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#206 - 📑 Journal Club - The Complete Episode




Hello Friends 👋

In this episode of The Incubator Journal Club, Ben and Daphna discuss several recent neonatology papers. They review a NEJM trial on nutritional support strategies for moderate to late preterm infants, finding no effects on time to full feeds or body composition at 4 months. Next, they discuss a study on umbilical cord blood cultures for early onset sepsis, noting good concordance with neonatal blood cultures. A Japanese retrospective study found erythropoietin use was associated with increased ROP risk but decreased NEC and mortality. However, the hosts caution about limitations in EPO dosage data and variation between centers. They then discuss a trial showing breast milk enemas reduce time to meconium evacuation and full feeds compared to saline enemas in preterm infants. A paper from Nationwide Children's reports good outcomes managing BPD without routine blood gases, potentially saving costs. Lastly, a study suggests transcutaneous bilirubinometry may safely monitor rebound hyperbilirubinemia after phototherapy. Throughout the discussion, Ben and Daphna provide insightful analysis of each study's strengths, limitations, and implications for practice. They also highlight their upcoming 3-year podcast anniversary, announcing a special giveaway and listener survey. 


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

Fukui K, Ito Y, Kokubo M, Nakanishi H, Hirano S, Kusuda S, Ito S, Isayama T; Neonatal Research Network of Japan.J Perinatol. 2024 Mar 21. doi: 10.1038/s41372-024-01929-z. Online ahead of print.PMID: 38514743

 

Butterworth FR, Boulton R, Campbell S, Frew G, Mactier H.Arch Dis Child Fetal Neonatal Ed. 2024 Apr 10:fetalneonatal-2023-326145. doi: 10.1136/archdischild-2023-326145. Online ahead of print.PMID: 38604650

 

Bensouda B, Mandel R, Altit G, Ali N.Pediatr Res. 2024 Apr 15. doi: 10.1038/s41390-024-03183-7. Online ahead of print.PMID: 38622259

 

Zheng L, Gai L, Wu Y, Kong C, Sun F, Gao J, Yuan W, Liu M, Jiang H, Tuo N, Yang F.JAMA Netw Open. 2024 Apr 1;7(4):e247145. doi: 10.1001/jamanetworkopen.2024.7145.PMID: 38648060 Free article. Clinical Trial.

 

Kielt MJ, Eldredge LC, Shepherd EG, DiGeronimo RJ, Miller AN, Bapat R, El-Ferzli G, Welty SE, Nelin LD.J Perinatol. 2024 Apr 23. doi: 10.1038/s41372-024-01955-x. Online ahead of print.PMID: 38654082

 

Alexander T, Asadi S, Meyer M, Harding JE, Jiang Y, Alsweiler JM, Muelbert M, Bloomfield FH; DIAMOND Trial Group.N Engl J Med. 2024 Apr 25;390(16):1493-1504. doi: 10.1056/NEJMoa2313942.PMID: 38657245 Clinical Trial.

 

Javed R, Gowda H.Acta Paediatr. 2024 Apr 30. doi: 10.1111/apa.17259. Online ahead of print.PMID: 38687140 No abstract available.


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


Ben Courchia MD (00:00.686)

Hello everybody, welcome back to the Incubator podcast. It is Sunday, we're back with an episode of Journal Club. One week overdue, but here nonetheless. Daphne, how are you this morning?

 

Good, counting down the, I mean, I guess when this airs, PAS will be in full swing. We will both be moderating sessions. But at this moment, I am counting down minutes basically, till I hop on my flight. So, a frenzy.

 

It's a full swing.

 

Ben Courchia MD (00:26.734)

That's right. Yeah, no, I mean, if when this episode airs, we'll be in PAS, maybe no one will listen to this considering PAS usually sucks up all the energy that's in, I know. But it's going to be a good journal club nonetheless. There's a lot of important papers published. We apologize for derailing a little bit the usual release schedule. We are thankful for David McCauley.

 

That's right. All your bandwidth for sure.

 

Ben Courchia MD (00:54.798)

and Betsy Crouch for Manning the Fort this past Sunday with a phenomenal episode of At the Bench. If you haven't listened to it, I suggest you do so. It's just very interesting stuff. They had on Dr. Donna Ferreiro. I don't know if I'm pronouncing this correctly, but anyway, she was great talking about neonatal brain injury. Check it out. And yeah.

 

Very interesting.

 

Daphna Barbeau (01:22.611)

Well, and I'm glad it was a Sunday episode because I'm not sure everybody's had a chance to listen to At the Bench and I think that people will find it more clinically relevant than they might expect. So I hope people will be listening to those episodes as well.

 

Mm -hmm. Yeah.

 

Yeah, they don't they don't just talk about like how much can you put in a pipette? They talk about very relevant stuff.

 

That's yeah, I think for every, I mean, certainly if you're a basic scientist, are you looking to be a basic scientist? I mean, you can't, I don't think you can miss these episodes. They're gold, but and I should say, I think it's good for all of us. Even if you're mostly clinical to know what's coming down the pipeline and to understand some of the things that are happening.

 

Yeah.

 

Daphna Barbeau (02:11.283)

at the bench as they say. All right.

 

Yeah. Yeah. So, yeah, my apologies. By the way, it was all my fault for derailing the release schedule. Had to deal with some French travel. Can I tell my story of the French travel just maybe for therapeutic purposes?

 

Yeah, please. And hopefully people getting to PAS won't get stuck anywhere. But yeah, let's hear your story.

 

No way they get stuck the way I get stuck in France. It's just, France is just another beast. And if you're going to the Olympics, if you're going to the Olympics, good luck. God bless you. This was a, a strike that was announced to start on the day I was supposed to travel from the air traffic controllers. And then like the day before they're like, no, we found an agreement. Like we, we agreed. Whatever our demands were met. So I was like, great, that's great. And then all the flights got canceled anyway. And then.

 

It's like every time.

 

Daphna Barbeau (02:56.627)

Oh.

 

And then we're like, what's happening? Like I thought the strike was lifted. Like they were not going to do that. Like, yeah, you know, but we canceled the flights already. So we might as well just. I was like, I was like, what does that mean? What does that mean? There's no strike. Why are you not putting back the flights? And so it was a disaster, especially with a, with a two month newborn. That was interesting to take a 2 a .m. cab rides. That was, that was an experience. But yeah, to the.

 

Yeah, well, it's a lot of work to put them back on.

 

Daphna Barbeau (03:13.587)

They gave them the day off, you know?

 

Daphna Barbeau (03:23.411)

But you made it back safe and sound.

 

to the delight of my colleague who was expecting me to relieve him on Friday night.

 

That's right. Yeah, by the skin of your teeth, you made it to your shift. And now a quick turnaround. I gotta go.

 

That was one of my excuses to the airline company. I was like, I got to shift on Friday night, man. Like I got to be there.

 

All right. None whatsoever. None whatsoever.

 

Daphna Barbeau (03:45.395)

Do you think it helped your case? I don't think, I don't, I mean, I've had some run -ins with the reservation people these days and I don't think there's any empathy in the decisions made on the reservation teams.

 

Zero, zero. Anyway, all right. We're going to start today. We have, by the way, an E .B. Neo segment to look out for. The Oscar trial is being reviewed. But we start with another paper from the New England Journal of Medicine called Nutritional Support for Moderate to Late Preterm Infants, a randomized trial. I feel like maybe I've not been on Twitter enough, but I feel like it did not have the buzz that...

 

All right.

 

Daphna Barbeau (04:21.043)

No, lots of buzz. There's buzz.

 

the New England papers usually get.

 

That's true, that's true. Not as much as one would anticipate for a paper like this.

 

Right. First author is Taneith Alexander. It's the Diamond Trial Group. It's out of New Zealand. And basically, the background is not earth shattering, saying that there's no clear guidelines with regards to when or how nutritional support beyond breastfeeding should be provided in the population of moderate to late preterm infants that the European Society for Pediatric Gastroenterology, Hippotology and Nutrition has identified research gaps.

 

data on nutrition practices for moderate to late preterm infants and on the benefit risk balance of providing nutrient -enriched support. The purpose of the trial itself is to investigate maybe new strategies to palliate this gap in order to support moderate to late preterm infants and to see the effects of these various strategies on body composition and time to full enteral feeding. So the design of the trial, it was a multi -center factorial randomized controlled trial.

 

Ben Courchia MD (05:27.918)

that was conducted at five hospitals across New Zealand. I hate factorial trials. I know Dr. Wally Carlo loves them. It makes it so confusing when you read them. It's very elaborate. It's very strong. It's just my... I still like them. The eligibility criteria was that you had to be 32 weeks or up to... From 32 weeks to 35 and 6, you had to be admitted to the NICU, you had to be on IV fluids, and the mother of the baby had to intend to breastfeed.

 

The exclusion criteria were chromosomal genetic anomalies, potentially affecting growth, body composition, neurodermatological outcome, or if a specific mode of nutrition was indicated. And they randomized the babies one -to -one within the first 24 hours of life. And the intervention, this is what we get to the factorial design, was designed as follows. So you had three interventions, basically. In the beginning, while you're on the IV fluid phase, basically you could be on either IV dextrose or like more of a

 

TPN type of solution. They call this the amino acid solution. Then as you start getting fed, you could be either receiving milk supplement, either donor breast milk or formula, or you could be on exclusively breast milk from the infant's mother as entero nutrition. And then while you're being fed, there was this exposure of smell and taste of milk before tube feeding. What does that mean?

 

That means that they did a taste intervention, which basically was provided by placing 0 .2 ml of milk into the baby's mouth with a syringe immediately before the infant was fed through the NG tube. And then the smell intervention was basically done by applying about like half an ml of milk to a piece of gauze and was placed near the infant's nose and remained there throughout the duration of the tube feeding.

 

And these interventions continued while the baby was getting tube fed or until the time of discharge. So basically, because it's a factorial design, you had nine, eight, sorry, eight potential setup where you could be on either or TPN or D10, either or breast milk or formula, either or taste and smell or no taste and smell. So in the end, there's like a big table and this is the factorial design. The primary outcome of the paper,

 

Ben Courchia MD (07:50.126)

is for the babies who were receiving parenteral nutrition and milk supplementation intervention, it was the body fat percentage at four months, correct, or gestational age. For the last intervention, the taste and smell intervention, it was really time to full enteral feeding. That was the primary outcome. So in terms of results, 532 infants are enrolled in about five centers, and they have data that's available on the primary outcome in 61 % for the body fat percentage at four months.

 

And they have obviously the time to full enteral feeding data on 99 % of the kids. In terms of body fat percentage at four months, it was similar between the TPN group versus the IV dextrose group and between the milk supplementation and the mother's breast milk only intervention. The time to full enteral feeding also similar among the babies who received the taste and smell intervention versus those who did not. They had a bunch of secondary outcomes and nothing really came to it. The

 

the characteristics of body composition measured by these air displacement plethysismography were basically largely similar between the intervention and the comparator group. The time to full sucking feeds feeding by mouth independently was similar between the IV and the TPN group, between the milk supplement group and the mother's breast milk only group, and between the taste and smell versus no taste and smell. The time to full enteral feeding without looking at oral...

 

intake independently, also similar between the groups. Breast milk feeding status at the time of hospital discharge and at four months corrected of gestational age, also similar between all intervention groups. Change in Z -score weight, length, and head circumference from birth to hospital discharge and from birth to four months of corrected gestational age, also similar between all the groups. I guess that's why I didn't create such a buzz because there's really nothing to sink your teeth in. The conclusion are that the trial...

 

of this routine nutrition interventions to support moderate to late preterm infants until full nutrition with mother's breast milk was possible, did not show any effects on time to full enteral feeding or body composition at four months of age. And to me, it's an interesting paper because number one, I don't know if some of these interventions are such high cost, like taste and smell feels like something kind of nice to do. But it's also reassuring that if, you know, like, for example, Daphna and I had been

 

Ben Courchia MD (10:09.102)

facing in our unit a situation where they're like, hey, we have some TPN shortage. We can't provide you with TPN the next two days while there's some back order. I don't know what that was. But it's good to know that for this specific population, if you had to resort to dextrose infusion in the beginning, then it's not the end of the world. So maybe from that standpoint, it's kind of nice to know. But I don't know if it changes much or really redirects how we do things. I don't know. I don't know what your thoughts are.

 

Yeah, no, I agree. I think there's so many papers about being behind a few days on fat or protein. So you feel like, gosh, if we don't get every little micronutrient right that they're going to be behind. And that's probably not the case. Obviously, there's some profiles of babies that...

 

really depend on the nutritional status. They all depend on the nutritional status, but I mean, I think when taken as a big group like this, that we still haven't figured out exactly what all the babies need. And I think it just shows that still some babies need certain things and some babies need other things. So more questions to be answered.

 

Uh huh. Yeah.

 

Ben Courchia MD (11:27.438)

Yeah. Where are you taking us next?

 

Okay. Perfect, buddy, perfect. Well, I was going to do this paper, umbilical cord blood culture for early onset sepsis in preterm infants. Lead author, Brahim Bensouda, senior author, Nabil Ali, and I see our friend Gabriel in the author list. This is in pediatric research and...

 

It is coming out of Canada. So it's a retrospective observational cohort study that looked at infants at or before 34 and zero weeks gestational age who had an umbilical cord blood culture drawn. And then they were looking at the rates basically of sepsis, what organisms, and how did those compare to the neonatal blood cultures drawn at the neonate.

 

So interestingly, they had already, as a center, started implementing the practice of obtaining umbilical cord blood cultures in infants born less than 34 weeks as of 2019. And who did they draw them on? They drew them on all babies, like I said, less than or equal to 34 weeks that were considered at risk for early onset sepsis. And those risk factors include prolonged rupture of membranes lasting 24 hours or more, maternal fever, obstetrical suspicion of choreo.

 

And of course, in cases of isolated preterm labor with none of these additional risk factors, um, umbilical cord blood culture, I'm going to call it UCBC from now on, um, was drawn at the discretion of the attending neonatologists. Um, and then infants without any risk factors for early onset sepsis didn't undergo systemic blood culture as part of their protocol. Um,

 

Daphna Barbeau (13:23.571)

Okay, so early onset sepsis was defined as a positive UCBC or a positive neonatal blood or CSF culture within the first 72 hours after birth with an identified pathogenic microorganism as per previously reported literature. So the, I mean, agreed upon literature for organisms. And having received antimicrobial therapy for at least five days.

 

Now a UCBC contaminant was defined as a positive UCBC result in an asymptomatic infant who did not receive antimicrobial therapy for more than 48 hours with a morca organism species considered to be a contaminant. Additionally, UCBC samples that had a positive result for two or more species were also classified as a contaminant. So let's get into the data.

 

From April 2019 to November 2022, a total of 505 infants below 34 weeks or less were admitted to the facility. 195 had a UCBC at birth. None of the infants with a negative UCBC, this was 170 out of 195, exhibited clinical signs of early onset sepsis within the first seven days of life.

 

So conversely, out of the 195 infants, 25 had a positive UCBC. And out of the 195 infants, 18 had a positive UCBC that were considered a contaminant. Those babies also were found to be clinically asymptomatic and they had negative neonatal blood culture. A non -pathogenic bacteria is found in 14 infants with a positive UCBC.

 

And in four cases of a positive UCBC with a pathogenic species, they were found to be polymicrobial. So they were also considered contaminants. So in all, there were seven out of 195 infants diagnosed with early onset sepsis to the UCBC. There was E. coli in four, Candida in one, MRSA in one, and enterococcus in one. They looked at the average time to positive umbilical cord blood culture. So for the contaminants,

 

Daphna Barbeau (15:38.931)

the average time to positivity was 26 .6 plus or minus 18 .9 hours. And for the cases of early onset sepsis, the time to positivity was 11 .6 plus or minus 5 .8 hours. There were no significant differences in maternal fever, maternal antibiotic usage between infants with or without early onset sepsis. However, a prolonged rupture of membranes exceeding 24 hours increased the risk.

 

of early onset sepsis to an odds ratio of 26 .22. There were no deaths reported in the cohort. They also looked at delivery type. So of the 195 UCBCs performed, 82 were after C -section and 6 % of these were early onset sepsis and 5 % were contaminants. Of the 113 vaginal deliveries, 2 % early onset sepsis and 12 % contaminants.

 

They also drew, had this really nice graphic of what I, my question was, what do the UCBCs look like compared to the neonatal blood cultures? So they had a nun, like I said, 195 UCBCs drawn of the 87 % of negative UCBCs. 44, only 44, had concomitant neonatal.

 

Mm -hmm.

 

Daphna Barbeau (17:03.219)

blood cultures. Okay. And of the 44, so they had negative UCBCs, they drew 44 neonatal blood cultures. Yeah.

 

Yeah, so that's the key was that they did the concomitant newborn blood culture in basically anyone that had a positive umbilical cord culture, right? But yeah, but the negative ones not necessarily basically. So that's why there's not the same number. Like it was 170 and now only 44 were concomitantly done.

 

For sure the positive ones, but not all the negative ones.

 

Daphna Barbeau (17:32.883)

But notably, of the 44 drawn, all of them were also negative. So they were consistent with the UCBC. Now the 25 UCBC positives, I'm just gonna go to the seven that were considered early onset sepsis. All of them had a concomitant newborn blood culture. And five out of seven had a peripheral venous...

 

Mm -hmm.

 

Daphna Barbeau (18:01.907)

blood culture that was negative. One out of seven had a peripheral venous blood culture that was positive. And then one used umbilical venous blood, which was also negative. So only one of the seven that had a UCBC positive culture had a positive peripheral culture.

 

So I thought that was interesting. I would have, I, optimally I would have liked to see all the babies have both cultures and see, see that data, but.

 

Mm -hmm, yeah.

 

Ben Courchia MD (18:39.054)

Which I think there's some data out there to show that. And to be fair, I think in fellowship, we did not used to do this. But since I've been attending, we've always done this everywhere we've been. Of course, you're...

 

Yeah, that has been done.

 

Daphna Barbeau (18:50.419)

Mm -hmm.

 

Daphna Barbeau (18:54.355)

When we can, yeah, when we can. We don't always get them. But that's another, that's a story for another day.

 

Yeah, very interesting and kudos to the team in Montreal. Okay. Yeah, I have a paper that really like got me stressed out. And so the paper is called Erythropoietin and Retinopathy of Prematurity, a Retrospective Cohort Study in Japan, 2008 -2018. What? Well, you know, it's always the same thing. I don't love EPO.

 

Your turn.

 

Daphna Barbeau (19:21.939)

Mm -hmm, mm -hmm. Because you love Epo.

 

Ben Courchia MD (19:30.734)

I don't really, I am actually now fed up with EPO. But I've been, it seems like people have asked for an EPO protocol, which I've written at the last two institutions we've been at. And so it feels like it's my responsibility now. Right. And it's like, now everything comes out. It's like, Oh my God, did I, did I now put these babies at risk? Cause it's like, cause it's the protocol I drafted and I'm just fed up with it. So enough.

 

I love you, though. I guess I should say I love you.

 

Daphna Barbeau (19:44.851)

You became the EPO guy. That's what happened. Yeah.

 

Ben Courchia MD (19:56.558)

enough of EPO and everything else. But in any case, so why is it a big deal? Because obviously, first of all, there is Kana Fukui, and it's in the Journal of Parentology. Obviously, the data is coming out of the Neonatal Research Network of Japan. Anyway, the data is, we've discussed this with Robin Holes on the Neonatology Review Podcast when we talked about the ESAs, if you want to go listen to that.

 

And there was some discrepancies in the Cochrane reviews about whether there is an association between the use of urethrapoietin and ROP. And there's some conflicting data. There was some data that actually may be questionable. In any case, the PNAT trial came out and really showed that there was no association between use of EPO in low birth weight infants and ROP. But in the background, there's sort of...

 

putting this into context and saying, well, we wanted to see if there was an association between the use of Epo and ROP in Japan using our very large registry database. And I think it's important for us to review the paper because the conclusions are concerning, but the data needs to be interpreted very carefully. There's a bit of a few red flags about how much we can use this data at face value. So I'll walk you through that carefully. So this is retrospective data.

 

collected on babies that are born at 22 to 27 and six weeks of gestation between 2008, 2018 in the Neonatal Research Network of Japan, which is kind of different from the peanut trial. If you remember, peanut trial starts at 24 weeks. So they're really including this cohort of which they are so good at these very micro -premies. And they exclude babies with congenital anomalies, those with mystic data on EPO use and so on and so forth. Now, the big thing about this paper is that the first question I had was,

 

what was their regimen. And I quote the paper saying, well, we did not have data on individual dosage of EPO administered to study infants. However, erythropoietin was most likely to be administered at a dose of 200 units per kg twice a week, because that's what it says on the Japanese package insert. And that is to me the first, obviously the first problem with the paper, because if you don't have a good grasp on how you're giving it, then that's an issue. But at least...

 

Daphna Barbeau (21:56.627)

Very interesting.

 

Ben Courchia MD (22:17.902)

I mean, again, to their credit, they're very upfront about it and they mentioned that right off the bat. It's to me, it's an issue, but it's not an issue too, because if we did the same thing with caffeine in the US, like most of us, what they load with, we load with 20 and then we do what, five to 10 afterwards. Like, it's not like the range is crazy, but in any case, we'll see why it's important. The data collection included some maternal demographics.

 

It included some infant demographics, it included some gestational age at birth, It included ABGAR scores, it included infants complication like death, ROP, BPD, neck, et cetera. The primary outcome of the study was ROP requiring treatment by laser coagulation or by the administration of anti -VEGF or both. Secondary outcomes was death before discharge, bronchopulmonary dysplasia, neck stage two or greater.

 

And they had some composite outcome like death before discharge or ROP or death before discharge or BPD and so on. Going to the results, the data includes about 16 ,000 infants of which 14 ,090 % receive EPO, which it's quite impressive that they give you put to a lot of babies. The proportion of infants receiving EPO was similar among the various weeks of gestation. But the other thing that's very interesting is that, and that's something that you have to keep in mind.

 

They said there was wide variation in the proportion of infants who received EPO among the NICUs. So not only do they not have great grasp on the dosage, but they also, um, they don't have a good homogeneity as to how the EPO is being given. And I think to me, it's another red flag for the study just because then the outcomes could be very different going from unit to unit. So if you compare our unit to Boston children, we're not on equal footing.

 

And so that's an issue. And that's why randomized control trials are designed in such a way so that you can actually put together units that may not have the same outcomes, but at least you control for as many of the variables as possible. Now, the baseline characteristics, obviously, since it's retrospective, they're not the same. And the inference in the EPO group had a higher risk of clinical choreo. They had a high risk of having premature rupture of membrane. They had a high risk of needing antenatal steroids.

 

supplemental oxygen at birth, tracheal intubation at birth, and they had a lower risk of vaginal delivery. In terms of the primary outcome, they said that the risk of the primary outcome, which is ROP requiring treatment, they said was significantly higher in the EPO group than in the control group, even after the adjustment for potential co -founders rates were 33 % versus 26%, which by the way, also is quite high. So take that with a grain of salt because for many rates of ROP are much lower.

 

Ben Courchia MD (25:14.958)

especially when you look at, and I'm not talking about us, I'm talking about data reported by the Neonatal Research Network in the US. So it's an interesting piece of data to look at as well. The risk for chronic lung disease also was significantly higher in the EPO group, 49 % versus 35%. On the other hand, they showed that EPO was significantly lowering the risk of death before discharge from

 

Right, right.

 

Ben Courchia MD (25:41.902)

13 % to 2 .3 % and also reduce the rates of NEC from 7 .8 % to 2 .6%. When they looked at these combined outcomes, death or ROP or death or BPD, no differences. And then when they looked at the subgroup analysis, the estimated adjusted odds ratio were significantly higher in the 22 to 24 group compared to the 25 to 27 week group for ROP and significantly lower for death. And so...

 

The study concludes that this large sample size found that EPO use was associated with increased risk of EPD and ROP requiring treatment while being associated with reduction in neck and deaths. And again, the big issue, as they mentioned, the conclusion, the timing, dosage, duration, and indication of EPO were not known in this study. Further studies incorporating this detail, along with the frequency of vision impairment, are required. Absolutely true. To give you a point, in the discussion, they mention how...

 

EPO administration was really unknown. And they said that sometimes it's administered starting after 32 weeks in some units. So that's like whether you start on day of life one versus after 32 weeks, it's a big difference. So this is a big gap in this study. And the results fly in the face a little bit of some of the data that was obtained through the peanut trial, especially when it comes to NEC BPD and specifically ROPD.

 

So I don't think it changes much right now because I think this data needs to be cleared a little bit and maybe another trial should be designed with this network to find out exactly if this is the case. I think it's interesting they're including a more immature group, but yeah. Yeah.

 

Yeah, I mean, we're all looking for data on that group, right? And we're all looking for more data on the medications that we routinely give to babies. So I thought that was a really great paper. Do you want me to do another one or are we gonna do our segment?

 

Ben Courchia MD (27:47.214)

I think we should take a break and come back with the EB -Neo segment. Let's cue the jingle.

Daphna Barbeau (28:00.755)

Okay, today we have the distinct honor of having on two real experts, Dr. Harsha Gowda and Dr. Rashta Javed. Today we're discussing the hot topic which we discuss every few weeks, it seems like, of the PDA. And they are reviewing for us today the Baby Oscar Trial, Trial of Selective Early Treatment of Patent Ductus Arteriosis with Ibuprofen.

Dr Harsha Gowda (28:19.049) Thank you.

Daphna Barbeau (28:30.043) Now, Dr. Gauda, you are going to give us some background and why this study is so important.

Dr Harsha Gowda (28:38.051) Thank you, Daphna. Thank you very much for the introduction. Yeah, I mean, you know, the PDA is being like an odd topic for probably for last two or three decades. And there's multiple trials have been done on PDA to find the answer. And unfortunately, none of the studies, if you look at the Cochrane, there are 16 Cochrane reviews out there on PDA. And none of them didn't give any.

Rashida (28:51.744) the concert hall and I'll be in the hall for the first call.

Dr Harsha Gowda (29:02.271) valid answer like you know to treat PDA early or not to treat. So that's why there's ongoing debate and ongoing big trials are coming up. What we know is like you know for sure that you know PDA does increase the morbidity and mortality for the babies. We know that like a significant PDA, Immodemically Significant PDA, but what we don't know clearly is treating this PDA early on in the first few days of life whether that improves the outcomes.

Rashida (29:03.413) the

Rashida (29:12.981) So, I just hope that we can keep up on this work.

Dr Harsha Gowda (29:30.779) That's what we doesn't know. And that's what this study is trying to address in this paper.

Daphna Barbeau (29:38.935) Okay, yeah, thank you for setting the stage for us. Dr. Javed, you'll tell us a little bit about the paper.

Rashida (29:45.722) Yes, thank you so much. So yeah, so this paper basically it explores the use of iberbruphin for treating a large PDA in extreme preterm patients. And the main focus of this paper was to treat the large PDA with iberbruphin, whether it improves the short term outcomes or mortality. And short term outcomes was in the form of this moderate or severe bronchopulmonary dysplasia. So what did they do in this study? They basically

compared ibuprofen versus placebo to treat large PDA and extreme phetum patients in terms of outcomes like mortality and more greater severe bronchocomorbid dysplasia. So this was a multi-center study that was carried out in 32 neonatal intensive care units in the UK. And they included extreme phetum patients who were between the age of 23 weeks to 28 plus six weeks of gestation. And they were less than 72 hours old.

And they basically confirmed the large PDA by transference echocardiography. To have them had a large PDA, they should be a size of more than or equal to 1.5 millimeter in diameter, which they saw it. And the echocardiography, they basically did echocardiography at first at 72 hours of age. And then again, they repeated it three weeks of age, as well to assess the eligibility criteria. And what they did, the primary outcome they made, that was basically a composite of that.

or moderate to severe bronchopulmonary dysplasia at 36 weeks post menstrual age. And the statistical approach was basically the intention to treat analysis, and the analysis they were adjusted with various factors that were the size of the PDA, gestational age, and mode of respiratory support. And they were a little bit more factors which they adjusted for analysis.

In terms of results, they recruited basically the randomized 653 infants. Out of them, 327 were randomized to the ribobriefing group, and 326 were to the placebo group. And data was only available for the outcome. That was 318 infants in both of the groups, because some of the infants, they were out of the study, because some of them, they had the missing data. And there were some other factors out of them. They were out of the study.

Rashida (33:04.878) So what did they found in terms of the results? Just kidding.

Rashida (33:14.579) So the main primary outcome, which they saw in the study, basically the main primary outcome was the composite of death or moderate to severe disability. So that was 69% in the Brufin group and 63% in the placebo group. Motility rate was 13.6 in the ibuprofen group and 10.3% in the placebo group. And if we see isolated moderate or severe bronchopulmonary dysplasia, that was found in 64% in the ibuprofen group compared to 59%.

of the placebo groups. It was a little bit high in the iboglutin group but that was not statistically significant. And some of the other secondary effects they also found they were higher in the iboglutin group which were intraventricular hemorrhage, periventric leukomalacia and clinically significant pulmonary hemorrhage. But again there was no difference in between the two groups.

And they also found that those babies who were in the placebo group, there was the need for surgical ligation was more as compared to the iboglutin group. So it was 9.6% in the placebo group as compared to 2.8% who needed surgical ligation in the iboglutin group. And they found close and or non significant PDA at three weeks of age. It was definitely high in the iboglutin group which was 57% versus 37% in the

Let's see both groups.

Rashida (34:40.09) So I think basically also this is interesting to mention about the use of this open label treatment for any indication of PDA, which they use it. And in this study, the percentage of the infants who received open label treatment for any clinical indication of PDA, it was 14% in the iboglutin group but 29% in the placebo group. So basically what they concluded in this study, although iboglutin, it closes the PDA, but it doesn't...

show any effect in terms of reduction of mortality or moderate to severe bronchial pulmonary dysplasia at 36 bps of menstrual age. So that's where this study concluded.

Daphna Barbeau (35:20.755) Yeah, thank you for that synopsis. I think it's so important that we highlight what the outcome, you know, the primary outcomes were because so many different PDA trials are looking at different outcomes. So I think that's important. And I know there's a lot of discussion in the community about some of those other secondary findings that didn't read statistical significance, but had some signals that I think people were concerned about, thoughts about those things.

Rashida (35:21.498) See ya.

Dr Harsha Gowda (35:51.803) Yeah, I mean, just to keep in depth now, like, you know, yes, I mean, you know, this study, like, if you look at both the groups, you know, they were quite well balanced groups, actually, like, you know, the well balanced group. And if you look into the, when the babies were recruited for the study, they kind of recruited on 48 hours to 72 hours. And that most of them were recruiting that time, like 67%. And

Dr Harsha Gowda (36:36.267) Yeah, the

Dr Harsha Gowda (36:41.391) to these babies by giving ibuprofen in the first three days of life. That is a bit of a worry. I know none of them are statistically significant and the study was not designed to evaluate those secondary outcomes. Maybe in future we need to come up with some trials to evaluate those secondary outcomes, like appropriate numbers. But what worrying is definitely some of the secondary outcomes were higher in the ibuprofen group. That is a bit of a concern actually. Like you know, yes, yes.

Rashida (37:03.226) Well, thank you. I'm going to go to bed. Good night.

Daphna Barbeau (37:13.441) And Dr. Javid, any thoughts about other strengths and limitations of this study?

Rashida (37:20.682) Yes, in this study, there was some limitation because of one of this, like they stopped it, they could not recruit the desired number of patients. One of the cause for that one is that because of the pandemic of COVID-19, that was one thing. And also, like, although early assessment of randomization was encouraged, but you know, the first dose of iboglutin, like it was administered at the median age of 61 hours.

Although it was within three days, but it was given within 61 hours of birth. And another important limitation was, in spite of this strict criteria, open-label therapy, basically. So open-label treatment was received in 29% in the placebo group, so which made it more difficult to identify between group differences in the study. So that were the main limitations.

Daphna Barbeau (38:12.846) Something to add, Dr. Gowda?

Dr Harsha Gowda (38:14.349) Yeah, I mean, what clearly the study shows is like, you know, ibuprofen does work to close the PDA because they did see that, you know, number of like, you know, open label treatment was higher in the placebo group, which was significant. So ibuprofen is helping to close the duct. But unfortunately, it is not improving the one of the important outcomes that is BPD. It's not improving the outcome. So the question comes like, you know.

what is the point in giving ibuprofen in the first three days of life where it doesn't improve the important outcome because you know like the number of preterm babies are increasing gradually because of the survival of 20 to 23 vikas are increasing globally. So PPD is a major problem in preterm infants. So treating the duct in the first few days doesn't look like it's going to improve any of these outcomes.

Daphna Barbeau (39:06.347) Okay. And Dr. Gowda, so what do you think this added to the PDA controversy, which, you know, it's a broad wealth of articles and studies and it's plaguing the neonatal community. What do you think? How do you think this changes the conversation?

Dr Harsha Gowda (39:26.127) I mean, I think recently like, you know, baby Oscar came and recently another study like, you know, Benedictor's trial was published as well. And that's also a very important trial and very similar gestational age group and similar population. And both the trial were given similar results, like, you know, and Benedictor showed that, you know, it is non-inferior, like in expectant management is non-inferior rather than treating the duck. And Oscar didn't show any improvement. So in the big conversation of period debate,

I guess like, you know, people move, may move towards expectant management in the first few days of life, because previously a lot of scoring came into practice and people were scoring the PDA, evaluating the duct very early on, and hoping that, you know, treating the duct in the first few days may prevent a lot of adverse events. But now probably, like, you know, like, you know, as a new native community, the new native team may go slightly towards expectant management, especially the first few days of life.

and maybe to go towards a targeted management, like later on, or maybe in the end of first week, or maybe in the second week when the duck is used, maybe we'll go for targeted management of PDA, rather than like a prophylactic management. I think that is the move now in the next, like what we're going to see in the next few weeks or days, I guess.

Rashida (40:37.702) And I think that's a great way to make things work.

Daphna Barbeau (40:44.375) So it sounds like you're saying there probably are still some studies to help us decide what to do with the PDA because many in the community are saying that the discussion on PDA is over. So I'd love to hear both of your thoughts about that.

Rashida (41:01.97) Okay, so yeah, second thought is also fine because you know, like the spontaneous closure of PDA is also very high in extreme P term infants like 73% of PDA can close spontaneously in the P term. So this question can come like there is no use to treat the PDA in the early hours of age. If there is no clinical concern, but if like there is significant clinical concern like is causing problem and significant hemodynamic problems it is causing.

then we can think about it, although like there have been, because there have been like lots of RCTs have been done to create PD or not. And 16 of them has been reviewed in the Cochrane Review as well. And none of them showed any effect on the short term outcomes. They just showed that it may close the PDA, but it has not been shown any benefit on the short term outcomes. So, yes, you're right. The other thought is also correct.

Dr Harsha Gowda (42:00.04) Yeah, I mean to add on like you know what Rastaf said, yes, I think the debate on PDA will continue. I think I don't think it won't stop for the next decade or two decades. The people will be doing more studies and more trials will go on. I think what these two studies have shown is like, you know, treating the first few days is not beneficial. Maybe the future trial will be on like, you know, maybe treating a bit later, like in a second week,

Dr Harsha Gowda (42:27.475) that what will come, I guess, like that what I am thinking. But another thing is like, you know, still the study is ongoing because they're going to look into two year neurodevelopmental outcomes. So hopefully it will be published in a couple of years time to see whether at least like, you know, ibuprofen improves the neurodevelopmental outcome by closing the duct early on, but reduces the variation in the oxygen levels to the brain.

So that improves new development. We don't know, like we need to wait and see. None of the previous studies have shown improvement, but we need to wait and see the outcome of new development of this BPOSCA trial to see whether that improves or not. So that is still in the, we need to wait and see. Yeah.

Daphna Barbeau (43:09.235) And my last question for both of you is, as we're doing these big trials with whole cohorts of extremely low birth weight and premature infants, I wonder, we've brought up a few times on the podcast, is it possible that we're picking the wrong group of babies or the wrong aspect of the PDA to study?

Dr Harsha Gowda (43:37.207) I mean, I think when we discuss about the PDA, you know, people, you know, always a school, two school of thoughts. For historically some neonatal community doesn't believe in duct and there's few units in UK, like, you know, they don't treat PDA at all. Like, you know, they don't use any medications. And there's some school of thought, like some units quite aggressive in the PDA management. I think what will happen is like, you know, the people, like, you know, the neonatal community believe in PDA. I'm sure like, you know, that what

they will raise like, probably the studies were not done. They didn't target the right population. That's when you need to redesign the study with the right population. Maybe a bit later on when the one baby is like a few days old, when the duct is becoming significant, then they have to redesign the trial. That's what they'll come. But I'm sure like some other school of thought is like, don't believe in period, they say like, stop doing period trials. We already got the answer. We should completely close down. So I mean, the debate will go on. I don't think the debate will stop at this point.

with these two studies.

Daphna Barbeau (44:38.809) Dr. Javed, any closing thoughts?

Rashida (44:41.475) Yes, I agree with Dr. Gorda, but I think like the age, but if we take the little bit slightly more gestational age of babies, because they in those babies, the large PTA, I don't think so it won't cause much problem as compared to these little babies, because these are the babies who are at the risk of some size secondary side effects. Some of them are very severe, which are like one of them is this bronchopulmonary dysplasia. for intraventricular hemorrhage. So if we are going to treat PDA or not, if we are going to discuss, and if we have to see something, then this age group is better as compared to like, if we seen the little bit mature age group, but we don't know, like we have not done any, we have not done any studies and any researches. So we can redesign and then see.

Daphna Barbeau (45:32.839) Okay, Dr. Harsha Gowda and Dr. Roshna Javed, thank you so much for joining us today.

Rashida (45:39.61) Thank you.

Dr Harsha Gowda (45:40.135) Thank you. Thanks, Raphna. Thanks for having us. Thank you very much. It was a pleasure talking to you.

Daphna Barbeau (46:00.371) I had another article for you. I thought this one was interesting. This one was called breast milk enema and meconium evacuation among preterm infants, a randomized clinical trial. This is JAMA Network Open, lead author Dr. Zhang and senior author of Fan Ang. So basically what they... We're putting breast milk everywhere. We're putting, well, which you know I love is coat the babies, can't coat the babies with breast milk. Um, the yet, yet maybe we can avoid any prophylactic antibiotics for VUR. In the nose, in the mouth, in the butt.

Ben Courchia MD (46:45.75) The VCUG is being, VCUG is the only test saying, what about me? Yeah.

Daphna Barbeau (46:59.227) That is not what this paper is about. Anyways, the question, which is an interesting one, does breast milk enema facilitate meconium evacuation compared with normal saline for preterm infants? Now interestingly, this is a study out of China and for many units, even doing enemas with normal saline is not standard of care. So that's just something to keep in mind.

The study was a randomized open-label parallel group single-center clinical trial from September 2019 to September 2022. Now, these were the enrollment criteria, a gestational age of less than 30 weeks, and basically informed consent signed by the guardian. Infants were excluded if they had congenital malformations, if they had congenital GI anomalies, anorectal deformities, diarrhea, and a deception neck.

PDA, sepsis, neutropenia, and coagulapathy. And randomization was stratified also by gestational age. So they did a group of 23 weeks to less than 28 weeks, 28 weeks to less than 29 weeks, and the 29 weeks to less than 30 weeks. So what did this actually look like? Premature infants in the groups received either normal saline as the control or breast milk as the intervention in the form of enemas.

Basically 48 hours after birth, the preterm infants, regardless of group, started to receive the enemas twice a day at 9 a.m. and 9 p.m. They used a dose of five mls per kilo. It was preheated to 37 degrees centigrade and then it was administered using silicone tubing placed just inside the rectum.

it looks like over three minutes. Okay. Now, when did they stop doing it? So criteria for termination of the intervention included complete meconium evacuation or discontinuation of the intervention for infants experiencing adverse events deemed unsuitable to proceed or withdrawal of the guardian's consent. So the data, among the 433 infants screened,

Daphna Barbeau (49:14.939) 12 parents declined to participate. 135 infants met at least one exclusion criteria. So overall they had 286 preterm infants with a mean birth weight of 1.115 kilos who were eligible and included in the study. 145 infants were randomized to normal saline, 141 to the breast milk group.

And then bi-gestational age groupings, they had 78 infants in the 23 to less than 28 weeks, 100 in the 28 to less than 29 weeks, and 108 in the 29 to less than 30 weeks. And then this kind of loss to follow up group, they had 22 in the breast milk and 12 in the normal saline group. So they actually have a really nice table that shows all of kind of their outcomes measures.

and then outcome measures by this gestational age group. So for time to achieve complete meconium evacuation, this was statistically significant for the whole group. It was 13.7 days for the normal saline group compared to 11.4 for the breast milk group.

Now, it was not statistically significant in the 23 to 28 week group, but it was significant in the infants age 28 to 29 weeks and in those 29 to 30 weeks. Now time to achieve full enteral feeding, this was significant across the whole group. 35.4 days in the normal saline group compared to 29.5 in the breast milk group. This was statistically significant in the youngest group.

but not significant in the two older groups. Duration of TPN, 35.8 days in the normal saline group, 30.5 days in the breast milk group. This was statistically significant, and it was significant for the youngest group, but not the two older groups. Now, hospitalization and weight at discharge, there was no difference between the two groups. So,

Daphna Barbeau (51:25.435) They also did a safety analysis. There were no significant differences observed between the intervention and control groups across all safety outcomes, including BPD, late onset sepsis, retinopathy of prematurity, IVH, neck, bloody stools, and mortality. And these remain consistent in the subgroup analyses. However, they did have a adverse event that they monitored. They looked at colorectal and anal injuries. I'm not sure.

exactly what consisted of the colorectal imagery, but they had four cases and all four cases coincidentally occurred in the breast milk group and they were confined to infants age 29 to less than 30 weeks gestational age. The only thing I'll mention, so notably if you open up the supplemental material, more infants in the breast milk group discontinued as compared to the normal saline group, 11 babies as compared to two babies.

four in the 23 to 28 group, one in the 28 to 29, and six in the 29 to 30 week group. Potentially that was related to these four cases of colorectal and anal injuries, but this is more than four. So I thought that was interesting. So like I said, many units here in the US are not doing even...

normal saline enemas as a standard of care. So it's an interesting thought for discussion, I think, just about routine enemas to begin with and might breast milk offer some improvement seeing as how they had early evacuation of meconium, early time to achieve full enteral feeding.

What did you, am I, no I'm not muted, very good. The one time I get concerned whether I'm muted or not, I am not muted. In any case, what do you think of that comparison group? Like do you think they should have randomized the breast milk and MS compared to nothing? Because that would have been standard of care technically, no?

Daphna Barbeau (53:19.867) You

Daphna Barbeau (53:32.155) Well, I'm not sure what their standard of care is. It sounds like potentially ENMA is part of their standard of care. So that's the difference. I think they feel, I don't know exactly. Is that the standard of care everywhere, this hospital? I don't know. But that's what I was saying. So for so many of us, it's not. So it would have been nice maybe if there was a third group that was not randomized to anything and really see the difference, for sure. For sure.

I see.

Ben Courchia MD (53:55.862) Yeah.

Ben Courchia MD (54:00.342) But it's funny, yeah. Yeah, it's an interesting point. Is that something you would consider in terms of your practice? Because we're quick in our units.

Yeah, I love the breastbone. Okay. To do what in our unit you said?

Because here's what I was asking you a bit of a leading question, but think about it. Like we use enemas, we use glycerin enemas. And so my point here is that when work, let's say a preemie hasn't pooped day five, day six now, you're feeding them. There's no other issues. And you're considering that glycerin suppository. Do you say instead now, shove some breast milk in there? It's.

Yeah. Yeah.

Daphna Barbeau (54:44.123) So, it's interesting because with the glycerin suppositories, the volume is different. So, I mean, I say that's a whole different question, right? Enemas, which are a volume of some amount, and we don't have a good standardization of volume, glycerin suppositories, which don't use a volume, but you really have to actually put something into the rectum. And in general, my bias is that breast milk sounds safest.

That's right. That's, that's, that's my, I mean, it's, but I don't think you should, um, hide, hide away from that. I think it's our collective bias. I think we're all like, if you ask me, um, glycerin versus breast milk, I think probably safer to shove some breast milk in there. I mean, let's be honest. Um, obviously considering the fact that you have enough breast milk that you could spare some for an enema because obviously like, um, but.

But that's why we need the studies to do it.

Daphna Barbeau (55:22.459) Yeah, probably.

Daphna Barbeau (55:27.579) Yeah, that's right.

Daphna Barbeau (55:34.651) Right, that's true. Yeah, no, I mean, that's a great point. I mean, we're lucky to have donor milk in our unit. Is donor milk equivalent to breast milk in enema form? I don't know, but... Because it's 10 mLs per kilo per day, right? Starting on the second, after the second day. So you're right, you may not even have it. And it may be a lot of milk to ask for. Very interesting.

The hospital might not be happy if you start using the precious donor milk for enemas. Yeah.

Ben Courchia MD (55:56.63) Mm-hmm.

Yeah.

I have two quick papers that I wanted to mention. The first one is one that I'm very proud to see because it's something we've been discussing. It's called Managing Established BPD Without Using Routine Bud gas Measurements. First author is Matthew Kilt from Nationwide and the Journal of Perinatology. So I wanted to give this a highlight for several reasons. Number one, again, to give the team at Nationwide a big thank you for hosting us so nicely. And because if you...

Yep, love it.

Ben Courchia MD (56:27.702) If you're following the work that we're doing, if you're following the Delphi conference, which by the way, a new website is coming for the new edition, which should be quite good. And if you've watched the talks, Leaf, Neil, and I'm probably, yeah, it's a great lecture on collaboration talking about BPD. And he does give us a little bit of a preview of this data about what they're doing with blood gases. So we've been knowing about this result for some time. And we were talking to Leaf about this during our visit at Nationwide.

It was a great lecture.

Daphna Barbeau (56:50.747) Mm-hmm.

Ben Courchia MD (56:57.75) because it has influenced how we practice and it's a fascinating approach. Now, they're looking to see, they have a big BPD unit, right? They have a 24-bed NICU that's dedicated to BPD patients. And they wanted to see if we eliminate routine blood gas measurement, how does that affect the care of our patients, how early they get discharged, and so on and so forth.

And they have a very interesting approach to the care for BPD. When you get there, it's not so much like some fancy ventilators or respiratory management. It's really a comprehensive approach that includes respiratory interventions, but also heavy focus on nutrition and neurodivermental care. As we toured the BPD NICU at Nationwide, it's not uncommon to see therapists on the floor on mats with babies working on therapies. And so I think, I think,

It's a very innovative way of looking at the management of BPD. Now, to give you some of the results, they had about 485 patients and about 62% of these infants referred to them for BPD at 36 weeks, never had a blood gas. And I think that's mind boggling.

And then obviously they looked at the others 38% that did get a blood gas. And when they looked the median number of blood gases for their hospitalization for these other kids is about four. So which for many units, you would burn through those four within 24 hours. Yeah. Q12 done. Um, so what's interesting too, is that they talk about cost and they said that in those patients that had at least one clinically indicated blood glass, blood gas, um,

The total additional cost of blood gas sampling was $247,000 or an average total cost for blood gases of about $1,362 per patient. So something that we don't often think of reminds us how insane the US healthcare system is that this is the price of a blood gas, but something that we should be thinking about for our patients. In their cohort, by the way, like that's the other half of this paper, which is like maybe they're

Daphna Barbeau (58:56.635) think about.

Yeah.

Ben Courchia MD (59:11.766) babies are very poorly taken care of. But no, 20% are discharged on room air, 70% on some form of oxygen and 3% only on positive pressure at excellent outcomes. And so...

Yeah, they have excellent outcomes. Excellent. Especially they get so many babies transferred in, right? As a second opinion, old babies. Yeah. Yeah.

they should be having bad outcomes considering they get the frustrating cases from everyone else. But when they compare their data to the CHNC, to VON, to the neonatal research network and the BPD collaborative, there were no fundamental differences in mortality, age at discharge, length of stay, rates of tracheostomy, grade 3 BPD compared to these four other networks. And so I think it poses the question of, can we manage babies with BPD with, maybe not with.

That's right, that's right.

Ben Courchia MD (59:57.718) ever out ever like, I don't think we should all say, okay, no more blood gases, but maybe start in that direction of saying, like, can we judiciously think about how do we assess, um, respiration and ventilation in these babies? So fascinating paper. Um, kudos to the team at, uh, nationwide love what they do. And again, uh, we had a great visit there. So totally biased.

Ben Courchia MD (1:00:21.27) Okay. Do you have a, do you want me to do one more? All right. So my last paper for today is a paper you're going to like published in the archives of disease and childhood out of Scotland called can transcutaneous bilirubinometry safely be used to monitor rebound hyper bilirubinemia after phototherapy in babies after 35 weeks of gestation? First author is Frances Rose Butterworth. And it's a fascinating question. If a baby has had photo.

Yeah, please.

Daphna Barbeau (1:00:39.163) Hmm.

Ben Courchia MD (1:00:47.99) Obviously you don't do transcutaneous measurements once photo began, but they said once you stop it and you're going to get that rebound, could you just get a transcutaneous instead of a serum? And I read this and I'm like, definitely I was going to like this. And, um, and so that's the question they asked. Um, it's a prospective comparative study done at the princess Royal maternity in Glasgow in Scotland, which is a large tertiary obstetric unit. And they looked at babies that were born beyond 35 weeks of gestation that were more than 24 hours of age. Um,

And they basically measured rebound bilirubin after phototherapy about 12 hours after it was stopped. And they did a coincidental serum level at the same time. They did, I think it's important for us to measure to mention the device that they're using. They use the Billy care device from that's manufactured in Israel. It's one I'm not familiar with, but again, it's if you're going to take that data, you might be inspired to know which devices they were using.

And interestingly enough, that device says that they should measure the billy on the ear, in the helix of the ear, which is not where we usually measure it with our bilirubinometer, I guess, whatever we call this. And so that's pretty much the design of the study. They recruited 100 neonates, median gestational age 37 weeks, median weight at birth 3,200 grams.

And the median age at testing is about 109 hours. Six of these neonates weekly direct Coombs positive test. And so the timing at which they did these rebound bellies were about six to 22 hours of age. Sorry, six to 22 hours after stopping phototherapy. They looked at both the helix of the ear and they also looked at the earlobe. Interestingly enough, and I'm surprised they mentioned this in the paper, they're like, the nurses say it works better on the earlobe. So we tested that anyway.

I was like, it's unny, right? That's exactly right. So they said that on the Helix, the TCB tended to underestimate bilirubin with a mean difference of about 50.1 micromoles per liter, which in milligram per deciliter is about 2.9. Because I think for me, the micromoles don't mean much. I'm thinking of bilirubin always in milligrams.

Daphna Barbeau (1:02:45.851) You gotta know your audience, right?

Ben Courchia MD (1:03:09.91) So 50 micromoles, about 2.9 milligrams per deciliter. When they looked at the earlobe to maybe cater to their nursing staff, it overestimated the bilirubin compared to the serum by a mean of 13 micromoles, which is about 0.8 milligram per deciliter. So the nurses may have been onto something right there. The Helix TCB resulted in the same clinical outcome as serum billies 77% of the time.

And when they looked at the earlobe 60% of the time. None of the neonates required recommencement of phototherapy assessed by serum Billy. The TCB was always within about 30 micromoles of the intervention line, which is about 1.8 milligram per deciliter. And what else? What else can I tell you? Adding 120 micromoles, which is about seven milligram per deciliter to the helix TCB value.

and only undertaking serum in those babies for whom the total result fell above the intervention line would have safely avoided invasive serum measurements in 51% of babies. So I don't think it's data that changes much for me tomorrow, but I think it's starting to ask the question that we all would like to ask, which is, do we really need to stick these babies? And I think just like the new phototherapy recommendations from the AP say, well, if the difference is this much, then you should confirm with a serum. Maybe we'll define a range where we can say, all right, if...

Yeah.

Ben Courchia MD (1:04:35.798) Within this range, you're fine. Don't get a serum. Above this range, get a belly. And so the conclusion are that TCB is variably inconsistent with the serum belly following phototherapy in well neonates for at least 35 weeks of gestation with no demographic factor predictive of the degree of inconsistency. And they're saying that adopting a general safety margin of 120 micro moles, which is seven points basically on milligram per deciliter, has the what? That's a lot.

That is generous. That is generous.

It's generous, has the potential to have the invasive blood test monitoring of rebound hyperpulary aerobinemia. And that the recommend of phototherapy is already very uncommon in this population. So, but you know, why not? Like, what does it cost to see? Maybe it is way, way down and maybe you can, and it takes time to, I mean, I don't know, for some of you, it may be very quick to send a serum and get it back. Sometimes it frustrates us because the one kid that's waiting for discharge is the one sample that somehow finds its way in the cafeteria.

Yeah.

Daphna Barbeau (1:05:34.939) Got lost in the land. Yeah, that's right.

Right. It's like of all the tests I need today, this is the one I really need to make a decision. And it's like, well, we're going to, we're going to look for it, doc. We're going to find it. And I'm like, great.

I really needed things.

Daphna Barbeau (1:05:50.011) I mean, just like the blood cast paper you did, we cannot underestimate, you know, 50% less, 75% less. I mean, those are all more episodes of poking kids, stress and pain and things like that. So, can't underestimate that.

There's a lot of papers coming out on phototherapy these days about like trying to measure phototherapy more diligently, knowing exactly how much we're exposing babies to and so on and so forth. So a lot of interesting reads, we'll post them on our Twitter account and yeah, no, but I mean, interesting stuff. All right, Daphna, what are we looking forward to?

Mm-hmm.

Daphna Barbeau (1:06:32.539) Well, we're looking forward to our big trips coming up here, obviously. They're gonna be a lot of fun. What did you want to mention?

I have something that I forgot to mention at the front of the show though. We're gonna, I mean, this is May, so technically this has now been three years that we've been doing the podcast. And so in order to celebrate this, yeah, May the 4th is I think, yeah. And I think in order for us to, in order to celebrate this, what we wanted to do was that we're gonna do a giveaway. It's gonna be a pretty special giveaway. And we were thinking about like, how do people enter the giveaway?

Uh-huh.

That's right. The fourth, right, is our anniversary.

Ben Courchia MD (1:07:04.822) We wanted to maybe ask a favor of our audience, which is if we put together online a little survey as to how the things you're liking from the podcast, things you would want to see more of, how do you feel about these new shows that we've been putting out with the more extended team, then that will be your entry into the giveaway. And there'll be a bunch of prizes. And this way, because to be fair, every time we tell people like this is how to enter, it's mostly so that we can keep track.

Mm-hmm.

Ben Courchia MD (1:07:33.974) We don't care about the reposting, not reposting, like all the stuff we used to do, but it was the only way for us to keep track. But this is also a good way for us to keep track and it actually will help us and help the content that we provide you. So look out for this. We'll post it on our social media accounts and then look out for the Delphi website with all the information for the reflections evening where we...

Mm-hmm.

Daphna Barbeau (1:07:44.123) Yeah.

Ben Courchia MD (1:08:03.807) We do a little bit of narrative medicine and looking for the trivia competition for fellows. And so this is going to be all very exciting. Tickets are selling and we're very happy to see that. Make sure you reserve your spot. And that's all I have for today.

I think those are some big things. We love getting feedback from the audience. This is a new way for us to do that. So I hope people will tell us what they're thinking, what they like, but what they'd like to see more of because we've always made changes to the show based on community feedback. So absolutely.

Mm-hmm.

Ben Courchia MD (1:08:37.238) Yeah, yeah. All right, enjoy PES for those of you who are remaining at PES today and tomorrow, and we will see you this week with more shows and another interview next week. Definitely have a good rest of your day.

Thanks, bye everybody.

Bye.

 

 

 

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