Hello friends đ
In this episode of The Incubatorâs Journal Club, hosts Ben and Daphna open with exciting announcements, including details on the upcoming Delphi Neonatal Innovation Conference and new video content for their âBeyond the Beepsâ series on YouTube. They also share updates on the Board Review Podcast, geared toward both board preparation and ongoing learning in neonatology.
The teamâs first paper discussion highlights the ECLA trial from The Lancet, which examines higher versus lower CPAP levels for extubating extremely preterm infants. Ben and Daphna explore how higher CPAP may decrease extubation failure and the implications for clinical practice. Next, they review a large population-based study on intraventricular hemorrhage (IVH), underscoring the persistently high rates of IVH in very preterm infants and emphasizing its impact on neurodevelopmental outcomes.
They then welcome guest speaker Dr. Tim Barr from the University of Utah, who introduces the concept of end-tidal carbon monoxide monitoring as a noninvasive tool for detecting hemolysis and guiding bilirubin management. Dr. Barr explains how this method may help clinicians identify and treat high-risk neonates earlier. The discussion closes with a look at recent data on early hydrocortisone use in neonatal shock and a paper examining discrepancies between parental and medical classifications of neurodevelopmental impairment. Through in-depth research reviews and expert commentary, this episode showcases The Incubatorâs commitment to advancing neonatal care.
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The articles covered on todayâs episode of the podcast can be found here đ
Richter LL, Janvier A, Pearce R, Bourque CJ, Church PT, Luu TM, Synnes A.Pediatrics. 2025 Feb 1;155(2):e2024066148. doi: 10.1542/peds.2024-066148.PMID:Â 39786567
Rees P, Gale C, Battersby C, Williams C, Carter B, Sutcliffe A.JAMA Netw Open. 2025 Jan 2;8(1):e2452883. doi: 10.1001/jamanetworkopen.2024.52883.PMID:Â 39761048Â
Kidman AM, Manley BJ, Boland RA, Malhotra A, Donath SM, Beker F, Davis PG, Bhatia R.Lancet Child Adolesc Health. 2023 Dec;7(12):844-851. doi: 10.1016/S2352-4642(23)00235-3. Epub 2023 Oct 27.PMID:Â 38240784Â Clinical Trial.
Dudeja S, Saini SS, Sundaram V, Dutta S, Sachdeva N, Kumar P.J Perinatol. 2025 Feb 13. doi: 10.1038/s41372-025-02222-3. Online ahead of print.PMID:Â 39948354
Bahr TM, Moise KJ Jr, Lowry K, Monson MA, Hammad IA, Goteti S, Ilstrup SJ, Vanasco P, Ohls RK, Christensen RD.J Perinatol. 2025 Feb;45(2):268-270. doi: 10.1038/s41372-024-02163-3. Epub 2024 Nov 14.PMID:Â 39543241Â No abstract available.
Christensen RD, Bahr TM, Wong RJ, Vreman HJ, Bhutani VK, Stevenson DK.J Perinatol. 2023 Dec;43(12):1541-1547. doi: 10.1038/s41372-023-01730-4. Epub 2023 Jul 19.PMID:Â 37468612Â Review.
Bahr TM, Shakib JH, Stipelman CH, Kawamoto K, Lauer S, Christensen RD.J Pediatr. 2021 Nov;238:168-173.e2. doi: 10.1016/j.jpeds.2021.07.008. Epub 2021 Jul 11.PMID:Â 34260896
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The transcript of today's episode can be found below đ
Benjamin Courchia (00:01)
Hello everybody. Welcome back to the incubator podcast. We are back this Sunday for a new episode of journal club. Daphna, how are you today?
Daphna Yasova Barbeau, MD (00:09)
I'm doing well. am coming back from a few days off, but you know, sometimes you, sometimes you forget how much you have to come back to when you're off for a few days. So catching up, catching up. How about you?
Benjamin Courchia (00:19)
Yeah. Catch.
I'm doing very good. Very excited to be back in the studio. And we have some very interesting articles to review. Let me see. have some announcements that we wanted to make today. A few things are coming down the pike for the Incubator podcast. So in case you missed the latest episode this week of Beyond the Beeps that came out this past Wednesday.
Just check it out. We're really experimenting with continuing to release the episodes the way you're familiar with them, but also adding a new video component so that you can watch these episodes on YouTube. If that's something that you prefer, something you're more comfortable with, then definitely check it out on the Incubator Podcast channel on YouTube. For those of you who are studying for boards or who are just lifelong learners,
The Board Review Podcast and Neonatology Review Podcast is back in full swing. We released a set of episodes, and we're going to be basically trying to go over some of the new questions. So just check that out. Then we're reorganizing the episode library so that it's basically all the episodes related to questions and specific systems will be aggregated together.
So definitely check it out if you have not done so already. We're very excited to announce the dates for the upcoming Delphi conference and our TEDx event. we're basically going to be 11 months away. And so the Delphi Neonatal Innovation Conference will take place in January 2026.
The dates are going to be January 26th, 27th, 28th. This is a Monday through Wednesday. And it will happen again in Fort Lauderdale. We're going to be in the same location as the previous event. Everybody was very excited about having a Neonatal Conference on Innovation in the Museum of Art. So we're going to just come back to this venue this year. It's a beautiful auditorium.
And actually, right after that, they're renovating the neighborhood anyway. So there's going to be a new green space right across from the conference hall. So this is very exciting.
Daphna Yasova Barbeau, MD (02:46)
Yeah, I mean,
we thought about moving, but people love the location so much because of the art museum, which is very unique and because of the surrounding neighborhood, lots to do if you're coming to visit Walkable. And yeah, they're putting in some exciting new things in that area, which will make the visit, I think, even easier for people.
Benjamin Courchia (03:05)
Yeah,
so the conference hall is beautiful. Then in between talks, people tend to just roam into the museum and watch some of and visit the museum and look at some of the art. And then the Las Olas Boulevard in Fort Lauderdale is full of very cool eating places. So people went and got some very good food. There's a wharf, there's a river walk. then people used, I think in the morning, a few of them actually ran.
If you run down the street, you end up at the beach and you can actually run on the beach. It's a perfect location, if you ask me. And the conference is growing, so we're very excited about that. But for now, until we outgrow the place completely, we will probably continue to host the conference there. A few more announcements, guess. Look out on our website. We are very excited to welcome...
Daphna Yasova Barbeau, MD (03:48)
That's right.
Benjamin Courchia (04:02)
Professor Huang from China for a special lecture. She's basically going to give a lecture on monitoring of cardiac function in extremely preterm infants. It's going to be a website only event where basically the video of her talk is going to be posted. Something Daphne and I are very passionate about trying to learn a little bit from people around the country, around the world, learning how they do certain things.
And that's kind what we did for Delphi, number one, when we brought Fumihiko from Japan, trying to learn a little bit about how do they do what they do. And I feel like there's a lot of politics involved. And so we're not really able to understand what kind of practice really China has. And it's interesting. I mean, I think we should be able as scientists and physicians to put politics aside and actually learn from one another. mean, the US and the West is very open about their practices, but
I feel like we're not getting back from China as much information. So we were very interested in learning from them. So thank you to Professor Huang for taking the time to record this lecture and sharing it with the incubator community on the website. We're going to try to continue to partner up with physicians from the Far East and trying to establish these bridges because that's what we're all about. So stay tuned for
More collaboration with our colleagues who are Mandarin speaking. Yeah, more coming soon. All right, we're going to get into Journal Club. have a special guest this week. Dr. Tim Barr is going to be joining us from the University of Utah. We're going to talk a little bit about hemolysis and end-tidal carbon monoxide. We thought it was going to be an interesting...
segment to record because Dr. Barr, because we have a Tech Tuesday episode coming up this week, specifically with the company that actually manufactures end-tidal carbon monoxide. so there's a lot of papers that have been published on the subject. And so we thought it would be nice to have this sort of preemptive discussion on the evidence with somebody who has published, Dr. Barr has published in the Journal of Perinatology and Journal of Pediatrics on this particular subject. And he is not
the point that he's not funded by the team that we're speaking to on Tuesday. So it's really looking at the evidence because the Tech Tuesdays are really talking about the devices and the solutions. But sometimes if there's good evidence behind it, it might warrant having that discussion separately. So that's what we're doing with Dr. Barr today. And I think that concludes the announcements and we can actually get into Journal Club. What do you think, Dafna?
Daphna is muted, but she's nodding along and for people, yeah, so she's in agreement.
Daphna Yasova Barbeau, MD (06:53)
I'm a game on game on
Benjamin Courchia (06:55)
Let's do it. The first paper I really wanted to review is a paper that was published in the Lancet some time ago. it's the ECLA trial, the Higher versus Lower Nasal Continuous Positive Airway Pressure for Extubation of Extremely Preterm Infants in Australia. It's a multi-center randomized superiority trial. First author is Anna Kidman. There's a lot of people on this paper that you may be familiar with. Second author is Brett Manley. Atul Malhotra is on it, Risha Bhatia is on it, Peter Davis is on it. So a very impressive group of people. And the thing is that this paper is a paper that I've been very interested in. We've reviewed it on the French podcast some time ago, but every time we thought we were going to talk about it on a variety of different special episodes that we were going to record, and these have been postponed, delayed, whatever that is. And we never really ended up talking about the A-Class trial. So I thought, you know what?
Let's just do it. Let's just talk about it because it's an important trial. The introduction is very interesting. think there's some statistics there about extubation and extubation failure that sometimes I didn't really grasp that kind of the magnitude of the issue. They're mentioning that as many as 60 % of infants experience extubation failure and require re-intubation and ongoing mechanical ventilation when we're talking about very preterm infants.
And we know why extubation failure happens, right? So if we're studying long immaturity as one component, poor chest wall compliance, an immature respiratory drive, and re-intubation is not benign. I think that sometimes in the unit, we tend to say, no problem. We fail, we'll re-intubate. Especially if we've gotten good at intubation, it feels very much like a benign type of process, but it is associated with physiologic instability. It's associated with upper airway trauma.
And extubation failure has been shown to be independently associated with both mortality and other morbidities, including BPD and prolonged hospital stay. Now, the authors are mentioning that after extubation, setting a higher level of nasal CPAP might help maintain expiratory lung volume and reduce the level of atelectasis. Now, there is no consensus on what is the optimal CPAP setting for
extremely preterm infants after they've been extubated. So what they try to do is to randomize, it's just to create a randomized trial comparing two groups of patients, those who would receive higher versus lower nasal CPAP levels to prevent extubation failure in extremely preterm infants within a seven day period after their first extubation. So it's a very interesting question. It's a very interesting, it's a very robust design trial. It's a multi-center
randomized parallel group open label superiority trial that took place at three tertiary perinatal centers in Australia. The infants were selected to participate in this trial based on their eligibility, which included being born before 28 weeks of gestation. Obviously, you had to be on mechanical ventilation via an endotracheal tube and you were extubated for the first time and you had to be extubated for the first time
two nasal CPAP, which I think that might be a bottleneck, but it's an important component. And they were very careful that all the infants that they were going to include in the trial had have received previously surfactant and caffeine. I think that was a very clever thing to do because obviously if a baby had not received caffeine or surfactant and failed extubation, you might say, but maybe if you had given these medications, it could have made the difference. So anyway.
They were all covered from that standpoint. They excluded babies who were being extubated to any mode other than nasal CPAP. So if you went on an IMV, were not eligible for this particular trial. Any major congenital anomaly affecting breathing or if you were being extubated because you were going to stop intensive care. Obviously, these are not the types of patients that were entered into this trial.
In terms of the procedures, these units are NICUs that practice volume targeted ventilation. Their goal is to extubate babies as soon as possible. They have a standard pre-extubation management that includes caffeine within 24 hours of extubation, aiming for tidal volume between 3.5 to 5 ml per kilo and immediate pressure of about 10 centimeters of water. And then for them, there's really no...
ladder to come off invasive support, meaning if a baby is on high frequency, they can be extubated to CPAP from high frequency. Now, the decision and the timing of extubation, that was left at the discretion of the clinical team. And they're very clear about the fact that there were no clinical extubation criteria pre-specified in this trial protocol. Now, the infants received their assigned CPAP level immediately after extubation. And basically, babies were randomized to two groups.
So the infants who were assigned the higher CPAP group, they were extubated to a CPAP level of 10. And for the first 24 hours after extubation, they had to remain within a range of 9 to 11. So they could tweak the CPAP by plus minus 1, but they really had to stay within that narrow range. After 24 hours, the CPAP could be altered within the assigned range or win below the assigned range or stopped altogether if that was not deemed to be necessary. At the discretion of the treating team,
but they could not exceed 11 centimeters of water for a seven-day period after extubation. If the infants were re-intubated, that means that they satisfied what they described as their extubation failure criteria. The other group was assigned to be on a CPAP level of seven. Same protocol applied. They had to remain within a range of plus minus one, so six to eight. And again, they could not exceed eight for seven days.
of centimeters of water for seven days after extubation. Otherwise, they would have considered that failure. Now, the primary outcome of the study was extubation failure within a seven-day period after extubation. So, how do we say that we met extubation failure? I think the criteria, you'll listen to them and you'll say maybe they're a bit rigid, so pay close attention. Extubation failure was defined as an infant receiving the maximum
permitted CPAP level, so 11 if you were in the high CPAP group or 8 in the standard group, and meeting at least one of the following criteria. So you had to be capped out at your CPAP level and plus one of the criteria. Criteria number one is probably one of the most stringent ones, an FIO2 of 20 % or more above the FIO2 before extubation.
if you were on 21 % FIU2 before being extubated and you were now on 45 % post-extubation, you were meeting criteria. That's something we see fairly frequently. That's pretty stringent. The rest, I think, were pretty self-explanatory. A pH less than 7.2 with a partial pressure of CO2 that was above 60 on blood gas. Number three,
more than one apneic episode requiring intermittent positive pressure ventilation within a 24-hour period or six or more apneic episodes requiring stimulation within six consecutive hours. And finally, four, an urgent need for re-intubation. Duh. Okay. Now, the expectation was that babies who experience what's defined as treatment failure would be re-intubated if infants were escalated, meaning maybe you say,
The kids on CPAP, I don't want to re-intubate, I'm going to put them on an IMV. If you go to an IMV, they were considered to have gone through extubation failure and these babies were meeting the primary outcome. So they had some pre-specified secondary outcome that they looked at. I think none of these are surprising. They looked at BPD, defined as a requirement for supplemental oxygen or respiratory support at 36 weeks post-menstrual age. They looked at the duration of mechanical ventilation.
any respiratory support after trial entry in days, they looked at the duration of oxygen supplementation, they looked at the length of stay, they looked at necrotizing enterocolitis, they looked at severe IVH, they looked at retinopathy of prematurity, and finally, they looked at mortality death before discharge. Because we're talking about high CPAP levels, they also had some serious adverse events, outcomes that were predefined. Pneumothoraces was one of them requiring drainage via thoracocentesis or intercostal catheter.
They looked at the development of pulmonary interstitial emphysema. They looked at spontaneous intestinal perforation and death within seven days after randomization. Everything was done on an intention to treat basis for all the outcomes. So I think that that covers pretty well the methods and let's go into the results. the study started in March 3rd of 2019.
And they had some, as I'm going to quote the paper, they said, after several unavoidable pauses in enrollment due to COVID-19 pandemic, the trial basically was halted by the steering committee on July 31st, 2022. So about three years later. So it's not like they had to stop six months into it, but I think that's an important point. I'm going to spare you all the different selection, but 139 infants were enrolled.
Daphna Yasova Barbeau, MD (16:09)
No.
Benjamin Courchia (16:34)
70 in the CPAP group that was higher and 69 in the standard CPAP group. Now the baseline characteristics for these infants are interesting. Obviously there's a high rate of antenatal corticosteroids exposure. Most of the babies were born via C-section and the mean gestational age was 25.7 weeks and the mean birth weight is 777 grams. So we're not talking about big babies. Okay, let's talk a little bit.
about the outcome of interest. Extubation failure occurred in 24 infants. So the extubation failure occurred in 35 % of the higher CPAP group compared to 57 % in the standard CPAP group. That was statistically significant. So a 22 % difference between the groups in the rates of extubation failure. Now the number needed to treat was five, meaning that
meaning that five infants needed to receive a higher CPAP instead of the standard one to actually prevent extubation failure, which is not a very high number needed to treat. mean, this is pretty impressive. Now, they did a test of interaction between gestational age subgroups and it was not significant, indicating that there's little evidence for a differential effect of CPAP level by gestational group. this basically, it didn't really matter how pre-me...
the groups were. Extubation failure was less common with higher CPAP in both the higher and the lower gestational age group. Extubation failure was less common, right? That's what I said. Yeah. The most common reason for extubation failure, obviously, like we discussed in the methods, was the increased supplemental oxygen requirement. I mean, that's not really surprising. Obviously, any baby that has a 20 % increase in their RFI O2, if that...
that means you meet the requirement, then yeah, that was the most common reason. In the higher CPAP group, apnea and higher supplemental oxygen requirement were the most common cause of extubation failure. And they are showing that the extubation failure, even though they were looking at this over seven days, it was most likely to occur during the first 72 hours after extubation in either group. And there were no significant...
So as we're looking at some of the secondary outcomes, we're talking about minuscule numbers. So the rates of NEC were seen to be six babies in the higher CPAP group versus only three in the standard CPAP group. This is obviously not significant, but it's obviously 9 % of one cohort versus 4 % of the other cohort. And similar sort of difference was seen for spontaneous intestinal perforation.
But not so much for pneumothoraces. mean, two in the higher CPAP group, one in the standard CPAP group. So I think that was quite interesting. Now, during the primary outcome period, protocol deviation occurred in 11 % of infants. These infants had their CPAP increased above the prescribed maximum CPAP level for their treatment group or were changed to an IMV. And all of the infants in whom this protocol deviation occurred, they ended up requiring intubation. So they met the primary outcome.
So that's pretty much it for this study. The conclusion are that despite so many advances in our care, extubation failure rates in extremely preterm infants remain quite high in the case of this paper. mean, if we think about it, mean, 35%, we said, versus 57%. I mean, it's quite impressive numbers. And this trial found an important reduction in extubation failure in this
high risk population using a higher standard CPAP level compared to a lower one. And again, it didn't really matter whether the babies were smaller or older. There was not much difference. And again, I just want to make sure I don't know if I mentioned this, but extubation failure within seven days stratified by gestational age group, they looked at babies that were 22 to 25 weeks and there they saw that. Are you okay, Dafna?
Daphna Yasova Barbeau, MD (21:23)
Okay, sorry about that.
Benjamin Courchia (21:23)
It looks like some
explosive went off. But the 22 to 25 group saw 56 % extubation failure in the CPAP of 10 group compared to 69 % in the standard group. And when we're looking at the 26 to 27 week of gestation, then the difference is even more pronounced. 16 % failure in the higher CPAP group versus 42 % in the standard group.
Daphna Yasova Barbeau, MD (21:26)
No, it's just carry on. I'm excited about the findings. That's what's happening.
Benjamin Courchia (21:52)
Yeah, a very interesting paper, something that could have dramatic implications at the bedside right now. I know this is a paper that's nominated for Impact Article of the Year by the EB-NEO team. So yeah, very interesting paper for sure.
Daphna Yasova Barbeau, MD (22:06)
Well, that's what I was going to ask. I mean, I think you are already practicing this in a way, but how do you think this changes what you're doing for babies, big and little, I guess.
Benjamin Courchia (22:17)
Yeah, I think that sometimes we tend to extubate number one babies to NIMV, but number one, we can see that we can potentially extubate to CPEP. That's a good reminder of that. Number two, the delivery of positive and expiratory pressure through an endotracheal tube is much more effective than through a nasal mask or through nasal prongs. So there's definitely, in my opinion, there always needs to have some form of correction factor where you have to increase a little bit.
Daphna Yasova Barbeau, MD (22:29)
Mm-hmm.
Benjamin Courchia (22:47)
the PEEP in order to maintain that same positive and expiratory pressure. But what's interesting about this is that for the purpose of preventing extubation failure, if you just say, for 24 hours, we're going to do, we're going to go to a CPAP of 10. And then you can actually try to win. mean, you can decide if you want to follow their protocol or not, but at least for 24 hours maintain recruitment at all costs. I think that's something that you can apply directly. And I think there's a lot of PEEPophobia, as we say in the NICU.
Daphna Yasova Barbeau, MD (23:16)
haha
Benjamin Courchia (23:17)
of
like, I'm not going to go above seven. I'm not going to go above eight. Remember, these were babies extubated standard to CPAP of 10 with the caveat that they like, you could go to 11 and there's lots of data to show that CPAP of 10, 11, 13, 14 rarely has a negative effect on cardiac function. I think that's the biggest concern, but you can potentially do this safely. And I think that at the end of the day,
I'm always very much weary of doing something like the same for everybody. But as a starting point, extubate to a higher CPAP level and then assess your patient. Some babies will have issues with higher CPAP. Some may not, but then treat the baby. Treat the baby. Just, yeah.
Daphna Yasova Barbeau, MD (24:00)
Yeah.
abdominal distension, things like that. Yeah, yeah, that's right.
Yeah, you know, I think when we trained, there was a threshold in every unit that like, if you had to get to this peep, then you had to intubate. And I think at least maybe we can move away from that dogma. And like you said, yeah, there's some babies. We can't treat every baby the same. And it looks like we could probably start a little higher for everybody than we previously thought. Very interesting paper.
Sorry for my excitement over here.
Benjamin Courchia (24:35)
I
was actually looking at my notes so I don't know what happened. I just heard the boom.
Daphna Yasova Barbeau, MD (24:40)
There
was a domino effect here on my desk, but it's okay. Okay. I had this paper, JAMA Network Open, entitled, Intraventricular Hemorrhage and Survival, Multimorbidity and Neurodevelopment. Lead author, Philippa Reiss, senior author, Alastair Sutcliffe. This is coming to us from the UK.
And they basically wanted to look at this question, which has been asked before and I think concerningly has been, we were trying to answer, know, we were making all these advances in neonatal care, just like you said about your last paper, are we changing the rates of IVH themselves? Are we changing the survival or are we changing their neurodevelopmental outcomes? So this was a population cohort study and they use the data from the UK National Neonatal Research Database.
So infants born less than 29 weeks gestation with any grade of IVH between January, 2013 and December, 2019 in England were included and matched with controls. Just a reminder of how awesome it is to have these whole population-based cohorts. Then they did the data analysis and then infants were followed up for neurodevelopmental evaluation at two years of age.
And they wanted to look at the functional outcome data for those surviving infants. So like I told you, all extremely preterm infants with any grade of IVH one through four identified on imaging born at less than 29 weeks of gestation were included. They have the routine process for ultrasound in UK neonatal units in the first days of life. And then they use the Papille classification.
They use the highest recorded IVH grade and they split them basically into two groups. Grades one and two were classified as low grade and grades three and four were classified as high grade. And infants with IVH were then matched one to one to preterm infants without brain injury using propensity score matching. They accounted for gestation, birth weight, Z-score, sex, mode of delivery, multiple births, maternal smoking status, receipt of antenatal steroids,
recede of antenatal magnesium sulfate and birth year. Okay. So what did they want to look at? I told you they were interested in looking at neurodevelopmental impairment. So the primary outcome was survival without severe neurodevelopmental impairment at two years corrected age, including a severe developmental delay, inability to understand words or signs, inability to use more than five words or signs, being unable to walk, sit or use hands.
blindness or uncorrectable hearing impairment. Secondary outcomes included gross and fine motor function, receptive and expressive communication, overall development, visual impairment and hearing impairment. Okay, so they wanted to look at a number of developmental outcomes. So of the 26,700 infants live born at less than 29 weeks during that time period,
8,461 received a diagnosis of IVH and were included in these estimates. There were about 5,500 with low grade and about 2,800, almost 2,900 with high grade IVH. And of these, 98 % with IVH survived beyond 24 hours and they had 89 % match controls included in the analyses. So.
I told you they had about 5,500 infants with low-grade IVH. They had a median gestational age of 26 weeks. They were 44 % male. They had a maternal age of 30. And then their matched controls, like I said, were pretty similar. They had 2,800 infants with high-grade IVH. median gestational age was 25 weeks, 60 % male.
the mean maternal age was 30 weeks. And they had similarly matched controls. And then the primary outcome data was available for 78, almost 79 % of infants. All right. So let's get into the results. The mean incidence of high grade IVH, that's grades three and four, was 6.7 per 1,000 live extremely preterm births.
And there was an increase in incidence between 2013 and 2019, but this difference was not statistically significant. And when excluding infants born at 22 to 23 weeks, so lots of people think, the increase in IVH must be due to the smallest babies that we're now resuscitating, the incidence still showed an increase, but again, not statistically significant. The mean incidence of low-grade IVH
was 10.4 per 1,000 live preterm births. And this increased slightly during the study period. And the increased incidence was attenuated when restricting to infants born at 24 to 28 weeks. So it increased over that time period, but was less of an increase when you took out the smallest babies, 22 to 23 weeks. So then they wanted to look at survival and its effect on neurodevelopmental impairment.
They looked at these group of babies that has survival without severe neurodevelopmental impairment. So infants with high grade IVH had a 74 % reduction in survival without severe neurodevelopmental impairment compared with controls. This is an adjusted odd ratio of 0.26. So they were less likely to have survival without severe neurodevelopmental impairment, which is not surprising. The absolute crude risk of surviving without neurodevelopmental impairment was 32.7%.
for those with a high grade IVH compared to 60 % for controls. So I'm going to say that again, this is survival without severe neurodevelopmental impairment, 60 % of controls, so those babies without IVH had survival without severe neurodevelopmental impairment. It wasn't 100%, was 60%. And it was about 33 % for those with high grade IVH.
And of those with high grade IVH who survived, the subsequent absolute risk of severe neurodevelopmental impairment was 44 % compared with 20 % of controls. Now those infants with low grade IVH had a 12 % reduction in survival without severe neurodevelopmental impairment compared with controls. So they had lower rates of survival without impairment, but not as low as those babies with high grade IVH.
The absolute risk difference though was small and most survivors with low grade IVH had no neurodevelopmental impairments. Of infants with high grade IVH and infants with low grade IVH, so 67 % of those with high grade IVH and 36 % of low grade IVH, it was still a very high number that died or had severe neurodevelopmental impairment at two years corrective age.
Not surprisingly, there was a stepwise reduction in the likelihood of surviving without severe neurodevelopmental impairment by each grade of IVH. So there's no major difference for grade one. There was a 25 % reduction in survival without severe neurodevelopmental impairment after a grade two.
Benjamin Courchia (32:33)
the auto transcript function is going to have a hard time with.
Daphna Yasova Barbeau, MD (32:39)
I'm managing, I'm working. There was a 56 % reduction after grade three and an 82 % reduction after grade four IVH. So overall, the absolute risk of surviving without severe NDI was 70 % for those with a unilateral low grade IVH compared with 60 % for those with bilateral low grade IVH. So they did find some difference in laterality.
Benjamin Courchia (32:41)
Yeah
Daphna Yasova Barbeau, MD (33:08)
And then they wanted to look at, again, high-grade. Those are the babies we are most concerned about. So did it matter if they were unilateral or bilateral? The absolute risk of surviving without severe NDI was 54 % for those with unilateral high-grade IVH compared to 33 % for those with bilateral high-grade IVH. And I think this is a really important key piece of this paper, that the unilateral versus bilateral matters.
And I think a decade ago, we didn't really take that into consideration. There was also a trend toward an increasing absolute risk of surviving without severe NDI with each additional week of gestation from 12 % at 23 weeks, all the way to 44.5 % at 28 weeks for those with high grade IVH.
What are some of the other outcomes of those with high grade IVH? 13 % developed post hemorrhagic ventricular dilation. 5 % had a VP shunt inserted and 12 % went on to develop cystic periventricular leukomalacia. In my opinion, these are also lower rates than previously, not in my opinion, these are lower rates than had previously been reported. And in my opinion, this is something that the community thinks will happen to all babies with high grade IVH, but.
It's obvious that it does not. They looked at the other major morbidities, so high grade IVH, BPD, severe ROP, and surgical neck. And each major morbidity significantly and independently reduced the likelihood of survival without severe neurodevelopmental impairment. And there were no significant interactions between morbidity pairs. So if a baby had severe IVH plus another morbidity, then they again had a lower likelihood of survival without severe neurodevelopment.
I'm going to do just a few more kind of finer details about NDI. So compared with control survivors of high grade IVH had a 70 % increased odds of mild developmental delay. This is an adjusted odd ratio of 1.7, a 174 % increase in odds of moderate developmental delay and adjusted odds ratio of 2.74 and more than five times the odds of severe developmental delay and adjusted odds ratio of 5.4.
Survivors of low grade IVH had an increased risk of severe developmental delay in adjusted odds ratio of 1.38. But the majority of survivors of low grade IVH had no developmental delay. They looked at gross and fine motor. So surviving infants with high grade IVH had substantial increases in both gross and fine motor impairment at two years corrected IVH across the spectrum of severity. Almost one half of children with high grade IVH
This is about 45 % had some difficulty walking compared with 11 % of controls. And gross motor impairments were more prevalent than fine motor impairments. This was seen in low grade IVH. They had this increased risk of gross motor impairments compared with controls, but far less prevalent than in high grade IVH. Communication, communication difficulty was common in both the high grade IVH
group about 49 % in the high-grade IVH compared to 36 % in controls. There was an increased risk, I told you, and adjusted odds ratio of 1.74. There was increased risk of both receptive and expressive communication impairments across the spectrum of severity after high-grade IVH. Compared to infants with low-grade IVH, they had increased risk of some expressive communication, but
less so in receptive impairments. again, regardless, the absolute risk difference between those with low grade IVH and controls were small. Vision, infants with high grade IVH had increased risk of any visual impairment and adjusted odds ratio of four and a visual impairment that was not fully correctable and adjusted odds ratio of 5.82 compared with controls. Although most surviving infants with high grade IVH did not have any visual impairment. So nearly 70 % didn't have any visual impairment.
Complete blindness was rare in any group. And infants with low-grade IVH had an increased risk of visual impairment and adjust odds ratio of 1.48, but again, the absolute risk was small. And they did not have increased risk of more severe visual impairments. There were some differences in hearing, increased risks of any hearing impairment and uncorrectable hearing impairments were seen after high-grade IVH, but these were rare. And there were no increased risks of hearing impairment seen after low-grade IVH.
So the overall take home message is that both low grade and high grade IVH is increasing still a little bit over time. I think we'd hope that it was stagnant or improving. However, I think having these developmental follow-up is super valuable about how we counsel families. I think it was
tricky to include grades three and four together, but that's what they chose to do. And I think especially this piece about unilateral versus bilateral IVH
Benjamin Courchia (38:40)
No, thank you for reviewing that paper. I mean, I think that it echoes another paper that we reviewed a few weeks back on the podcast that the rates of IVH are not coming down. I think the BPD community wants to have the monopoly on, our morbidity is the one that's going up. Everything else is going down, but it may not be true. I also think what's important for people is that there's an easy cop out in neonatology where you say, it's going up, but we're saving a lot more.
Daphna Yasova Barbeau, MD (38:56)
That's right.
Benjamin Courchia (39:09)
sicker babies or whatever. In this particular cohort, the this is a very modern cohort and it is not so historical that it includes the 1980s or anything. It's really 2013. So this is on us. Like there's no there's no there's no wiggling out of the fact that it is on the on the rise. And while, like you said, it's not like the slope of the curve.
Daphna Yasova Barbeau, MD (39:24)
Agreed. Yeah.
Benjamin Courchia (39:39)
is still relatively flat, which is quite good. But you are seeing that the increase incidence of low grade IVH is there. And then figure two is such a good picture. mean, that's a picture you probably save on your phone, show to parents, because it does show you how very nicely, in stepwise fashion, how basically
Daphna Yasova Barbeau, MD (39:44)
That's right.
Let's see.
for sure.
Mm-hmm.
Benjamin Courchia (40:08)
Number one, I really like this figure. I've been looking at it like the whole time you were speaking, because it's such, right, you see number one that as I've.
Daphna Yasova Barbeau, MD (40:15)
Yeah.
And that figure does go by grades of IVH, one, two, three, and four.
Benjamin Courchia (40:20)
Yeah,
so you have coordinates, you have on the y-axis, you have the imputed adjusted odds ratio, on the x-axis, you have the IVH grade, and you have four dots showing that with grade one, grade two, grade three, as you increase in the grade of IVH, the odds ratio of surviving without severe node impairment goes down. What's even more interesting,
is that we have these error bars around each point. And you can see basically that the level of confidence with which that data evolves as you go up with the grades of IVH basically shrinks. And so the odds, the error bar for a grade for IVH being associated with severe and other mental impairment is very narrow. Grade one is probably the widest of them all. Again, showing that while a grade one is probably the least
probably the best one, the better one to be dealing with, there's still some uncertainty as to what are going to be the potential ramifications, something that the literature has shown before. So a very, very interesting paper and showing that there's a lot of good work that needs to continue to be done in order to stave off IVH. Also,
take a look at table one, re-looking at some of the maternal characteristics, because we never talk too much about which are, like maybe we say that the babies are quite the same in terms of their gestational age and their birth weight, but are the mothers the same? Are we making strides in allowing some mothers to carry through closer to term out of the prematurity window? And who are the mothers who are still stuck in this window of delivering early?
Daphna Yasova Barbeau, MD (41:53)
Right.
Benjamin Courchia (42:14)
And maybe that has an impact that could be addressed prenatally even. I think that's something that to me is worth looking into. All right. We're going to take a quick break. We're going to come back with Dr. Tim Barr. see you in just a minute.
Benjamin Courchia (42:58)
We are joined today by Dr. Barr. Timothy, thank you so much for joining the podcast today.
Tim Bahr (43:05)
Great to be here, thanks Ben.
Benjamin Courchia (43:07)
Of course, you're an assistant professor in the division of neonatology for Intermountain Health and you have a faculty appointment at the University of Utah. We know all the great work that has come out in the field of neonatal hematology from your institution, whether it is the work done by, I think, your close collaborator. I don't know if you consider him your mentor. I don't want to leap, but Dr. Robert Christensen.
Tim Bahr (43:30)
I was trained by Bob.
Benjamin Courchia (43:34)
And Robin Oles also is, mean, Utah is the place to be if you are interested in neonatal hematology. So what we wanted to talk about today, you have a brief communication published in the Journal of Perinatology. It came out on November 14th, a couple of weeks ago, and it's called, Duration of Hemolysis Among Infants with Hemolytic Disease of the Fetus and Newborn. And in there, there's
obviously mention of end-tidal carbon monoxide measurements. really reading this paper, it really sent me down the rabbit hole of trying to understand a little bit what is the value of end-tidal carbon monoxide in the diagnosis and in the management of hemolytic disease of the newborn and babies, obviously, that may have hyperbilirubinemia. There's a lot of papers that have been published on this. And it's so funny to me that as I read this brief communication and then went down the rabbit hole, you see more and more papers I had not noticed.
that this really was something that was studied. guess the first question that I had for you was what is the physiologic basis for using carbon monoxide production as a marker of hemolysis? And maybe how does that even compare? Because what we are familiar with is the traditional maybe DAT or Coombs test. So how does that differ? So can you tell us a little bit about that?
Tim Bahr (44:52)
Yeah, absolutely. Billy Reuben is a product of heme, which is a product of hemoglobin. And I often say that our red blood cells are a sack of hemoglobin. They're primarily designed to carry oxygen. So when a red blood cell lysis or dies, it releases that bag of hemoglobin and the heme is separated from the hemoglobin molecule. And then the first step in heme metabolism is heme.
is metabolized by hemoxygenase into biliverdin. And one of the byproducts of that is a molecule of carbon monoxide. And then the next step is bilirubin. So the great thing about studying the production of carbon monoxide in the human body is for every molecule of carbon monoxide that is produced in the human body, you also know that one molecule of bilirubin was produced, so in equimolar amounts. And so
Primarily the only way to get rid of carbon monoxide is in the exhaled breath. And so when we measure the exhaled carbon monoxide or the end tidal carbon monoxide, we are essentially measuring roughly in an equimolar amount heme product, or I'm sorry, bilirubin production and hemolysis.
Benjamin Courchia (46:10)
That's very interesting. so obviously, based on what you're describing, there is potential to measure even carbon monoxide levels from the blood. Obviously, this would be traumatic for the infant. And so I think there's a kind of an interest in trying to use an end tidal form of measurement because it's non-invasive, can potentially provide some valuable information.
Tim Bahr (46:32)
Absolutely, yeah. Like you said, it's not a blood test. when we use the devices we have, it's a single pronged nasal cannula. It looks just like an oxygen nasal cannula that goes in the nose of the baby and no blood. So it has a CO2 detector that measures the title, the breaths of the baby, and then it's sort of the end title carbon monoxide that's sampled in the device.
Benjamin Courchia (46:56)
Yeah, this is a very cool device. is FDA approved. And then we're going to have a separate episode of Tech Tuesday where we're going to talk to the president and the directors of this company so that they can tell us more about the tech aspect of it. And we'll try to focus a little bit on the medical and pathophysiology portion of end tidal carbon monoxide measuring during this episode. Interestingly enough, as I was reading more paper, you've published you yourself with your colleague and Dr. Christensen on this subject.
And there was a very interesting paper in 2021 that your team released in the Journal of Pediatrics. The paper is called Improvement Initiative entitled Comparative Monoxide Measurements in Newborn Receiving Phototherapy. I think what's interesting about this technology is that potentially it could be a good marker for hemolysis. And that's really what we all fear, right? mean, think it, I mean, the reason I was interested is because it plays
to my fear of like, I'm so afraid of this baby that hemolysis constantly and that the bilirubin goes so high, so fast, and then I have a hard time catching up. What has been your experience in utilizing end tidal carbon monoxide measurements and how that has allowed you to stay maybe even a bit ahead of hemolysis or not? don't know, but because that's what it, to me, that's what it feels like the big appeal is obviously.
Tim Bahr (48:16)
Yeah, you're right, Ben. We sort of hypothesize, we really think that the kids that get in the most trouble are the aggressive hemolyzers when it comes to bilirubin neurotoxicity and kernicterus. And that's the whole reason why bilirubin screening is universal. So in our data, and as far as we can tell, it's really the...
the kids that have hemolytic conditions that end up with kernicterus. I don't think, except in rare cases like curriculum HR, I think the kids at greatest risk are the hemolyzers. So our ability to quantify or to detect hemolysis, I think is important, like you said. The two clinical contexts that we have been successful in utilizing, end tidal carbon monoxide in our first sort of the newborn nursery, a widespread screening and...
that paper that you mentioned, Journal of Pediatrics, was where we implemented a program at the University of Utah, Newborn Nursery, where we screened every baby that met a threshold for requiring phototherapy. Asterix, Asterix, this is on the previous hyperbilirubinemia guidelines from AAP.
Benjamin Courchia (49:29)
The 2004 I believe, right?
Tim Bahr (49:31)
So we would capture about 8 to 10 % of the babies. We would do N-tidal carbon monoxide. And we saw some pretty good signal between the association between N-tidal carbon monoxide level and duration of phototherapy, know, max bilirubin length of stay. And then all of our babies that got readmitted in that cohort, I'm sorry, I can't remember the sample size. There were three babies that got readmitted.
due to hyperbilirubinemia, all three of them had an end-tidal carbon monoxide that was elevated.
Benjamin Courchia (50:04)
Your
cohort at the time was 170 infants. Thank you. Yeah, no, for sure. For sure. And there's another very interesting article in the Journal of Perinatology talking about specifically n-tidal carbon monoxide and talking about what are the gold standard tests for diagnosis of hemolysis. And so in theory, it makes so much clinical sense that this would be a great test. However, when we are looking at the data,
It's not a direct proxy that will give you all the information you would love to have for every baby. so there is this number, the N-tidal carbon monoxide is measured in parts per million, and there seems to be this level of 1.7 that people use as a marker of if it's above that, it's kind of concerning for hemolysis if it's below that, so. And in your study, what was found was that N-tidal carbon monoxide
was associated, an elevation by one part per million was association with phototherapy being initiated earlier and phototherapy being needed for a longer amount of time. However, it did not correlate with the rate of total serum bilirubin increase after cessation of phototherapy as well. So it does have some limitations. I'm just wondering if in your experience, what has been some of the areas where you found the limits of end tidal carbon monoxide or maybe some of the pressure points from the tech just being in its early phases.
Tim Bahr (51:37)
Yeah. So like I said, I think the first one, we do think that there is value for risk stratification of babies that are in the newborn nursery that are being discharged within 24 hours and may have some risk of hyperbilirubinemia. So I think we've all been shocked sometimes with that kid that gets readmitted at three days with a bilirubin of 25. And when we discharged him at 24 hours or 36 hours, the bilirubin was seven.
You know, our ability to predict which kids are going to bilirubin is poor. And I do think there is good evidence to suggest that, or good evidence that high bilirubin producers, those who are hemolyzing, have a high end-tidal carbon monoxide, are at greater risk of developing severe bilirubin or neurotoxic bilirubin. The second area that we use the device is in HDFN.
so hemolysis of the fetus and newborn and alloimmunization. our more recent efforts and we have some more funding coming in so that we can do this more widely is we follow about 150 babies a year in Intermountain Health who are born to mothers who are alloimmunized. And the shocking thing about that disease is the heterogeneity of the disease. And so we're trying to study how long do these kids hemolyze.
because sometimes they humanize for a couple days and sometimes they humanize for months.
Benjamin Courchia (53:06)
That's something you mentioned in your paper about we don't really know this duration of hemolysis. I mean, we sort of have some theoretical idea of like how long these immunoglobulin can stay in the baby system. how does that actually translate into a duration of hemolysis sort of phase? Yeah, we don't know.
Tim Bahr (53:22)
Yeah, yep. our ability, like I said, just sort of like, you know, the well baby nursery hyperbilirubinemia baby of whatever cause is very difficult to predict. Likewise, our HDFN kids born to allot immunized mothers, also very difficult to predict how long they're going to, going to hemolyze. So we're trying to get a better idea of the duration and maybe there's other markers that we can use to predict how long they're going to hemolyze and how closely you need to watch those kids.
Benjamin Courchia (53:47)
Interesting, interesting. And then, so I wanted to also clarify something. We won't talk too much about the machine themselves. You are not a consultant or paid by the company. So we're just here to talk about the pathophysiology and the potential use. It was interesting to me that the 2022 AAP guidelines for phototherapy did sort of make a note of n-tidal carbon monoxide. And to be honest with you, I had to go back and see it because
It was not one of the bold key opinion statements, but it did mention if available measurement of enteral carbon monoxide production is a potentially useful method for quantifying hemolysis. So I was quite surprised to see it there. And then I also found out that when we use billytool.org, there's actually a section where you can say, hey, I have that measurement. So it's sort of like, my God, this has been staring me in the face and I had not seen it before.
I wanted to ask you, how has it been to get this? You said you try to almost do a little bit of a universal screening for the babies who are requiring phototherapy, especially during that earlier phase. How hard was it to roll this new tool in the unit? seems like it's fairly easy to use, but I'm sure there's always obstacles to adoption when it comes to new technology in the hospital.
Tim Bahr (55:06)
Absolutely. You know, the colleagues that we worked with in the Well Baby Nursery or the Newborn Nursery at the University of Utah, they were fantastic. I mean, if you, know, Carole Stipelman and Julie Shakib, you'll see their work in hyperbilirubinemia and in an entitled carbon monoxide. Excellent partners. So I think great physician leaders. And, you know, that implementation was one unit. They did a great job because we sort of had to change our, you know, the
every morning routine. So we had to have like a technician that would be responsible for it when they were doing the newborn screenings. that was rather feasible. The one thing we've worked on more is trying to roll it out to like a hospital system. So Intermountain Health is our other big system at the University of or I'm sorry, in the state of Utah. And we have, you know, 21 delivery hospitals in the state of Utah. And obviously, stretching from
mass, you know, very large delivery centers to small ones. So that's been a much more difficult rollout. One of the sticking points is obviously we is cost. And so showing the value to, you know, in these in a very value driven health care system, well, at least we hope showing that it is worth the cost is a difficult thing. Getting somebody to pay for it is always a is always a challenge.
Benjamin Courchia (56:32)
Yeah, that's such a great point. Any intervention obviously comes with an associated cost and then the benefits we reap from the intervention have to be justified, which by the way leads me to my next question. We're talking about babies who have hemolysis. I am wondering if in your years of experience using end tidal carbon monoxide, have you figured out that maybe your approach needed to be tweaked?
Is this something you believe that like in the 2021 paper, do you believe that this is something every baby that has a rise in bilirubin needs to have checked? Is this something that needs to be reserved for a more high yield population? What do you think are the next steps in how we can make even more meaningful use of that of that tool?
Tim Bahr (57:18)
Yeah. So, you know, in that publication, we just did the babies that required phototherapy. I would, you know, I hesitate to ever claim that every baby needs something. Well, every kid needs to be read to right and every kid needs vaccinations. But
Benjamin Courchia (57:35)
From a medical standpoint, whenever we say that every kid needs something, it's usually not the right answer, which is why I'm asking the question. Yeah, every time we've tried to give hydrocortisone to all the kids, that's not been good.
Tim Bahr (57:45)
Yes, so right. So do I think that we can avoid readmissions? Do I think that we can, that I could, we could probably catch more kids before they get into a dangerous range? Or, you know, we still have chronic dress that occurs in the United States. Do I think that this tool could help us screen for those babies? I do, I do certainly think we could do that. I do think there is good evidence to support that value. We haven't proven it though.
so do I think, I think there's the hard thing has been to show something like that. The occurrence of even readmission, let alone kernicterus is the rates are very low, thankfully. And so you, need very large numbers to show that. And again, how many, the cost to benefit, we need to have a large investment to be able to do it. I I'll be frank. I wish right now we have to pay per use.
for device. I wish I had a device. I'd be even willing to pay $10,000 for a device that I could use as much as I wanted.
Benjamin Courchia (58:53)
Kind of like the Transcutaneous for example, where you get the device and then, yeah. Right.
Tim Bahr (58:57)
I would use it, I would use it, and we would do those studies. And I think we would be able to show, because in my experience, the kids that get into trouble, oftentimes those readmissions that are 25 or 30, we'll measure them. Oftentimes their end-tidal carbon monoxide levels are very elevated. And so I think it might be too sensitive, but it is specific. So when I get a level that's three or four,
That's a kid you want to party that I on. Yep.
Benjamin Courchia (59:28)
Do you think I have two more questions before I let you go, but do you think that the new update to the AP guideline might actually go in that sense where since we have raised the threshold for phototherapy, we're allowing babies to sort of rise to levels that for us who practiced before the old guys were like, oh my God, this is such a high number compared to 2004. I feel a little bit uncomfortable. Do you think that that
that this might be more suitable now with these higher thresholds do you think it doesn't really make a difference?
Tim Bahr (59:59)
I do. think because we are less aggressive with our treatment and I feel like we're just not checking quite as much and our phototherapy rates have dropped because whenever you initiate phototherapy that kid's going to be followed a little bit closer, right? Because you're probably going to follow up a little bit more. I have felt like maybe this is an opportunity for us to and I love that we're using less phototherapy safely but do we need to be a little bit more diligent?
on the screening. So yes, I do think it opens up an opportunity if we can make it. Again, the practicalities in healthcare are just a big deal. Being able to cost and to put it in implementation are a big deal.
Benjamin Courchia (1:00:43)
One last question. Utah is known for its relative routine use of erythropoietic stimulating agents, the ESAs, whether it is DARB, EPO, or EPO. Has that played a role in the kind of numbers you see with end tidal carbon monoxide? does that interplay, is there an interplay between the two?
Tim Bahr (1:01:02)
Not that I know of. Certainly, so here's the context I could put it in. HDFN, so you have a baby that's born with a large antibody load, red blood cell antibody load, baby's antigen positive, and the mom, we transferred a lot of antibody. There has been some thought that, man, I can't give that kid darbepoetin because it result in more production of red blood cells that have antigen are going to be destroyed. That has not played out in the studies.
So if you look at Enrico Lopriore's group from the Netherlands, their randomized clinical trial of darbepoetin for the treatment of anemia associated with HDFN, I think gives us a pretty clear idea that you don't have to worry about that. So we have actually not specifically studied whether administration of darbepoetin results in elevated end tidal carbon monoxide levels, but I don't think so.
Benjamin Courchia (1:01:56)
Okay. All right. Tim, thank you so much. This was so informative. Congratulations again on not just the latest paper you've published, but on this body of work that you have now compiled over the years. And we wish you the best of luck in your future work.
Tim Bahr (1:02:11)
Great, thanks Ben.
Benjamin Courchia (1:02:17)
Welcome back. Thank you to Dr. Tim Barr for joining us. And stay tuned for more discussion on end tidal carbon monoxide and hemolysis for our upcoming episode of Tech Tuesday. We're running short on time, so I'm going to try to maybe you.
squeeze in one more paper, if that's okay with you, Daphna. It's a paper that actually made the rounds on social media. It is published in the Journal of Perinatology. It's called Early Hydrocortisone versus Placebo in Neonatal Shock, a double-blind randomized controlled trial. First author is Sankalp Dudeja. This is a study out of India. We have a great team of Indian neonatologists doing this.
Daphna Yasova Barbeau, MD (1:02:35)
Let's do it.
Benjamin Courchia (1:03:02)
podcast for the community in India. Check them out. They're doing great work. The introduction is very interesting. The administration of exogenous corticosteroid therapy has demonstrated improved outcomes and neonatal illness associated with adrenal insufficiency. Glucocorticoids, know, enhance vascular tone, ink and myocardial contractility. And it does so by up regulating expression of the beta adrenergic receptors and increasing their responsiveness to circulating catecholamine.
Now hydrocortisone therapy in neonatal shock has been shown before to improve blood pressure and to reduce the requirement for vasoactive agents. I personally love hydrocortisone in those scenario. Daphna will tell you that it is probably one of the first medications to come out of my holster. Now.
Daphna Yasova Barbeau, MD (1:03:47)
Mm-hmm. Mm-hmm.
Benjamin Courchia (1:03:51)
In a recent multicenter cohort study of about 1600 neonates with septic shock, the adjuvant use of hydrocortisone given alongside other vasoactive drugs resulted in a 40 % reduced odds of mortality, which is why I wanted to express my love for hydrocortisone beforehand. Now, currently hydrocortisone is indicated in the management of pressor resistant hypotension, and there's recent data that has shown
that serum cortisol concentrations are substantially decreased even at the onset of neonatal shock, maybe reinforcing the favorable use of this medication. Now these studies have also shown that a substantial portion of neonates with hemodynamic instability have adrenal insufficiency at the onset of shock and that early hydrocortisone was associated with improved intermediate outcomes, justifying the need to explore the utility of this medication. Now,
What this group has done was to try to explore the potential benefits of early hydrocortisone compared to a placebo in neonatal shock. So we'll talk about it. mean, they didn't just watch the kids in shock and didn't do anything. And their question was, does early hydrocortisone compared to placebo can reduce 14-day all-cause mortality by about 30 % in neonates having fluid refractory shock, who
are initiated on vasoactive drugs, you're starting to get some of the answer of what that placebo group will look like. This was a double-blind placebo control randomized control trial that was conducted in a level three NICU of a research institute in northern India between September 2016 and December 2018. Basically, the participants were consecutive neonates with fluid refractory shock.
And the question here is how do we define shock? So they had criteria A and criteria B. Criteria A is either a systolic or a diastolic blood pressure less than the fifth percentile. I'm not going to get into the discussion of how do we measure blood pressure. Put a pin in that and then we can have that conversation the other day. Shock criteria B is any two of the following five criteria, meaning your capillary refill is
over four seconds, you have a core temperature difference of more than three degrees between different areas of the body, maybe upper or lower limbs. The urine output of less than 0.5 ml per kilo per hour in the past six hours, a base excess worse than minus five, and a lactate over five.
Now fluid refractory status was diagnosed if shock persisted after providing a 10 to 20 ml per kilo, normal saline bolus given over 40 to 60 minutes. The neonates were given one to two boluses, 10 ml per kilo each as per the unit protocol based on the clinical condition of the infant. The neonates with clinical settings of obvious blood loss, dehydration, HIE, congenital heart disease, congenital adrenal hyperplasia, necrotizing enterocolitis.
ongoing GI hemorrhage or who had received postnatal steroids in the last seven days were excluded. Obviously, these are very different types of condition. In terms of sepsis, obviously, they had culture proven sepsis and probable sepsis. Culture proven sepsis was if microorganism grew in blood culture or CSF within 48 hours of incubation. Probable sepsis was defined as the presence of two or more lab markers, CRP above 10, procalcitonin outside the normal range.
total leukocytes and absolute neutral field counts outside the reference range. A hemodynamically significant PDA was defined as a PDA above 1.5 millimeter in size and any one or more of the following absence or reversal of flow in the descending thoracic aorta, an LA to AO ratio of 1.4 or more, diastolic flow in the left pulmonary artery of more than 30 centimeter per second, early passive filling, too late atrial wave ratio above one or isovolumetric relaxation time.
less than 45 millisecond. So the babies were basically randomized. Either you went into the early hydrocort group or you went into the control. The early hydrochort group received one meg per kilo every six hours for the first 48 hours, followed by one meg per kilo Q12 hours for three days. The placebo group received basically normal saline injections equivalent to that. If a neonate developed catecholamine resistant shock before the completion of the trial drug, the drug was stopped.
and was replaced with open label hydrocortisone at the same dose. Now catecholamine resistant was defined as shock persisting even with dopamine infusion rates above 10 microgram per kilo per minute and a directly acting drug, either dobutamine or epinephrine. The terms of the unit protocol were to initiate dopamine as a first line vasoactive drug at an infusion rate of five microgram per kilo per minute in the babies who were hypotensive.
and basically, increased by increments of five every 15 to 20 minutes to a max of 20. Dobutamine was initiated at a five micrometer per minute dose, also titrated up. The main outcome was all-cause mortality within 14 days of shock onset. They had some secondary outcome, but I'm going to get into the results because we are short on time. So, 142 infants developed shock. Among them,
58 were excluded and 84 were enrolled in 43 in the early hydrocortisone group and 41 in the placebo group. I would say relatively small study but consider how difficult it is to actually identify these infants, enroll them and get them included. So it's not so surprising either. 43 % of the neonates were enrolled in...
were neonates who were born before 30 weeks of gestation and 57 % of the cohort was above 30 weeks of gestation. So the median gestational age was 30.3 weeks. The median birth weight was 1,148 grams. 32 % of the neonates had culture proven sepsis, which reminds you again of the prevalence of that particular pathology in the context of shock. 46 %
of the neonates had hemodynamically significant PDAs requiring treatment with either oral ibuprofen or IV paracetamol or Tylenol for those of us in the US. Hypotensive shock was present in 67 % of the cohort, while the remaining 33 % of the neonates were normotensives with sign of peripheral circulatory failure at presentation. The median cortisol level was 6.
ranging from 1.6 to 15.
In terms of the baseline demographics and maternal characteristics, they were comparable between the two groups. The primary outcome of the study was to see how many of these kids were going to die in the 14 days after shock. And what they found was that all cause mortality within 14 days after the shock onset did not significantly differ between the early hydrocortisone and placebo group. The difference was 72 % in the treatment group versus 83 % in the placebo group.
the confidence interval 0.19 through 1.52 with an odds ratio of 0.5. Now the duration of vasoactive drugs, mean and total inotrope scores in the first 24 hours. Total inotrope scores for the entire duration of vasoactive drug use and the maximum inotrope scores were not significant between the two group. The incidence of catecholamine resistance, hyperglycemia, gastrointestinal hemorrhage, GI perforation,
neck, ROP, BPD, comparable between the two groups. In terms of the babies who displayed catecholamine resistance, 71 % displayed catecholamine resistance in the early hydrocortisone group, compared to 81 % in the placebo group. What else can I tell you? 23 % of the neonates survived, which again, makes shock such a terrifying pathology.
I think that it's interesting to look at the different things. Obviously, the one thing that I was very interested in was the mean blood pressure. In the early hydrocortisone group, the mean blood pressure was, the map was 26, in the placebo group 24. So, I mean, you can look at some of these data, it's quite interesting. But the conclusion are that they're saying that comparing the early administration of hydrocortisone to placebo with neonates with fluid refractory shock,
There was no significant difference in the 14 day mortality that was observed between the two groups and the adverse effects of hydrocortisone as well as medium term complications were not significantly different between the two groups. So I don't know if the discussion is going to revolve around resource utilization or not, but I'm sticking to my guns. I'm not dropping hydrocortisone.
Daphna Yasova Barbeau, MD (1:13:22)
Well, I'm glad it's being studied. think, careful about using what I think on the podcast. I feel as we have not explored adrenal insufficiency enough in these, especially the extremely low birth weight infant. think we don't know enough about it to even make the best suggestions for research design. So anyways, I think it's an exciting opportunity for young people.
to be exploring for us and give us more information. I agree with you. I think we've had a lot of success on a, let's say an N of one basis for administering hydrocortisone and seeing improvement in blood pressure, being able to wean off of pressors, extra fluid, extra sugar, all sorts of all things. Yes.
Benjamin Courchia (1:14:18)
All right, Daphna, can you tell us about one last paper before we head out?
Daphna Yasova Barbeau, MD (1:14:21)
I'd like to. I'm going to try to do it quickly. It kind of relates to my first paper because it is entitled, Parental and Medical Classification of Neurodevelopment in Children Born Preterm. Lead author, Lindsay Richter, senior author, Anne Sines, includes some friends of the podcast, Ani Chavier and Paige Church. This is coming to us from Canada and it was in
Benjamin Courchia (1:14:26)
Mm-hmm.
Daphna Yasova Barbeau, MD (1:14:50)
pediatrics. So basically what they wanted to look at is how does our level of impairment classification, how good are we? So we give babies a level of classification of impairment and then parents also express their own level of impairment and are we consistent? So basically
This is looking at a, it's a cross-sectional observational study. Parents and caregivers of children born with for 29 weeks gestational age and seen at the 18 to 20 month corrected age follow-up visit at any of the participating CN funds. So that's Canadian, gosh, I had a follow-up at follow-up network. Yeah, site. And so they have really good follow-up.
Benjamin Courchia (1:15:37)
Canadian Neonatal Follow-Up Network.
Daphna Yasova Barbeau, MD (1:15:45)
from May 2017 until September 2021 were eligible to participate. And the primary outcome was this agreement between the parents classification of their child's overall NDI status and the CN Fund classification. So just for review, the CN Fund classification, a child is considered to have a mild or moderate NDI if they had any one or more of the following CP with
a gross motor functional score of one or two, a Bayley three motor cognitive or language scores 70 to 84, hearing loss without requirement for hearing devices or unilateral visual impairment. Okay, so that's mild to moderate. A child is considered to have severe neurodevelopmental impairment if they have any one or more of the following. CP with a motor functional score of three, four or five.
So five is the inability to ambulate independently. And three and four both require kind of assistive devices. If they had a Bayley-3 motor cognitive or language composite score less than 70, if they needed a hearing aid or cochlear implant or bilateral visual impairment. So I'm going to skip a lot of the details because we're running behind on time, but basically before the evaluation, parents were asked the following question. So.
They didn't get the scores from the doctor yet or the team yet. Please tell us how you would rate your child's development. One, my child is developing normally. Two, my child has a mild developmental impairment. Three, my child has a moderate developmental impairment. Or four, my child has severe developmental impairment. So they had 13 sites. They had nearly 1,400 patients seen at the 18th to 21 month corrected age visit.
And let's see, children and participants were born at an average of 26 weeks, then an average birth weight of 919 grams, and they were assessed at an average of about 20 months corrected age. 45 % were identified as having at least one impairment, and parent participants were pretty well educated. They wanted us to have some information about that. 92 % completed post-secondary education.
Benjamin Courchia (1:18:04)
But I think
that's a very important point you're bringing up because obviously these were parents who technically had a high level of education and could potentially entertain these very sophisticated conversations about degrees of neurodevelopmental impairment.
Daphna Yasova Barbeau, MD (1:18:06)
Yeah. Yeah.
For sure.
And I think they wanted us to understand a little bit about the homeland. There's only one really data point, but they were 5 % single caregivers. So 95 % of these infants had two caregivers at home. So I'm going to, there's a lot of data here, but I'm going to kind of cut to the chase. So they wanted to look at the overall agreement. There was overall poor agreement. So parents were more likely to describe their child's development as normal or less impaired than their class of.
I will say 60 % of children, parents, and the CN Fund agreed on the neurodevelopmental classification, but for 31%, parents rated their child's neurodevelopment more positively than the classification that they were given. According to the classification, 54 % were classified as having no neurodevelopmental impairments, and parents rated 67 % as none.
29 % mild to moderate, parents said 31 % of their children were classified as mild to moderate. 17 having severe neurodevelopmental impairment and only 2 % of parents used the severe NDI denotation. Among the children who were considered to have no NDI, 82 % were also perceived by such as parents.
The babies who had none were more likely to be received by parents. Among those with mild to moderate agreement with parents was 42%. And among those with severe, only 12 % received a similar rating by their parents. Children who were classified as having severe were most often considered to have mild or moderate by their parents. And even in those who were classified as severe NDI, almost a third were rated as having no NDI by their parents.
When there was disagreement, these children typically displayed higher Bayley-3 cognitive scores and motor composite scores. So they were on the higher, they were on the less impaired spectrum when their parents disagreed, but they still met the criteria. Now, parents are more likely to agree with the classification of severe when the child had a physician's rating of severe global developmental delay. So then they wanted to look at this mild to moderate group, those babies,
who were classified as mild to moderate, but were classified much more commonly by parents as having no NDI. And if they had agreement, they were mostly in those kids who had cerebral palsy or had hearing or visual impairments. Interestingly, parents of children who required health resources, so they needed re-hospitalization,
technology in the home or referral to services were more likely to agree with the classification from mild to moderate. And then they looked at this group of parental and classification by no neurodevelopment impairment. So children who were classified as having none by CN Fund, but were classified as having mild to moderate or severe by parents. So this did happen where occasionally parents rated babies as having more neurodevelopment impairment. Those babies were also in the more impaired
range. So they had lower Bayley 3 language of motor composite scores. Parents were more likely to disagree with this classification of no developmental impairment when the child required use of any technology in the home. So oxygen, feeding tubes, any mobility aids, or they received any referrals since NICU discharge. That meant OT, PT, psychology, rehab, speech, language, pathologists. So I think this is, yes, that's...
Benjamin Courchia (1:21:51)
That sounds fair enough. Yeah, that's fair.
Daphna Yasova Barbeau, MD (1:22:00)
Everybody, that's everybody. So I really thought this was interesting about what these outpatient services meant to parents and the opportunity to normalize some of this for families. So even in the babies who were classified as not having any NDI, the parents who did think they had NDI, it was because of all these services or the baby went home on oxygen. So the medical complexity really increased.
Benjamin Courchia (1:22:10)
Mm-hmm.
Yeah. That's the interesting part is that the parents were fairly objective about it. It's not saying like, no, I perceive my baby is doing less well. Like they were saying, hey, I have to do all these very tangible things. And so that is not being completely free of any environmental impairment. So I think that's fascinating.
Daphna Yasova Barbeau, MD (1:22:29)
the parent's perspective of the neurodevelopmental impairment.
That's right.
Yeah, that's my first take home point. The second take home point is that, I mean, even in some of these really severe cases, parents, you know, really thought, felt that their baby had none, had mild to moderate most commonly, or some even felt none. So, you know, the point, the conclusion from the authors was parental perception of neurodevelopmental and children born extremely preterm differ from our medical classifications.
In particular, this term of severe neurodevelopmental impairment may be misunderstood. And I think the question should go either way. Should we educate parents about what that means? Or maybe our classifications are not as important as we think they are for parents. So that's that.
Benjamin Courchia (1:23:31)
Mm-hmm.
Yeah, table two of that paper is something that you could spend hours looking at. think it's fascinating because, like you said, basically you have the classification from the CNFUN. And so, for example, it's interesting to see that to me, I'm looking at the level of agreement that you've mentioned, obviously, but like the follow-up network found that maybe 596 infants met was no neurodevelopmental impairment. And 491
Daphna Yasova Barbeau, MD (1:23:39)
Looking at you.
Benjamin Courchia (1:24:05)
Infants or parents believe that yes, this is accurate. So you can see a pretty high level of concordance. But beyond that, it's pretty interesting to see the staggering difference when it comes to mild to moderate. The CN Fund says 315 babies are classified in this category, but the parents agree on only 131 infants. So not even half.
Daphna Yasova Barbeau, MD (1:24:08)
Correct.
for sure.
Benjamin Courchia (1:24:32)
And when you're talking about severe NDI, the CN Fund says 185 infants meet the criteria for severe NDI. And of these, the parents agree only on 23.
Daphna Yasova Barbeau, MD (1:24:34)
Mm-hmm.
I
know. And I told you what those criteria were. I think most healthcare professionals would agree that they're severe, know, the severe range.
Benjamin Courchia (1:24:54)
Uh-huh. So you're
absolutely right. I think that we are using these metrics to measure the functional aspects of our babies, but maybe this has to be revisited. And I would encourage you to look at Annie Janvier's talk that she gave to us at the TEDx events. So if you go on the TEDx YouTube channel, the official TEDx YouTube channel, and you look for Annie Janvier, you can actually see her talk that she gave to us at Delphi. Again, these are the types of talks you get to see when you come to Delphi.
Daphna Yasova Barbeau, MD (1:25:10)
Mm-hmm.
Yes.
Benjamin Courchia (1:25:24)
So definitely go check it out. And she mentioned some of that data.
Daphna Yasova Barbeau, MD (1:25:28)
Yeah, she,
I mean, she had everybody spellbound really with her talk. So I hope people will check it out.
Benjamin Courchia (1:25:31)
Yep, yep, yep. I'll
put a link into the description, so I'll remind myself to do that. All right, Daphna, we're way over time. This was fun. Check out Tech Tuesday coming up this week, and send us questions, email. Please give us some reviews on Apple Podcasts. This helps boost the visibility of the show. Let us know if there's anything we can do for you guys. Have a good rest of your Sunday, and see you this week.
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