Hello Friends 👋
In this week’s Journal Club, Ben and Daphna discuss six impactful studies shaping neonatal care. The conversation opens with a retrospective study exploring the timeline and factors influencing liberation from respiratory support in infants with severe bronchopulmonary dysplasia (BPD), offering valuable insights for parental counseling and care planning. A survey on enteral nutrition practices in U.S. NICUs highlights variability in feeding protocols and fortification strategies, with an encouraging trend toward donor milk use.
The hosts then delve into a study on anti-seizure medication protocols, showing how structured pathways can significantly reduce the number of infants discharged on these medications. A European survey on anemia of prematurity reveals wide variations in iron supplementation and erythropoietin use, emphasizing the need for standardized practices. They also review a commentary on the evolving design of NICUs, which warns against sensory deprivation and advocates for balancing protective and nurturing environments.
Finally, the discussion turns to a Spanish study on bemiparin, a low molecular weight heparin for neonatal thrombosis. While safe, the treatment faces challenges in achieving full thrombus resolution, highlighting the complexities of managing neonatal clotting disorders. Packed with insights and updates, this episode is a must-listen for neonatal professionals.
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The articles covered on today’s episode of the podcast can be found here 👇
Reibel-Georgi NJ, Scrivens A, Heeger LE, Lopriore E, New HV, Deschmann E, Stanworth SJ, Carrascosa MA, Brække K, Cardona F, Cools F, Farrugia R, Ghirardello S, Krivec JL, Matasova K, Muehlbacher T, Sankilampi U, Soares H, Szabó M, Szczapa T, Zaharie G, Roehr CC, Fustolo-Gunnink S, Dame C; Neonatal Transfusion Network.J Pediatr. 2025 Jan;276:114302. doi: 10.1016/j.jpeds.2024.114302. Epub 2024 Sep 13.PMID: 39277077 Free article.
Kielt MJ, Zaniletti I, Lagatta JM, Padula MA, Grover TR, Porta NFM, Wymore EM, Jensen EA, Leeman KT, Levin JC, Evans JR, Yallapragada S, Nelin LD, Vyas-Read S, Murthy K; Children’s Hospitals Neonatal Consortium Severe BPD Focus Group.J Pediatr. 2024 Nov 7:114390. doi: 10.1016/j.jpeds.2024.114390. Online ahead of print.PMID: 39521174
Romero-Lopez M, Naik M, Holzapfel LF, Tyson JE, Pedroza C, Ahmad KA, Rysavy MA, Carlo WA, Zhang Y, Tibe C, Salas AA.J Perinatol. 2024 Dec 9. doi: 10.1038/s41372-024-02198-6. Online ahead of print.PMID: 39653781 No abstract available.
White RD, Browne JV, Inder T.J Perinatol. 2025 Jan;45(1):1-2. doi: 10.1038/s41372-024-02204-x. Epub 2024 Dec 19.PMID: 39702828 No abstract available.
Barber D, Chang J.Acta Paediatr. 2025 Feb;114(2):456-457. doi: 10.1111/apa.17529. Epub 2024 Dec 4.PMID: 39630589 No abstract available.
Nangle AM, He Z, Bhalla S, Bullock J, Carlson A, Dutt M, Hamrick S, Jones P, Piazza A, Vale A, Sewell EK.J Perinatol. 2024 Jul 23. doi: 10.1038/s41372-024-02044-9. Online ahead of print.PMID: 39043995
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The transcript of today's episode can be found below 👇
Ben Courchia (00:00.763)
Hello everybody, welcome back to the incubator podcast. It's Sunday, we are back with another episode of journal club. Daphna, how are you?
Daphna Yasova Barbeau, MD (00:07.96)
doing good, buddy. Things are going well here. We are enjoying the cool weather in Florida, but it's nothing compared to our colleagues up north, you know? So it will be summer soon enough for us.
Ben Courchia (00:18.321)
Yeah, mean, it's we definitely feel fortunate that I mean what's happening in in California on the West Coast is terrifying. Our thoughts with our colleagues in California who are affected by the wildfires. mean, is it's.
Daphna Yasova Barbeau, MD (00:24.398)
Yeah.
Yeah. Yeah.
Daphna Yasova Barbeau, MD (00:38.466)
Yeah, you know, we worry so much about hurricanes here, but this fire situation, that is really terrifying, you know? And it's unpredictable.
Ben Courchia (00:45.671)
It's interesting how the thing that terrifies us down here in Florida is what would salvage the other. It's like, yeah, we are frightened by the flash floods and the water and the tides and whatever. And over there, they would pay a lot of money for excessive water. So it's just interesting that this sort of yin-yang sort of situation.
Daphna Yasova Barbeau, MD (00:54.136)
That's right, they just need a bunch of water. That's right.
Daphna Yasova Barbeau, MD (01:00.216)
Mm-hmm.
Daphna Yasova Barbeau, MD (01:12.91)
Yeah.
Ben Courchia (01:14.023)
Anyway, our thoughts and prayers with you guys in California. We are going to do an episode of Journal Club. There's some new articles that came out that are worthy of discussion. And we have a very good lineup of articles for this week. And we're very busy at the incubator with new episodes, new series. I would say look out for a new series starting this month. It's called Fellows Fridays.
Daphna Yasova Barbeau, MD (01:24.622)
Mm-hmm.
Ben Courchia (01:42.971)
with Rupa Gopal, where we interview neonatology fellows. Great series. We've advertised this on our social media channel if you're interested in participating. Let us know. We'll hook you up with Rupa, who's a great host. And she's a young attending, she is fresh. Memories are fresher of fellowship days.
Daphna Yasova Barbeau, MD (02:00.804)
Mm-hmm.
Well, and I mean, we want to highlight fellows and support fellows. So doing some special, you know, special interest pieces kind of thing.
Ben Courchia (02:10.791)
Yeah, absolutely. And many people are using the podcast as a scholarly activity. Many people are listing this on their CVs the same way that you would present at PAS or at another conference. is fairly equivalent, in terms of, especially in terms of the audience size. mean, thank God people don't know how many people listen to the podcast. It would be terrifying. think if you walked into a room and every listener was in the audience, would, I would, would, yeah.
Daphna Yasova Barbeau, MD (02:32.91)
then maybe they wouldn't sign up. That's right.
Ben Courchia (02:39.545)
It would be scary. we do a good job with our host and our team to make people feel at ease and comfortable. So I hope so. Yeah. So that being said, I'm going to start with our first article, if that's OK with you. This is an article that I found to be extremely interesting. It was published in the Journal of Pediatrics. It's called, Liberation from Respiratory Support and Bronchopulmonary Dysplasia. Matthew Kilt is the first author.
Daphna Yasova Barbeau, MD (02:46.308)
I hope so. We like to think.
Daphna Yasova Barbeau, MD (02:55.876)
For sure, please do.
Ben Courchia (03:09.159)
Were you going to say something?
Daphna Yasova Barbeau, MD (03:10.82)
I just love that term, liberation from.
Ben Courchia (03:13.253)
Yeah. And apparently, it's a term that's been used outside the NICU to talk about patients who are being literally liberated from their respiratory support. And I think it does feel like that sometimes. But it's unclear from the title alone what this paper is going to be about. So let's just jump right into it. I'm going to spare you the introduction about BPD, what is BPD, and so on and so forth, the 2019 classification, et cetera, et cetera.
Daphna Yasova Barbeau, MD (03:16.91)
Mm-hmm. Mm-hmm.
Ben Courchia (03:42.939)
Where I would like to begin is that where the authors talk about how most preterm infants diagnosed with grade two or grade three BPD, they do convalesce over time. And even though they may go home with some form of respiratory support, they are eventually, quote unquote, liberated from their respiratory support and could be discharged home on nothing, could be discharged home on low flow oxygen. And then that convalescence continues at home. Now, what's interesting in the
The issue that the authors are bringing to light is that the expected trajectory of weaning from respiratory support, especially in babies who are quite ill with grade two and grade three BPD is unknown. And it's in part due to the lack of research centered on hospitalized patients with specifically this severity of disease. Understanding this trajectory for these specific patients might help us.
The authors say, refine phenotypic characterization of heterogeneous severe BPD population and hence parental counseling and highlight future areas of research. I think they could have even been more emphatic in that introduction talking about how we really don't know how long we should allow these babies to convalesce in the NICU. We don't know when that liberation from respiratory support is going to happen. And we don't know if waiting another month is OK. Should we wait two months, three months? It's very unclear.
I was very happy to see this study trying to answer that question. The study question for the paper is trying to find out what are the associations between the mode of respiratory support at the time of BPD diagnosis, i.e. 36 weeks post menstrual age, and time to liberation from respiratory support in infants with grade two or grade three BPD. This is a retrospective cohort study of infants who were admitted to NICUs who are participating in
the database collection of the Children's Hospital Neonatal Consortium, the CHNC. We are very familiar with CHNC. The team over there is our good friends of ours, and they do a phenomenal job doing this work of collating the data from all these exceptional hospitals. The data was collected from April 1st, 2017, going all the way through to June 30th, 2022. The inclusion criteria were all the infants born before 32 weeks of gestation.
Ben Courchia (06:05.841)
with grade two or three BPD who were admitted prior to 36 weeks in the institutions from the CHNC. So a little bit of background on grade two and grade three BPD. According to the Jensen definition, grade two BPD, you're treated with non-invasive modes of positive pressure respiratory support. And that includes nasal cannula at anything above two liters per minute. You might be on CPAP. You might be on NIPPV. All that at 36 weeks.
Grade 3 BPD in that categorization is anybody treated with invasive mechanical ventilation.
In terms of exclusion criteria, standard stuff, I'm not even going to go into it, genetic syndromes, patients who had already tried chaos to me and so on and so forth. So how did you look at the exclusion criteria? They were nothing. Really that jumped out at me. Now they categorize the patient based on their degree of respiratory support at 36 weeks post menstrual age. And that was defined as either needing high flow nasal cannula, two liters or more, CPAP, NIPPV, or mechanical ventilation. And mechanical ventilation, by the way, also included high frequency ventilation, which is fairly
Seems fairly okay to include those two together. The primary outcome of the study was the time to liberation from respiratory support. So you'll see this in the paper a lot, time to LRS. LRS stands for liberation from respiratory support. And this is defined in weeks of post-menstrual age. So liberation from respiratory support was defined as discontinuation of any positive airway pressure support.
inclusive of mechanical ventilation, NIPPV, CPAP, or high flow nasal cannula of two or more leaders, above two leaders, for a period of time that is greater than two days. I think people may have some discussion about like, well, is two days enough? Do you say that if a baby has been off the support they've been on for two days, it's sufficient to say they've been liberated? Now, granted,
Ben Courchia (08:02.319)
Like we said, this is a concept that has been well defined in other areas of medicine, and two days is usually what's considered LRS, or liberation from respiratory support. So that's what they used. They also defined it in an outcome known as time to LRS, which is defined as the number of weeks between 36 weeks and 66 weeks PMA at which the infants with grade two or grade three BPD met the above criteria. Trying to find out not only did they reach the point where they come off the respiratory support, but how long did it take?
And then in terms of statistics, I just thought I would mention one aspect of the statistical analysis that was interesting is that they did something called a restricted mean survival time, the RMST. And basically, it's used to estimate the adjusted difference in time to liberation from respiratory support between the groups. And that's done as an alternative to Cox proportional hazard modeling. And the restricted mean survival time represents the average time to liberation from respiratory support during the study period.
And so that's in short a little bit the methodology of this study. And if it's OK, we do that now. I'm going to go into the results. So they were able to include 3,483 subjects that were coming from a total of 41 centers. And impressively, about 81 % were able to achieve liberation from respiratory support. About 8 % survived with a tracheostomy.
4 % unfortunately passed away, 7.5 % were transferred to other hospitals before the time point that they had set for themselves at 66 weeks post-menstrual age. What's interesting is maybe we should look at what kind of respiratory support were they on at 36 weeks post-menstrual age. And that, I think, was relatively surprising. I think most of the babies were on CPAP. So that's 36 % of the cohort.
that was on CPAP, followed closely by 32 % of the babies that were on mechanical ventilation. And then 16 % were on high-flow nasal cannula, and another 16 % were on NIPPV. I didn't really expect to see it break down in this fashion, but that's very interesting. It is not surprising that the majority would be on CPAP, but I thought high-flow nasal cannula would rank a little bit higher.
Ben Courchia (10:23.067)
Now in terms of the clinical characteristic, it was clear that the babies that required a PDA occlusion, those who had medical or surgical NEC, those who had BPD-associated pulmonary hypertension, and those that had tracheobronchomalacia were more likely to be on mechanical ventilation at 36 weeks. Table two looks at the postnatal comorbidities of this cohort. And you can see that these particular variables that I mentioned were quite significant.
Other differences that were quite significant were the presence of bloodstream infection, the presence of a PDA, PVL, spontaneous intestinal perforation. So how many, what is the percentage of babies who actually achieve the outcome of liberation from a respiratory support? So we're going to go in and describe this in increasing level of support. So for the babies who are on
anything above two liters of nasal cannula, the rates of liberation from respiratory support was 95%. So far, I would say that makes sense. The babies who were on CPAP, 92 % achieved liberation from respiratory support. For the babies who were on NIMV, that's something that is surprising. I did not expect that number to be this high. 86 % achieved liberation from respiratory support. And for the babies who were on mechanical ventilation,
59 % achieved liberation from respiratory support. I think this is way more than I anticipated. If you're on mechanical ventilation and you give me a cohort of babies who are intubated on conventional or high frequency ventilation at 36 weeks and you ask me how many will be wind off from their support, I would not get close to 60%. So I think that's interesting.
Now among the infants who achieved liberation from respiratory support, the median time to that moment of freedom from this respiratory support was about 3.6 weeks after 36 weeks. So we're measuring everything, by the way, at 36 weeks, PMA being our T0. This is our initial time point. So about 3 and 1 weeks beyond that point. Now obviously, the time to liberation from respiratory support varied between what
Ben Courchia (12:41.159)
your exposure group was, i.e. what kind of support you were on. But it was interesting to see maybe how long we should be waiting for some of these infants. So for high flow nasal cannula, the time was 1.3 weeks. For CPAP, it was about three weeks. For NIMV, it was about five weeks. And for mechanical ventilation, it was 7.7 weeks with an IQR of 4.3 all the way up to 12.3 weeks.
Daphna Yasova Barbeau, MD (13:08.612)
Still better than I thought.
Ben Courchia (13:10.491)
Very much better than I thought. And if you think about it, if we're thinking of waiting about eight to 10 weeks, that means waiting too close to 46 weeks for these babies to come off mechanical ventilation. Now among the 2,811 infants who achieved liberation from respiratory support, 37 %
eventually got re-intubated later and they say that it's generally for planned surgical procedures. So I think that's fairly reasonable. The number initially I was like, oh my God, 37%, but when you consider that, then that's fine. The overall rates of tracheostomy, I would say, were relatively low, 2.2%. Finally, when we're looking at the restricted mean survival time, the RMST analysis, 36 week respiratory support remains significantly associated with the time to LRS, so obviously,
Daphna Yasova Barbeau, MD (13:41.41)
Mm-hmm. Mm-hmm.
Ben Courchia (14:04.551)
higher the amount of support, the longer it will take, but also was associated with that being SGA at birth, having tracheobronchomalacia, or having BPD-associated pulmonary hypertension, also the center in which you were being cared for played a role. All these, think, were described in the past as definitely high risks for being prolonged respiratory support. So was interesting that this paper also echoed that. So.
This was definitely a very interesting study. The authors conclude by saying that our findings, and I quote, provide valuable insight into factors associated with time to LRS in hospitalized infants with grade two, three BPD, and will aid clinicians in providing parental counseling based on their infants characteristics and therapies at 36 weeks PMA. We speculate that some of the variation in outcome predictions seen in this project reflect definitional flaws in BPD and the impact of heterogeneous BPD clinical phenotypes on time to LRS.
Future work will seek to understand the clinical, biological, and therapeutic differences in patients with BPD and their relationships on the short and long-term outcomes for affected infants. I think this is a very valuable paper. I think that whenever we have babies that are quote unquote stuck on whatever mode of support they're stuck on at about 36 weeks, and we talk to parents about what next steps could be, obviously the option to wait is always one of them. But the follow-up question inevitably from the parents is, well, how long are we going to wait?
Daphna Yasova Barbeau, MD (15:23.886)
Mm-hmm. Mm-hmm.
Ben Courchia (15:26.159)
And to have an idea of what the median time might be for when a baby is expected technically to come off the respiratory support is very, very, very valuable. So I think this paper was very, very helpful and very interesting.
Daphna Yasova Barbeau, MD (15:31.694)
Mm-hmm.
Daphna Yasova Barbeau, MD (15:38.696)
Well, I think it certainly adds to the literature about what is the right timing for tracheostomy, right? Because I think so. I think so.
Ben Courchia (15:44.729)
I don't know about that. Because the one thing that this paper does not take into account is this big debate which we haven't been able to answer, is what is the impact of doing an early versus a late tracheostomy on neurodevelopmental outcomes? Are you better off with a tracheostomy? Yeah, right. I think the proponents of either argument could discuss this and say, well,
Daphna Yasova Barbeau, MD (16:01.08)
Well, and you know I feel strongly about that.
Ben Courchia (16:10.791)
you might be waiting for this baby to come out for respiratory support, but what is the neurodevelopmental toll that this might take if you wait too long? I don't know the answer. I'm not saying they're hinting at anything, I, it's, yeah.
Daphna Yasova Barbeau, MD (16:22.5)
agree with that. I think this helps with those babies where you say like, well, maybe we just have to wait, not the early babies, but some of the babies were like, well, maybe we just have to wait a little bit longer and this baby can do it. I think it helps us in that upper later end of babies saying like, this baby's not even progressing as expected, you know, it's time. You're right. Does that help us decide about the early decisions? No, I don't think so.
but I think it helps us on the late decisions.
Ben Courchia (16:51.333)
No, it might absolutely and it might help you also say, all right, like we are actually now past the time point that would be reasonable to expect this baby to come off support.
Daphna Yasova Barbeau, MD (17:01.636)
Yeah, and I think in our time of kind of reason of our individualized medicine and understanding these little different groups of babies. So I mean, these risk factors of being growth restricted, right? We think like, maybe, maybe by the time their term corrected, that growth restriction is not such a big deal, but it is a big deal. And I mean, I think that's a good reminder. What was it growth restriction, pulmonary hypertension and
Ben Courchia (17:19.996)
yeah.
Ben Courchia (17:26.28)
Tracheobronchomalacia and center.
Daphna Yasova Barbeau, MD (17:27.758)
Tracheobronchomalacia. Yeah, absolutely. And so I think, you know, are we evaluating for Tracheobronchomalacia early enough, right? So there are some babies where we can say like, this baby's going to need more help instead of waiting and letting the baby fail a bunch of times. think that was really helpful. Okay.
Ben Courchia (17:36.359)
I don't know.
Ben Courchia (17:52.187)
Are you taking a s-
Daphna Yasova Barbeau, MD (17:52.874)
the other one I wanted to say, I'm not surprised, but it is a good reminder how many of our BPD babies still need additional surgeries, right? And I think that was really something that I took away. And I'm thinking when, you know, this paper talks about parents and things about these parents who their babies were so sick for so long and they were liberated from the respiratory support. And then we asked them to intubate them again. You can see why it's so traumatic for parents. Yeah.
Ben Courchia (18:02.523)
yeah.
Ben Courchia (18:19.473)
So traumatic.
Daphna Yasova Barbeau, MD (18:22.316)
to do that and maybe we can think of other ways, you know? Okay. We have a lot of descriptive papers this week. A lot of big names writing descriptive papers. So we of course have to highlight them. Hold on. Where did my paper go?
Ben Courchia (18:26.865)
for
Daphna Yasova Barbeau, MD (18:43.204)
Well, I'll tell you in just a second. I have.
Ben Courchia (18:52.551)
So while you look for this paper, I'm just going to, that's okay. I'm going to fill up the data, but just we're going to also have today on the podcast an EB neo segment with Daniel Barber and Jill Chang, who are going to talk to us about reducing the percentage of surviving infants with seizures discharged on anti-seizure medication. So if you've ever wanted to find out how could we potentially get our babies weaned anti-seizure meds before they go home, they're going to give you the answer. All right. You found your paper.
Daphna Yasova Barbeau, MD (19:11.108)
Mm-hmm.
Daphna Yasova Barbeau, MD (19:22.308)
Stay tuned. Yeah. Okay. So this is a paper in Journal of Perinatology. It's a communication, but it provides us some data. is, Enteral Nutritional Practices in Extremely Preterm Infants, a Survey of U.S. NICUs. And it has in the author list the lead author, Mar Romero Lopez, but it has Dr. Wally Carlo, Ariel Salas, Kashif Ahmad, Matthew Rysavy. So, I mean, you know, we got to pay attention.
But basically all they wanted to do was take a survey and just see like, actually, what are we doing across the country? Looking for variation and might this help us set up an opportunity for creating feeding guidelines that are a little bit more standardized regardless of what unit a baby ends up in. So basically they did an anonymous online survey between August and October, 2020.
three, and they wanted to look at feeding protocols, donor milk use, fortification, and target volumes. The question was developed with a kind of multidisciplinary group, and then people were recruited through a number of professional networks to try to fill out the survey. And that actually, I think, highlights another problem that we have in surveying neonatologists. I'll talk about that. But the results
They had responses from 253 NICUs. These were 63 % level 3s and 37 % level 4s. 57 % of the surveyed centers were affiliated with an academic institution. I'm not surprised. Much better connection between academic institutions in terms of communication. Then they wanted to see like how many of the academic centers did they get? So they were able to represent 81 %
percent of the academic centers in the country and over half of the level four centers, 62 % across the US. Obviously, representation from non-academic centers and level three NICUs was lower. So only 16 % non-academic centers and 23 % of level three NICUs. And then,
Daphna Yasova Barbeau, MD (21:47.012)
What did they find? So 87 % of NICUs had established feeding protocols. Centers used different, almost always used weight to distinguish their protocol levels. The most common categories were three using less than 750 to 1,000 and greater than 1,000 grams. But again, there was this range, some...
Units only use two weight categories. Some used greater than or equal to four weight categories. But.
Ben Courchia (22:15.591)
Thank
But, but I was very shocked by the number of NICUs that do have a feeding protocol. It's really encouraging. 85 % of level 3s, 91 % of level 4s, if you are a NICU reading this paper and you do not have a feeding protocol outline, I think you've been put on notice. I everybody, I mean, but you know, we talk about this all the time and for many, it's hard to implement. People shy away, they say, we'll just do it every day at the bedside.
Daphna Yasova Barbeau, MD (22:25.89)
Yeah, for sure.
Ben Courchia (22:47.739)
but you are in very small minority if you do not have a feeding protocol outlined.
Daphna Yasova Barbeau, MD (22:53.218)
Well, and you know, we've just done a liver view to present to our nurses about a neck and the one, mean, human milk. Okay. Yes, of course human milk, but you'll see in the survey that that's pretty much gotten across the board. the other one thing that's really been shown to reduce neck is a standardized feeding protocol. So, that's, that's very important.
Ben Courchia (23:12.336)
Right.
Ben Courchia (23:16.263)
Mm-hmm.
Daphna Yasova Barbeau, MD (23:17.38)
Almost all centers reported using donor human milk with the most common change to transitional formula according at 34 to 35 weeks post menstrual age. So 100 % of the academic centers, 99 % of the non-academic centers, I mean, it's really 99 % in the level three is 98 % in the level fours.
Ben Courchia (23:36.935)
And something we've discussed with Shador Shah, like if you are having difficulties obtaining donor milk for your population, use that data. Go to your C-suite and say, hey.
Daphna Yasova Barbeau, MD (23:44.036)
Mm-hmm.
For sure. Say we're, this is not the standard, we're not providing the standard. Yeah. Yeah. Okay. What else did I want to tell you? So there was some, there was, okay. The category that I think is probably the most interesting obviously is this goal target feeding volume. There was a lot of variability. So over 80 % of NICUs define full feeding.
Ben Courchia (23:51.428)
Absolutely.
Ben Courchia (23:56.527)
I'm waiting for some categories to pop up. I'm ready for some comments.
Daphna Yasova Barbeau, MD (24:13.764)
as 150 to 160 mLs per kilo per day. But the range was still pretty wide. The majority, so 45 to 60%, were using 160 mLs per kilo per day. But there was still 8 % of academics, 5 % of non-academics using less than or equal to 120 mLs per kilo per day. So I thought that was a pretty wide range.
Ben Courchia (24:18.235)
Mm-hmm.
Ben Courchia (24:41.927)
I just hope the survey was well worded, which I'm sure it was, because I hope people did not, because some people might use 120 as a way of saying, that's enough enteral feeds to transition away from TPN, away from enteral lipids, and sort of leave the baby just on that. And they will continue to move forward with the feeding advancements from 120.
Daphna Yasova Barbeau, MD (24:42.369)
of feeding volumes
Daphna Yasova Barbeau, MD (24:57.508)
Mm-hmm.
Daphna Yasova Barbeau, MD (25:02.488)
Yeah, that's true. The reported time to achieve target enteral feeds varied with, yeah, drum roll, with most centers, 76 % reaching this goal after day seven after birth. I mean, impressive, I think. I think that's really impressive, but the ranges as they're written are actually a little bit different. So it's a seven to 10 days.
Ben Courchia (25:07.313)
That's the one. That's the one.
Daphna Yasova Barbeau, MD (25:30.212)
61 % of level three NICUs, 63 % of level four NICUs. Okay, less than seven days, 14 % of level threes, 13 % of level fours. But, you know, 11 to 14 days, sorry, 22 % of level threes, 21 % of level fours. And there's three and 2 % greater than 14 days.
I think that's a target that we're all trying to figure out, reduce,
Ben Courchia (26:01.465)
Yeah, yeah. I mean, that's the one, that's the one in my opinion that is so critical because whenever we come up with feeding protocols, I think the biggest backlash you get, if you get any backlash is like, are we going too fast on these babies? And so what is the right target to get these babies to full feeds? And I think that the categories may be a little bit too granular, but what you basically need to leave with this paper is that 84 % will reach full feeds between seven and 14 days. So during that week,
84 % of NICUs will get to their target feeding volume.
Daphna Yasova Barbeau, MD (26:35.426)
Yeah. And I think that's exactly right. So, I mean, we should be reminding our NICU staff that like, this is the goal and it's based in, you know, community wide data. Now, if your feeding goal is only 120 per kilo per day. So then, okay. So that I will say, I think there's some variability there. If you're using lower feeding targets and you get there by day 14, yeah, you might get there sooner or you can spend a little more time.
Ben Courchia (26:50.895)
you.
Ben Courchia (26:58.311)
Might be able to get there sooner. Yeah, for sure.
Daphna Yasova Barbeau, MD (27:05.368)
getting there, so that's fine. Bovine derived human milk fortifiers were used in most centers and human milk derived fortification products were used in a third of NICUs. Okay, that's not surprising. What else did I want? The intended caloric density initiation and milk fortification also varied. So it ranged from 22 to 26 kcal per ounce, but the most common fortification target was 24 kcal per ounce.
And then often units were needing a higher calorie target if they were using the human milk derived fortification products. And then when do they fortify? So the most common volume used for initiating fortification was about 80 to a hundred mls per kilo per day. So that means when your babies get to 80 to a hundred mls per kilo per day, that was when most units were fortifying. But again, a really a big range. So 10 % of level threes
Ben Courchia (27:42.199)
extends.
Daphna Yasova Barbeau, MD (28:02.98)
15 % of level fours were fortifying at less than 60 mLs per kilo per day. Obviously, Dr. Salas and his team have shown us some new data regarding the safety of that. 60 to 80 mLs per kilo per day, that was 40 % of level threes and 30 % of level fours. This 80 to 100 target, 46 of level three is 54 of level fours and greater than 100 mL per kilo per day was certainly the minority. So I think
even since we graduated from fellowship, that has been a change in practice.
Ben Courchia (28:38.087)
Yeah. Another one where, again, if you combine categories, you end up with pretty outrageous numbers where you really see where you should be. So for most NICUs, basically, 85 % will fortify somewhere between 60 and 100. And yeah, I mean.
Daphna Yasova Barbeau, MD (28:44.066)
That's right.
Daphna Yasova Barbeau, MD (28:56.708)
So if you're waiting to full feeds, you missed the bus.
Ben Courchia (28:59.801)
Yeah, yeah, I don't know about fortifying less than 60. I know some people are doing it, but definitely you see where everybody is, where the peloton is. I think that's where you should try to aim for at the very least.
Daphna Yasova Barbeau, MD (29:12.804)
There were not that many differences in survey responses between the levels threes and level fours, but I did want to highlight that compared to academic centers, the non-academic centers that were surveyed set higher volume targets for full feeding. They began fortification earlier and tended to advance feeds more rapidly. I'm not surprised by that information either.
Ben Courchia (29:18.279)
you
Ben Courchia (29:37.169)
Mm-hmm.
Daphna Yasova Barbeau, MD (29:38.244)
Their overall kind of conclusion was that there was heterogeneity in enteral feeding practices. I agree, there's still some heterogeneity, but actually I think we were much more aligned than I anticipated. There's still variation in target feeding volume, fortification practices, and feeding advancement strategies. And they feel that this highlights the need for larger trials to establish really evidence-based practices that we can all...
follow, which I think would make things easier, certainly for everybody. And the other thing I want to highlight too is I think we still lack communication between academic and non-academic centers. The majority of babies are still cared for and not academic centers. So I think this communication is critical. Being able to access one another, communicate with one another, survey one another, and see what other people are doing, I think is one other thing I took from this paper.
Ben Courchia (30:34.947)
Absolutely, what a great article. Thank you for reviewing that for us. I'm sorry I barged in on many occasions. All right everybody, we're going to take a quick break and we'll be back with our EB-Neo segment.
Ben Courchia MD (00:00.93)
OK, and we are here this week with a eBneo segment. And this week, we have the pleasure of hosting on the podcast Dr. Danielle Barber from the University of Colorado. Danielle, you're a pediatric neurologist. Welcome to the podcast. And it's good to have you on.
Danielle (00:19.854)
Thank you so much, what an honor.
Ben Courchia MD (00:21.446)
The pleasure is all ours. You are joined today by your friend from the Off Air Conversation. You guys are definitely friends. Dr. Jill Chang, who's from the Division of Neonatology, also at the University of Colorado. Jill, thank you for making time to come on the podcast.
Jill Chang (00:37.542)
No, thank you for having me, because as I mentioned, I'm a long time incubator listener. So I was very excited about this opportunity. Yes, exactly.
Ben Courchia MD (00:43.076)
Long time listener, first time caller. And so this is a, we're going to talk today about a special manuscript. And again, I would like to make this a little bit more systematic. this is a manuscript that's been identified by the EB-Neo community as really most likely to have impact on neonatal care. And the article we're talking about today is published in the Journal of Perinatology. It's called Reducing the Percentage of Surviving Infants with Acute Symptomatic Seizures, Discharged on Anti-Sieger Medication, first author.
is Anne Marie Nangle and last author is Elizabeth Sewell. I just wanted to know maybe for the audience who is intrigued by the title already but has not had the chance to read the paper. Could you give us a brief overview of what these investigators were trying to do and what were some of their outcomes?
Jill Chang (01:32.732)
Yeah, I'm happy to go over it with Danielle. So the main question that this paper was investigating is whether infants with acute symptomatic seizures, which I'll define in a little bit, who had been treated with anti-seizure medication, which they abbreviate as ASM in this article, did inclusion of an ASM-wean protocol in a neonatal seizure pathway decrease the number or the percentage of infants discharged on ASMs?
So this is a retrospective cohort study. And in this study, infants with acute symptomatic seizures were evaluated from two epochs during the study time period from January 1st, 2018 to November 30th, 2023. Epoch one was pre-implementation of the ASM weaning protocol and epoch two was post-implementation of the weaning protocol. And they followed these infants from hospital discharge to one year of age.
The study included three hospitals, which I think is the very interesting part of the article, most interesting part. So there are two level three NICUs and one level four NICU. The level three NICUs were the delivery centers at which neurology was available for phone, but not in-person neurology consultations. And the level four NICU was the referral hospital with no inborn deliveries at which an in-person neurologist consultation was available.
And for these level three and four NICUs, continuous EEG monitoring was available. So the inclusion criteria is infants with acute symptomatic seizures confirmed on EEG, who had been treated with ASMs and who were discharged from one of the three study hospitals. And acute symptomatic seizures were defined in the study as seizures provoked by hypoxic ischemic encephalopathy, stroke,
hemorrhage, meningitis, or transient metabolic disturbances such as sodium or glucose abnormalities. The exclusion criteria included death before discharge and infants with seizures that did not meet the study definition of acute symptomatic seizures. And the intervention as previously discussed was the addition of a formal evidence-based ASM weaning protocol to an existing neonatal seizure pathway in October of 2020.
Ben Courchia MD (03:51.27)
Mm-hmm.
Jill Chang (03:52.424)
The primary outcome was discharge on ASM, which was also analyzed based on hospital type at discharge, so delivery versus referral center. And secondary outcomes were if the ASM wean was initiated prior to discharge, the number of ASMs at discharge per patient, and percentage of infants with seizure post discharge up to one year of age. So as far as the sample size, there were 193 infants with
electrographic seizures with final encounters in the NICU system. 38 or 20 percent were excluded due to death prior to discharge and 39, again about 20 percent were excluded for not meeting the study definition of acute symptomatic seizures. This ended them up with 116 infants for the study divided into the two epochs. Epoch 1 had 52 infants and Epoch 2 had 64.
And of those remaining 116 infants included in the study, only 96 or 83 % had a follow-up visit. Okay, so now I'm going to turn it over to Danielle, who's going to talk about the results and conclusions.
Ben Courchia MD (05:01.607)
Sure. It's a very interesting question to begin with because number one, it echoes a little bit some of the recent evidence that had come out about the approach to seizure management, where really the shift has been that the community really is emphasizing the need to try to do our best to win these medications before discharge, which seems like a daunting task and which seems like something it's really a new approach where in the past we've
we felt relatively comfortable letting the pediatric neurologist manage this as an outpatient and we as an outpatient. Now the impediment is on the NICU staff to do their best. And so what does that look like? Seems to be quite interesting as to what this center is trying to answer. You were mentioning, Jill, earlier that you found the fact that these three centers were included in the study, one of the most interesting aspect of the study. I just would like to ask you specifically why you thought that this was an important point to note. Was that because of the
a unique form of neurology coverage they had, or was there another aspect of that that you wanted to bring up?
Jill Chang (06:05.018)
No, that's exactly it. It's because, you from my experience at level threes and level fours, if there is in-person pediatric neurologists consulting, a lot of times I feel that people feel more comfortable sending these babies home, not on ASMs, as opposed to when there is no in-person consultation present, even though in this study there is phone consult. You know, so I think
Ben Courchia MD (06:22.746)
Yeah. Interesting. Interesting.
Jill Chang (06:34.236)
that is, in my perspective, a large hurdle from us discontinuing these medications prior to discharge.
Ben Courchia MD (06:40.206)
Yeah, it's definitely something that, from a scientific method standpoint, does potentially influence how patients are managed. And considering this was a retrospective study, this is a very important point. I wanted also to mention that I like these papers sometimes, where if you do the legwork of going to get the supplementary material, the actual protocol is so good. If you have to write that type of protocol for your unit, go take a look at this, because it's so well done.
It's in all honesty, it's the type of things that you could have said looks like whatever I have in my unit, whatever most people have in their units. It's very comprehensive. You have, it's a three page document, which by the way, I saved. has a diagnosis and workup sort of flow diagram. It does have an escalation pathway in case babies are unfortunately not doing too well. And then you have the de-escalation pathway, which is obviously, guess, the crux of this paper really trying to address that. So if you...
downloading the paper, download the attached supplementary material, is worthwhile. So Danielle, I'm going to turn to you and maybe you can tell us what is it that the group of investigators found.
Danielle (07:50.132)
Yeah, so I think we're all excited about the results. So let's say what they are. First of all, the demographic characteristics were similar between the epic group, so the early group before the implementation of the new pathway and after the second epic. And that included across gestational age, birth, weight, sex, discharge, hospital time, age at seizure diagnosis, and underlying brain injury.
The primary outcome was there was a decrease in the percent of infants discharged on anti-seizure medications across all hospitals, the delivery and the referral in EPIC 1 versus EPIC 2. So it was 69 % in EPIC 1 versus 34 % in EPIC 2. The secondary outcomes included three points. First, that there was a significant increase in the percent of infants who
had an anti-seizure medicine wean initiated before discharge from 44 % in EPIC 1 to 77 % in EPIC 2, so starting that wean. There was also a significant decrease in the number of anti-seizure medicines at discharge per patient from 0.9 in EPIC 1 to 0.7 in EPIC 2. And there was no difference in the percent of infants who had seizures after discharge by one year of age between the two EPICs.
32 % in EPIC 1 and 18 % in EPIC 2. So the conclusion for this manuscript was that inclusion of an ASM, anti-seizure medication, Wien protocol in a neonatal seizure pathway decreased the number of infants with acute symptomatic seizures who were discharged home on anti-seizure medication, regardless of the type of NICU or whether in-person neurology consultation was available. I think the...
Ben Courchia MD (09:18.096)
Wow.
Danielle (09:45.284)
point that you were starting to highlight is that in the neonatal neurology literature, we do have very good evidence that these kids should be going home off ASMs. They should not be going home on anti-seizure medications. And I can imagine that it may feel a little more daunting to the discharging neonatologist when there's not a direct conversation with a neurologist.
available at the time for any particular patient. But the evidence is very good. There were guidelines published from the International League Against Epilepsy from the Neonatal Task Force that made clear recommendations about, you know, of their six main recommendations. One of their main recommendations was after cessation of acute provoked seizures without evidence for neonatal onset epilepsy.
Anti-seizure medicines should be discontinued before discharge home, regardless of MRI or EEG findings. And so that's pretty clear. what I love about this paper is how do you bring that into real world practice? How do you change the practice in these NICUs, even without neurology being present in two of the three hospitals?
One other point that I would love to highlight about this paper is that, you know, in figure two, they go year by year. Yeah, they go year by year and show a bar graph of the percent of infants with acute symptomatic seizures who were discharged on anti-seizure medications by the birth year.
Ben Courchia MD (11:17.262)
Yeah, it's a cool figure. mean, it's kind of nice when you get to publish that. mean, go ahead.
Danielle (11:35.644)
And you can see it steadily decreasing in both the delivery hospital and the referral hospital year by year. And by 2023, the end of their second epic, they get to 0 % in the delivery hospitals, right? Yeah.
Ben Courchia MD (11:47.364)
I know.
Ben Courchia MD (11:51.706)
Yes, yeah. And so that's a point that I wanted to highlight because in the intervention, the algorithm really is comprehensive when it comes to de-escalation of the medications, really pinpointing what was the cause. What is the cause you identified as potentially being the source of these seizures? I'm sorry. And it includes a list of pathologies like HIE, stroke,
hemorrhage, infection, transient metabolic disturbances. And if these were the causes, there's an inclination to attempt the weaning protocol to say, well, this seems like this could be limited in time and you would be well served to try to wean the medication. However, if this is not the case, then the algorithm sort of dictates to stop and not attempt to win because the risk of having neonatal epilepsy is significant and then this would not be safe.
And I'm assuming this is probably what created the difference between the delivery hospitals, which were able to really go down to zero, basically being able to not discharge babies on the ASMs and the referral hospitals where maybe they are dealing more with these more complex neurological cases, potential neonatal epilepsy. Do you agree with that?
Danielle (13:10.124)
Yeah, presumably so. And I think that that distinction between acute symptomatic seizures, that is seizures that are a symptom of an underlying brain injury, we know that those are self-limited. even if you, not that I'm proposing that we not treat seizures, we should treat seizures, but those would stop on their own eventually, even if we didn't treat them. And so we need to treat them and then we need to stop.
Ben Courchia MD (13:34.854)
Mm-hmm.
Danielle (13:39.8)
the medicines. And there's very good clear evidence for that, including recent work from Hannah Glass and Renee Shellhass, both showing that stopping the medicine by hospital discharge not only does not increase risk for epilepsy by two years old, it also does not change developmental outcomes. And we know that continuing these medications longer term
can cause developmental impairment. we don't want to keep kids on medicines that are not helping them and may be causing long-term developmental changes.
Ben Courchia MD (14:14.031)
Mm-hmm.
Ben Courchia MD (14:21.151)
Yeah, yeah, we had the pleasure of reviewing the newest recommendation on episode 150 of the podcast, 150, and René Shellhass actually joined us that day. She's really phenomenal. Like she broke it down so well. So I recommend if you are interested in revisiting these recommendations, definitely go give it a listen because Dr. Shellhass did a phenomenal job. As we're getting towards the end of this segment, I wanted to come back to you, Jill, and maybe one of the themes to me that this paper really underscores
Danielle (14:31.489)
Yes.
Ben Courchia MD (14:48.258)
is the fact that you can reach pretty staggering outcomes with good multidisciplinary collaboration. Can you talk to us a little bit about how that could potentially be identified as a source of success for this paper in achieving these outcomes collaborating with the other specialties, in this case, pediatric neurology?
Jill Chang (15:06.758)
I mean, definitely. that's one of the reasons when I was asked to do this review, I immediately wanted to ask one of our pediatric neurology colleagues to join us just because for the patient population discussed in this article, mainly infants with seizures, we partner so closely.
Ben Courchia MD (15:16.71)
Mm-hmm.
Jill Chang (15:25.39)
in the NICU and then for these patients, the journey doesn't end once they leave the NICU. It's actually our neurology counterparts who will be seeing them at follow-up visits. And so to me, it just seems really important if we're going to make changes to partner with those specialists and in this case, having their expertise in a pathway so that they, you know, they don't even have to be there all the time. It seems like that alone.
And as we can see from this article, garners a lot of positive results.
Ben Courchia MD (16:01.284)
Yeah, and they're usually some of the nice ones to talk to. it only reinforces the need to get in touch with them. I'm just wondering if you have any parting thoughts on this paper, but not just this paper, but the theme of how are we going to get to a point where we can comfortably have mechanisms in place to try to attempt winning? Do you feel like this type of work needs to be reproduced and continued to try to optimize on this approach?
Jill Chang (16:04.072)
You
Danielle (16:04.149)
You
Ben Courchia MD (16:28.134)
What is going to do? Do you think that this is enough to even maybe start implementing these types of approaches in respective NICUs? I'm going let you take it for Danielle.
Danielle (16:39.68)
Yeah, I think this work is very strong and is a clear call that we can all do it. We can all take this evidence and implement it and make it happen for all our babies, right? And I think this work from Liz Sewell's group is outstanding. There's also another paper that was published in Pediatric Neurology. Jennifer Keene is the first author and Dr. Natarajan is the last author.
Ben Courchia MD (16:48.57)
I agree.
Ben Courchia MD (16:52.313)
I agree.
Danielle (17:08.11)
where they compared treatment pathways across 11 NICUs. that also is a great, Ben, you mentioned the supplemental piece in this paper, but as well, that's another great resource where if you're a NICU who doesn't yet have a seizure pathway implemented, here's another opportunity as a resource to build your own seizure pathway.
Ben Courchia MD (17:33.126)
I'll put that in the show notes because it's basically right, it's going through 11 different NICUs and it's just comparing, which as Neonatologists we love to just peek on the other side of that wall and look at like, how are they doing that?
Danielle (17:39.149)
Yes.
Danielle (17:42.646)
Yeah. Right. And there are many children's hospitals that have publicly available clinical pathways that you just Google them and they are publicly available. So, you know, dig around, find the ones you like and pick the parts that, you know, but at a minimum you could use one of those, including this one from Liz Sewell's group.
as a template for your own NICU. And the important piece is to get to implementing this in practice. Yeah.
Ben Courchia MD (18:13.318)
Mm-hmm.
Ben Courchia MD (18:20.302)
Absolutely. Joe, any thoughts?
Jill Chang (18:22.714)
No, I mean, I think that this pathway is the first step. And now we have a lot of good examples for people to initiate if they are kind of lost about even where to start. So there's a lot out there that's available. And then, you know, it's just continuing to collaborate, as you mentioned, with our counterparts in neurology to find other areas that we can kind of improve in our care.
Ben Courchia MD (18:42.244)
Mm-hmm.
Ben Courchia MD (18:48.304)
Very cool. Jill, Danielle, thank you so much for this commentary. Congratulations on the commentary. will be published and available on the ACTA Pediatrica website, as are all the other EBNEO commentaries. Jill, Danielle, thank you so much, and have a good rest of your day.
Danielle (19:04.11)
Thank you for having us.
Jill Chang (19:04.348)
Thank you.
Ben Courchia (30:52.709)
All right, we are back. This was a phenomenal paper. I really enjoyed reviewing this article about how to come off seizure medication. It's so important, especially considering as we said in the segment, that now that people are recommending, that the field is recommending to come off anti-seizure medication before discharge, how are we supposed to do that? was great that we were able to review a paper addressing that question.
Daphna Yasova Barbeau, MD (31:05.592)
Mm-hmm.
Daphna Yasova Barbeau, MD (31:17.976)
Mm-hmm.
Ben Courchia (31:22.811)
I'm going to continue our review of the literature this week with another article that comes from the Journal of Pediatrics. And it's an article that I read with great attention. It's called Supplemental Iron and Recombinant Erythropoietin for Anemia in Infants Born Very Preterm, a Survey of Clinical Practice in Europe. So I'm sorry we're doing a lot of surveys, but obviously this is interesting. I think this is very interesting to review.
Daphna Yasova Barbeau, MD (31:48.462)
Totally agree, yeah.
Ben Courchia (31:51.085)
And so the background is, to me, nailing an issue that we've had, I'm sorry to say, in our unit for some time now about the assessment of the iron status in preterm neonates is challenging owing to lack of gestational age and postnatal age specific norm reference values. And I'm not talking about just hematocrit, hemoglobin, reticulocyte count. If you are trying to get a sense of really erythropoiesis for your neonates, there's very little data.
What is a normal iron level? What is a normal ferritin level? Is a ferritin level reliable? Do we have reference range for total iron binding capacity? No. If you do, then please, we will give you a spot on a Sunday interview to tell us what the normative values are, because they're not really readily available out there.
They're saying also that there's variability in the diagnostic values of lab parameters in systemic pathologic condition like hypoxia or inflammation, especially when we're talking about erythema, for example. So the question that they're asking and they're posing is saying, given the uncertainties regarding the optimal use of iron, EPO and other non-transfusion alternative for managing anemia of prematurity, they conducted
this survey to describe the current practices of iron supplementation and EPO use in European neonatal intensive care unit. So this was a survey that was performed by the Neonatal Transfusion Network. I'm not going to spend too much time on the study design. It's a survey. You can go in the methodology and see if you have any questions that could be answered.
The survey contained three questions on the use of iron. It addressed indication, initiation, and cessation of treatment. They had four questions on the use of EPO addressing indication, initiation, administration, dose, and modification of the given dose. And they had one question on routine blood testing at 28 days of age for investigating anemia. So the results are that they obtained responses from 343
Ben Courchia (33:54.311)
surveyed individuals. They included nine responses on, they excluded some responses due to some inconsistency, but everything was relatively standard. in terms of the categories, so in terms of evaluation of anemia of prematurity, what was striking is that nearly two thirds, 65.3 % of NICUs reported routine blood testing to investigate anemia in infants at about 28 days of age.
which I would have expected to be much higher. The most common measure of iron storage or metabolism used by centers undertaking blood testing was ferritin levels in 35.7%, followed by serum iron concentration in 22%, and then 5.8 % used reticulocyte hemoglobin content, and 5 % used transferrin saturation, and 4 % used transferrin concentration.
A very interesting breakdown. In terms of the reticulocyte hemoglobin content, I think it's something that we will discuss a little bit later. There's a very good editorial by Robert Christensen, Tim Barr, and Robin Ohls in the Journal of Pediatrics talking about this paper. And obviously, reticulocyte hemoglobin content is something that the team at the University of Utah are advocating for. Basically, if you're thinking of
reticulocytes as the fresh red blood cells that are coming out of your bone marrow, the reticulocyte hemoglobin content measuring the amount of hemoglobin in this particular group of cells really is a true indicator of your bone marrow iron stores. So that's why it was presented as an option. In terms of iron supplementation, 97.7 % of the NICUs surveyed
By the way, I think I mentioned that there was 343 individuals. mean, individual NICUs is what I meant. It's not just 300 people, it's 300 NICUs, 343 NICUs. So 97.7 % of the NICUs routinely supplemented iron, which that's good. Nearly three quarters reported the gestational age at birth of less than 32 weeks as an indication followed by a birth weight of less than 1500 grams. What was interesting to me is that I still don't know if there's a consensus regarding the timing of initiation of iron supplementation.
Ben Courchia (36:19.269)
And this varied mainly between two and four weeks. So 48.7 % of NICUs supplemented at two weeks, 20 % at four weeks, and some centers, about 2 % starting before two weeks of life, and less than a percent started beyond four weeks of life. Almost one third, 29.7 % of the NICUs start iron treatment when the infants were on complete enteral nutrition. And most NICUs,
stopped iron supplementation after six or 12 months. The last piece of survey data that's interesting is the use of EPO. So of the 334 responses that they received on EPO, 71 % reported never using EPO. So you can tell that the University of Utah editorial is going to harpoon on that because you know that Dr. Oles is going to be offended by the lack of use of EPO in this population.
Among the 97 centers treating anemia with EPO, 74 reported routine use and 23 used EPO based on an individual decision basis. So that's it for this survey. The survey highlights obviously the heterogeneity in evaluating erythropoietic activity and iron deficiency in infants born preterm. Variation in iron supplementation during infancy likely reflects the inadequate evidence that is available. Current evidence on the efficacy and safety profile of EPO is only
poorly translated into clinical practice, and the survey demonstrates a need for standards to optimize patient blood management in anemia of prematurity. A very interesting survey indeed. I'm just going to go through a few points that I highlighted from the editorial led by Dr. Christensen. They're highlighting, obviously, that there's significant variation in how
the effectiveness of iron supplementation was being monitored throughout these European NICUs that were surveyed. And they mentioned how about two thirds of sample NICUs reported measuring iron sufficiency during the NICU course, but a third reported never doing so. I think that's something that to them is striking. Now, what's even more striking is that the biomarker that we're using to measure iron supplementation varied significantly. And they mentioned how
Ben Courchia (38:43.431)
The measurements of either serum ferritin or serum iron was reported in 58 % of the European NICUs that routinely check for iron effectiveness. Now, what they're saying is, and that's why the editorial is interesting, is because they're comparing some of this data from data that they have of US NICUs. And they mentioned that in the US, these markers for iron stores is only used in 5 % of NICUs.
talking about ferritin and serum iron. So this is a striking difference between 58 % of NICUs in Europe doing that versus only five in the US. And they're mentioning, obviously, the reticulocyte hemoglobin content, which is the most commonly used metric in the American NICUs, with 35 % of US NICUs using that measurement to evaluate iron stores, but very rarely used in Europe. They're obviously highlighting the issue with ferritin that it can help assess neonatal iron status only
when that is low because the values within the normal reference interval could be spurious elevated due to inflammation, particularly so in extremely low gestational age neonates. In addition, they mentioned that the measurements of serum ferritin takes additional blood and cost. They mentioned how the reticulocyte hemoglobin content or its equivalent is run with no additional phlebotomy loss and no delay in runtime and is a better metric for assessing iron sufficiency in growing infants born preterm.
So a very interesting survey. Again, something that I found particularly interesting, probably from an egotistic standpoint, because we're actively reviewing that aspect of our management in RNQ. But yeah, very interesting. And I would suggest that if you're going to review this paper, tack on the editorial from Dr. Christensen.
Daphna Yasova Barbeau, MD (40:33.25)
Yeah, I think there's a lot of opportunities really presenting themselves for research, for really, I think, career defining pathways. So I think that's cool. Well, I'm going to continue on with kind of this expert level discussion about things that are still changing in the NICU. This is in the Journal of Perinatology. It's a comment.
Ben Courchia (40:44.4)
Mm-hmm.
Daphna Yasova Barbeau, MD (41:00.612)
But I think it's an important one. So I did not want it to go unnoticed. It is by Dr. Robert White and Joy Brown. They co-direct the Gravens Conference, which is really our conference for developmental care, family engagement, trauma-informed care, lactation, some of these kind of critical hot topics in neonatology.
and the senior author on this paper is Terry Ender. So they're really working together, collaboratively, and they have for decades, about how important for brain development, some of these NICU design.
Ben Courchia (41:44.453)
Yeah, was going to, I'm sorry, I didn't mean to interrupt. just meant to mention that since you brought up the Gravens Conference, the 38th International Gravens Conference will actually be taking place quite soon in March, between March 5th and March 8th, 2025 in Clearwater Beach, Florida. And you can find all the ways to register online if you just Google the Gravens Conference. Sorry.
Daphna Yasova Barbeau, MD (41:51.064)
Uh-huh.
Daphna Yasova Barbeau, MD (42:00.388)
That's right.
Daphna Yasova Barbeau, MD (42:06.358)
Yeah, I think it's a no, Ian knows important point. It's accessible. It's not so expensive. I think everybody should go at least once. It's always been my sorry, say favorite conference. So I'll put that out there. But on the commonest
Ben Courchia (42:19.643)
Don't people are going to then say well, what about this com for I mean, come on Okay
Daphna Yasova Barbeau, MD (42:22.34)
Nope, this is my favorite gum. This conference as a fellow really set my professional personal trajectory and in my interest in neonatology. that's why. So it's called the road to sensory deprivation in the NICU is paved with good intentions defining an optimal environment of care. So they really just describe this pendulum swing in NICU design and our interactions with babies.
and how they worry that it's impacting long-term development. So I'm actually just going to read, and then I think maybe you don't even have to look it up, but I just think this is valuable to talk about. The current era of NICU care has been driven by recognition of how toxic the NICU environment can be. So facilitated by better technology, better design, and a better understanding of neonatal neurodevelopment, NICUs have become quieter, dimmer, more spacious, and more welcoming.
Over-stimulation, though, has been replaced by a more hands-off approach in an attempt to protect infants' sleep and neurodevelopment. Rooms that had been brightly lit around the clock are now dim 24-7, or alternatively, incubators are covered to protect, quote-unquote, the babies. Infants are variably offered auditory stimuli such as music or listening to a parent, nurse, or volunteer read to them, but this is most often prescribed when the infant appears to be asleep, which can be most of the time, or unpredictable.
As a result, language exposure for the preterm infant in a NICU is lower than would have been the case in fetal life. And that's a change from what we saw in early NICUs. This will impact auditory and language development in later life. Parents who want to hold their baby are often asked to wait until the baby is awake and may be prevented from doing so even then if it is believed that movement of the baby might put them at increased risk for IVH or accidental extubation. Parents suffer collateral damage.
by separation from their infant as well as emotional trauma associated with the loss of their primary role. There's a little bit more detail about the things we're doing to prevent this pendulum swing, but they highlight there is now sufficient evidence to suggest that the next step in the evolution of NICU care should be a middle road that avoids both over and now this concern for under stimulation. It should maximize parental interaction with their baby and considers bedside caregivers as providers of both medical
Ben Courchia (44:20.484)
Mm-hmm.
Daphna Yasova Barbeau, MD (44:43.532)
and neurodevelopmental support in partnership with parents. So really when they talk about the future era of nurturing, is somewhere between our early era of noxious and our current era really of sensory deprivation, moving to single patient rooms, really avoiding any sensory input, which these babies need to develop their brains. Fetuses get while they're in utero, but now we're doing even less than fetuses were getting in utero.
So they're commentary here and they have some articles to support the evidence, but extensive nurturing home and contact, including during sleep and during medical interventions. So we forget that some babies are never actually touched by skin to skin contact. So our nurses are touching with gloved hands. our professionals are touching with gloved hands, but there's something about skin to skin contact, not just kangaroo care that is valuable for babies.
Ben Courchia (45:24.57)
Mm.
Daphna Yasova Barbeau, MD (45:43.032)
mother sent tastes, through the administration of colostrum and non-nutritive breastfeeding, obviously skin to skin care, circadian ambient lighting. know that, cycled lighting better than all bright and all dark talking, reading music, even while asleep. And it should be coupled with other sensory type inputs being touched, being contained, being held, rocking vibratory senses and supporting sleep.
while encouraging human contact and sensory input that can be nurturing even during sleep. And I'll just say this comes up in our unit all the time. We're a unit who prioritizes kangaroo care, but if a parent comes to the bedside during a non-touch time, the nurses will say, well, it's time for the baby to sleep. My argument is always that this may be the only time in the day or this week that this baby will be held by their parent and that should be prioritized above.
keeping our touch times. So that's my soapbox for the week, supported by Dr. White and Dr. Inder and Joy Brown. And I'll keep reading articles like this out loud.
Ben Courchia (46:52.303)
You got it. You got it. Thank you for the PSA. OK, we are a little bit over time. I'm going to take a few minutes to review one last paper. This was an interesting study that was suggested to me by a few colleagues. It's called Bemiparin in neonatal thrombosis, therapeutic dosing and safety. First author is Maria Sanchez Holgado. This is in the Journal of Perinatology and it's a paper that's coming out of Spain.
Daphna Yasova Barbeau, MD (46:56.28)
Thanks.
Ben Courchia (47:19.079)
This is something that I found to be very interesting, mostly because it's a frustrating issue for all of us. And I'm going to go through the background a little bit, because I think that's probably one of the most valuable parts of the paper, considering what the results I'm going to present in a second. But the incidence of thromboembolic complications in neonatal intensive care units varies and is estimated to be between 2.4 and 6.8 per 1,000 NICU admissions.
The increased complexity of care, the use of invasive procedures together with the higher survival rates in complex neonatal condition have led to the growing frequency of such events in this population. Although spontaneous thrombosis is rare, intravascular devices, infections, or inflammatory disorders disrupt the delicate hemostatic-fibrinolytic balance, significantly increasing the risk of thrombosis. So far, thrombosis is typically a secondary phenomenon in neonates, and 90 % of cases are associated with indwelling central venous catheters.
Evidence supporting neonatal thrombosis management is scarce. No randomized control trial confirming the efficacy and safety of any anticoagulation therapy. Currently, unfractioned heparin has been the classic treatment for neonatal thrombosis for decades. However, it has been largely replaced by now low molecular weight heparin. And low molecular weight heparin presents several advantages over unfractioned heparin, such as the fact that it has a longer half-life, it is used subcutaneously,
It has more predictable pharmacokinetics and it has a lower incidence of heparin-induced thrombocytopenia, osteopenia, and hemorrhage. Now, before we talk about bemiparin, I think this is very true. mean, how many times have we ultrasounded some of our babies and we find like this pesky thrombus and, I don't know, we don't do very much about them. We re-ultrasound them every couple of weeks and we just hope it goes away. Very rarely do we...
Daphna Yasova Barbeau, MD (49:06.099)
Mm-hmm. We don't know what to do about it.
Ben Courchia (49:14.545)
We pull the trigger on an intervention unless it is recommended by some specialists who are co-managing with us. So it's definitely a frustrating issue, something that I was really eager to learn more about. They mentioned this medication that I was not familiar with, Bemiparin, spelled B-E-M-I-P-A-R-I-N, compared to low molecular weight heparin, it's...
part of that class, part of that family, but it has a lower molecular weight. It has a higher anti-factor 10A and anti-factor two-way ratio activity and a longer half-life, making it suitable for administration only once a day. So a very appealing medication. Now what the group was trying to do is to describe the use of Bemiparin during the neonatal period during thrombotic complications with a focus on dosage, monitoring, and side effects. So basically this is a medication that it appears...
this unit has been using. And so this is a retrospective descriptive study that's conducted in the Department of Neonatology at La Paz University Hospital in Madrid, Spain between January 1, 2018 and December 31, 2023. Now, the anticoagulation status of these infants was measured, was monitored using measurements of serum anti-TNA levels four hours after the sub-Q ejection of the Bemiparin.
with a therapeutic target range of 0.5 to 1 international units per ml. The bemiparin dose adjustments were based on anti-TNA levels, always guided by the hematologist. As I said, it's rare that we do these things without subspecialty support with step dose increase or reduction of 10 to 20 % based on the previous dose. So I mean, again, it's retrospective. It's not a randomized trial. So I'm going to go straight into the results.
So they're able to report to us their experience with 72 neonates that were treated with Bemiparin over the six-year study period. The mean gestational age of these infants was 37 weeks. And 20 infants, 20 % of the cohort were born preterm. So I don't know how I feel. would have liked, it feels like it's happening a lot more in our preterm patients, at least from my experience. But it is what it is. I think it's data nonetheless.
Daphna Yasova Barbeau, MD (51:25.7)
Agreed. Yeah.
Ben Courchia (51:29.927)
The median age and weight at the start of the baby per in treatment was 22 days and the weight was 3,200 grams. So a total of 358 anti-Xa determinations were carried out. 33 % were within the dosing range. 58 % were below. 9 % were above. In terms of the median number of blood samples undertaken per patient to monitor the anti-Xa level was four.
roughly once per five days of treatment. So that was quite good. Now what's interesting is that the total thrombus resolution before hospital discharge happened in 25 % of cases, while partial resolution was documented in another 22%. So it's very frustrating. I would have liked that if you are going through this extent of using a medication, calling the hematologist, I would have hoped that we can get rid of this thrombi.
Daphna Yasova Barbeau, MD (52:23.448)
Mm-hmm.
That's right. Well, maybe that's the lesson. It doesn't matter what we do to them.
Ben Courchia (52:30.329)
Of course. Of course. by the way, and by the way, I'm not blaming the authors in any way. I'm just like, this is an issue that's so frustrating. It's just, I mean, maybe it's benign. Maybe the babies are not suffering from these little, but it doesn't sit right with any physician that's like, yeah, there's a clot there. And it's just sitting there. And it's like, what? It'd be better if there was no clot. So there was no significant difference in thrombosis resolution rates between patients pretreated with unfractioned heparin and those who received the heparin as a primary therapy.
there was one severe adverse reaction that was reported in one patient who suffered a major bleeding during an emergency thoracocentesis, but this patient had not received prior treatment with, unfractioned heparin. guess that is also a lesson that if you are going to start these treatments, it's kind of what the adults do on a day to day basis. Like, are you on anticoagulants before we start sticking you or putting you through surgery? If you're doing it in the NICU, it's going to be a mental active process of remembering that you kind of, are on anticoagulation. And so.
any invasive intervention might have catastrophic consequences. No new onset thrombopenia was reported during treatment. 94 % of the babies remained on bemiparin upon discharge. That is not something I want to hear either. It's kind of scary to send babies on anticoagulation at home. Outpatient follow-up data was available for these patients, among whom 57 % demonstrated partial thrombus resolution. 41 % achieved complete re-canalization by the end of the three month.
Bemiparin treatment period. That is very long. Only one patient failed to attain any degree of vascular patency, subsequently developing collateral circulation. So they have a separate analysis for the use of Bemiparin in preterm infants. they were not the smallest babies. The median gestational age was 33.5 weeks, median birth weight 1,847 grams.
the median postnatal age and weight at the start of anticoagulation therapy was 56 days and 2.6 kilos, thrombus resolution did not differ between the two groups, i.e. preterm and term, nor did the incidence of side effects with no reported adverse events among the preterm infants. So I'm going to stop here. The summary of the conclusion is that the study offers preliminary evidence regarding the dosage safety and efficacy of Bemiparin as a convenient treatment for neonatal thrombosis despite challenges in monitoring and dosing.
Ben Courchia (54:53.297)
Their findings suggest that Bemiparin may be a safe and acceptable option for population. That is true. It is definitely a takeaway that this might be just as good as what's currently available. The safety profile is of utmost importance due to the longer half-life and further well-designed prospective trials are needed. I think it'll be very interesting to see how Bemiparin does compared to babies who are not being treated with anything in a head-to-head comparison. They say here in a head-to-head comparison with Enoxaparin, but
Daphna Yasova Barbeau, MD (55:00.153)
Mm-hmm.
Daphna Yasova Barbeau, MD (55:07.63)
Right.
Daphna Yasova Barbeau, MD (55:14.958)
That's right.
Ben Courchia (55:22.279)
I'd like to see what some controls with no intervention, maybe a sham treatment, would do. So a very interesting paper. I think we've all had these babies with some form of clot somewhere that we keep ultrasounding and we're like, what are we doing? We're not doing anything. And the parents, they know about the clots. And they ask you, so what's going on? And it's like, well, still there.
Daphna Yasova Barbeau, MD (55:25.432)
Mm-hmm.
Daphna Yasova Barbeau, MD (55:41.206)
Yeah, well, I think it's such like you mentioned such a different approach than what happens in adults. So they're like, what do you mean? You're not going to get rid of the clot, right? And so and then sometimes you feel like, what do we mean? We're not going to get rid
Ben Courchia (55:47.727)
Absolutely. Absolutely.
Ben Courchia (55:53.445)
Yeah. I mean, I'm married to a cardiologist. All I hear about is anti-coagulation. Should you anti-coagulate? Should you not anti-coagulate? my God. yeah. So when she hears that we are just leaving clots in there, it's definitely, no, it raises eyebrows.
Daphna Yasova Barbeau, MD (55:56.28)
That's right.
Daphna Yasova Barbeau, MD (56:01.528)
Yeah, when and how, Very interesting. She doesn't like it.
Well, I've been looking forward to you covering that paper, so thank you for doing that.
Ben Courchia (56:14.161)
For sure. I think that concludes Journal Club for today, right? I mean, we are way over time. thank you for, yeah, you suffer through people. That's okay. We do this work for you. We are very excited this week to have an episode of the French podcast. Friendships of Journal Club will be coming out tomorrow. We have an episode of Beyond the Beeps. Beyond the Beeps is coming back for the 2025 seasons. Jayanetti is interviewing...
Daphna Yasova Barbeau, MD (56:18.02)
think so. That's right. We always are.
Daphna Yasova Barbeau, MD (56:38.5)
Mm-hmm.
Ben Courchia (56:41.479)
Nick, parents, so look out for this episode coming out this Wednesday. And then this week we will have next week we will have our second episode of Neo News where we review articles related to neonatology from the mainstream media. And after that, we will Crescent our new series, Fellow Friday with Rupa Gopal. The first episode might actually come out on a Wednesday. I realize that it might come out on the 29th, but ignore the fact. I mean,
Daphna Yasova Barbeau, MD (56:53.738)
Mm-hmm.
Daphna Yasova Barbeau, MD (57:07.588)
Just pretend it's a Friday.
Ben Courchia (57:10.287)
It's some Fellows Friday sounds so much better.
Ben Courchia (57:15.729)
So.
Daphna Yasova Barbeau, MD (57:15.758)
Well, we'll get it to Friday, one day.
Ben Courchia (57:18.703)
Yeah, so it's Rupa's Fellows Friday Corner, whatever. It's a great episode. The first episode is coming out at the end of the month. Look out for this. again, we're going to have a brand new website rolling out by the end of the month. Lots of new content on there, lots of information that you're to be able to access. We have a brand new store that's going to be open as well. So look out for that. We'll announce that at some point. So stay tuned.
Daphna Yasova Barbeau, MD (57:44.824)
Well, and to your point about the website, I think it's going to be super easy for people to navigate and use. You have been working very hard. Our team has been working very hard. You don't want to promise anything.
Ben Courchia (57:52.071)
I don't want to bury the lead here, but we'll have no. No, I can promise actually this time, but we will have a special episode, maybe a YouTube video to go over some of the features. right. All right, Daphne, I'll see you later. Bye.
Daphna Yasova Barbeau, MD (58:00.8)
Okay, yeah, that's a great idea. Love it. Okay, bye everyone.