And at 22 to 24 weeks 75%. Yeah. So when you counsel these parents at we, I mean, you you tweeted about that doing these consults. I think I think there's it's a no brainer to mention BPD as a as a likely outcome when

Daphna 1:08:16

not a not a possible outcome. Right? Really, truly, like very likely. Yeah.

Ben 1:08:21

I mean, hopefully, you look at only three priests only 8% had grade three BPD. So hopefully not severe. But this is a significant outcome to discuss. We went over a lot of things. I think that the paper was very nice about saying like looking at our old data, where did we do better or worse? Worse? Where do we do the same? So better outcomes were found in for NEC for late onset sepsis, for severe ivh. And for ROP. Oh, good, BP. All good. BP got worse, and everything else was the same. I'm gonna let you talk about NDI. But obviously, the big the big discussion is that as it's the same discussion that's been we've been having for years, which is as smaller and more immature babies are surviving. Are the outcomes just getting worse? Or are we just we just this is survival bias where this organization that's super super at risk is now causing these numbers. And they've done a good job to show you that the numbers really differ when you're looking at 22 or 23 weeks and 28 weeks. So I think this is very important. Yeah, the good. Go ahead. No, no, I'm sorry. Yeah, the

Daphna 1:09:25

only other thing I'll mention just since we're having so much discussion on Twitter right now about resuscitation or a trial of intensive care, you know, how do we present that to families? I did want to note that the rate of they use withdrawal of care but that that's a that's a discussion for another whole nother episode. We could have a discussion but it's okay. We're withdrawal of invasive care. So into invasive severities like intubation, ventilation, nutrition and medication was actually in 10%. So they didn't tell us that by gestational age. But as we can imagine that would be higher in the lower gestational age. So just something of note. So let's talk a little bit about follow up. 87% of surviving infants were seen for follow up incredible, that's amazing that they were able to do that. And 84% had enough information to be evaluated for neurodevelopmental impairment still amazing, really valuable work. mothers of children seen at follow up had an older median age were more likely to have a college degree and be of black or white race. Even give us maybe enough data on that, but compared with those last to follow up, and And interestingly, more children seen that follow up were born at lower gestational ages and with lower birth weights. And if anybody's done follow up clinic before, I think none of those things are surprising. So let's get to the meat here. A total of 48% of the children evaluated had no or mild NDI. 29% had moderate and 21% had severe. The proportion with no or mild NDI increased significantly, obviously by gestational age, so 31% at 23 weeks, to 58% at 26 weeks, and of the 29 infants born at 22 weeks who survived and were able to be evaluated 13% or 13 infants 44% had no or mild NDI. 24% had moderate and the NDI and 31% had severe NDI. So that's something a data point people were looking for.

Ben 1:11:43

Yeah, and those bar graphs are pretty, pretty impressive, very helpful. She would probably post them on Twitter, but they're they're very cool to look at.

Daphna 1:11:51

So there obviously is a lot of data evaluated from the Bailey's. But among children born at 2223 to 24 weeks gestational age, the mean cognitive language and motor scores were significantly lower for those born at 23 weeks, compared with those born at 24 weeks. But the statistically significant differences were not found between scores for children born at 22 weeks compared to those born at 23 and 24 weeks. That being said it was a much smaller group. So as we see more babies born at 22 weeks, I wonder if that might change. The proportion of children with language and mortar scores of less than 70 was significantly higher for children born at 23 weeks, compared with those born at 24 weeks interesting. But the proportion with cognitive scores of less than 70 did not differ among children. Born at 22 weeks compared to 23 and 24 weeks, the proportion of cerebral palsy of any severity was 18% and decreased significantly from 50% in those born at 22 weeks, to 12%, born at 26 weeks, which again, I think is not surprising. It's one of the major causes of morbidity for the extremely low birth weight infant. A total of 50% of children are we hospitalized after initial discharge. So a big burden on parents and certainly contributes to health care costs and should play a role in our anticipatory guidance at discharge. The 1200 children who were we hospitalized had most of them more than one admission, almost 3000 admissions, total respiratory disease was the most common reason for readmission. 54% followed by surgery 15% and infection 10%. The other things about like activities of daily living, so 81% of children were feeding themselves independently. And obviously this varies significantly by gestational age 11% had no oral feeding or limited oral feeding requiring some sort of feeding conduit. And at follow up the most common assistive device for all the children was a G Tube 15% of children were using an apnea monitor oxygen or required, ventilator or CPAP, a feeding tube tracheostomy. And, of course, this ranged significantly depending on gestational age, so 22% at 22 weeks, down to 10% of assistive devices at 26 weeks. So I don't think any of this is surprising, but I think it's really useful information, especially as we're really trying to narrow down how to do our prenatal consults and providing guidance.

Ben 1:14:41

I could not agree with you more. The fact that 81% of babies are feeding independently is very valuable data for parents, I think. I think this is huge. The other thing that was interesting was the rates of cerebral palsy was quite quite interesting. 18% Mostly mild, but 22 weeks 48% rates of CP I think yeah, 1.5% for blindness 2.5% for hearing impairment, these are very invaluable information for parents. The neonatal Research Network sets the bar for the standards, I think, and these are reasonable numbers, I think to go by they should be the expectation. So, yeah, this is this is fascinating data. I don't think I don't think this is a paper where you look at the numbers and saying, Does that make sense, right? I mean, you have to look, this is just a report of this is where the level of care is at those 19 centers. And you take it as you wish, you can say, Well, my rates of NCR much better, it's like, good for you. And maybe your outcomes are better. But this is this is very, very valuable in terms of finding where our mean is in the country. And this is, this is super useful.

Daphna 1:15:50

Yeah. And when we talk about, again, so much, there's been so much discussion in the neonatal community, just in the last few weeks about, you know, these very, very early babies were, you know, the data shows that I mean, some of them are, are doing what some might describe as, quote unquote, reasonably well. And so that's something we have to take into account. That's something that parents know it's in the lay press. So it's something that will definitely come up. And the other thing that we haven't measured in this study is really what do parents feel about the long term outcomes of their babies and what do preterm you know, previously born preterm people feel about their outcomes, and that has been well published will continue to be published and is very valuable when we continue the discussion about resuscitation. Anyways, we've gone way over time, but such

Ben 1:16:42

a way over time. Something to think about for the future journal clubs definitely have been talking about this. Should we break up the podcast episode into individual articles? That could be done? Half hour episodes? That is? Yeah, that's perfectly fine with us. Definitely. This was fun. Yeah, see y'all tomorrow for board review. Sounds good. Thank you for listening to this week's episode of the incubator. 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 NICU podcast. Personally, I am on Twitter at Dr. Nikki spelled Dr. NICU. And Daphna is at Dr. Duffner MD. Thanks again for listening and see you next time. 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 practitioner. Thank you

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