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#107 - 📑 Journal Club 42

Hello Friends 👋

Journal club is Back! We have a great series of paper to review this week. We talk about CRP in early onset sepsis, lumbar puncture attempts in late onset sepsis evaluation, indomethacin prophylaxis and so much more. We also announce the winner of our end-of-year giveaway, generously sponsored by Reckitt-Mead Johnson. We hope you enjoy this week's episode. Happy Sunday.


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

Dhudasia MB, Benitz WE, Flannery DD, Christ L, Rub D, Remaschi G, Puopolo KM, Mukhopadhyay S.J Pediatr. 2023 May;256:98-104.e6. doi: 10.1016/j.jpeds.2022.12.007. Epub 2022 Dec 16.

Brumbaugh JE, Bell EF, Do BT, Greenberg RG, Stoll BJ, DeMauro SB, Harmon HM, Hintz SR, Das A, Puopolo KM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.JAMA Netw Open. 2022 Dec 1;5(12):e2245826. doi: 10.1001/jamanetworkopen.2022.45826.

Clyman RI, Hills NK.J Perinatol. 2022 Dec;42(12):1662-1668. doi: 10.1038/s41372-022-01547-7. Epub 2022 Oct 30.

Jasani B, Mitra S, Shah PS.Cochrane Database Syst Rev. 2022 Dec 15;12:CD010061. doi: 10.1002/14651858.CD010061.pub5.

Raina JS, Chawla D, Jain S, Khurana S, Sehgal A, Rani S.J Pediatr. 2023 Mar;254:54-60.e4. doi: 10.1016/j.jpeds.2022.08.061. Epub 2022 Oct 18.

Nevill E, Mildenhall LFJ, Meyer MP.J Pediatr. 2023 Feb;253:94-100.e1. doi: 10.1016/j.jpeds.2022.09.025. Epub 2022 Sep 22.

Glass HC, Wusthoff CJ, Comstock BA, Numis AL, Gonzalez FF, Maitre N, Massey SL, Mayock DE, Mietzsch U, Natarajan N, Sokol GM, Bonifacio SL, Van Meurs KP, Thomas C, Ahmad KA, Heagerty PJ, Juul SE, Wu YW.Pediatr Res. 2023 Jul;94(1):252-259. doi: 10.1038/s41390-022-02398-w. Epub 2022 Dec 5.

Chung PK, Schornagel F, Oudesluys-Murphy AM, de Vries LS, Soede W, van Zwet E, Vossen A.Arch Dis Child Fetal Neonatal Ed. 2023 May;108(3):302-308. doi: 10.1136/archdischild-2022-324699. Epub 2022 Dec 22.

Abu Jawdeh EG, Hunt CE, Eichenwald E, Corwin MJ, McEntire B, Heeren T, Crowell LM, Ikponmwonba C, Saroufim A, Kerr S; ICAF Study Group.J Perinatol. 2023 May;43(5):653-658. doi: 10.1038/s41372-022-01592-2. Epub 2022 Dec 29.


Find some of our notes here 👇

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

Ben 1:02

Hello, everybody. Welcome back to the incubator podcast. Happy New Year Daphna. Pre is here today. How you guys doing

Daphna 1:08

right? Doing good. Happy New Year to everybody.

Unknown Speaker 1:12

Good. Happy New Year, guys.

Ben 1:15

Priya, we've missed you. It's been a while.

Speaker 3 1:17

I know. Thanks for having me back. Super excited to be here at the beginning of the year.

Ben 1:22

Yeah, excited. Yeah, this is gonna be fun. So we have our first journal club of the year, there's a lot of articles to cover. We did take a week off of journal clubs. So we have to catch up today. Before we get started, before we begin, we do have to do some take care of some business. For the people who have participated in our end of year giveaway. Thank you to all of you. We could not have been more touched by your messages and by the affection shared with us on social media by email. And the winner of this year's giveaway, which was again generously sponsored by recognized Johnson is Dr. And apologies if I mispronounce your name, Dr. Pierre, what our reach i Who is on Twitter at Neo reach i. So we will be in touch with you try to get you some of the details and get you your brand new iPad in the mail as soon as possible. So congrats. Yay, exactly. He left giveaway day. And with that, I guess we can. Yeah, I guess we can begin would you guys say?

Daphna 2:45

If my chief used to say if we don't begin however will we finish?

Ben 2:50

That's exactly right. All right, I guess. Do you want me to get started? Definitely. You want to go? No, you go. All right. I always always ask and I always pushing the front of the line. I'm going to start I'm going to start off with a with a with a nice paper. That is going to be a great starter for us today. It's It was published in the Journal of Pediatrics. first author is Marin do dassia. And the title of the article is diagnostic performance and patient outcomes with C reactive protein use in early onset sepsis evaluations. So starting off the year, again, giving CRP A Closer Look again. The reason I picked this article is really because it doesn't seem like no matter what we say about CRP, it doesn't seem to go away. And there's a it's always there. And and so I think this was interesting in the context of early onset sepsis. And so that's why I picked this this paper. So the background is interesting. And it sets up some some some, I think, some ground rules. Number one, they're saying that the clinical utility of a test can be measured using two approaches, right? It's diagnostic performance and the impact it has on patient outcomes. And in the case of early onset sepsis, and the gold standard is really the blood slash CSF culture, with or without additional clinical findings of infection. So the question that the authors are posing is, what is the clinical utility of CRP in the diagnosis of early onset sepsis, using two separate approaches, they wanted to look at this from measuring the diagnostic performance and the impact it has on patient outcomes with and without routine use, as they've defined in the background. So they conducted a retrospective cohort study of all infants that were admitted between Day Zero and day three of life, right? Otherwise, it wouldn't be really early onset sepsis to to NICUs in the University of Pennsylvania health system, and they divided basically the two periods into period a And period B, period a start from 2009 to 2014. And the reason that's period is picked is because that's when routine CRP use was done for evaluation of an onset sepsis, then this sort of transitioned to the early onset sepsis risk calculator. So there's like a buffer period that they've sort of removed and then you enter period d, which is 2018, to 2020. And that is, when really CRP was not routinely used. They collected a ton of data through this retrospective, the retrospective, nature and and through the EMR. So you can you can get through the paper for that information. The definition of early onset sepsis was defined as the isolation of some organism from the blood and or CSF before three days of life, they define the use of prolonged antibiotics as antibiotics administered for more than two days, in the absence of pathogen isolation from the bredow, CSF, so almost like culture, negative kind of sepsis, situation, CRP kind of values, I think that's obviously something that we're all interested in. There, they use the CRP of 10 or more for the main analysis of diagnostic performance. But they also ran an analyze diagnostic performance metric for other thresholds between five and 15. So they looked at if CRP were around the 10, and they never went below five. So I think that's also something that's important to note. So what were some of the relevant patient outcomes that they defined, so they looked at the proportions of NICU infants on whom cultures were done both before three days of life and after four days of life, they looked at the rates of positive blood or CSF cultures, they looked at the time from birth to obtaining the blood culture, and its antibiotic administration. Among those culture confirmed cases, the rate of antibiotic initiation, the duration of antibiotic use, in the absence of positive cultures, the length of stay the transfer to a higher level of care, and all cause mortality overall, and in the first seven days after birth, so far, so good. All right, I get nods. So what were some of the results from 2009 to 2014 10,000. And something infants were admitted to the study NICUs with a median gestational age of 37 weeks, and a birth weight average of 2800 grams, a total of 74.5% of infants had at least one blood culture obtained, and between the Zero to Three after birth, and of them only 14% also had a CSF culture. So I think one of you guys is going to talk to us about meningitis. And but I thought that was an interesting study. among infants with the blood culture obtained on the zero to 341, which is 0.5%, were diagnosed with early onset sepsis. So it's still it's still pretty low. And the most common organism is GBs. 39%, an E. coli 39%. Dr. Karen popolo is on this paper as well. And she's extensively published on their data. So anyway, so I'm sure you can find that in some of these articles that she published with Dustin in pediatrics as well. They were no infants. That was something that I'm sure definitely you're going to appreciate. There were no infants with a positive CSF cultures in the absence of a positive blood culture.

Daphna 8:26

That's so interesting, given the article that I guess I'll present after this one, but

Ben 8:31

I mean, you could you could wonder. Yeah, I don't remember reading in the article, whether they only did CES. I mean, I don't remember exactly what was the trigger to do a CSF culture. So if the trigger to do a CSF culture was a positive blood culture, then maybe maybe it's not so surprising. The diagnostic performance of CRP. So how did it do the total of 9000, and something infants had one or more CRP obtained between the zero and three and have them 23% had at least one value above 10, or equal to 10. Among these, among 7500, something infants with a blood culture on the Euro 390 8.6% also had a CRP obtain at that time. And that's going to be the population that's going to be interesting to us where we have both to compare with increasing duration, between time when blood culture and CRP were obtain, the sensitivity of CRP increased to our specificity decreased. So let's do a little bit of board review, since it's the beginning of the year, right. So sensitivity and specificity. I mean, I don't know how you guys remember that I usually use the spin and snout situation. So the sensitivity means you're going to have a test that's going to include that's going to flag a lot of kids as potential sepsis. Right? And, and it's going to be very rough and tough. There's not going to be it's not going to be it's going to capture all of them, but it's also going to capture a ton of kids who don't have sepsis. and spin is going to be something that rules in the disease. So spend meaning you're not going to catch a lot of them, but the ones you do catch, you're going to be pretty certain that they have sepsis. So that's if you need a refresher on sensitivity versus specificity. So let's read that again. When you extend the duration between the time when the blood culture and the CRP were obtained, so like you, you don't draw the CRP as the sensitivity of CRP increases, while the specificity decreased. Further CRP obtained for 24 hours after both blood culture had the highest area under the curve on the receiving operating characteristic curve. Alternate thresholds of CRP demonstrated similar pattern with the highest sensitivity at low cut offs farther from time of bread culture, and higher specificity for high cutoff closer to the time of rock culture, which is not really surprising. And if you go through some of these table, you can see that, for example, when you're looking at CRP within four hours from the blood culture, the sensitivity is like 41%, the specificity is 89.9%. And the positive predictive value is like 2.3%. So not great, when you go to four to 24 hours, it's like 80%, sensitive, 76% specific, and then 24 to 72. It's 89% sensitive, and the specificity goes down to 55. And then they have these tables where they go at, like, if it's five, if it's seven, if it's 10, if it's 15. And the same thing really happens, which is that as you have a lower threshold, so if you have a CRP of five, then your sensitivity is high. So for example, if you look at a CRP collected within, I'm going to give you the example in Table three, I'm going to go through the first first row, so that we can just go through an example. But like, let's say you talk about, I'm getting a CRP within four hours from the blood culture being drawn, assuming that sort of done around the time of birth, because you're doing your early sepsis evaluation fine. If the CRP is five, or more than the sensitivity is 50%, and the specificity is 85%. And as the CRP increases, so like let's say from you go from five, and you go to 10, then the sensitivity drops from 50, to 41%. But your specificity increases from 85 to 89. And then if you look for CRP, above 15, then your sensitivity is now 29%. But your specificity is now 92%. And that sort of holds true. And it's not really surprising considering what CRPS meant to do for other time points as well. So the clinical management of infants without early onset sepsis, so of all these kids that had the CRP, what, how did that help or not help the investigators, so of the 7500 infants without early onset sepsis. 98.7% of them had a CRP obtain on day 03. And of these 26% had a CRP of 10 or more, which is right, which is really concerning, because then what are you supposed to do, right. And what they were describing is that the infants with a CRP of 10 or more were more frequently males born via vaginal delivery, and higher gestational ages, and with higher birth weights. They were also and that's the kicker, more likely to be started on empiric. Antibiotics received prolonged antibiotics despite negative blood, or CSF cultures, right? Because now, you don't just give them two days, because you've given them more because you're like, oh, for the CRP was 12. And in truth, they don't have early onset sepsis. They received antibiotics other than penicillin, ampicillin and gentamicin. They were more likely to have a CSF culture obtained on day zero to three or four to seven days of life, and have longer hospital length of stay. And so the last piece of the results, which is interesting is when they compare when they moved on to the EOS Risk Calculator, they found that comparing the two periods among culture confirmed infection cases to time from birth to when blood culture was collected, and empiric. Antibiotics initiated was not different between the two periods. There was also no difference in the hospital length of stay between the two periods overall, or among term and preterm infants considered separately, the proportions of infants who died or were transferred for higher level of care in the first week after birth. And the proportion of infants who died at any time during the hospitalization was also not different between the two periods. So really, they're moving away from doing CRP in early 20s, early onset sepsis scenario really did not impact very much. And they sort of mentioned that in their conclusion when they said that in this pre post cohort analysis, initial CRP testing for early onset sepsis evaluation was not sufficiently sensitive to support decisions to withhold antibiotic treatment. Right and it's and I think that's so interesting because you want something that helps you not start antibiotics because you could always find I was, you know, you're thinking about this ERP to start antibiotics, but then you realize, I have all the reasons in the world to start antibiotics. I could pin it on some grunting on some anything but you want something that helps you not start antibiotics. Although later CRP measurements were more sensitive, they were too nonspecific to support decisions to continue treatment. And what we just spoke about discontinuation of routine CRP use during EOS evaluation was not associated with changes in rate of in rate or promptness of us detection or management. And then the last piece I wrote or I copied from their paper was that they said discontinuation of routine CRPS was not associated with more serious adverse outcome despite an associated reduction in rates of antibiotic use the using the aforementioned method to test the utility determination, we did not identify a clear advantage of using CRP in US evaluation. So, it may be 2023. But us and CRP is not invoke still sorry.

Speaker 3 15:49

CRP is such a tough one, though, it's always like, you know, you try to get rid of it, and it always comes back in some fashion or form

Ben 15:56

do lavar CRPS?

Daphna 15:58

Well, I think, I think we're all desperate for something, quote unquote, better than our clinical observation. And our, our, our, what's the word? risk stratification, right? We're looking

Speaker 3 16:17

right, okay, said, Okay, 10, but five to 15. And when you have gets a wide, it's like, what does that mean? Like, in terms of what it corresponds to clinically or? Or what that means? And I think that's, it's very hard. Everybody likes a safety net. But it's really hard to sort of correlate what that means in terms of how to interpret.

Ben 16:37

They were smart enough not to get into the weeds of like, trending this ERP. Revolt?

Daphna 16:44

Yeah, because I mean, I think that's what I thought was especially salient was when it was most reliable. And that's like, you know, almost in 12 to 24 hours after obtaining blood culture, for whatever reason that you felt strongly enough to obtain the blood culture. So that's certainly using CRP to rule out infection. That's it. And that's

Ben 17:10

the thing. That's the thing that was that was so impressive is that there's no number where you say, well, above that number or below that number. I have a definite piece of information. Yeah. You never have anything tangible to go on. So yeah,

Daphna 17:21

yeah. All right. Well, then, should I do my meningitis paper?

Ben 17:28

I don't tell anyone I would get went first. Now it's up to you guys. You fight it.

Daphna 17:33

Okay, I'll do the meningitis paper. Because we have some of the same star studded authorship here in this paper. So we might as well move that direction. And this was called incidence of a neurodevelopmental outcomes after late onset meningitis among children born extremely preterm. And so sorry, just in reference to the previous article, this is looking at late onset meningitis and infections as compared to the previous article, which is definitively looking at early onset sepsis. So lead author Jane Brom bow, the senior author, Dr. Karen, poop below, but again, some big stars in sepsis work and neurodevelopment work, including Dr. hints, who, we just had her interview this last week on the podcast, and this was in The JAMA Network open and the question is really what is the incidence of late onset meningitis in children born extremely preterm? And what are the outcomes following these episodes of late onset meningitis? So this is a cohort study. But it's really a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks between 2003 and 2007. Teen with follow up from 2004 to 2021. And again, this is part of our major NIC HD, neonatal Research Network centers. So, inclusion criteria I told you were children born 22 to 26 weeks during that timeframe, and the exclusion criteria were deaf before 72 hours after birth, any evidence of early onset meningitis so within 72 hours after birth, major congenital anomalies presence of a ventricular center reservoir of viral meningitis, a poly microbial meningitis to having more than one bacteria involved and then missing late onset sepsis or late onset meningitis data, so having the information to decide on on either of those, and the primary outcomes included. late onset sepsis LP performance as part of the late onset sepsis evaluation, which speaks to what you mentioned, when we were discussing the previous article, do you get a LP because you have a positive blood culture did you get the LP to begin with, and then they wanted to look at the outcomes of neurodevelopment neurodevelopmental impairment or death before follow up. And then neurodevelopmental impairment was determined by follow up at 18 to 22 months using the Bailey two or three depending on the time point because we crossed over during the study period, and the use of the palo santo gross motor function classification system. They also looked at intracranial hemorrhage, defined by the pipe APPEAL criteria and severe hemorrhage defined as grades three or four. So I wanted to go over some of the definitions. late onset sepsis was defined as isolation of a bacterial or fungal pathogen from blood obtained more than 72 hours after birth and accompanied by treatment for at least five days, or death before completed treatment. late onset meningitis was defined as isolation of the bacterial or fungal pathogen from CSF obtained more than 72 hours after birth and accompanied by treatment for at least seven days or death before completed treatment. And they did touch on cons, which is always a topic of discussion. coagulant coagulase negative staph was only considered a pathogen in the CSF, if concurrently identified in the CSF and the

Ben 21:29

blood. What if it was a bloody tap?

Daphna 21:33

Yeah, I mean, they don't mention that, but it's definitely something to consider.

Ben 21:40

Anyways, I'm just I'm just trying to make things tough for you. I'm sorry.

Daphna 21:44

It's always tough right in the clinical scenario, anyway, see, you seven blood cultures are considered quote unquote, concurrent if obtained within seven days of one another. And then the definition for neurodevelopmental impairment includes the presence of one or more of the following moderate to severe cerebral palsy with gross motor function classification level of two or greater a Bailey score less than 70 if using the Bailey two or Bailey three score less than 85, bilateral blindness or bilateral hearing impairment. Okay, baseline data, so they had 13,372 infants with a median gestational age of 25.4. And then some other baseline. Characteristics mothers of infants with late onset meningitis were younger, less likely to deliver by C section. They're more likely to have private insurance have a college degree or have a hypertensive disorder, and infants with either late onset meningitis or late onset sepsis had a lower gestational age and birth weight than infants with neither infection. Month multiple morbidities, including severe intracranial hemorrhage and PVL were more common among infants affected by late onset meningitis. Interestingly, later birth year within the study period, and severe intracranial hemorrhage remains significantly associated with late onset meningitis. So for the primary outcome, 167 infants or 1%, had late onset meningitis. 4564 infants 34%, had late onset sepsis without late onset meningitis, if you had both data, and 65% of infants had neither late onset sepsis or late onset meningitis. The incidence of late onset meningitis decreased from 2003 to 2017, as did the incidence of late onset sepsis, but of note the incidence of late onset sepsis is relatively stable between 2011 and 2017. So, from 2003 to 2017, there was a decrease among those infants with late onset meningitis. 16% occurred in the absence of a concurrent positive blood culture, of which 11% occurred in the absence of any positive blood culture during the hospitalization. Therefore, you know, the nod that you can have meningitis without a positive blood culture, especially when you're looking at late onset and infections. Let's talk about the pathogens among the 167 infants with late onset meningitis. The median age for diagnosis was 16 days in general 10 to 31. These the incidence of late onset meningitis varied across centers from 0% to 7%. The most common pathogens in the CSF were cones 60%, Canada 23% E. coli, 16%, Klebsiella, 9% GBS 9%, and Enterococcus 9%. Now then they wanted to look at how often did you get the lumbar puncture. So I thought this was really interesting data, which complicates how we interpret all of the data altogether. The rate at which lumbar puncture was performed as part of the late onset sepsis evaluation decreased from 36%, in 2011, to 24%, in 2017. And I told you there was data from 2003, but they didn't have the lumbar puncture data necessarily before 2011. So that's why they use this part of the cohort. So significant difference from 36% to 24%. During this period, 30% had an LP performed as part of the late onset sepsis evaluation, and 3% had late onset meningitis. And the, the use of lumbar puncture as part of the late onset sepsis evaluation varied across centers, 10% to 59%.

Ben 25:59

That's that's the range, the big range.

Daphna 26:03

But um, you know, it's, it's interesting, because they didn't mention, right, and it's these are big datasets, like you asked, was this done, empirically LP, or was the LP done, you know, after a positive blood culture, but they do kind of give a hint to that, because then they look specifically among infants with late onset sepsis. So these are babies who I don't know if it was before or after the LP but had a positive blood culture. So LP performance, still varied by center. So in babies who had positive blood cultures, a range of 23% to 79%, which I thought was surprising, the incidence of late onset sepsis was relatively stable from 2011 to 2017. However, the performance of lumbar puncture among infants with late onset sepsis decreased from 58% to 45%. The only thing I can think of is that a lot of these babies had cones in the blood, and maybe that's why they were less likely to get lumbar punctures, I, I don't know. They didn't speak to that. And then, the last part of their study was really to look at neurodevelopmental impairment. So the cohort was then broken up into three groups, those affected by late onset meningitis alone, those affected by late onset sepsis. Without late onset meningitis, and those affected by neither late onset sepsis or late onset meningitis, and they do speak to the fact that not all babies with late onset sepsis, got a lumbar puncture. So might some of those babies be in the wrong group, potentially. In the babies who had just late onset meningitis point, I'm sorry, 29% died before discharge, and the babies with late onset sepsis but no meningitis. 25% died before discharge, and in the group without either infection 18% died of discharge among survivors, neurodevelopmental impairment was present in 42% of the children with late onset meningitis, and in 43% of children with late onset sepsis without meningitis compared to only 33% of children with neither infection, the incidences of cerebral palsy 24%, abnormal visual acuity 24% and bilateral hearing impairment 8%, or highest among infants with the history of late onset meningitis. The adjusted risk of the composite outcome of death or neurodevelopmental impairment was obviously highest among children with late onset meningitis, although the adjusted risk was higher among both those with late onset meningitis and those with late onset sepsis compared with the infants who had neither infection. In addition, the composite outcome death or neurodevelopmental impairment was 48%. Still, and those children with cones, meningitis, so you can't brush cones off is not a potentially very violent pathogen 64% of the children sorry, the composite outcome of death or neurodevelopmental impairment was present in 64% of children with non cons, late onset meningitis, so higher and highest 79% of children with the fungal late onset meningitis. So the take home message is that in this cohort 1% of children were diagnosed with late onset meningitis. 16% of these cases occurred in the absence of a concurrent positive blood culture. And not all the babies who had positive blood cultures got lumbar punctures, so it may be higher than that and those affected by late onset meningitis had a high incidence of death or neurodevelopmental impairment. Thus, he says seizure of late onset meningitis with death or neurodevelopmental impairment highlights the importance of lumbar puncture during the evaluation of late onset infection. Thoughts?

Ben 30:10

I'm disappointed? I'm scared of giving my thoughts. I mean, I mean, it's I think I think the conclusions are very accurate. I mean, I think we're going to need to find out if if we're going to need to do prospective studies. And this is usually sort of a wishy washy answer to say, Oh, more studies are needed, but in this case, right, but in this case, you do you do need these prospective studies to find out if you are very consistent with your evaluation, and whether being consistent and attempting DLP as frequently as you can, will actually have significant improvement on these infants outcomes, both short and long term. Because yeah, it's it's difficult. I mean, I was looking back after reading this paper about all the things that says, Well, you know, if you suspect meningitis, it's hard to have a strong index of suspicion when it comes to, to meningitis and these small infants. And as you mentioned, in the baseline characteristics, these these were babies with ranging gestational age, like a median gestational age of 25. Weeks. Yeah. And they do also diagnosed around like 10 days of life. So it's

Daphna 31:18

very dimension. Yeah. Also, though, that the babies are quite possibly quite sick, right. Not not stable enough for lumbar puncture. But it's interesting data. And that's what they mentioned it, maybe you had a suspicion for meningitis. So you treated without the lumbar puncture, or you had been on antibiotics already a number of days before the baby attains stability. Yes, so you didn't think it would be valuable anymore? So there's so many reasons, right.

Ben 31:51

Okay, just gonna try to be more mindful, I guess.

Speaker 3 31:53

I thought the breakdown of the organisms was was interesting also, just to put into perspective, what they're seeing and meningitis. I mean, some of the data is really older. And so I was, I didn't expect that much Candida, honestly. Yeah.

Daphna 32:10

Yeah. I I'm thinking back to just just a year and a half ago, you know, when we're doing our board review and the pathogen makeup is, is seems to be changing a little bit, right. Alright, Priya.

Speaker 3 32:26

All right. I'm gonna present today, the article that is effects of prophylactic indomethacin on morbidity and mortality in infants less than 25 weeks gestation. It's a protocol driven intention to treat analysis. And the first author here is Ron Kleinman from UCSF, this was published in the Journal of Perinatology. So just to like level set the background here. Clinical trials really haven't shown a benefit for early PDA treatment. But there are several studies using large retrospective databases that have reported improved neonatal, more mortality and morbidity in nurses nurseries that use early PDA screening, and or treatment. And there was a meta analysis of 11,000, very preterm infants that found that prophylactic indomethacin, which I'm going to call PinDot, at this point, was associated with a significant, albeit small reduction in neonatal death.

Daphna 33:25

I think we should feel that I think we are we should, at the end of the year, give her give awards for best acronym of the year, but PinDot to start the year, I like very much.

Speaker 3 33:39

Yep. So this PinDot may act in a gestational age dependent manner, which they're thinking may be beneficial in the sickest and smallest baby. So lesson 750, less than 25 weeks. So the question the authors are posing hair, as does prophylactic indomethacin and decreased death, or BPD, grades two and three and newborns less than 25 weeks. The study design is actually, you know, kind of unique, it's single center cohort controlled study, using data from an ongoing QI project looked at neonatal outcomes associated with a protocol driven treatment approach. The interesting thing here is this is done over 17 years. So we had two groups. One were infants had been during an epoch where all infants were eligible for PinDot and those then admitted during an epoch where all infants received expectant management so none received the prophylactic indomethacin. The inclusion criteria were delivery before 25 weeks gestational age, admission to the NICU within 24 hours and then survival beyond 24 hours. So one of the things that the authors here considered is they really didn't have a lot of love less than 25 weekers. So like I said, it was over 17 years to me To enroll the study's 106 infants, so 2005 to 2022. And they noted okay, we know that there are differences in in care. So they tried to minimize these differences by bracketing the expectant management in the middle. So we had expectant management 2011 to 2017. And it was bookended with two PinDot epochs are 2005 to 2011, and then 2017, to 2022. So in the PinDot group, we had 68, infants, all of these infants were started within 24 hours, providing no contraindications. And it was five potential doses every 24 hours. So point two milligrams per kilogram load than point one milligrams per kilogram for the second, third and fourth doses. And those third and fourth doses were only given if there was evidence of PDA on the echo after the second dose. And for the expectant management group, it was 38 patients, they did not receive any prophylactic NDMS medicine. And no one from was treated with indomethacin, during the first seven days to allow for spontaneous PDA closure. So in both of those groups, they did routinely perform the echo on day seven or eight. And the primary outcome here was death before 36 weeks, or BPD, grades two or three. And they define BPD with a modified room air challenge at 36 weeks, and they use the Johnson criteria to define PDD BPD stages. And then the secondary outcomes they looked at where death during hospitalizations, you know, BPD, grades two or three alone severe ivh, pulmonary hemorrhage, neck or sip. And so the results they had.

Ben 36:47

So that's yeah, so that's interesting that the design basically reflects the pendulum swing. So basically, they went like treatment, no treatment back to treatment. Right. It's it's so funny, I've never seen that before. I thought

Speaker 3 36:58

it was really interesting, because this isn't, you know, it's the single unit. So you know, they realize that practices changes change. And you'll see in the results, there are a couple of things that they do know is different are different. So they had 111 infants less than 25 weeks gestational age, admitted during the study period, and only 106 of those survived beyond 24 hours. One thing that they noticed in the demographics was that preeclampsia chorioamnionitis. An out born births were significantly associated with the birth year. So those changed. The other thing they noted were the clinical practice changes. They saw an increased use of indomethacin for Toka lysis and increased use of rescue beta methadone for mothers greater than 10 days beyond the first dose, increased use of delayed cord clamping, increased NIV avoidance of tracheal intubation ventilation at delivery. But where they did not see any changes were no changes in the initiation or duration of caffeine therapy. They said there are no changes in feeding advances. And they did not use probiotics or vitamin A, during any of that time. So I mean, that definitely again, Ben, just like you're talking about shows the changes in practice that we know right? So 91% of the infants born in the PinDot epoch received indomethacin within the first 24 hours, and only 24% of those kids had a moderate to large PDA shunt at the end of the week. In contrast, when you look at the expectant, expectant management epoch 85% of those babies had a moderate to large shunt at the end of the first week. And from those 85 45% received indomethacin or acetaminophen, rescue therapy, or rescue treatment after seven days. One thing that you would expect is that there was a statistically significant difference, you know, in the in the observance of moderate to large PDS, seven days at 14 days 23 In the expectant management group and zero in the the prophylactic indomethacin group. Obviously, this is, you know, like we talked about, it's a smaller study. It's over 17 years. It's single center. And so the authors did say, you know, the incidence of PDA, and other morbidities could vary. By center, it's not generalizable. We also talked about confounding variables, they did adjust for these, but there could have been unmeasured changes that could have affected some of these morbidity rates overall, so the conclusion was they found no significant differences in the incidence of BPD grades two or three, or death or any of the secondary outcomes in unadjusted comparisons. They also created multivariable models to adjust for these confounding effects. But found, again, no significant relief relationships between the outcomes, when prophylactic indomethacin was used routinely in infants less than 25 weeks. I think this is interesting. I mean, I think, you know, there was a time where people were using prophylactic indomethacin in the tiny babies to run ivh. And so this really shows that there is no difference there. And I don't know, you know, how many people are still doing that. But it's, it's an interesting article, and it shows that, you know, you really can track and trend the changes in your unit this way.

Ben 40:35

First of all, it made me feel old, because you read, like, the span over 17 years, and you're like, oh, like, let me see, like 1990. And you realize it's 2005, like 17 years ago was 2005. And it's like, Oh, shit.

Daphna 40:49

It also gives you some perspective, you know, when you have those, when your fellow you have the senior attendings and you're like, how do they remember, like, all of these things that happened? And you're like, oh, it's happening now, like, I am remembering these changes. Like, Mike as my career progresses?

Ben 41:05

That's right. But I thought it was, first of all, I think it was very, I mean, Dr. Climate is is a household name when it comes to PDA. And so if you haven't, for the audience members who have not read some of his other papers, like he's, he's, he's the guy. And, and I think it's interesting to see that it's, it's a, it's a frustrating, that's the thing that, here's the thing, I'm going to I'm going to go on and out on a limb here, but I'm saying it's a frustrating endeavor for for very, for a minority of patients, right? I mean, it's if you look at it, it's 17 years, they ended up it ended up including about what 100 babies and the outcomes were not that pronounced. And we've been what we've been beating this horse for, like, how many years now? What should we do? Should we not do it? I mean, it's just one of these, to me, it's a reminder of, maybe maybe we should just move on and focus on something else, I don't know until something until we have more. But it's just you read this, and you're like, Oh, my God, 17 years worth of data in a single center? Fine. But I mean, I only work in a single center. So that's going to be right. I mean, and they're working in a in a in a in orange single center. And that's, that's 17 years of back and forth, and less than 25 weeks, it's 100 kids, and there's nothing really measurable that they weren't able to notice. It's but the Yeah, and and reassured me also of some things like neck and sip, similar 29 and 27% between the two groups. So it's like, not 27% I'm sorry, 29 out of the 30 and 27, out of the 60. Tinder. Yeah. And

Daphna 42:39

it's interesting what you said about like, single center data, because that is really what matters, right? At every individual institution, because there's so many things that we still don't understand that probably impact or that do impact all of these outcomes, right? And it's the, it's the bundle effect, right? The combination of the way your unit does it impacts those outcomes and we keep that's hard to study. Right? So it's, it's interesting. It's also always hard on these, these, you know, 20 years studies so much of the way we manage babies and the types of babies that we have now are totally different than they were 20 years ago. So

Speaker 3 43:25

and the way you know all the technology, I also will credit the author's they did not say more studies are needed. It was not.

Ben 43:34

Like that's it. That's interesting. This episode is proudly sponsored by rocket meat Johnson. Recognized Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive and female portfolio for premature and low birth weight infants. Learn more at HCP dot meet Go ahead. I'm sorry.

Daphna 43:59

No, did you want me since we're talking about the PDA to touch on the COC rain, or did you want to? Oh, please,

Ben 44:04


Daphna 44:06

I obviously the Cochrane articles are huge, but they do a very good job of summing up the data. I think that anytime one comes out, we should definitely be talking about them and you should know what they say. So I'm gonna give you the brief author conclusion. I think this paper is entitled paracetamol or acetaminophen for paid and ductus arteriosus and preterm or low birth weight infants. Authors Bonnie Giussani Subic Mitra, and Prakash Kumar Shah, and this is coming to us out of Canada obviously a big name in in PDA

Ben 44:49

Dr. Mitra, who will be a guest speaker at our Delphi conference in March if you haven't yet registered,

Daphna 44:56

if you haven't registered or you haven't seen that we released news speakers and we will be releasing new speakers next week. So we have so many speakers coming. It's awesome.

Ben 45:06

If you're listening to the podcast Now technically, the speakers being released will be tomorrow

Daphna 45:11

will be tomorrow. Yeah, January 9. Yeah. Okay, back back to the work. So, as their objectives were really to look at the efficacy and safety of acetaminophen as monotherapy as part of a combination therapy via multiple routes of administration, they compared it with placebo, no intervention or another prostaglandin inhibitor for either prophylaxis or treatment. So there were many kinds of therapeutic harms of this meta analysis, they included RCTs and quasi RCTs, in which paracetamol was compared, as I just listed, and they included 27 studies enrolling 2278 infants, and they identified 24 on going studies. So, again, we're already halfway through the show. So I'm just going to give the author conclusion even though there's a lot more information to look at in the in this document paper and aid for for all of our trainees. I think the Cochrane Reviews are so valuable to kind of understand the breadth of of papers for any given topic. So I think if you have a question, that's the first place you should go, Look, and then work backwards. Okay, other conclusion, moderate certainty. Evidence suggests that there's probably little or no difference in effectiveness between paracetamol and ibuprofen. Low certainty evidence suggests that there's probably little or no difference in effectiveness between paracetamol and indomethacin. Low certainty evidence suggests that prophylactic paracetamol may be more effective than placebo or no intervention, and that's on rates of failure of closure. Low certainty evidence suggests that early paracetamol treatment may be more effective than placebo or no intervention. Low certainty evidence suggests that there's probably little or no difference between late paracetamol treatment and placebo, and probably little or no difference in effectiveness between the combination of paracetamol plus ibuprofen versus ibuprofen alone for the closure of PDA after the first course of treatment. The majority of neonates included in these studies were of moderate preterm gestation, thus establishing the efficacy, efficacy and safety of paracetamol for PDA treatment and extremely low birth weight. So less than 1000 grams and extremely low gestational age neonates less than 28 weeks, requires further study.

Ben 47:55

So what do you think?

Daphna 47:57

Well, you know, I was really hopeful Tylenol changed the conversation, obviously, the first step of the conversation is, does the PDA need to be treated, which PDAs need to be treated, but if you're going to treat if you're committed to treatment, then you're looking for the most effective therapy with the least amount of side effects.

Ben 48:19

And the advice I would give trainees and anybody reading these Cochrane Reviews is, obviously it's nothing to do with the authors. But take a look always at the at the numbers, right? Look at these relative risks, look at these confidence intervals, look at the number of studies that they are able, because they're able to get a certain number of studies for the entire review, but for

Daphna 48:38

individual outcomes, one, two or a handful,

Ben 48:41

right, exactly. And in this paper, it actually goes to show you how how difficult of a subject this is to study because even though it's a Cochrane Review, you'll see that it's every every outcome is basically like three to four studies. Maybe like sometimes 50 patients, sometimes 100 patients, it's not much it's not much it's

Daphna 49:01

and I think it speaks to the problem with studying anything but particularly PDA right? The PDAs are different sizes, the babies are of different gestational ages. Do you do it empirically for all babies, or do you pick the PDAs to treat and the studies are so different? That that's what's made the discussion so complicated

Speaker 3 49:27

and with the treatment choices, right so endo medicine, ibuprofen, acetaminophen, like they're all given at different frequencies, how often are you You know, what are the side effect profiles like can you give it orally? Can you not I mean, should you should you not, do you have to hold other medications? I mean, I think there's just so much nuance around, treating the PDA and which options you have I don't you know, I think it's it's, it's very complex and it's probably why we have not not put our finger on that.

Ben 49:56

And you're so right Priya because it's, it then creates a whole different realm. When you say Early then what is early? And how early? Are you doing it early? Are they doing it? And so it's Yeah, I have this funny story when I was, I think a college or a medical student, I went back home to France and I went to the pharmacy to get some Tylenol. So can I get some Tylenol? And they're like, We don't have that. And then I thought, Oh, the generic name. So I said, Can I have some acetaminophen? And they're like, We don't want that. And I'm like, how does the pharmacist not know what Acetaminophen is? And and then I went back and my mom's a pharmacist. I was like, Do you guys don't have acetaminophen? They're like, No, it's called paracetamol. And I'm like,

Unknown Speaker 50:32

I'm a Brit. We called it that too.

Ben 50:36

But I was like, oh, man, I gotta go review anyway. Alright, I have three more papers. Two of them. I'm going to bundle the other one is very, very quick, but definitely you're going to be interested in that one. I feel like okay. Okay, so the two ones that I wanted to review were related to resuscitating babies after birth with an intact cord, you know, and the first one is in the Journal of Pediatrics first author is just Preet Singh Raina. It's called resuscitation with intact versus clamped cord in late preterm enter neonatal randomized controlled trial. The question that they're asking is, would you get better physiological transition from fetal to postnatal life in late preterm internment, neonates through resuscitation with an intact cord or with immediate clamping. This was a single center, open label parallel group randomized controlled superiority trial in a tertiary care center in north India, they included babies who were born at 34, or more weeks of gestation in the context of pregnancy or labor complications requiring resuscitation at birth. And they basically list all the risk factors that would basically trigger a pregnancy to be eligible for this study. They did not consider eligible mothers who had routine routine deliveries. So I guess, I guess probably coincides with when they were called probably to attend those deliveries, they excluded. They have a long list of exclusion criteria, congenital malformation, chromosomal abnormalities, fetal hydrops, and so on and so forth. Let's look at their intervention. So basically, they had two groups, you had intervention with an intact cord, which means that the resuscitation is done with the cord intact by the mother, like by the by the side of the mother, and the cord is clamped around three to five minutes after delivery. Then you have the other group, which is an early cord clamping, which is the usual thing where they actually clamp the cord at 30 seconds. So if you were wondering, we're really talking about preserving evidence based practices, because technically there is evidence to keep to do some delayed cord clamping, but they would basically do 30 seconds and then take the baby away to a resuscitation table away from their mother and do the work they had to do over there. So far, so good. And then they used for the primary outcome, something that I was not so familiar with called the extended Apgar scores. And the extended Apgar score is basically your regular Apgar score. But then it actually gets inflated to 17 points and includes an additional few categories, which are oxygen, CPAP, PPV, endotracheal, intubation, surfactant, chest compression medications, and so on. And for everything that you do, you get a zero. So that's kind of confusing, right? So you get to zero. And if you don't need to intervene on any of these funds, you get a one. And so you can get to a max of 17 points.

Daphna 53:27

Which which would be a better outcome? Yeah, you would absolutely like the regular app.

Ben 53:34

And I think it's interesting because it actually gives you such a long, a wider range of numbers. So technically, you can potentially see maybe more differences, secondary outcomes, where the app got the Apgar score at one five and 10 minutes need for PPV intubation, chest compression. time of onset of spontaneous respiration, admission to the nursery court, pH based access, etc, etc. I'm going to get into the results because I think it's interesting remember, this study is taking place in north India, and that's going to be important. 10,000 or so infants were eligible, they weren't able to consent 496 families 70. So they then randomize them to two groups 250 And each and they were, they were able to study 71 infants in the intact chord group and 91 in the early clamping group, meaning once you can send like the babies have to need interventions, because obviously, right so you can send them and then maybe the baby comes out and doesn't need anything and that's it. So, interestingly enough, the baseline characteristics were similar between the intact core group and the early core group. The primary outcome of the study, which was the median expanded Apgar score at five minutes was significantly higher in the intact chord group 15 versus 14. The expanded Apgar score at 10 minutes was also significantly better in the intact chord group rather than In the early CT group, they saw some differences in heart rate. So the heart rate was comparable in the two groups at one minute but was significantly higher in the early CT early clamping group at both five and 10 minutes. And so, like the intact core group had a heart rate of like 138, at five minutes, 134 Attend minutes versus 150 and 154. In the early configure, so even though they were higher, on average, they were they were still normal. The oxygen saturation was higher in the intact core group at one five and 10 minutes, the duration of PPV. And the time to spontaneous breathing effort were significantly lower in the intact core group. So that's interesting. The duration of PPV and time to spontaneous breathing efforts were significantly lower in the intact group. What really struck me were the two following outcomes. A significantly lower proportion of neonates in the intact core group needed NICU admission 20 versus 34%. So they were able to reduce their NICU admission by 15%. The mean core gas pH was significantly higher in the intact chord group and the lower proportion of neonates in the intact core group had a pH of less than seven. Both hematocrit and bilirubin at 24 hours were significantly higher in the intact cord group, but the need for partial exchange and for therapy were not different between the two groups. The conclusion is that in late preterm neonates resuscitation with an intact cord is feasible, safe and results in better physiological transition, then the standard of practice of early cord clamping followed by resuscitation, I think this is I think, to me, we've, we've known about this for some time now, right? I mean, the evidence keeps coming in that this is feasible, etc, etc. And to me, it's data from low to middle income countries where they're seeing dramatic reduction in the utilization of their resources that are precious to begin with, that is going to drive this to become standard of care, I think. Because they're able to reduce lower pH. They're, they're able to reduce NICU admissions. And that's very much very much feasible. I want to go on to the next paper, but I'm going to let you weigh in before I before I do that, this way, I can pull up my notes for the other one.

Daphna 57:22

Well, I mean, I think it's exciting. And I think it's exciting, not just for low middle income countries, right? We I agree, studying it here in the States. And I looking forward to seeing that data. What I think is interesting is like, why are you born? These are late preterm determined things, but for some of these infants, and as we push the technology, right. Sometimes the placenta is part of the problem. Right? So you know, picking the right group of babies for for this type of resuscitation, I think will be important into I mean, that's what they're trying to do. They're trying to use a healthy population who mostly made it to term hoping

Ben 58:08

I didn't I obviously did not mention that because it to me it went without saying but these were exclusions. These were definitely exclusion criteria, study, abruption. Court anomalies, presenter Krita, previa, ruptured uterus, etc. So for

Daphna 58:22

shaping, we're, I think we're hopeful that using this in this smallest, most fragile babies will help with the transition, but many of them are delivered early because there's a problem with the, you know, listen to it in either environment. So anyways, it's exciting. It's really,

Ben 58:41

I can't wait, it reminds me of phototherapy. When that's right to middle income countries started doing phototherapy. And in the US we were we were not using for whatever above it, or because we didn't the the evidence never really translated over. And I feel like sometimes some people are going to come to more developers and say, Why are you not resuscitating? By the mother's bedside? Like why are you cutting the cord and moving away? Like there's right and it's just, it reminds me of these of these stories. Anyway.

Daphna 59:06

You did a great review of the history of phototherapy and our board review podcast if somebody if you have if you're not familiar with it, check it out.

Ben 59:13

That's a good story.

Unknown Speaker 59:14

I need to go listen to that then. Yeah, that's really good. Really good.

Ben 59:18

The next study is in the Journal of Pediatrics. It comes from New Zealand. It's from Elizabeth Neville and a colleague colleagues and it's called the effect of breathing support in very preterm infant and not breathing during deferred cord clamping a randomized control trial. It's called the ABC study. Very interesting paper they looked at. They were saying and we're gonna give you some background information. There's improved survival that's been noted in Infants who are born less than 34 weeks where the cord is clamped at 30 seconds or later compared to kids who have immediate cord clamping. So far, so good. We've talked about that. We know that. But the question they were asking or the group was wondering is that what if the baby undergoing delayed cord clamping is not breathing spontaneously? And this group had actually published a study in 2000 15 that showed how these infants were the babies who were getting delayed cord clamping, who were not breathing Well, during the delayed cord clamping were more likely to be intubated, they were more likely to have chronic lung disease and severe ivh. Now, I actually went back to look at this study. And it's a small study, I think, I think they had like 34 infants in the group that was breathing versus 12 in the group that was not reading. So it was a small study. But that's the Background section. The question they're asking is, would preterm infants who are not breathing at birth benefit from some PPV with an intact cord, and they hypothesized that if this is what they found in 2015, that these kids had more BPD more intubation more ivh maybe by providing them PPV while the cord is being clamped, or delayed the clamping, then you will improve all these variables. It was a single center study, they enrolled babies were born at less than 31 weeks undergoing delayed cord clamping, providing that they were either not breathing or making irregular nonsustained breathing efforts. They excluded bunch of things present abruption, as we've said severe fetal growth, et cetera, et cetera. And the basically, the babies were born and they assess the baby's breathing for about 15 seconds. So the baby is born, they look at the baby 15 seconds, the intervention group received positive pressure ventilation on the mom's thigh. So like we did by the intravenous over there, the control group just got gentle tactile stimulation. So even though they were not really breathing spontaneously, well, they would just get like the usual you know, rub the back kind of thing and then they would wait until the could do delayed cord clamping. And then the cord was clamped at around 50 seconds. And the primary outcome of the study was blood transfusion during the NICU admission, and the secondary outcomes were composite of death, chronic lung disease or severe ivh. They had other secondary outcomes, including the Apgar scores delivered from resuscitation requirements for intubation, temperature, etc. 130 and 13 infants were eligible, they randomized 57 in the intervention 56 into control. maternal and infant characteristics were similar between the groups. The thing that was interesting, and I think, again, it's worth mentioning, in all cases, the neonatal team member was able to carry out the required procedure by standing adjacent to the surgeon wrapping and positioning the baby and providing the required ventilation. I think we need to have papers mentioned that that information is feasible, it's easily done. There's there were no issues in no cases was the cord too short. Similarly, the intervention proved feasible in all eligible vaginal births. The proportion of infants transfused between the groups were similar 28% versus 30%. In the control, the median number of transfusion received and the median difference between groups of in total milligrams of per kilogram of red cells was 10 ml and was not difference. It was not significantly different between the two groups. The number of infants in the composite outcome of death before discharge, chronic lung disease and severe ivh was similar between both groups. Providing brief early the conclusion is that providing early brief early PPV in preterm infants who were not breathing during DCC did not significantly improve findings during the early transitional period, or in relation to the assess neonatal outcomes. Having a skilled neonatal attendant alongside the delivery in either the operating room or birthing suite may facilitate achieving the desired timing of cord clamping, with more than 90% of infants attaining the 52nd target in our study. So remember, this is different from the Indian study where you really did the whole thing by the mother's bedside. This was just while delayed cord clamping was happening 30 to 50 seconds, right. But I thought this was an interesting study, nonetheless, because it sort of came to negate some of the findings from that small study that they had before where really, it didn't make a difference whether they were providing the TPV at the bedside. And so it's nice when you have a paper coming to follow another paper to actually answer some of the lingering questions. And so that's why I sort of wanted to discuss these two, these two articles.

Daphna 1:04:12

I think it does highlight the ability to perform delayed cord clamping, right because sometimes depending on what attention is being given to this infant getting delayed cord clamping, sometimes it's not much attention, right, that's when you really can get into trouble or you have to you have to abort delayed cord club clamping because the baby has deteriorated in front of your eyes. But I mean, I think I think this showed that even just having somebody attended to the baby and stimulating the baby. And during that time is very important. And it may not it our ROV colleagues may not be the right person for the job is

Ben 1:04:57

to have other software busy,

Daphna 1:04:59

right They got a lot going on.

Ben 1:05:01

There's a lot of there's a lot of fluids and blood and stuff going on. But I think that was interesting. Because if you had just left it at their study from 2015, you may say, Well, you know, you're doing delayed cord clamping. And during those 15 seconds, these kids were not breathing, well, then they're going to have worse outcomes, right? And it was super nice to see that like, no, they actually went back. And when they did fix that, it didn't make that much of a difference, which again, goes to show that sometimes small studies are difficult to generalize, because it was a small study in 2015. But anyway, I digress. Priya, you have one more?

Speaker 3 1:05:33

I do have one more. I'm gonna try and sort of go through this. Because it is a ancillary study.

Ben 1:05:41

Don't. You don't I mean, I know we're a bit over time, but we're going to since we started publishing the podcast, and also we are providing the little visual bits, so we're okay. I think I think if we go a little bit over, don't don't feel like you need to rush. Just

Daphna 1:05:55

never, never don't go oh,

Speaker 3 1:05:58

okay, well, I'll just keep on going. So, yeah, I'm gonna present risk of seizures in neonates with hypoxic ischemic encephalopathy receiving hypothermia, plus Erythropoietin, or plus placebo. And this is first author, Hannah glass, you are all familiar with the heal study. So this is an ancillary study from that. And it was published in pediatric research. And so just Just a reminder, the heal study was looking at, you know, Ico versus placebo for neuroprotective results in neonates with moderate to severe HIV, and it showed no difference in the groups and the rate of death or disability at age two to three years. What the study didn't do is it didn't assess the timing and the electrographic seizure burden. So that's the purpose of the study. The question is, is really what's the effect of Igbo unprovoked seizures as compared to placebo, and the group hypothesize that it would have a lower risk burden. So one thing I'm going to say here is that, you know, EPO has been shown to decrease both acute and late seizures in animal models. And I did not know as a pharmacist, that there is an FDA label warning and adults that this is proconvulsant is based on old trials in the adult population with renal disease. And what we don't know in neonates is is this applicable to our babies. We know that there's been small studies with the PCO, but most of these actually lacked the gold standard, which is the video EEG monitoring for seizure diagnosis. So like I mentioned, this is ancillary, he'll study it you seven sites from the annual study. And what you had to be to be eligible for the study was obviously part of the heal study, but you had to have a C E. G, recorded without interruption throughout cooling and rewarming. Except for those babies that died during admission and that EEG quality had to be really high quality sufficient for interpretation by a neuro fit physiologist for review. They also looked at the anti seizure medications, the timing of these drugs, and the CE G's were de identified and independently reviewed by two neurophysiologist. Definite definition of seizure was a sudden abnormal EEG event with repetitive and evolving pattern with a peak with a minimum two micro volt peak to peak voltage and duration of least 10 seconds, they gave a definition for Status Epilepticus, and that was defined as a sum duration of seizures comprising greater than or equal to 50% of any one hour epoch of the recording. And only the electrographic confirmed seizures were considered so anything that was considered a clinically detected seizure was not considered for this study. So that is an important fact to remember. So the primary outcome here was looking at the E G maximal seizure burden in minutes per hour. After Ico administration among neonates with seizures, they did quite a few secondary outcomes. So the response to the initial dose of the anti seizure medication defined as no seizures, no further seizures greater than 30 minutes after a loading dose until the end of the recording. They looked at overall seizure burden, the seizure period and then the presence of Status Epilepticus. So, there are 235 patients was randomized in the heal study, about 11% of those patients did not have the C E G file available. And what the authors did here or in the study is they took 185 of the C EGS reviewed them to reach what they determined was the appropriate sample size of 150. So we had 83 in the e po group 67 in the placebo group. And we saw The first dose of lipo was administered at a median of about 18.5 hours 20 Out of the 150 or 13%, died six with CEE G removed prior to completing the 72 hour monitoring period. And there were no significant differences between the groups and maternal characteristics, pregnancy and delivery complications, the infant characteristics, including the severity of the encephalopathy, or the EEG monitoring, so that's

Ben 1:10:31

something I mean, their their, their inclusion of continuous EEG monitoring was so thorough, I mean, the quality of the EEG that they use, like there was no doubt like, I mean, right, like you said, they had like about two they had 100, about in each, and they reviewed them and they excluded the one that were low quality. So whatever they were left with was really super reliable. And these are still high numbers, right 83 said in the, in the, in the EBO group and 67, high quality G's in the in the in the plus in the placebo, that's phenomenal. And they even

Speaker 3 1:11:03

had extra, so there was extra, they just went through the first 185 to meet their 150. So that was one of the things that they talked about was limitation, they didn't review all of them. But so electrographic seizures occurred in 46 out of 150 of the patients, so 31%. But there was no difference between the placebo and the PO group, the timing of the seizures. So 27% were before the study drug was given 27% were between the first and second dose 11% After the second dose. But again, similar rates in both groups, EPO versus placebo, anti seizure medications, so 36% in the PO group versus 54% in the placebo group. They also found no meaningful difference in the medium maximal hourly seizure burden after the first dose of study drug between both groups. So an APR was about 18.1 minutes per hour, and the placebo is 21 minutes per hour 43 of the patients or 29% received an anti seizure medication loading dose. And of those only 30% had a complete response to that remember saying, you know was it after that initial loading dose did the seizure go away after 30 minutes. And so the thing that they did find here is that EPO treated patients at a lower complete response to the medications five out of 24 or 21%, as compared to placebo, which was eight out of 19 or 42%. But when you adjust for the severity and the baseline seizure burden prior to the first study drug drug dose, there was no difference between the group the seizure burden was higher in the peer group. So 63.8 versus placebo 31.5. But again, when considering the total CE EEG recording time, and the percentage of the time with seizure seizures, there was not a significant difference. And the medium period over which the neonates had seizures was 16.3 hours. And that was not significantly different between the groups, Status Epilepticus was present in 10 out of 46 patients, so 22%. And it occurred more frequently among the neonates treated with EBO. So 35% versus 5% in the placebo group, again, not statistically different when you adjust for the pretreatment seizure burden and the HIV II severity. So in conclusion, the state really doesn't align with the animal research. You know, he'll was EPO plus hypothermia. So maybe there's a thought that these to act on similar mechanisms in terms of you know, the injury cascade. What about like, the timing? So should it have been given earlier? Would that have made a difference? Or what about the dosing? Was it suboptimal? So I think, you know, there are a couple of things that they sort of, say, could be a reason why we're not seeing what we see in the animal models. And one thing to note here is that there is a lower lower seizure rate than anticipated and previously published in studies. So we said that seizure rate was 30% about Yeah, 31%. And in other published studies, it's anywhere from 34 to 65%. Could be you know, improved OB care neuro protective measures that we're doing now that that data might be older. The other thing to remember here is that seizure identification and treatment was at the discretion of the local care team, so it was not standardized in this protocol. And when looking at the anti seizure medications, they didn't look at interactions with those plus EVO, and there was a lot of differences in the anti seizure medication use. But that could have been based on what they were treating. Right. Like was it a clinically detected seizure was at one that was eg seizure. So that was,

Ben 1:15:25

you mentioned that the burden was higher, right in the one of the groups like the seizure burden was higher in the in the epoch group. So it's sort of

Speaker 3 1:15:32

Yeah, so yeah, I mean, I think overall, they say the findings are consistent with the overall trial results that do not support EPO for neonates with HIV undergoing therapeutic hyperthermia. There's no significant increase in risk and, and seizures after April admin, but there's a potential for worse seizures. And so they talked about total seizure duration, overall maximum hourly seizure burden, seizure period, and Status Epilepticus. And so, you know, one of the other things that they they mentioned is that they did not find that it was a proconvulsant, or any site tort type of effect that they had seen in adults. So they did confirm that, but it does, it does align well with the heel study in the sense that, you know, we don't need to be using a bow probably in these patients,

Ben 1:16:25

right. Yep. Well, I think that

Daphna 1:16:29

for you, this is disappointingly but it still was an important study because we use Eboo for other things right in the in the NICU. So I thought it was interesting. I have one more paper. Oh, okay. I actually have two more papers, but I'm going to do this short one and save the last one for next time. This is called targeted new screening for congenital cytomegalovirus infection, clinical audiological and neuro imaging findings lead Arthur Pugh Chung, senior author and Vossen, this is in the archives of disease and coming to us from the Netherlands. This is to evaluate the these clinical ideological and neuroimaging findings in a cohort of infants who were eventually diagnosed with congenital CMV. After failure of newborn hearing screening, I think this is an important paper to again, just highlight the findings in congenital CMV. But that we should have a really high suspicion for CMV. And the babies who fail the newborn hearing screening, and some institutions are moving to universal screening for CMV for babies who fail the hearing test, and I think this adds to that data to the study design. They have a pretty robust hearing screening infrastructure in the Netherlands, and they babies go kind of staged screening and after failing the third round, infants are referred to this regional audiology center. And so CMB testing was offered to all referred infants. Trial subjects were then underwent screening consisting of medical history physical exam laboratory assessments. And and I will tell you more about that. So this study period was July 2012, to November 2016. And 1381 children were enrolled for CMV testing again after failing the hearing screen. And I think they said that in general, the hearing failure, hearing screening failures about point 3%. So these were babies who failed the hearing screen, and 1% Something happened with the CMV testing, so they didn't have that data in seven infants. CMV was confirmed in 59 infants 4.3%, which is much higher than our baseline CMV. Incidents and no CMV infection in 1315 infants 95% of the CMV infected infants. Most of them were still born at term average 39.3 weeks gestational ages random range from 32 to 42 weeks. They had significantly lower birth weights and smaller head circumferences. And they did undergo awful, awful ammaji up whole logic exams, and 33 of the 59 and infants have head off though exams without any abnormalities found. One infant had abnormal bilirubin and Trans Am nieces that persisted. In 48, or 89% of those infants with CMV were diagnosed with sensory neural hearing loss or mixed hearing loss. And of those 24 or 50% of infants had bilateral hearing loss. And the infants with bilateral hearing loss 34 years or 71% were found 71% of the ears were found to have severe or profound hearing loss, and 20 of the infants or 83%. With unilateral hearing loss, were also diagnosed with severe or profound hearing loss. So we know that hearing loss is associated with CMV. But the hearing loss was was significant in this cohort. Um, neuro imaging was available in 48 Out of the 54 infants. They did had ultrasounds and 24, MRI and six and both had ultrasound and MRI in 18 infants, that ultrasound was performed at a median of 67 days, and the median age of MRI was 219 days. So often the MRIs followed abnormal head ultrasound. abnormalities were found in 40 of the 48 children who had neuro imaging. So 83% 34 or 71%, had mild abnormalities. Three or 6% had moderate abnormalities and three or 6% had severe abnormalities. The moderate abnormalities included severe ventriculomegaly temporal lobe involvement and diffuse white matter signal abnormalities, which one might consider severe. And then the severe abnormalities found were poly micro diarrhea, and all three patients. One patient additionally showed extensive calcifications, atrophied and dysgenesis dysgenesis of the corpus callosum. In addition, there was a significant correlation between severity of neuro imaging abnormalities and sensory neural hearing loss. So in general, these were babies that were not being evaluated for CMV, except that they missed that they failed their newborn hearing screens. So I think pretty abnormal findings with significant implications for neurodevelopment.

Ben 1:22:20

Yeah, I think, as you said, Until universal screening does or does not become a thing, then screening babies who failed hearing MS is at least it's the way to go. I think that's such a practical, practical piece of information. If you're not screening, if a baby fails the hearing screen in your unit, and you're not checking for CMV men, maybe maybe review that evidence and decide if that's when implement.

Daphna 1:22:42

That's why I felt like I had to I had to do this paper today, because this is something I'm going to take to the bedside.

Speaker 3 1:22:48

I have a question for you guys. So the way that they check for CMV was via PCR like dried blood spots, is that the way that you all would check or is it urine? Because I remember I was in my Nikki where I worked was doing a study with urine, seeing it looking at CMV in the urine. So I didn't know if that was. Is that universal? That's,

Ben 1:23:07

I think, yeah, I think there's a lot of variability. Yeah, there's a lot of variability. And I think I was listening to a talk at the Miami conference recently by Pablo Sanchez, from from Columbus, Ohio, who was mentioning that urine PCR is is the way to go, especially in the first like, couple of weeks of life. And he was even saying, and I'm, I'm only quoting that the cotton balls can fool you that he's had. He's had false negatives with the cotton balls. And he says, just he would say, I would, I would order PCR from the urine. And he seemed pretty intense. He would talk about the confirmatory test and stuff. But that was something to me that was because you can check CMV IgM is in the blood, you can check many other ways. But it looks like CMV PCR from the urine should be the way to go.

Daphna 1:24:02

Yeah, I mean, these dried blood spots are convenient, because you might also be doing like the discharge PKU. Right? So it would you'd be doing the same thing. But also, you don't have to you don't necessarily have to get blood if you do the urine CMV PCR since we have moved away from urine CMV cultures, which used to be the standard, but

Ben 1:24:26

Okay, can I do one last one, you guys, you just couldn't help yourself? Because it's not really, it's not really. I mean, it is. Technically okay. But listen to this. I was I think this paper was shared on Twitter by Ibnu. It's called adverse effects of COVID 19 pandemic on a multicenter randomized control trial. It's the icap study group. It's in the Journal of parasitology. It's done in the US. They're talking about

Daphna 1:24:49

how that wasn't even on your list of papers today. You just couldn't help us.

Ben 1:24:53

I was reading that last night. They were talking about how the COVID 19 pandemic has significantly disrupted family community stability. It has also increased stress on healthcare providers, families decreased the research activity of investigators and study and study coordinators. And then it has exacerbated parental stresses typically associated with NICU admission, including visitation restrictions. So what they did is that they're here to report the effects of COVID-19. On their trial, the icap trial, which is basically the intermittent hypoxia and caffeine in infant born preterm multicenter trial that involved both inpatient and post discharge protocol. So I'm not going to get into too much what the icab study is basically, they were trying to see if you could continue caffeine after 34 weeks, and then they would follow these kids at home. And they were looking at intermittent hypoxia, that almost that almost does not matter. But for the purposes of the study, they, they. They were they had this data coordinating center that was able to track the number of infants who became eligible for the study, and who were approached, not approached and what were the reasons for parental refusal of consent. And they created these four epochs, where they looked at pre COVID. They looked at COVID, one and COVID, two, so pre COVID, was December 2018, to march 2020. And then they had the COVID one epoch which is March to July, which is like the when when the world was in chaos, where there was locked down, severe restrictions on the clinical sites, suspended all clinical research activity, etc. Then they have a COVID two epoch which was from August to March of 2020, August 2020, to march 2021, which is sort of like the beginning of the recovery when sort of the peak had passed. And then they have the post COVID one epoch which is from March 2021, to Nov, which is sort of recovery from the peak adverse of the pandemic and that they have the post COVID two, which is basically where we are now, okay, and they're going to look at how did these phases of time affected their study. What's interesting is that the the, because of the different restrictions, despite the onset of the pandemic, and March 2020, all clinical sites were able to continue entering infants in the screening long so they were able to know which babies were eligible. However, only one site was permitted to continue any other clinical research activity during the peak pandemic epochs, including parents interactions and approaching during consent. During the peak pandemic epoch and beginning of recovery, several site specific actions were approved to try to mitigate some of that which included approval by telemedicine, red cap, consents, and so on, and so forth. So, what's interesting is that they noticed and want to go over the results fairly quickly. But over the three and a half years, 2760 infants were screened, of which 700 and something were eligible. They saw differences in the ethnicities of the families who were approached. So the families of eligible subjects approach for consent differ significantly on race ethnicity, from those of those who were not approached. And you can look into that in the paper, compared to the 32% have not approached rates for consent in the non Hispanic white reference group. 44.9% of Hispanic families were not approached, or families who were approached consent rate vary significantly among non Hispanic whites, 28% non Hispanic blacks, 20%, Hispanic 8% and non Hispanic other 12.8%. So, like, this is shocking, and and and, um, so I was that's what I'm, that's why I'm bringing this up. Now, I was gonna say I was reading this as like men. During the pre COVID epoch research staff were able to approach the families of 95% of eligible infants. During the initial pandemic lockdown COVID, one epoch only 13% of eligible infants could be approached for consent, the percent of eligible families approached for consent has gradually improved, improved since COVID, 150 9%, then 71% and then 84.9%, over the COVID, to post COVID, one and post COVID to epoch respectively, but they remain significantly less than in the pre COVID epochs. How crazy is that? Differences in approach rate across the epochs compared to pre COVID remains significant ly lower after controlling for race ethnicity through multiple logistic regression. And I guess I'm gonna stop here. But the bottom line is that there were restrictions right that so it highlighted or it it widened some some disparities that that were probably already underlying. And then the administrative restrictions to approaching families definitely got the numbers to go down from like 95% to 13%. But at the COVID pandemic had an effect that they were never really able to recover back to where they were pre pandemic. And I think that's fascinating because the effect on the information we're going to be able to get from clinical studies is affected by this pandemic. And I had not thought about that.

Speaker 3 1:30:10

I heard it anecdotally, when I talked to neonatologist study coordinators, you hear about it, it's great that they published this because I think it will, like you said, you don't really realize that some of these studies were put on hold for a really long time they lost research coordinators, or that there was no resources to keep these moving. And yeah, I didn't think of the effect it was going to have on studies being published, or on trials being completed, all I knew is that everybody was on the holding pattern. And then just to hear that it still hasn't really gotten back to where it was is is alarming.

Ben 1:30:47

Because you assume that because you can't access you decrease the visitation that has been published as well, that the lower visitation you like, okay, so it's going to go down, but the fact that there is a scar, and it's a stigma from this, that's continuing. Yeah, it's it's surprising. And does that have to do with parents having to wait so many clinical decisions for their own with COVID? And stuff that there's like, I'm not doing any experimental stuff, because of what we went through? COVID? God knows. I don't know.

Daphna 1:31:14

Yeah, well, I think there's been a lot of distrust in the medical system also, right. That that was a chasm that we we were teetering on. And I think the pandemic made it worse, sadly. So I think that's going to be an ongoing problem for research. But I think I'm glad that you presented the paper because it does highlight still this tremendous ongoing disparity, we have particularly racial disparity in research, and applicability. Right? And does the research represent our patient populations? So that's it.

Ben 1:32:02

And it's an it's an it's always another thing that I mean, we try to identify these variables that you can potentially these knobs that you can dial and then it's like, I had not thought of the pandemic as something that we had to now sort of was correct for.

Speaker 3 1:32:14

And I've now in studies will they say like, you know, one of our limitations for enrollment was the COVID, 19 pandemic, a lot of

Ben 1:32:21

the studies have been, yeah, they haven't seen many of them have. But the fact that some of these studies are now lagging behind because they're they it's crazy. Anyway, you see, I knew this was gonna

Daphna 1:32:35

matter much, much props to all of our, our coordinators, doing clinical research, because gosh, it was hard as it is, and, and it's even harder now. You know, I was thinking about that this morning, as I was walking the dog preparing for Journal Club. For the journal clubs, definitely, no, that's just something I had to do this morning. But anyways, I just think it you know, what we, the papers go into publication, and they're in this journal, and we talk about them at some at some conferences, and we review the paper, right, it takes us anywhere between five and 30 minutes to review the paper. But gosh, the work, the work that goes into these studies is just tremendous, tremendous, tremendous, tremendous. And that's

Ben 1:33:25

why even though this is the theme of the show, there's always something to learn. Certain if the outcomes were not different, even if you say, Oh, well, we were hoping the hypothesis was not really proven. There's always something to learn from all that work that's being done. There's no way that people can spend this much time doing all this work, and that you could come up with a conclusion. There's nothing good for me to learn here that I

Unknown Speaker 1:33:48

see. Yeah.

Ben 1:33:50

Okay, we're going to conclude the show. For the people who are traveling this year. We have our traveling circus as well. Definitely. You are next going on the road. Right. So you are going to Where are you going to Scottsdale for which

Daphna 1:34:04

well, we have a local conference here, but then we'll be going to Scottsdale

Ben 1:34:08

I wish so you know what actually I wish I was I was going to mention the conference we're going to hear in Florida on January 20. But I didn't get we were asking them for some details. And I haven't received I would like to give people more detail. I don't have all the details. So when Claire sends us the deets we will we will give them props. But you're going to be what is what is in Scottsdale, what is what is it? When is it?

Daphna 1:34:29

February 3 through the fifth AP Scottsdale conference,

Ben 1:34:33

DAP Scottsdale conference. All right. So if you guys want to meet, I want to be there. I definitely won't be there. So you get to meet Daphna and ask her all the questions that you have on your mind.

Daphna 1:34:45

And then we'll be all over. We'll do it one

Ben 1:34:48

at a time. I think we can do it. I can do them one at a time. So for now. Yeah. Anyway. All right. Thank you guys very much Priya. This was fun. Thank you again for joining. I really appreciate your pharmaceutical inputs your Ico A disclosures were actually something that was not aware of so. Great. Thank you. Thank you. And it was fun, guys. We'll see you next time. Bye. Thank you for listening to the incubator podcast. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you so feel free to send us questions, comments or suggestions to our email address NICU You can also message the show on Instagram or Twitter at Nick you podcast or through our website at WWW dot v dash This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns. Please see your primary care professional. Thank you

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