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#150 - Journal Club - 📑 Long term effects of delayed cord clamping, seizure management, and more...


NICU journal club the incubator podcast


Hello Friends 👋


What is the potential impact of delayed cord clamping on severe IVH and neurodevelopmental outcomes? We explore this and more in our latest episode. We kick things off with a deep dive into a riveting paper from the Archives of Disease in Childhood that scrutinizes the approaches to umbilical cord management and their effects on death and neurodevelopmental impairment.


We also discuss the heterogeneity of treatment effects of hydrocortisone by risk of bronchopulmonary dysplasia or death among extremely preterm infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial with our EBNEO colleague Nic Bamat from CHOP.


Join us as we welcome Dr. Rene Shellhass, co-author of the recent paper on neonatal seizures, to discuss the six PICO questions from the paper and their implications for the neonatal community. We take a hard look at the use of EEGs in diagnosing and managing neonatal seizures and the challenges involved. To wrap things up, we highlight the long term outcomes of the OPTMIST-A trial —a must-listen for anyone involved in neonatal care. We guarantee you'll walk away from this episode with a lot of valuable insights, thank you all for listening.


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Articles discussed on today's episode can be found below 👇


Handley SC, Kumbhat N, Eggleston B, Foglia EE, Davis AS, Van Meurs K, Lakshminrusimha S, Walsh M, Watterberg KL, Wyckoff MH, Das A, DeMauro SB.Arch Dis Child Fetal Neonatal Ed. 2023 May;108(3):224-231. doi: 10.1136/archdischild-2022-324565. Epub 2022 Oct 17.PMID: 36253076


Gentle SJ, Rysavy MA, Li L, Laughon MM, Patel RM, Jensen EA, Hintz S, Ambalavanan N, Carlo WA, Watterberg K; National Institute of Child Health and Human Development Neonatal Research Network.JAMA Netw Open. 2023 May 1;6(5):e2315315. doi: 10.1001/jamanetworkopen.2023.15315.PMID: 37256621 Free PMC article. Clinical Trial.



Watterberg KL, Walsh MC, Li L, Chawla S, D'Angio CT, Goldberg RN, Hintz SR, Laughon MM, Yoder BA, Kennedy KA, McDavid GE, Backstrom-Lacy C, Das A, Crawford MM, Keszler M, Sokol GM, Poindexter BB, Ambalavanan N, Hibbs AM, Truog WE, Schmidt B, Wyckoff MH, Khan AM, Garg M, Chess PR, Reynolds AM, Moallem M, Bell EF, Meyer LR, Patel RM, Van Meurs KP, Cotten CM, McGowan EC, Hines AC, Merhar S, Peralta-Carcelen M, Wilson-Costello DE, Kilbride HW, DeMauro SB, Heyne RJ, Mosquera RA, Natarajan G, Purdy IB, Lowe JR, Maitre NL, Harmon HM, Hogden LA, Adams-Chapman I, Winter S, Malcolm WF, Higgins RD; Eunice Kennedy Shriver NICHD Neonatal Research Network.N Engl J Med. 2022 Mar 24;386(12):1121-1131. doi: 10.1056/NEJMoa2114897.PMID: 35320643 Free PMC article. Clinical Trial.


Harer MW, Rumpel JA, Stoops C, Slagle CL, Liberio B, Daniel J, Hoffman SB, Agarwal N, Khattab MG, Rais-Bahrami K, Perazzo S; Children’s Hospitals Neonatal Consortium Kidney and Urology Focus Group.J Perinatol. 2023 Aug;43(8):1047-1049. doi: 10.1038/s41372-023-01648-x. Epub 2023 Mar 17.PMID: 36932136 No abstract available.


Walsh MC, Yao Q, Horbar JD, Carpenter JH, Lee SK, Ohlsson A.Pediatrics. 2006 Nov;118(5):e1328-35. doi: 10.1542/peds.2006-0359.PMID: 17079534


Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC.J Pediatr. 2014 Dec;165(6):1258-60. doi: 10.1016/j.jpeds.2014.07.049. Epub 2014 Sep 10.PMID: 25217197


Poindexter BB, Hair AB.Clin Perinatol. 2023 Sep;50(3):xvii-xviii. doi: 10.1016/j.clp.2023.05.001. Epub 2023 Jun 15.PMID: 37536778 No abstract available.


Pressler RM, Abend NS, Auvin S, Boylan G, Brigo F, Cilio MR, De Vries LS, Elia M, Espeche A, Hahn CD, Inder T, Jette N, Kakooza-Mwesige A, Mader S, Mizrahi EM, Moshé SL, Nagarajan L, Noyman I, Nunes ML, Samia P, Shany E, Shellhaas RA, Subota A, Triki CC, Tsuchida T, Vinayan KP, Wilmshurst JM, Yozawitz EG, Hartmann H. Epilepsia. 2023 Sep 1. doi: 10.1111/epi.17745. Online ahead of print.PMID: 37655702


Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, Cetinkaya M, Kornhauser-Cerar L, Derrick M, Özkan H, Hulzebos CV, Schmölzer GM, Aiyappan A, Lemyre B, Kuo S, Rajadurai VS, O'Shea J, Biniwale M, Ramanathan R, Kushnir A, Bader D, Thomas MR, Chakraborty M, Buksh MJ, Bhatia R, Sullivan CL, Shinwell ES, Dyson A, Barker DP, Kugelman A, Donovan TJ, Goss KCW, Tauscher MK, Murthy V, Ali SKM, Clark HW, Soll RF, Johnson S, Cheong JLY, Carlin JB, Davis PG; OPTIMIST-A Trial Investigators.JAMA. 2023 Sep 11:e2315694. doi: 10.1001/jama.2023.15694. Online ahead of print. PMID: 37695601

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

[00:00:00] Ben C: Hello everybody, welcome back to the incubator podcast. It is sunday. We're doing journal club. Daphna. How are you?


[00:00:05] Daphna B: I'm doing great, buddy. How are you?


[00:00:08] Ben C: I'm doing good It's a busy week and uh, i'm very happy about uh, despite the fact that we're working a lot I guess we're paying back a lot of these shifts that we took out to go to the next society but uh, we're still a


[00:00:21] Daphna B: must always pay the piper. Isn't that


[00:00:23] Ben C: no such thing as a free lunch, but Um, I'm very happy that we have a packed journal club today.


[00:00:31] Ben C: So this is very


[00:00:33] Daphna B: lot going, a lot of interesting avenues.


[00:00:37] Ben C: Yeah, so Just to give you a preview of what's coming today. We have some articles that we would like to review we are Very excited to have nick bammett from chop to go over his commentary for the eb neo article of the month And we have a special guest this week on the incubator podcast talking to us [00:01:00] about the recent Talking to us about the recent paper on the management of On the management of seizures in the neonate we have one of the co authors.


[00:01:12] Ben C: Dr Renee shall has to come talk to us about the paper some of her interpretation. So it's very very cool. So This is definitely going to go over an hour. I think So we better get started soon anything you need to go over. Um dafna, I think I'm just going to plug this right now before we get started. Um, I know there's been some issues with the website.


[00:01:34] Ben C: We're rolling out a new version of it. So Some pages are coming up as i'm getting time to update them and um But the exciting thing is that we're gearing up for delphi 2024. So if you are interested in purchasing, uh your seats for delphi It's if you've been to delphi 2023, it's it's limited seating. So if you want to purchase a seat The the tickets are available already and there's also tickets available for a TEDx event [00:02:00] that we are hosting Now if you are coming to Delphi you automatically get a seat for the TEDx event So you don't need to purchase both and if you want to nominate a speaker for Delphi just send us an email Uh, we'll be happy to we're actually in the planning phase We have a lot of the speaker lineup already planned out But if you want to see someone on the Delphi stage or or anything like that, then please let us know And We're releasing videos of the Delphi


[00:02:27] Daphna B: Up, And


[00:02:28] Ben C: 2023 conference once a week and this week we, it was very cool to see the release of Fumihiko's talk.


[00:02:35] Ben C: He came all the way from Japan to be at Delphi this year and his talk about how they care for ELBWs in Japan is It's quite fascinating, quite unique. I think I would not have suspected that they were doing a lot of the things that they were doing and they have published their outcomes, uh, far and wide.


[00:02:52] Ben C: And we know how good the outcomes are coming out of Japan. So it's very, very nice to get a glimpse into, um, what they're [00:03:00] doing. So the video is available for free. It's a 20 minute video. He has videos, he has pictures. So check it out on our, uh, YouTube channel. Our YouTube channel is linked on our web. On our web page and you go and go on youtube you type in the incubator podcast and you should find us And there's a lot of other cool talks the one from the week before with diana montoya williams is a is a popular one as well Um about the cups of advocacy.


[00:03:23] Ben C: So, um, it's we're very proud of the fact that our youtube channel is, uh, Has great content. Yeah, that's right. That's right


[00:03:32] Daphna B: got a lot of good stuff.


[00:03:34] Ben C: yeah, we're that's very exciting


[00:03:37] Daphna B: And I'm glad that you made the, finally made the announcement. We're so excited about the conference and having people all together again. And,


[00:03:47] Ben C: place in because we know there's boards. I think that's an important point. As I mentioned, we know there's boards. We don't want to disrupt. We want fellows and trainees to be able to attend. So September 23rd to the 25th in Miami, Florida, [00:04:00] 2024. So there's time. It's about a year away.


[00:04:02] Daphna B: There's time, lots of time to plan. We have a discounted price for trainees, so that's exciting also. And we've got other exciting opportunities. Like,


[00:04:13] Ben C: If the cost of the conference, as we've said, for everything we do, we try to make sure our initiatives are sustainable, but if for any reason, the cost of the conference is going to be what's preventing you from attending, then email us. And we will gift you a ticket like we won't pay for your plane ride or for for hotel, obviously, because I mean, we can't do that.


[00:04:36] Ben C: But like, just like seriously, like, it's not a problem.


[00:04:40] Daphna B: yeah, we'll figure it out.


[00:04:41] Ben C: Yeah. And most of us have CME money that we could use. So so that's exciting that you could just use that. Yeah. All right. Now that the PSAs are done, let's get into it. I guess i'm starting today. I have a paper that I wanted to review It's a paper that came out in the archives of disease in childhood And it's something that I [00:05:00] think a lot of us are speaking about we spoke about this topic with anoop Katheria on the podcast and the title of the paper is exposure to umbilical cord management approaches And death or neurodevelopmental impairment at 22 to 26 months corrected age after extremely preterm birth first author is sarah henley and This is coming from the Neonatal research network.


[00:05:25] Ben C: Um, this is a paper, obviously, that is, um, very, um, it's, it's, um, it's obviously very Timely because we're talking a lot about the different approaches to umbilical cord management the the the paper has Authors that are again. It's a very star studded lineup. Liz fogley is on there Michelle walsh is on there satyan is on there christy waterberg is on there.


[00:05:53] Ben C: Sarah de moro is a senior author So a very serious group of authors, uh publishing this paper [00:06:00] um the background, um is fairly straightforward, right? Babies born preterm are at a high risk of having neurodegenerative mental impairment. Severe IVH is something that contributes to that outcome significantly.


[00:06:12] Ben C: And delayed cord clamping is, uh, thought to provide a protecting, a protective option for these infants. evaluating the relationship of delayed cord clamping, umbilical cord milking, and immediate cord clamping, um, with some mixed findings, leaving a lot of questions about neuroprotection and neurodevelopment unanswered. So most studies examining umbilical cord management and neurodevelopmental outcomes usually are limited by several things, small sample size, single cohorts with heterogeneous neurodevelopmental measurements, um, and variable assessment time points.


[00:06:48] Ben C: Now, the team at the Neonatal Research Network had a, done a study about cord management in ELBW infants. And so for that reason, [00:07:00] they felt, um, compelled to run this study and try to compare the outcomes of death or severe neurodevelopmental impairment at two years corrected between 22 and 26 months corrected age after exposure to either immediate cord clamping, delayed cord clamping, or umbilical cord umbilical cord milking in infants that are born at less than 27 weeks of gestations.


[00:07:29] Ben C: So far so good so, um for um, one second. Yeah, so I think if you are if you are Wondering about the paper that the N. R. N. has published. I'm just trying to pull this up now from my database where, um, it was published in the Journal of Pediatrics in 2021. Um, and I think


[00:07:55] Ben C: it was called umbilical cord milking versus delayed cord clamping in association with in hospital outcomes [00:08:00] among


[00:08:00] Ben C: extremely preterm infants.


[00:08:01] Ben C: So obviously, something, um, that made the rounds at the time. Was the podcast even in existence by then? I don't remember. Probably not. It was like the the first month that we ever started the podcast, so we may not have had the opportunity to review it.


[00:08:13] Daphna B: Yeah, we couldn't review all the articles. You want


[00:08:16] Ben C: No, that's right. And so the study design is that this is a retrospective analysis.


[00:08:21] Ben C: Now, the Neonatal Research Network follow up database includes neurodevelopmental assessment of all eligible survivors born before 27 weeks of gestation at the time point between 22 and 26 months. Corrected age they included infants that were born either between between 22 weeks to 26 and 6 26 weeks and 6 days At any nrn centers between 2016 and 2018 Now for babies that were missing an exposure documentation those with congenital malformation congenital heart disease genetic syndrome those who received compassionate Care at the time of birth all these infants were excluded for the purpose of this study And in terms [00:09:00] of the infants that received neurodegenerative mental assessment, they actually excluded babies who fell out of this four


[00:09:07] Ben C: month Window, so if they completed an assessment more than four months outside the target of


[00:09:13] Ben C: 22 to 26 months They excluded them and I made me chuckle because when you're doing your mental research You never want to exclude anybody like if you have one if you if you got one You want to use them?


[00:09:25] Ben C: So I was like, oh


[00:09:26] Daphna B: Every single one. That's it. It's such an endeavor to enroll a


[00:09:31] Ben C: so kudos to them to keep the data super clean Um, they determined the exposure to cord management with either delayed Immediate or milking basically the primary outcome of the study was a composite of death before follow up or severe neurodemental impairment at follow up.


[00:09:48] Ben C: Now, um, the follow up included a standardized neurological exam with a Bayley 3 and the follow up subcommittee defined severe impairment as the presence of any one of the following severe [00:10:00] CP, cerebral palsy, a Bayley 3 cognitive composite score of less than 70, a motor score of less than 70, bilateral blindness, or hearing impairment.


[00:10:09] Ben C: They had a lot of secondary outcomes, which were basically each and Every one of the primary outcome measures. So either death, severe n d i, moderate to severe c p, the different daily metrics and bilateral blindness and hearing impairment. Now, what was interesting is that, uh, the risk adjusted Association of Cord Management technique with a primary composite outcome were estimated using a.


[00:10:30] Ben C: complete case analysis and multivariable logistic regression. And so the logistic regression that they used incorporated the following variables. Number one, the risk factors for death or severe neurodegenerative mental impairment identified, um, a priori, which means that some of the factors that we know we're going to cause these possibly increase the risk of NDI.


[00:10:52] Ben C: These include gestational age, sex, race, ethnicity, maternal education, and antenatal steroids. Number two, they looked at covariates occurring [00:11:00] prior to the exposure that were statistically imbalanced across the three exposure groups. So like if they had any baseline differences. Knowing that this is a retrospective review.


[00:11:08] Ben C: They looked also at birth year and this random the nrn center as a random effect um The last thing I want to mention about the methods which is quite interesting is that they created a pre specified mediation analysis that examined whether Severe ivh mediated the relationship between cord management and the primary outcome So could it be that if you had a delayed cord clamping and then had bad outcome later on could that be mediated?


[00:11:33] Ben C: Because you also had like a severe ivh Um, so let's talk a little bit about the results. So, uh, 2, 277 infants. So, um, we're born between, uh, the gestational age, uh, of 22 weeks and 27 weeks and the met inclusion criteria. And, um, infants seen more than four months outside the target neurodevelopmental assessment window were excluded.


[00:11:58] Ben C: That was 77 [00:12:00] patients and those with. follow up data was, uh, were, uh, that didn't have follow up data who were deemed lost to follow up. That was 300 patients. So the final cohort really includes 1900 infants. 583 died before the assessment, uh, at two years and 1, 317 had a complete neurodemental assessment.


[00:12:22] Ben C: Now compared with, it's always interesting when you're doing neurodemental study, look at who are you not studying. So when they're looked at their attrition rate, they found that compared with the infants in the


[00:12:33] Ben C: analytic cohort, those that were lost to


[00:12:35] Ben C: follow up were actually slightly older,


[00:12:36] Ben C: had higher birth weight, higher


[00:12:38] Ben C: ABGARs and lower rate of severe brain injury. And so I think it's always interesting to


[00:12:41] Ben C: see based on your center if you're losing the sick ones or you're losing the the non sick ones and it looks like in this cohort, they were losing the relatively healthy ones. Um, and I think


[00:12:52] Daphna B: which is not uncommon. Right? Like, if parents feel like their kid is doing well, they go to less appointments.


[00:12:59] Ben C: percent 100%. [00:13:00] Um, now in terms of what was their exposure. So in the final cohort, um, 64%, so 1, 218 infants were exposed to immediate cord clamping. So that was most of the cohort. 528, which is about 27. 8 percent were exposed to delayed cord clamping. And then 8. 1%, 154 infants were exposed to umbilical cord.


[00:13:21] Ben C: milking. Now, there were some baseline characteristics that differed from the three groups. Babies who received immediate cord clamping were younger in terms of their gestational age. They were smaller. They were more likely to be growth restricted. They were more likely to be born to a mother that had limited prenatal care, and they were actually less likely to have received antenatal steroids.


[00:13:39] Ben C: And I think that usually makes sense because Um, it's usually the ones who get immediate cord clamping are sort of the chaotic deliveries where Nothing is planned and you're sort of finding yourself in a very tedious situation So that's not really completely surprising But it's an important baseline difference between the patients that needs to be highlighted The primary outcome and the results of the primary outcome is that compared to [00:14:00] immediate?


[00:14:01] Ben C: To immediate cord clamping, delayed cord clamping exposed infants had significantly lower adjusted odds of death or severe NDI. 36 percent in the delayed


[00:14:11] Ben C: cord clamping versus 50 percent in


[00:14:13] Ben C: the immediate cord clamping. So something that was quite significant. By the way, if I did fail to mention this, this is my bad.


[00:14:21] Ben C: What is delayed cord clamping for the purpose of this study is anything above 30 seconds. So if you're doing 30 seconds or 32 seconds, you're good. This still applies to your patient.


[00:14:29] Daphna B: was waiting, I was waiting for you to define it for us.


[00:14:32] Ben C: I'm so sorry.


[00:14:33] Daphna B: given our recent discussions.


[00:14:34] Ben C: I know. I hope Anup is not listening. A statistically significant difference, however, was not observed in the primary outcome for the remaining two comparisons when they looked at umbilical cord milking versus immediate cord clamping or when they looked at delayed versus milking.


[00:14:50] Ben C: Remember, the number of babies who had cord milking was quite small. Now, delayed cord clamping exposed infants had significantly lower adjusted odds of death prior to follow up. [00:15:00] Uh, compared with immediate cord clamping infants, so the rates of death before follow up were 22 percent in the delayed cord clamping group versus 34 percent in the immediate, uh, uh, cord clamping.


[00:15:12] Ben C: There were no statistically significant differences in severe, uh, neurodegenerative mental impairment between the infants exposed to, uh, delayed versus immediate. Cord clamping. Um, again, that's right. What we talked about before was death or severe NDI. This is just looking at severe NDI. There were no differences in Any of the secondary outcomes comparing umbilical cord milking to immediate cord clamping or delayed cord clamping.


[00:15:39] Ben C: The last thing we want to talk about is this mediation analysis with severe IVH. That's something that I was quite eager to, uh, to read. But compared with immediate cord clamping, delayed cord clamping directly reduced death or severe NDI with no indirect effect on the primary outcome via severe IVH with an average [00:16:00] indirect effect of minus 0.


[00:16:02] Ben C: 009 and a p value of 0. 52 and there was no statistically significant direct or indirect effect that were found in the remaining comparison. So


[00:16:10] Ben C: it doesn't Right. It's like delayed cord clamping impacts IVH and maybe it's the


[00:16:15] Ben C: IVH that impacts the neurodevelopment, but on this mediation analysis, which by the way, I hope nobody asks me any more question about what is a mediation analysis.


[00:16:23] Ben C: But when I Googled it, I understand the concept. I would not be able to do it, but


[00:16:28] Ben C: that's


[00:16:29] Daphna B: Something else I was hoping you were going to define


[00:16:31] Ben C: Nope. But it is, um, it is one of these things, right? It's to me, the way I think about this mediation analysis is the same way we think about surfactant and BPD. So it's like surfactant reduces the amount of RDS.


[00:16:43] Ben C: But it doesn't impact BPD because. Surfactant doesn't have that effect. But if you're minimizing rds, could you reduce bp, right? It's that three step The conclusion of the study is that it's a large contemporary observational study of infants born before 27 weeks of gestation and [00:17:00] that Delayed cord clamping was associated with improvement In the primary composite outcome of death or severe


[00:17:06] Ben C: ndi at 22 to 26 months corrected age


[00:17:08] Ben C: compared with immediate cord clamping The protective effects of delayed cord clamping on death or severe ndi was not mediated by severe


[00:17:16] Ben C: ivh.


[00:17:18] Ben C: That's great


[00:17:19] Daphna B: Yeah. Great. Okay. Good. Good to know.


[00:17:23] Ben C: Um any thoughts?


[00:17:27] Daphna B: I mean, the conversation continues is what I feel about this paper. You know, I think we are getting, we are honing down


[00:17:36] Daphna B: on, on umbilical cord management. And I think in the next


[00:17:43] Daphna B: handful of years that we'll, we'll have a much better understanding about what is the best route.


[00:17:49] Ben C: Should we proceed with our ebneo commentary?


[00:17:53] Daphna B: Let's do it.


[00:17:53] Ben C: All right Let's cue the jingle.


[00:17:55] [00:18:00]


[00:18:13] Ben C: So we have the pleasure of having on with us today, Dr. Nic Bamat from the Children's Hospital of Philadelphia. Nick, how's it going today?


[00:18:21] Nic Bamat: It's going great. It's a pleasure to be here.


[00:18:24] Ben C: Yeah. Pleasure to have you on. I feel like it's been well overdue, so I'm glad that through the eBeneo, there'll be more opportunities. We have some things in mind. We'll talk to you about that afterwards, but, uh, um, thank you, uh, for, uh, making the time you're, uh, here to present your commentary on the eBeneo article of the month.


[00:18:41] Ben C: Um, this is an article that was, uh, published in JAMA Network Open and first author is Samuel Gentle from the University of Alabama. And the title is heterogeneity of treatment effects of hydrocortisone by risk of bronchopulmonary dysplasia or death among [00:19:00] extremely preterm infants in the National Institute of Child Health and Human Development Neonatal Research Network trial, a secondary analysis of a randomized, it's not over, a secondary analysis of a randomized clinical trial.


[00:19:12] Ben C: So Nic, I think as we were discussing off air, I think maybe, uh, you want to give us maybe a little bit of context when it comes to, uh, how did we even get to this paper?


[00:19:20] Nic Bamat: yeah, I'd love to. Um, so I had the pleasure of writing this EBNEO commentary together with, um, one of my fellows, Tim Nellen. He was a chief resident at CHOP and is currently one of our third year fellows. And so I'm leaning on the thoughtful and hard work that he did for this. And I want to acknowledge him up front.


[00:19:40] Nic Bamat: I love this paper. Um, I love this paper because it's about BPD, I love this paper because it's about medication exposures, um, I love it because it's about heterogeneous treatment effects, um, and also this is a paper that is really best understood in the context, um, of a rich [00:20:00] history, really a 35 year old saga of corticosteroids for neonatal Lyme disease.


[00:20:06] Nic Bamat: So, I think we have to set the scene a little bit. Um, and I'm gonna make, I'm gonna start with a couple of statements that I hope we can agree on. You can let me know if you don't agree, but statement number one. I think we can all agree that inflammation plays a key role in the multifactorial pathogenesis of BPD


[00:20:31] Ben C: I agree. We can, we can agree with that.


[00:20:34] Nic Bamat: and that corticosteroids are potent anti inflammatory medication.


[00:20:41] Nic Bamat: In the late 1980s. All right, neonatology, we begin to see trials that are showing that dexamethasone leads to respiratory benefits. And in the 1990s, use of postnatal [00:21:00] dexamethasone starts to become widespread.


[00:21:04] Nic Bamat: And then the other shoe drops, okay? Research from the late 1990s, early 2000s that are evaluating long term outcomes suggests that there is an increase in neurodevelopmental impairment. Particularly with concerns for cerebral palsy. Uh, there's a couple of meta analyses in the early 2000s that confirmed this finding.


[00:21:26] Nic Bamat: In use of dexamethasone, rather than rising, now begins to drop.


[00:21:31] Ben C: And to be, to be fair, um, those studies and those practices used some pretty incredible doses of dexamethasone.


[00:21:38] Nic Bamat: Yes, some did, and, you know, those trials used, um, they're very variable in the way that they used. Um, so, in 2002, the AAP puts out a statement. Um, citing the findings of those meta analyses. And essentially suggesting to neonatal providers that we pump the [00:22:00] brakes on postnatal serious use and use declines further.


[00:22:04] Nic Bamat: There's a really nice paper, uh, first authored by Michelle Walsh. It's in pediatrics, I think, in 2006. That describes these changes in postnatal use using data from, uh, both the NRN and... Right, so, so here we are. And so the neonatal community is saying, well, shoot, you know, that's, that's a shame. Um, because it sure as hell seemed like this was helpful lung disease.


[00:22:30] Nic Bamat: Um... Can we find a corticosteroid that seems to deliver the anti inflammatory benefits, um, without the neurodevelopmental part? Um, and hydrocortisone is seen as a hopeful alternative based on a body of literature that I honestly don't know well enough to comment thoughtfully on. But, you know, among other things, there's animal models that...


[00:22:58] Nic Bamat: Um, suggests there's less harmful [00:23:00] effects on, um, and the NRN hydrocortisone trial, which is the parent trial of this secondary analysis, is the largest trial to date, um, on postnatal hydrocortisone. So, uh, I know that this has been covered before, but, um, you know, to briefly summarize this, this parent trial, and in fact, um, you know, we often tried to.


[00:23:27] Nic Bamat: When we write up the BNEO Commentaries, we try to start with a PCOT question. Um, and in this case, I actually think it's a lot easier to frame the PCOT question for the parent trial, and then to describe how this secondary analysis tweaks that. , so the NRN Hyde to Corazon trial, um, asks, Uh, among 800 preterm infants born at less than 30 weeks gestation, that are on mechanical ventilation between 14 and 28 postnatal days [00:24:00] and have received mechanical ventilation for at least 7 days leading up to that point. How does a tapering 10 day course of either IV or enteral hydrocortisone compared to placebo on The primary efficacy outcome of survival without moderate or severe BPD at 36 weeks post menstrual age and the primary safety outcome of survival without moderate or severe neurodevelopmental impairment at two years.


[00:24:32] Nic Bamat: Okay, um, and so the take homes are that they did not notice, um, a statistically significant difference between hydrocortisone and placebo on either. Um, there is A modest suggestion that, um, there may be a small benefit for hydrocortisone on survival without moderate or severe DPD, um, 16. 6 percent of the babies that receive hydrocortisone [00:25:00] survive without this outcome, uh, compared to 13. 2 in the placebo group. Um, and then for the neurodevelopmental outcomes, they're more similar, um, 36. 9 percent that receive hydrocortisone, have no, no. Moderate to severe neurodevelopmental impairment or death in two years compared to 37. 3 to the placebo. Okay. So pivoting a bit to think about how this secondary analysis is a little bit different.


[00:25:33] Nic Bamat: So Sam and colleagues ask, does the effect of hydrocortisone depend on the baseline risk of developing Grade 2 or 3 BPD as estimated by the now updated and newly published NICHD BPD outcome estimator. Um, another key [00:26:00] difference between this paper and the parent trial is that In this study, the primary efficacy outcome swaps out BPD definitions, okay? So here we're looking at death or grade 2 or 3 BPD, as proposed by the 2019, um, Jensen definition, whereas the parent trial had used the 2001, um, consensus definition of mild moderate severe BPD. Um,


[00:26:39] Nic Bamat: another thing that I think it's important to describe is that this does it depend question, does it depend on the severity of lung disease is also not coming out of thin air. Okay. Um, there's a history here too that makes it a very worthwhile question, right? So, um, in the mid 2000s, [00:27:00] as most of the neonatal community is curbing their dexamethasone use, Lex Doyle and colleagues publish the original version of their meta regression.


[00:27:13] Nic Bamat: And so in short, they say, all right, so it seems like postnatal corticosteroids are good for lung disease, but bad for the brain. But we know that lung disease isn't good for the brain


[00:27:31] Nic Bamat: possible that this harm, and in this case, uh, the harm is being ascertained as an outcome of death or cerebral palsy depends on the severity.


[00:27:44] Nic Bamat: of lung disease in the population being treated. And so they gathered data from a bunch of randomized controlled trials of systemic postnatal corticosteroids. Um, and almost all of these looked at dexamethasone [00:28:00] specifically. And they asked, well, is there an association between the rate of chronic lung disease in the control group of each trial and the effect on death or survival?


[00:28:16] Nic Bamat: And they conclude, yes. Uh, they say when the risk of CLD is low, There's an increased risk of death or cerebral palsy, but when the risk is high, um, there is a decreased risk. This is the paper that includes this now famous figure with the circles of varying sizes and you know, this down sloping line with the confidence intervals.


[00:28:39] Nic Bamat: Um, and I would say that, you know, this paper has influenced clinical practice. So I remember When I was a trainee, and we were caring for infants that had evolving BPD, um, we would navigate online our way to the prior version of the [00:29:00] NRN BPD Outcome Estimator, and we would plug in the clinical characteristics of the infant that we were caring for to estimate the probability of death of BPD, right?


[00:29:11] Nic Bamat: And then with these estimates in hand, we would circle back to our attending to talk about whether or not we saw that it was worse. Initiating the course of, um, Odexamethasone. Right? So, an influential, um, paper for sure.


[00:29:28] Ben C: I think you're, I think I'm just going to maybe hammer in that point that we're through this historical context. We, we get, I mean, basically it's this baseline. Risk assessment is really something that helps us figure out, as a field in general, that maybe blanket prophylaxis for everyone is not the way to go, and that we should assess the risk of each patient individually to then determine if the benefits of the medication are there compared to risk.


[00:29:59] Ben C: And I think, [00:30:00] I think that's, that's both a, it's a, it's a shift on so many levels for our field that, yeah, I think, I think this is, this was great that you went over that.


[00:30:06] Nic Bamat: yeah, absolutely, absolutely. Alright, so, so in this paper what, um, what Jentle and colleagues are saying is they're saying, okay, you know, so based on these metaregressions, Um, we believe that the effect of dexamethasone on death or CP likely depends on the degree of underlying lung disease. So let's probe whether the effect of hydrocortisone seems to also depend on the degree of underlying lung disease as measured by the predicted risk of developing grade 2 or 3 BPD based on clinical characteristics available at 14 days.


[00:30:50] Nic Bamat: All right. So, so what do they do? So for each of these 800 infants. They estimate this predicted risk by inputting gestational age, [00:31:00] birth weight, infant sex, ventilator mode, surgical neck, and FiO2, right? And so, the calculator or the model, um, spits out a predicted risk for each of these infants. And on the basis of this, they divide the 800 infants into 4 buckets containing 200 infants.


[00:31:21] Nic Bamat: Risk quartile 1, risk quartile 2, 3, So, risk quartile 1 contains the 200 infants from the trial with the lowest risk of grade 2 or 3 BPD, uh, or death, I should say. And quartile 4 contains the 200 infants with the highest risk of grade 2 or death. All right. And then with these quartiles or buckets in place, they ask, Do the efficacy and safety outcomes depend on which quartile the infant is in?


[00:31:57] Nic Bamat: Right? And so in other words, they're asking, Is [00:32:00] there evidence of effect modification by predicted risk, uh, as measured by the presence of a statistically significant interaction? Uh, and the long or the short of it is no. There is no appreciable, okay, and I think that's the word here. There is no appreciable evidence of effect modification, uh, for either the efficacy or the safety.


[00:32:30] Daphna B: I think you did a great job of, of giving us the back story, um, and, and reviewing, um, the trial and, you know, to be clear, in, at any of the quartile levels, none of them showed statistical significance, so, um. That was a little bit of a bummer, I think I, I have to say for myself, the whole, I mean, we've been, we've been watching the saga develop throughout our training, right?


[00:32:56] Daphna B: It's, you know, and, um, as early, uh, [00:33:00] attendings, and we keep hoping, I think, that something will show us that, that, it will be helpful in this, uh, group of babies. Um, I think the paper did a good job discussing, um, some of the strengths and limitations. Um, I didn't know if you wanted to talk about any of those.


[00:33:21] Nic Bamat: so let's jump on one that very much relates to kind of what you just commented on, right? That, that it is a bummer, right? Um, but I would say that perhaps it's not an unexpected. And one of the things that I'm getting at with that comment is that the parent trial was not powered for this question. Not meant for this.


[00:33:44] Nic Bamat: Um, in general, you know, we, we as a neonatal community really struggle to, um, conduct neonatal trials. That are large enough to detect [00:34:00] minimally important, uh, because it just requires an awful lot of babies. Um, but in general, when you are designing a trial and one of your objectives or your main objective is to show effect modification, you need a substantially larger sample size.


[00:34:26] Nic Bamat: Uh, and so those are really, really difficult to do. And you could argue that even the parent trial may have, um, you know, underpowered and was hoping for a relatively large effect size. Um, and it's designed. So, you know, when you dig into the numbers a little bit, um, you, you can begin to question whether or not maybe there is a signal there, right?


[00:34:50] Nic Bamat: So, um, if you look at, at quartile one


[00:34:55] Ben C: quartile one is the one with the risk between 18 and


[00:34:57] Nic Bamat: Yep.


[00:34:59] Nic Bamat: the [00:35:00] lowest


[00:35:00] Nic Bamat: risk. And I think, so my point that I'm trying to make I think is best appreciated if you look at table two. So if you look at the top of table two, you can see that, um, for quartile one, all right, Instance that are exposed to hydrocortisone seem to have Uh, an absolute risk difference of 5% more death, uh, or high grade b p d, grade two or three B p d.


[00:35:31] Nic Bamat: Or as you, if you look at quartile four, um, the hydrocortisone group seems to have 5% less death of B p D, right? And so I think if, if we leave. The very substantial statistical uncertainty that exists here alone for a second. And I'm not saying we should do that, but if we leave that alone for a second and we just look at those effect estimates, you can ask yourself, huh, you know, maybe there [00:36:00] is a signal there.


[00:36:01] Nic Bamat: And if this was a trial of not 800 infants, but rather 8, 000 infants, Then maybe we would see, um, statistically significant effect of mutation if we branch.


[00:36:14] Daphna B: To your point, I think they did a beautiful and eloquent job in the figures, actually. So, figure 1A obviously shows that the babies who are at the highest risk did, in fact, end up having, uh, the most. uh, adverse outcomes. And when you contrast the, the slope there, uh, to, to figure 1c, which was the risk reduction, um, it's basically an, an inverse relationship.


[00:36:43] Daphna B: Um, so that, you know, they had the greatest risk reduction. So that, I mean, definitely there's a trend there, it feels like.


[00:36:49] Ben C: And so, and so to that point, I guess, uh, I'm curious to hear your comment on the fact that, as we said in the beginning, right, we're trying to look at whether the baseline [00:37:00] risk really makes a difference in the, uh, treatment effect of hydrocortisone. But then looking back at the, even the parent trial, these were babies that were pretty much all at very high risk.


[00:37:09] Ben C: They were all very sick patients. And so do you think that if they had a more homogeneous population with a, with a few babies, maybe even enrolled earlier on that were on less, uh, support, maybe we could have had a more homogeneous spread of the baseline risk. And maybe we would have seen a signal that would be stronger


[00:37:27] Nic Bamat: Yeah. I think it's, um, so absolutely. I think that's a great point. And, and, um, and Daphne, absolutely. Right. You look at, you look at figure one, see, that's not a straight line, you know, like


[00:37:37] Nic Bamat: a little bit,


[00:37:38] Ben C: It wants to curve. It wants to do the little,


[00:37:41] Nic Bamat: probably not the first hill that I would choose to go sliding down, but you know, there's, uh, there's something there, um, that, that could definitely catches your eye. Um, and, and Ben, your point, I think, you know, Um, I do think that the authors did a really wonderful job of, uh, of calling out the limitations of their study.


[00:37:59] Nic Bamat: There's another one that they [00:38:00] called out. Um, but, you know, absolutely, if you just, you know, if you, if you just stop and think about who were the babies that were, um, enrolled in parent trial, right? These are babies that were still on a vent between 14 and 28 days and had been on a vent for at least seven days.


[00:38:16] Nic Bamat: Um. You know, if you look back at, um, if you look back at the results of the parent trial, I don't have it in front of me, but if you look at the rates of


[00:38:29] Ben C: yeah, it's like 16


[00:38:30] Nic Bamat: is they defined it, right? Yeah. You know,


[00:38:32] Ben C: I mean, 16, 16 or 13 percent was survival without moderate or severe. So like rates of BPD were like in the, in the 80, 80, 80 something percent.


[00:38:41] Daphna B: Right. So their quartiles don't necessarily represent our entire NICU population, right? Or the at risk population.


[00:38:50] Nic Bamat: um, yeah. And so, you know, I, I think an important message for this paper and it's all papers really and it's something that we're frequently [00:39:00] guilty of is that we love to extrapolate data from a study to other populations or broader populations. Um, to whom that, those data don't necessarily apply, right?


[00:39:11] Nic Bamat: Um, and so yes, you know, I think that, I think you should not look at this data and assume that there would be a lack of effect modification if you were looking for an interaction in a population that was more heterogeneous and had infants that were very, very low risk of, um, developing death of BPD, uh, and perhaps some infants at, at higher risk.


[00:39:37] Nic Bamat: Although there was. I'd say that this, uh, this core was enriched in a sense that we're very high with, um, I think another, another thing to that point is if you look at, um, Ben, you referred to that, the table one, right when we first started to look at this, I was scrolling my paper to try to find it. Um,


[00:39:58] Ben C: Did I refer to table one? Sure, but


[00:39:59] Nic Bamat: [00:40:00] table one.


[00:40:00] Nic Bamat: Um, yeah, I think he did. I think he did.


[00:40:03] Ben C: yeah, yeah, I'm happy doing it.


[00:40:05] Nic Bamat: Uh, if you look at, right, so they took these 800 tits and they put them into four buckets, 200 each, and they described. The estimated risk of grade two, three year deaths in each of those quartiles. And you can, you can get the sense that this population is a bunchy group.


[00:40:28] Nic Bamat: So, risk quartile 1 ranges from 18 to 45. That's a pretty good spread for risk quartile 1. You look at risk quartile 2, it's a pretty tight spread from 46 to 53, which isn't that different from quartile 3 at 54 to 65. And then 84, you know, there's a little bit more spread there.


[00:40:52] Ben C: barely, barely 10 percent, 10 percentage points and, and the quartile one really includes like almost 20


[00:40:57] Nic Bamat: Yeah, right. So


[00:40:58] Ben C: more than


[00:40:59] Nic Bamat: it's really [00:41:00] quartile one and quartile four that, that are the most distinct quartiles two and three are awfully similar.


[00:41:06] Ben C: yeah, yeah.


[00:41:07] Nic Bamat: you know, and it speaks to this limitation that, um, this is a specific population that had all of them had fairly significant. Lung disease, which is what was required to make them eligible and relevant to


[00:41:25] Ben C: What's interesting to me about this is that I like when, when we are conducting trials that are kind of similar in the idea of what they're trying to test across different institutions, different countries. And so to me, I look at this and I cannot not think of the Premalok trial, right? Where, uh, they also used hydrocortisone and, and they are showing, and they are showing a benefits, uh, they are showing a benefit.


[00:41:48] Ben C: And one of the big criticism of the Prerog trial was that the rates of BPD were quite high, but still they were less than, than in, in this parent trial. And it's funny that very recently they did the same kind of [00:42:00] analysis, not using, using sort of a modified BPD calculator. They didn't use the NRN one, but they're looking at the same thing and they are seeing a bit of a signal.


[00:42:07] Ben C: So I think


[00:42:08] Nic Bamat: that's good.


[00:42:09] Ben C: interesting about this whole commentary that we're having now is that you may be tempted to think by reading this current paper, maybe even the parent paper that It's all done for hydrocortisone and we're probably not going to need to revisit this, but it, it may not be, it may not


[00:42:21] Daphna B: That was going to be my question


[00:42:23] Ben C: Oh, go ahead.


[00:42:25] Daphna B: No, just that, and we posed this question to Dr. Waterberg. And we said, are we done studying, uh, postnatal steroids? But it seems like the answer is still probably


[00:42:37] Nic Bamat: Oh,


[00:42:38] Daphna B: I think we're, we're getting, we're refining it.


[00:42:40] Ben C: He gave you a no way, that was a no way.


[00:42:44] Nic Bamat: Boy, you know, I mean the thing a thing with steroids what makes them what makes them compelling What makes this hard is that we all know in our hearts of hearts based on our own experience that they work in some


[00:42:57] Daphna B: Yes.


[00:42:58] Nic Bamat: They work


[00:42:58] Daphna B: Deaf, some kids definitely [00:43:00] respond. Yeah. I wonder too. If, um, as we're in this era of individualized, personalized medicine, maybe it's something else about the patient and not their risk, you know, that, that predisposes them to, to, uh, be successful on a certain medication. I think as we're starting to do this, uh,


[00:43:22] Ben C: want to discriminate between, you want to discriminate between the steroid responders and the steroid


[00:43:26] Daphna B: that's exactly right.


[00:43:27] Daphna B: That's exactly right. So what's different about those two groups, um, and work our way backwards, I guess.


[00:43:34] Nic Bamat: Yeah, and really, you know I mean, you're highlighting the reality that, that clinical medicine is nuanced, right? And like, we all have this goal of, of personalized, individualized medicine. Um, and I think, I think to me what's really interesting about heterogeneity of treatment effects from a clinical research standpoint is that it's an effort to bridge evidence based [00:44:00] clinical practice and, you know, that.


[00:44:04] Nic Bamat: aspiration of individualized medicine by acknowledging in the same way that, you know, we know to be true in clinical medicine, that things are nuanced, that, you know, from a research perspective, you know, the devil's in the details and, and things are also 100 percent nuanced. You know, you described the Permalock trial, Ben, Um, yeah, you know, same, same general preterm population, same drug, but the intervention is done at a completely different time.


[00:44:33] Nic Bamat: And in a lot of ways in populations that are very, very different, we're talking about prophylaxis and babies at risk, um, for adrenal insufficiency versus babies that now seem to be a very high risk of developing lung disease because, you know, they're two to four weeks out and they're still requiring a certain amount of support.


[00:44:51] Nic Bamat: And so. You know, extrapolating the results of early hydrocortisone to decisions about late hydrocortisone is [00:45:00] inappropriate. Um, but, you know, it's, it's hard to, um, to generate good evidence for all of those distinct nuanced differences, um, in the decisions that we're making with medical medicine and that we should.


[00:45:20] Ben C: Yeah, because, because I think the NICU has evolved tremendously as well, right? We, we, our babies survive. Number one, our babies have, there's a, a wide variety of patients where it used to be, oh, the preemies of the NICU, but now a 20 to 24 weeker is very different from a 28 weeker. And, and then the late, uh, preterms are a different part.


[00:45:38] Ben C: And so we end up having this really multifaceted population. And so I think. Um, it's that's that's that was my point originally, but I think it's very good that we're studying, uh, the same kind of medication in various trials trying to to get to circle the question at the very least, and maybe glimpse at an answer.


[00:45:57] Ben C: It almost like this picture of the black hole, right? It's [00:46:00] like you don't really see anything, but it's the surrounding that maybe gives you an idea of where it is and and where the truth lies. And I think, um, yeah, I think it's, um, yeah, It's a, it's super interesting intellectual endeavor for sure.


[00:46:13] Nic Bamat: Absolutely.


[00:46:16] Ben C: Nick, thank you so much for making the time to be with us. This was phenomenal. And, um, yeah, we look forward to chatting with you again soon.


[00:46:23] Nic Bamat: Thank you. I do as well.


[00:46:25] Daphna B: Thanks.


[00:46:27]


[00:46:45] Ben C: That was great. We're very thankful for the collaboration that we have with the ebneo team. It is a robust group of people that is always providing very insightful [00:47:00] Comments about some of these articles and it always gives us the opportunity to revisit some of these articles that we we briefly mentioned on the podcast.


[00:47:06] Ben C: So that's


[00:47:06] Daphna B: That's what I was going to say. Very commonly, we've already reviewed the article, but it's nice to revisit it and have somebody else's perspective


[00:47:17] Ben C: I think in the book, make it stick about like how to


[00:47:19] Ben C: memorize things. Always asking you about like revisiting something. So that to me is great. And the the historical context that Nick gave about the use of steroids and neonatology is priceless. So thank you for doing that.


[00:47:29] Daphna B: very helpful.


[00:47:30] Ben C: All right, definitely.


[00:47:31] Ben C: What are you looking at today?


[00:47:32] Daphna B: Okay, well, we knew this was going to be an interesting journal club on like hot topics, so I wanted to introduce two different


[00:47:42] Daphna B: things. The first is


[00:47:43] Daphna B: this, um, survey by our friends at the CHNC.


[00:47:49] Daphna B: Uh, we're very excited that we'll be going to the CHNC conference. We've got some, uh, an interview about the CHNC to come out shortly.


[00:47:59] Daphna B: Um, [00:48:00] but this was a brief communication in the Journal of, Journal of Perinatology, current state of renal NEARs monitoring in the NICU results from a CHNC survey. Um, lead author, Matthew Herer, and this is, um, again, the Children's Hospital Neonatal Consortium, but specifically they have the Kidney and Urology Focus Group, and that's one of the things we talked about with our, um, upcoming interview.


[00:48:24] Daphna B: Regarding the CHNC is they have all of these focus groups, um, for units to get involved in if they're working on any one particular thing. But I thought this was interesting. Uh, it's, it's a topic of discussion in our own unit about using NIRS, uh, monitoring, um, or near infrared spectroscopy, um, and monitoring of regional tissue oxygenation.


[00:48:46] Daphna B: And, I'm pretty familiar with NIRS, I used it a lot for cerebral oxygenation, um, but they were interested in looking specifically at renal NIRS, which is something that our team is doing. So that drew my attention, [00:49:00] um, they had a 22 question survey and they really just wanted to give an indication of what the community was doing.


[00:49:07] Daphna B: They had a 75 percent completion rate, so 34 out of their total 45 sites responded, and I was surprised to see this. 77 percent are using renal mirrors. I thought that was a lot, don't you think?


[00:49:23] Ben C: Yes, it made me. Yes. I'm so sorry. I


[00:49:26] Ben C: was muted. Um, yeah, 77%. I mean, we just started, Uh,


[00:49:31] Ben C: using nears routinely in our unit. Uh, so, um, and I feel like we're pretty innovative. We're pretty quick to adopt new things in our,


[00:49:37] Ben C: in our group. So 77 percent made me feel less excited about how cool we were.


[00:49:43] Daphna B: that's right. And, and I think the rest kind of is pretty familiar with the rest of the community. So, um, some of them are using it exclusively for clinical purposes, about 46%. Um, and then in the other 54, they're using it for both clinical and [00:50:00] research, which makes sense, because I think we still have a lot to learn about NEARs.


[00:50:03] Daphna B: The most common indications were ECMO, uh, congenital diaphragmatic hernia. and congenital heart disease and HIE. Um, and interestingly, very few units were using renal NEARs in the preterm infant, even though that's probably the most common thing being studied right now is how can we use NEARs to manage the ELBW.


[00:50:25] Daphna B: Renal oxygenation is discussed. on rounds at 73 percent of sites. So that's almost everybody. But interestingly, only five sites had a protocol or guideline to say what you should do with the information that you found on your renal mirrors. And the limitations, not surprisingly, that were discussed are that they're unclear normative values and it was unclear what to do about the values, even once you got them.


[00:50:57] Daphna B: So I just thought this was interesting because I think it [00:51:00] represents what's happening in our unit. We want to use renal years. We're hopeful that they will be valuable. Um, and we still don't have a really good idea about how to change our management based on. So, uh, that's a hot topic. I wanted to make sure to bring that up and give a shout out to our friends at the CHNC.


[00:51:20] Daphna B: And then I definitely wanted to draw people's attention to this. entire issue of Clinics and Perinatology on Neonatal Nutrition. It's entitled Neonatal Nutrition, Evidence Based Recommendations for Common Conundrums. Um, and it's a, like you said, this week is a star studded lineup. Um, the foreword is by Lucky Jane.


[00:51:47] Daphna B: He gives a humorous, um, forward to the entire issue. Um, the preface and the editors, um, are, uh, Dr. Poindexter and Dr. Hair. And so you name [00:52:00] it, they got experts in the fields. And then they have amazing articles. So I'll just run the list so you know what to look for. Early fluid and nutritional management of extremely preterm newborns during the fetal to neonatal transition.


[00:52:14] Daphna B: Administering parental nutrition in the neonatal intensive care unit, logistics, existing challenges, and a few conundrums. There's parental nutrition in the neonatal intensive care unit, intravenous lipid emulsions, calcium and phosphorus, all you need to know but we're afraid to ask. The practice of enteral nutrition, clinical evidence for feeding protocols.


[00:52:37] Daphna B: Human milk fortification for very preterm infants toward optimal nutrient delivery, neonatal intensive care unit growth, and long term outcomes. Human milk fortification strategies in the neonatal intensive care unit, um, nutrition management of high risk neonates after discharge, red blood cell transfusion, anemia, [00:53:00] feeding, and the risk of neck, current practices, challenges, and recommendations in enteral nutrition after neck.


[00:53:07] Daphna B: Nutrition for infants with congenital heart disease. And then there's a commentary on special populations, surgical infants, controversies and conundrums in newborn feeding, the role of the registered dietitian, nutritionist, past, present, and future. So it's a basically all you need to know about.


[00:53:26] Daphna B: Nutrition in the in the NICU. What have we done? Where is the current state? And what still needs to be done? I wish I had the time to review all the articles, but I definitely wanted people to to know that that was out there and to take a look.


[00:53:40] Ben C: And it's a great compliment to the, discussion that we had with


[00:53:42] Ben C: Amy and Misty, um, about some of these conundrums, cause we asked them a lot of these questions. Um, so, so it was great to see that paper come out.


[00:53:51] Daphna B: And I think if you wanted to make a conference about nutrition, those would be the topics you would want to see and the, that would be the [00:54:00] lineup of people you would want to hear from.


[00:54:01] Daphna B: So definitely take a look.


[00:54:04] Ben C: Um, I think what we should do next is talk about this paper called treatment of seizures in the neonate guidelines and consensus based recommendations, special report from the ILAE task force on neonatal seizure. seizures. This is a paper that definitely will, uh, fly by most of us because it's published in Epilepsia.


[00:54:21] Ben C: It's something that we do not, something that we talk about at the incubator very frequently that a lot of very impactful papers are published in journals that we don't follow routinely. And this is a paper


[00:54:30] Ben C: that is written for neonatologists. It has a star studded lineup. Terry Ender is a co author.


[00:54:35] Ben C: René Chalhas is one of them. We have Linda DeVries. Um, so it's, I mean, I could go down the list, um, of all these authors. There's, there's, it's, it's


[00:54:43] Daphna B: neonatal neuro Rock stars,


[00:54:46] Ben C: Yeah, absolutely. And so, um, we're very excited to bring on Rene Shellhaas to talk about this paper with us and talk a little bit about the impact, uh, that it has.


[00:54:55] Ben C: So, uh, without further ado, please welcome to the show, Dr. Rene Chalhas.


[00:54:59] [00:55:00]


[00:55:01] Ben C: . René, thank you so much for being on the podcast.


[00:55:03] Renee Shellhaas: It's an honor to be here. Thanks for inviting me.


[00:55:05] Ben C: Thank you. You are a professor of neurology at Washington University in St. Louis School of Medicine, and you are one of the authors of the recently published special report in Epilepsia, a journal that, as neonatologists, we don't consult very often, but on a very important paper called Treatment of Seizures in the Neonate, Guidelines and Consensus Based Recommendations, special report from the ILAE task force.


[00:55:34] Ben C: on neonatal seizures. So first of all, congratulations on being part of this effort. And I guess I wanted to maybe ask you for people who are driving in their car, who have maybe not even aware that this paper came out. Can you bring us up to speed as to what this paper is and what it intends to do and what are some of the takeaway points of the, of the article?


[00:55:57] Renee Shellhaas: Absolutely. Thank you. So, the [00:56:00] first thing is that this paper is a guideline that's coming from the International League Against Epilepsy, and the paper was, uh, spearheaded by two phenomenal, uh, epileptologists, Ronit Pressler and Hans Hartmann, so lots of credit to them. I am a co author on this. Uh, but it took a big team of, uh, people.


[00:56:20] Renee Shellhaas: Uh, multidisciplinary contributors from all over the world to bring this together. Uh, we've been working on it


[00:56:25] Ben C: you're, you're very humble, but Linda DeVries is also a co author. Terry Ender is also a co author. So I feel like there's no, uh, there's no ranking. Everybody is pretty, it's a star studded lineup.


[00:56:36] Renee Shellhaas: it's a, it's an important lineup. Uh, and, and these individuals all put a lot of work into this over the last five or six years. Um, this is a really, in my view, as somebody who's really interested in neonatal seizures, this is a really important step forward for the field. This is a very carefully done systematic review of the literature on neonatal seizure treatment, uh, and where there was [00:57:00] insufficient.


[00:57:00] Renee Shellhaas: Uh, literature and not enough data to make a recommendation. This was an expert, um, Delphi process in order to come up with recommendations that make sense, um, not just in the very high resource, uh, locations, but also other less resource institutions around the world. I think this is gonna set a new standard for


[00:57:21] Ben C: that was very satisfying because so many of these papers on this topic specifically are suffering from the lack of evidence. And sometimes you end up with. A question left unanswered and you're like, Oh, I wish there was an answer. But here, I think thanks to the design and thanks to the Delphi consensus statements, when evidence was lacking, you still had a recommendation coming from a panel that was actually very well composed.


[00:57:41] Ben C: We'll talk about that in a second, but, um, you were able to address every single question that you guys had set out to do.


[00:57:48] Renee Shellhaas: Yes, that was the idea. Make this as practical and useful as


[00:57:54] Ben C: And so how many questions? Um, so, so obviously it's a system, it's a systematic review that [00:58:00] aims to answer a very specific number of questions. Which I think we're all asking ourselves when managing patients neonates with uh seizures So can you can you walk us through a little bit what some of these questions are?


[00:58:12] Ben C: And maybe we can talk afterwards about some of the actual recommendations


[00:58:16] Ben C: so that we can then have a proper conversation about those


[00:58:19] Renee Shellhaas: Absolutely. So, this panel came up with six, uh, PICO questions. PICO, patient population, intervention or issue, comparison, and outcome of interest. The six were, what should we use as the first line anti seizure medicine? What should we use when the first doesn't work? So, the second line anti seizure medicine.


[00:58:38] Renee Shellhaas: When should we stop the medication? Is there an effect on seizure burden of therapeutic hypothermia? How does treatment of electrographic or EEG defined seizures associate with outcome? And when and how should we use pyridoxine or pyridoxal 5 phosphate for infants who have concurrent seizures? So, those are the [00:59:00] six questions, um, as the main question.


[00:59:03] Renee Shellhaas: Then there were a couple of additional ones, one about, um, standardized treatment protocols at a, at an individual institution level, and a second about communication.


[00:59:15] Ben C: And so, um based on the based on the literature review, um and the consensus, um Of the of the of the panel what were some of the uh, Can you can you walk us through the answers to each one of these questions? Obviously, we're not doing a paper just as each of these questions does have an attached recommendation Which we'll go over but also goes over how that recommendation was Was uh, how how the how the group arrived at this recommendation and that I think is a very valuable especially if you're a trainee Understanding how we make recommendations for practice guidelines, but obviously this may be going beyond the scope of this podcast But can you walk us through some of these recommendations?


[00:59:54] Ben C: uh to these six questions


[00:59:56] Renee Shellhaas: Sure thing. So first thing is, um, the first [01:00:00] question is what, what is the first line out of the gate? And it's so that we use her neonatal seizures. Uh, and the answer is phenobarbital. So all of the evidence that we have points to phenobarbital being, uh, the most likely to control the seizures as the first line method. Um, that has been true over a lot of time. It's been true, um, in practice worldwide, um, and it really hasn't changed, but the truth is the data that we have say phenobarbital is the first line. For almost every baby with neonatal seizures, the one exception is that there are rare infants where they have a familial and inherited neonatal epilepsy syndrome caused by a specific channelopathy.


[01:00:43] Renee Shellhaas: You can get an idea from Family History and Clinical Futures. Um, and for those babies where you're really sure that that's what they have, there are some instances where you can use a different. For the most part, um, phenobarbital, I'm not a fan at this time.[01:01:00]


[01:01:01] Ben C: I have some questions about that, but I'll let you, I'll let you and by the way, before we even move on, I think it's important to clarify. We're not talking full term. We're not talking premise. We're talking neonates,


[01:01:11] Renee Shellhaas: we're talking preemies, we're talking full time term, any, any neonate who is less than, uh, 48 weeks postnatal age.


[01:01:20] Ben C: right? I


[01:01:21] Renee Shellhaas: Some will, some will use 44 weeks, but we're getting into


[01:01:24] Renee Shellhaas: semantics there, But anybody depending on the age,


[01:01:26] Ben C: yeah, because we're talking about, uh, first line agents, including patients with H I. Thank you. And I think some people say oh, are they then talking about only full time? No, we're talking about the whole spectrum and I think that's also very important.


[01:01:37] Ben C: And so the the second question that was addressed um in the in the paper was uh, what about uh Second line agent, uh, what is what is the recommendation?


[01:01:48] Renee Shellhaas: Yeah. So the second line, uh, so the recommendation about second line is that, um, Phenytoin, Levotiracetam, Midazolam, or Lidocaine, uh, could be used as second line [01:02:00] for most etiology. Um, if... The child has a congenital heart disease and there's concern about arrhythmia, then of those levotriacetam might be a preferable agent, um, above phenytyl and oligodine.


[01:02:18] Renee Shellhaas: Uh, if the child has a suspected neonatal Epilepsy caused by a channelopathy than a sodium channel blocker, like Carine or Tonin would be considered. Uh, but we have far fewer data on the first line. The


[01:02:39] Renee Shellhaas: that's the, that's the answer that we have for the, that second question. The third question that we looked at was when to stop the anti seizure bus. And, um, in practice, there's been wide variation on this.


[01:02:53] Renee Shellhaas: Um, turned out that given the time frame of when the papers needed to be published, [01:03:00] there weren't any, um, large studies to include when we did the systematic review. During the time that we were doing our work, uh, another paper came out, um, in full disclosure, I'm the senior author on that paper, so, um, I, I may be a little bit biased, but I think it's important work, and in fact, having that paper come out, um, allowed for the group to have, uh, consensus stuff, um, and so the recommendation, uh, is that following cessation of acute symptomatic seizures, whether they be electrographic or electroclinical, um, Without evidence for neonatal epilepsy, anti seizure medicines can be dischar uh, can be discontinued prior to discharge to home, regardless of MRI or EEG.


[01:03:47] Renee Shellhaas: So what does that mean? The first means that we've decided that we are confident the baby has acute, provoked neonatal seizures and does not have neonatal armpit epilepsy. That the seizures have come [01:04:00] under control, um, at least for 24 hours, many of us will wait a little bit longer than that. Um, and that, you know, overall, the baby is looking like they're getting better, right?


[01:04:10] Renee Shellhaas: Their trajectory is improving. Uh, that the, the anti seizure medicine can, can be stopped, not switched to a different medicine. Tapered down to something, something else, but stopped before the baby goes, um, and that's based, um, in part on this study, um, where the first author is Hannah Glass from UCSF. This is based on a study that we did with the neonatal seizure registry.


[01:04:35] Ben C: I think that's a huge point because I think what you're saying is important. It's that it doesn't mean that it definitely needs to be stopped, but if the parameters are met where it is safe to do so, then we shouldn't have the neonatologist reflex of saying, well, we got to this point. Just, just don't touch anything and just let them go home and somebody else will deal with this.


[01:04:56] Ben C: That is not the right approach. Um,


[01:04:59] Renee Shellhaas: Right, [01:05:00] um, the neonatologist approach there is, do we have confidence? Does this family know what to do and who to call should they have a concern? Um, do they have follow up with a child neurologist and a pediatrician? Um, so we're not letting them go off and nobody's ever going to see this child again.


[01:05:15] Renee Shellhaas: But what the data show is that staying on an anti seizure medicine, um, does not prevent the child from developing epilepsy in infancy. Um, in the, in the study that we did with the neonatal seizure registry, this was a, an observational comparative effect of the study. It's a lot of statistical gymnastics to get at, um, causal inference.


[01:05:36] Renee Shellhaas: And what we found was the babies who developed epilepsy early on, within four months, they all went home on anti seizure medicine. So that medicine didn't prevent them from developing epilepsy. Um, additionally, many of the babies who did develop epilepsy developed infantile spasm, which is a very specific kind of epilepsy, and it requires specific treatments.


[01:05:58] Renee Shellhaas: And none of those treatments are [01:06:00] treatments that we would send a baby from the NICU, so they wouldn't, it wouldn't work for that kind of um, and the median time of onset to epilepsy, you know, unprovoked seizures in the infant period was seven months, uh, which was longer than most infants were maintained on a medicine.


[01:06:23] Renee Shellhaas: They did go home. Those rationales as far as I want to prevent the onset of epilepsy or want to put off unprovoked seizures didn't hold and staying on a medicine does not. It doesn't change the chance of developing epilepsy, it doesn't make the epilepsy happen later. And the medicines that we would go home on, most often phenobarbital, do not treat the most.


[01:06:50] Renee Shellhaas: Next thing is about development. And we found, right, there was no difference in neurodevelopmental outcomes if the baby went home on or off. [01:07:00] Third thing was to ask parents, when it, what is acceptable to you, uh, and you know, we could have seen parents say, you know, I want to stay on medicine because I want to feel like I'm doing something.


[01:07:11] Renee Shellhaas: I could have seen parents say, I don't want to stay on medicine because it reminds me of this really difficult time that we had. Turned out in our data from neonatal seizure registry that one of the factors that, that was associated with. parent well being with going home often. And so the preponderance of evidence really suggests that we should be sending children home off of medicine with appropriate follow up with their pediatrician and child, and all...


[01:07:39] Ben C: And that's another important point that, um, part of the consensus based recommendation included parents. That's huge. I mean I was when I was reading the paper. I was not expecting to see that I was expecting a panel of experts and um, I think I think this was this was very innovative of you guys to include families and into the discussion so I think that's also [01:08:00] something that people should know about as they read these recommendations was that Parents were involved in the in the recommendation when it came to uh, obviously the evidence based recommendation is evidence based recommendation Is whatever the literature says, but these consensus based recommendations are actually uh, including parents, which I think is really cool And then, um, in terms of, um, the, do you want to go over quickly over the last few recommendations so that, yeah,


[01:08:26] Renee Shellhaas: Yeah. So we can do that. So, uh, the question about the effect of therapeutic hypothermia on seizure burden... There are several, um, studies that, that document that therapeutic hypothermia may reduce seizure burden, um, which hypostatic ischemic encephalopathy. Um, however, none of us would recommend using only cooling to try to, to treat seizures, right?


[01:08:52] Renee Shellhaas: Uh, we still know that about half of babies who have mild to moderate, sorry, moderate to [01:09:00] severe HIE, uh, have EDG confirmed seizures. And we want to treat those just like we would treat any other baby who has managel seizures, first line. So that was the next one. Um, Is decreasing seizure burden associated with better seizure outcome?


[01:09:18] Renee Shellhaas: Fifth PICO. Um, This turns out to be a very difficult question to answer with a trial. There are a couple of randomized controlled trials that have looked at this. They have all been underpowered because it is difficult to recruit to this kind of trial study design. Um, And so this went to Adelphi Consentverse, um, and the consensus based recommendation saying that treating the seizures, um, to achieve a lower seizure burden may be associated with improved neurodevelopment and reduction of subsequent output.


[01:09:50] Renee Shellhaas: And the last of these big six pico questions was about the use of pure vaccine or pure doxal vaccine. And the idea here is that there are very rare neonatal onset [01:10:00] epilepsies don't respond to anti seizure. And so that a trial of pyridoxine should be attempted for a baby who's presenting, um, with clinical or aging features suggestive of, uh, vitamin B6 dependent epilepsy, uh, and who have not responded to anti seizure medicine, uh, or to babies who have seizures that are unresponsive to, to a trial of two usual dosed anti seizure medications.


[01:10:27] Renee Shellhaas: And who don't have an identity, uh, so that was, um, a very, uh, clear consensus among, um, and those last two recommendations, one is about, um, developing a standardized treatment pathway for management of neonatal seizures in your local unit, um, and within the manuscript that you're referring to, there is a proposed treatment pathway that folks can take a look at, um, and modify as appropriate [01:11:00] for their needs.


[01:11:01] Renee Shellhaas: The idea here is that for a high stakes, uh, low frequency, uh, problem, like neonatal seizure, it's an emergency, um, you don't want to be trying to, to recreate the wheel at 3 a. m., right? Uh, that if everybody knows what medicines are available and why ICU, what can I get quickly, how do I get them to the bedside, uh, then we can treat efficiently and we can measure quality and do some quality improvement.


[01:11:28] Renee Shellhaas: Studies if need be, and really get the whole team on board to, to efficiently and effectively treat babies with man seizures. So that's a, that was a strong among my.


[01:11:43] Ben C: I think what's very interesting about this is that in the background section of the paper, you mentioned obviously, and you've mentioned this, uh, earlier in our chat about the fact that there's a lot of variability in how we approach seizures and for some of these recommendations looking at, um, sometimes in, in these.


[01:11:58] Ben C: Uh very nicely done [01:12:00] boxes. We have the evidence based recommendation and we have the consensus based recommendation I was was actually interesting to see that the strength Of the recommendation is Always maybe moderate or sometimes even weak but when it comes to the consensus agreement, it's always moderate to high I thought there was a there was truly a consensus among The experts that were at the table and I was Honestly, expecting to see maybe a bit more dissonance when it comes to, since there is so much variability, I was expecting these, uh, Delphi consensus to be maybe, uh, a potluck of different opinions.


[01:12:36] Ben C: And I was not expecting to see such a high consensus. What, what do you make of that?


[01:12:39] Renee Shellhaas: Yeah, it's a really good question. So your point is that the, the grade level assessment of the literature, uh, was not often very high, right? There, there are certainly holes in our methods and, and there's plenty of scope for really good research. Having reviewed together in great detail [01:13:00] the state of the literature and spoken with one another, you know, over the course of years about what is our clinical experience and practice.


[01:13:07] Renee Shellhaas: Um, yeah, I think you're right, it is interesting to note that these experts from across the world really all came to very similar conclusions about the best way, given the current state of the art, the best way to approach treatment for seizures. And there was not a lot of disagreement, uh, it's true, and we were honest in the paper about where people had some disagreement based, you know, based on their, you know, experience.


[01:13:33] Renee Shellhaas: their own opinions and, and the available evidence, but, but for the most part, people really did, did agree


[01:13:41] Ben C: I think many people are going to ask you about, many people are probably wondering about phenobarbital and, and, uh, the fact that as a first line agent, it comes back still yet as, as the first line option. And there's been a lot of research in, in the use of, uh, anti seizure medications. And yet here we are [01:14:00] with phenobarb yet again.


[01:14:01] Ben C: What is it about phenobarb that, uh, seems to always put it at the forefront of seizure management in a neonate? Is it? Something that makes phenobarb truly effective or is it just a default that really we haven't been able to uh to beat That's


[01:14:16] Renee Shellhaas: Yeah, it's a really good question. None of us really love Phenobarbital.


[01:14:20] Ben C: right That's


[01:14:21] Renee Shellhaas: and, but, but that doesn't mean that we can't, that we can't or shouldn't use it. And the truth is that the data show that compared to, um, most recently compared with levotiracetamines, uh, phenobarbital was far superior. And so it is, it's the best drug that we currently have and that we have evidence.