#248 - 📑 Journal Club - The Complete Episode from October 20th 2024

Hello Friends 👋

In the latest episode of the Journal Club on The Incubator Podcast, Ben and Daphna dive into a fascinating lineup of articles that are sure to spark your interest. Kicking things off, they explore the concept of teleneonatology and its potential to enhance neonatal resuscitation in resource-limited settings. Ben discusses a randomized simulation trial led by Sam Gentle, which compares the outcomes of teleneonatal resuscitation versus routine resuscitation for preterm infants. The conversation digs into the pros, cons, and implications for clinical practice, especially regarding the effectiveness of remote guidance during high-risk deliveries.

Daphna follows up with a review of a pilot study on virtual reality-based simulations for neonatal resuscitation training, offering an exciting glimpse into the future of education and training for NICU teams. The episode also tackles the neurodevelopmental risks for babies exposed to maternal motor vehicle accidents, providing a sobering discussion on the long-term impacts. Whether you're intrigued by innovative solutions like VR training or curious about new clinical research, this episode delivers thought-provoking insights across a range of neonatal topics.

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

Teleneonatal or routine resuscitation in extremely preterm infants: a randomized simulation trial.

Gentle SJ, Trulove SG, Rockwell N, Rutledge C, Gaither S, Norwood C, Wallace E, Carlo WA, Tofil NM.Pediatr Res. 2024 Sep 28. doi: 10.1038/s41390-024-03545-1. Online ahead of print.PMID: 39341942

Neurodevelopmental disorders in children born to mothers involved in maternal motor vehicle crashes.

Chang YH, Chien YW, Chang CH, Chen PL, Lu TH, Yen CF, Chiou HY, Tsai KS, Li CY.Pediatr Res. 2024 Sep 30. doi: 10.1038/s41390-024-03608-3. Online ahead of print.PMID: 39349820

A pilot study of a virtual reality-based simulation platform for Neonatal Resuscitation Program training.

Trinh G, McAdams RM.J Perinatol. 2024 Oct 14. doi: 10.1038/s41372-024-02145-5. Online ahead of print.PMID: 39402131

Fetal haemoglobin and oxygen requirement in preterm infants: an observational study.

Ulinder T, Hellström W, Gadsbøll C, Nilsson L, Gebka M, Robertz G, Bruschettini M, Hellstrom A, Ley D.Arch Dis Child Fetal Neonatal Ed. 2024 Sep 25:fetalneonatal-2024-327411. doi: 10.1136/archdischild-2024-327411. Online ahead of print.PMID: 39322316

Outcomes after intranasal human milk therapy in preterm infants with intraventricular hemorrhage.

Gallipoli A, Unger S, El Shahed A, Fan CS, Signorile M, Wilson D, Hoban R.J Perinatol. 2024 Oct 9. doi: 10.1038/s41372-024-02147-3. Online ahead of print.PMID: 39384614

Clonidine as Monotherapy for Neonatal Opioid Withdrawal Syndrome: A Randomized Trial.

Bada HS, Westgate PM, Sithisarn T, Yolton K, Charnigo R, Pourcyrous M, Tang F, Gibson J, Shearer-Miller J, Giannone P, Leggas M.Pediatrics. 2024 Oct 15:e2023065610. doi: 10.1542/peds.2023-065610. Online ahead of print.PMID: 39403061

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

Ben Courchia MD (00:01.398)

Welcome back to the incubator podcast. is Sunday time for a new episode of journal club. Daphna, how are you?

Daphna Barbeau (00:09.282)

good. I'm very much looking forward to this journal club because we both have articles we were I think really looking forward to seeing. So it's fun. Yeah, come on. You know there are some articles where you're I was hoping somebody would do this. Yeah. I'm not sure. I'm not sure they're going to be. I'm not sure you're going to get the answers you were hoping for, but we'll review them nonetheless.

Ben Courchia MD (00:18.326)

I don't know, I'm looking forward to, but they were very interesting for sure.

Ben Courchia MD (00:26.164)

I was looking forward to your articles somehow, more than I'm looking forward to mine. Even though mine are quite interesting.

Ben Courchia MD (00:39.134)

Yeah, we're going to talk about it. think that's good. All right. I don't really have any announcements. feel like I was ready to talk about Delphi, and then I realized it's over. So let's talk about Delphi.

Daphna Barbeau (00:46.932)

I know.

It's over. It's over. We will be doing it again.

Ben Courchia MD (00:54.442)

What? It's not this is a topic for a different day.

Daphna Barbeau (01:01.57)

But I get, mean, but people have been asking, so we'll have the next date soon so people can be looking forward to it. Yeah.

Ben Courchia MD (01:07.146)

Yeah, we are actively working on meetings in the current, over the past few weeks and not about, yeah, over the past two weeks and over the next few weeks. There's a lot of meetings that are happening so that we could give you an answer to that very question. All right, journal club, journal club, journal club. Should I start or you start? I start journal clubs. Okay, so the first paper I'm going to review was in pediatric research. It's an interesting paper. It's called...

Daphna Barbeau (01:21.494)

That's right. All right.

Daphna Barbeau (01:27.638)

Yes, please. No use to it.

Ben Courchia MD (01:36.726)

it a teleneonatal or routine resuscitation, an extremely preterm infant a randomized simulation trial? The first author is our good friend Sam Gentle from the University of Alabama. So I think this is a fascinating question. The background is interesting to begin with. They're mentioning how having access to highly trained neonatologists and who are experienced in neonatal resuscitation really does improve outcomes in preterm infants.

Daphna Barbeau (01:40.918)

Hmm.

Ben Courchia MD (02:06.662)

and there's many, many papers with prior analysis of neonatal outcomes by hospital level that really support this finding. However, there is a continued decline in access to level three delivery hospitals. And, this decline leads to an increased risk for preterm infants that are delivered at quote unquote lower level facilities, either by chance or by design. just so happens. And then we know that we've had conversations on the podcast about.

the dwindling number of pediatric trainees who are pursuing careers in neonatology. And so I think this issue, this scarcity of highly skilled neonatologists for advanced resuscitations is going to be a more and more prevalent problem. Now they're talking about this concept that I mentioned in the title called tele-neonatology. And basically what it is that this uses video tele-medicine.

to connect experienced providers with newborn deliveries at hospitals lacking intensive care services. Now this approach has the potential to improve care for preterm infants born at quote unquote lower level facilities. I really hate the term lower level facility because I don't think any facility is lower. But you know what I mean. Like it's not. I know, I know. when I say it, I'm really afraid somebody is going to listen midway through and be like, why is he saying lower level? But that's what we mean. like,

Daphna Barbeau (03:17.953)

Yeah.

Daphna Barbeau (03:23.138)

They must mean like a level one, level two in the US. Yeah.

Ben Courchia MD (03:34.016)

Tele-Neonatology, potentially, while helpful, does have a cost associated with it and might be resource intensive. And so there's some previous studies that have looked at the feasibility of having tele-neonatology. And they reported that there was always some audio and video quality that was really unusable to about 20 % of consultation. And so there's been some issues. So what this group has tried to do is that they are trying to answer the question of whether

Daphna Barbeau (03:39.521)

Mm-hmm.

Ben Courchia MD (04:04.638)

does teleneonatal resuscitation as compared to routine resuscitation reduce the no-flow fraction? What is no-flow fraction? It's something they introduce in the background. The no-flow fraction is the proportion of time during which the patient do not need to receive chest compression, what it's clinically indicated. So do we avoid situation in which the kid crashes and needs chest compression as compared to just being able to deliver a resuscitation now?

I thought the simulation, I thought the study design was brilliant. I really liked how they did this. So it's a single centered parallel randomized trial, done by the Children's of Alabama. And what they did was that they basically, the subject of the study are trainees, pediatric trainees, and they're between year one and year four. They're recruited by the hospital personnel from the residency program at the University of Alabama at Birmingham slash Children's of Alabama. And obviously they're

being consented for the participation. Now, the trainees that are recruited have all completed an NRP, right? So they're all NRP, quote unquote, certified. They have at least four weeks of NICU exposure. And there's at least three months that have elapsed since their preview NICU curation. So really trying to give you the feel of like a general pediatrician attending a high-risk delivery. To their credit.

Daphna Barbeau (05:25.218)

Well, and that really is kind of what you're likely to have, right? It's somebody who gets called, come take care of this very small baby who delivered here,

Ben Courchia MD (05:29.424)

Mm-hmm. Yeah, but I thought that was kind

Ben Courchia MD (05:35.382)

And they gave each participant a $10 gift card. The days of residency.

Daphna Barbeau (05:39.7)

One coffee.

Ben Courchia MD (05:45.102)

We should have a whole episode about what can you do with $10 as a resident. All right. So how does this work? So prior to entering the simulation, these trainees, these residents are provided with the following prompt. They said you have been asked to attend the C-section birth of Layla Thomas, a 25-week infant. The mother presented to labor and delivery one hour ago following a motor vehicle accident. There's no antenatal steroids, and the baby will soon be delivered. Prepare.

Ugh, terrible in any form of setting. And so in order to evaluate this no flow fraction, this avoidance of having to give chest compression, the mannequin in the scenario became bradycardic with a heart rate of less than 60 following establishment of effective ventilation with additional time relevant details are depicted on this timeline that they have in figure one. I'm just going to summarize this for you. So basically, the baby is born, the heart rate is 60, the idea is that you're supposed to give

non-invasive ventilation, go through Mr. SOPA, you're supposed to intubate, there's supposed to be a little bit of an improvement, then there's supposed to be a massive decompensation, you're supposed to do chest compression and epinephrine, and after epinephrine, the mannequin will display very good stats and the recovery should happen. So they have a very nice timeline as to how these things are supposed to happen. The whole scenario is supposed to take about 10 minutes.

And they said that given the ability to perform the simulations objective within this timeframe or upon bradycardic resolution, whichever occurred first, so they may go through these steps faster. Both group received a debrief at the resuscitation's conclusion and they stratified everything based on the level of the residents. Now, in terms of what is the intervention, so the teleneonatologist is instructed to allow the participants to lead the resuscitation but provide directive communication in instance where

the participant did not timely adhere to guidelines from the NRP or failed to provide an indicated intervention. The teleneonatologist has access to the information gained from visualization thanks to this Amwell cart. Do you know what that is?

Ben Courchia MD (07:55.158)

You're muted. So the MWAL cart is kind of like this wow that we have to round, but it's the one that we use for consults. If you're doing tele-consults, it has a camera, it has a screen. So the teleneonatologist can actually see from this cart here. Now, the tele-connection occurred simultaneously as the trainee is entering. as soon as the resident enters the simulation, the connection happens. There's a research nurse assistant.

Daphna Barbeau (07:56.322)

Why don't tell me?

Daphna Barbeau (08:04.748)

Mm-hmm. Mm-hmm. Mm-hmm.

Daphna Barbeau (08:10.06)

Makes sense.

Ben Courchia MD (08:23.498)

that participates in the resuscitation by providing both nursing and respiratory support in the teloneo scenario and also in the regular scenario. And there's an additional research nurse that is pulled as the time to give meds arrives. So that's the person who will give meds. So this is sort of the team setup. The outcome of the study is that, again, we're looking at this no flow fraction defined at the time without chest compression.

divided by the time without spontaneous circulation when the heart rate is less than 60. So basically, looking at this delay, right? And so on. All right. So in terms of the results, they were able to get 51 trainees to be randomized into these two groups. 25 were randomized to the teleneonatal resuscitation, while 26 were randomized to the routine resuscitation. One of the participants, they had some issues with the connections.

But so they reported on that as well. Now in terms of the primary outcome of no flow fraction, they showed that it was significantly lower in the teleneonatal resuscitation group as compared to the routine resuscitation group. If we look at the individual aspects of the resuscitation, I think it gets very interesting. Regarding the aspects of the management, the teleneonatal resuscitation group more frequently placed the mannequin in a plastic wrap, 96 % versus 50%.

That's something that often gets forgotten, it looks like. They also were more likely to place EKG leads earlier at 35 seconds of life versus 46 seconds of life in the routine group. Other initial parameters, including the probe for pulse oximetry and so on, did not differ between groups.

In terms of the performance of the Mr. SOPA, including mask adjustment, repositioning of the airway, suctioning of the mouth, opening of the mouth, and increasing the pressure of the bag mask ventilation and using an advanced airway in the correct sequence happened in a higher proportion of the simulations in the teleneonatal resuscitation group, 60 % versus only 15 % in the routine group. Yeah. In terms of...

Daphna Barbeau (10:37.548)

Wow.

Ben Courchia MD (10:44.27)

the cardiac resuscitation parameters, the no-flow fraction, the time between the initiation of chest compression and epinephrine administration, all that was shorter in the neonatal, teleneonatal resuscitation compared to routine, the time to chest compression and the chest compression synchronization compliance, the epinephrine administration that did not really differ between the two groups. In terms of these debriefing sessions that they had with the participants,

Participants from the teleneonatal resuscitation group indicated that having the teloneo present improved the quality of resuscitation in 96 % of cases. Successful connection with the teleneonatologist occurred on 88 % of cases. So it's not too bad. I mean, I think in today's day and age, should be better, but it's OK. And then when they did this qualitative analysis, the themes identified from the prompts of providing any additional comments to the study team included the appreciation of experienced guidance.

and a noted reduction in anxiety and a sense of empowerment. Although some people said that the audio and the video quality had been insufficient and it could have been better, basically. And so I this was a very interesting study. The conclusion are that in the simulation trial, tending neonatal resuscitation reduced the no-flow fraction compared to routine.

as the no-flow fraction has been implicated in adverse clinical outcomes in other patient population, the use of tail and neonatal resuscitation may improve neonatal outcomes and that additional evaluation of this potential procedure within diverse clinical environments and additional modalities are needed to further substantiate the value of this intervention. I mean, I don't know, is that going to be the future? Are we going to be on tele-neonatal service? Are we going to do these times where we're going to be supporting a lot of outlying hospitals? Gosh, maybe international hospitals. I don't know.

Daphna Barbeau (12:20.674)

Hmm.

Daphna Barbeau (12:28.448)

Well, yeah, I mean, I love the idea. Super innovative definitely fills a need. Okay. But I, this is what I'm going to say. This is my political soapbox. I'm afraid for hospitals to catch wind of this paper and say like, I guess we don't need NEOs anywhere, right? We could just hire one NEO in the middle of the country to just do all the teleneo across the country because you know, they'll do something like that.

But what else I would say is...

Ben Courchia MD (13:00.107)

What do you think about these? I mean, I know that surgery, general surgery is leaps and bounds ahead of everybody when it comes to this. And you're seeing these reports of articles of a team of surgeon in Japan doing an operation in the top of Mount Everest remotely, right? I mean, I'm exaggerating. This was not the article, but you get the drift. So my point is, what if the technology reaches a point where, definitely, you get into a simulator and you're able to control everything on the resuscitation table?

Daphna Barbeau (13:18.54)

Yeah.

Daphna Barbeau (13:27.899)

Yeah, sure. I guess that's possible. I mean, is it possible that robots can intubate as well as NEOs do? Maybe. I don't know.

Ben Courchia MD (13:37.278)

I don't know if robots can intubate, but you see, example, with these robots, the surgical robots like the DaVinci, where the surgeon has very good control from like a little pilot booth into the instruments that are touching the patient. Again, I think that if that were to, my only thing is that if that were to happen, we need to get Satyan to represent us so that he could look out for our interests as professionals, because I feel like we're going to get screwed with our FTPs.

Daphna Barbeau (13:42.666)

Yeah, for sure. It was remote. Yeah.

Daphna Barbeau (13:57.676)

That's right.

Daphna Barbeau (14:02.742)

That's funny. The only thing about this article that I would say is, think, no, I know. No, it just made me think that actually if you had two physicians at every resuscitation, it would probably go better, right? Because for example, in PALS, right, there's usually a physician or a well-trained person at the head of the bed, but they're not running the resuscitation.

Ben Courchia MD (14:08.778)

Definitely doesn't like this article at all. Look at that.

Ben Courchia MD (14:21.834)

That's a good point.

Daphna Barbeau (14:31.84)

And in NRP, this is different, right? So the person who's managing the airway is still running the resuscitation. And I think that's something we should really think about as a community because there's a reason the rest of people who resuscitate people think that the person managing the airway shouldn't also be resuscitation. So this is basically what this does, right? It's letting the person manage the airway and having somebody else think about the rest of the resuscitation. So I just thought that was an interesting component.

of things.

Yeah, for sure.

Ben Courchia MD (15:07.434)

No, you're right. think it's an interesting take. It's an interesting take. And I think that if we want to go one step further, I believe that that second physician, many people would say, yes, it's there. It's the trainee, right? And it's like, well, but it shouldn't be, right? The trainee is there to train. And it would be nice if we had. It's interesting because as fellows, I'm sure this happened.

Daphna Barbeau (15:21.228)

That's right.

Ben Courchia MD (15:29.96)

I used to go to deliveries without attendings for very high risk deliveries, but sometimes we would go as two fellows. And whenever we were two fellows, it was so nice. I remember going to deliveries with my buddy Josh or Walid or Sunil. And whenever two of us were on, there was nothing that could come through the NICU that was going to foster us because you know that you had your buddy working with you. And that makes a huge difference. So I'm not going to dismiss that argument.

Daphna Barbeau (15:31.874)

Mm-hmm. Mm-hmm. Mm-hmm.

Daphna Barbeau (15:40.215)

Yeah.

Daphna Barbeau (15:51.51)

Yeah. Well, and you know, we've worked at institutions where you have multiple docs on at a time and you may not recognize during the day. That's You may not recognize how valuable that is until you're at an institution where you're the only doc on during the day. But you know, a resuscitation happens, a change of shift and you got lots of hands on deck, mean, it's, things go better for sure. For sure.

Ben Courchia MD (15:59.488)

during the day.

Daphna Barbeau (16:20.264)

So I think we could look at this paper both ways. I think we need more hands on deck, not less hands on deck is my ultimate takeaway.

Ben Courchia MD (16:30.76)

Okay. I have another paper, I guess, if you want to stay on this sort of topic, if you want.

Daphna Barbeau (16:38.988)

Fine, yes, and then I have a similar along the same vein paper, so go for it.

Ben Courchia MD (16:44.744)

Okay, so the next paper that I found, which sort of relates to this in the way that it's sort of related to the scenario, it's called Neurodevelopmental Disorders in Children Born to Mothers Involved in Motor Vehicle Crashes, which is kind of like the scenario that they had for these trainees. And I feel like we both live in Florida where driving is awful. People drive in such ridiculous ways.

Daphna Barbeau (16:56.223)

Mmm.

That's right.

Ben Courchia MD (17:09.916)

that basically when you take your car in the morning, it's not about just making it to your destination. It's about how do I just not have an accident? This is a paper in pediatric research coming out of Taiwan. And I feel like this is something that I didn't really have a good understanding or had never really thought of from the standpoint of, if the baby survives, is there anything that's associated with this? So.

Daphna Barbeau (17:10.626)

Yeah.

Daphna Barbeau (17:17.825)

Hmm.

Ben Courchia MD (17:36.287)

The background is interesting to talk about these motor vehicle crashes and the fact that during pregnancy it can cause trauma. It can lead to various risks to the fetus as we know, including preterm delivery, birth asphyxia and fetal death.

Now, blunt force trauma damaging the fetal central nervous system is one of the mechanisms contributing to these adverse outcome. They're saying that severe traffic trauma in the third trimester has been shown to inflict significant brain damages on fetuses regardless of the severity of the mother's injury. And what do the mother injury tell us about the potential risk to the baby? And they said that we don't really have a lot of data on the neurodevelopmental outcomes of the babies that are surviving these events.

And so the two-pronged question that they have is, what is the association between maternal motor vehicle crashes during pregnancy and the risk of neurodevelopmental disorder in their children? And how does the severity of the injury and the timing, in terms of which trimester this happens, affect this association? So again, I don't want to take too much time, so I'm going to go through the study design pretty quickly. They basically gathered data from a ton of different databases. And basically what they did is that among all singleton

born to mothers between the age of 18 and 50, because obviously if you're less than 18, you're not really supposed to drive, they found 20,844 children that were exposed to a maternal motor vehicle accident during pregnancy. So they were able to correlate that with some databases from public records. There's a whole, I'm sparing you the details, I do not, I'm not from Taiwan, so there's talk about all these different databases where they're correlating the different.

subjects and they're explaining how they did it, but I'm just sparing you the detail. They conducted an incidence density matching based on the time of the crash, the week of pregnancy, the mother's age. On the day of the crash occurred to a pregnant woman and her on-board child. Four non-exposed mothers and their on-board children were randomly selected from the larger database of people who did not have a car accident and matched them to each subject. Now the total

Ben Courchia MD (19:42.454)

The total number ended up being 19,277 children with maternal motor vehicle crashes. That was the exposed group and 76,000 and change for the mothers who were not exposed to a motor vehicle accident. In terms of what they were looking at, they were looking at the outcomes according to various neurodevelopmental codes like cerebral palsy, intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder.

So in terms of the results, I thought this was very interesting. It's kind of a difficult read, I'm going to warn you, because they have a primary analysis that shows a lot of different associations that sort of vanish when they're doing their adjusted hazard ratio. So I'm just going to take you straight to the results that are significant. The results show that children with maternal motor vehicle crashes were more likely to come from central or rural areas, have lower family incomes, and have native-born mothers. I think that's something that we don't tend to.

to think about parents who are not living in excessively, do we say urban? Urban areas where there's lots of cars, lots of roads, like they may not be so comfortable on the roads in the larger city, for example. And I don't know what the driving is like in Taiwan, but like if you've been to Paris, go try to drive by the Arc de Triomphe and try to see if you can make it past this roundabout. is, even for me, who have gone many times, it's terrifying. So I would consider myself coming from a rural area when it comes to that.

Daphna Barbeau (21:03.605)

you

Ben Courchia MD (21:10.034)

that specific example. Now the incidence of neurodevelopmental disorders was higher for children who were exposed to maternal motor vehicle accidents compared to those without exposure. And that was for intellectual disability, for autism, and for ADHD. Now children exposed to maternal motor vehicle crashes during the first two trimesters or whose mother sustained mild to severe injuries showed a higher risk of intellectual disability. I'm going to preface this. This is not something I...

is mentioned in the abstract. You have to sort of dig through the results. But the number of mothers who were severely injured was extremely low. So it's kind of hard to make big generalization about that. And they do mention it, by the way. They're very honest about that. Severe maternal injuries also increased the risk of infantile cerebral palsy. Maternal vehicle crashes in the third trimester or mild maternal injuries were associated with a higher risk of autism spectrum disorder as well.

Now, the conclusions of the article are that the cohort study suggests that the motor vehicle crash during the pregnancy is associated with an increased risk of neurodevelopmental disorders in children, particularly when the crash happens at a higher severity and crashes with higher severity show a higher risk of intellectual disability and cerebral palsy. Or if it happens in the third trimester where you have a higher risk of autism spectrum disorder.

Now considering that motor vehicle crashes is one of the most common traumatic injuries for pregnant women, its potential to contribute to the occurrence of neurodevelopmental disorder or other health effects needs to be further investigated.

Daphna Barbeau (22:46.21)

Well, fascinating and terrifying because, you know, those women come in and they're like, we watched her for 24 hours. We let her go home and that's that. And we think like no harm, no foul, right?

Ben Courchia MD (22:59.046)

I invite you to read the paper just because they have all this information about the speed or how much injury was to the mother. And what sometimes you would expect is that the injury to the mother correlates with injury to the baby. And that does not seem to be true. So you're like, the mother's fine. And hopefully the baby is fine. But that's not true. Table three is really where you want to go.

Daphna Barbeau (23:09.186)

Mm.

Daphna Barbeau (23:23.383)

Yeah, and I-

Ben Courchia MD (23:26.132)

and they have all these different, yeah, these different, yeah.

Daphna Barbeau (23:30.658)

That makes you wonder, do we need longer monitoring? Like would we be able to pick anything up on monitoring? I don't know, probably not.

Ben Courchia MD (23:38.876)

Mm-hmm. Table four is the table I mentioned. I'm sorry. But yeah. No, it's very interesting.

Daphna Barbeau (23:43.234)

Interesting. Interesting. Okay. I didn't like that paper. Yeah, for sure. It's not that I didn't like the study. I just didn't like hearing about it.

Ben Courchia MD (23:46.054)

Mm-hmm. No, but I it was related to the one that we were just discussing because that was the scenario.

Ben Courchia MD (23:57.878)

All right, so you've been teasing the entire audience with your exceptional papers today.

Daphna Barbeau (24:02.26)

No, I didn't say they were exceptional, but of course, of course, you've got such a great group of people doing research. But this one related to, I think the first paper, which I was really excited to see, the University of Florida has actually, through their anesthesia department, some really cool VR things going on for patient safety and patient care and patient resuscitation. So.

Now in neonatology, this is a pilot study of a virtual reality-based simulation platform for neonatal resuscitation program training. First author Gia Con-Trin and senior author Ryan McAdams. This is in the journal of Perinatology. basically, they wanted to, it's a pilot study, just see what participants felt in this virtual reality-based simulation platform.

for basically NRP. And so notably, they weren't efficacy, like how good is the training, but really just what did the participants think. So it's a survey-based study conducted at level three and level four NICUs. And again, the study aimed to enroll neonatal professionals and learners that are actively working in the NICU and the newborn nursery to assess

kind of the utility and the feasibility of this VR simulation for neonatal resuscitation. So they basically sent out invitations to anybody who is eligible. They look to have at least 30 participants, which would represent approximately 50 % of kind of their potential staff that would qualify. So they invited neonatologists, neonatal fellows, pediatric residents, advanced practice providers, and newborn nursery hospitalists.

So I'll tell you a little bit about their 3D virtual reality environment. looks super cool. And they do have a video posted on YouTube, so we can link that in the show notes. But basically, it's virtual reality. So everything's 3D. And they have this 3D virtual patient. The scenario happened to be a virtual 30-week infant. And they used...

Daphna Barbeau (26:15.158)

photographs to kind of simulate these clinical features. And the virtual neonate can do all the things. It has limb movements, it has chest rise and fall during breathing. It can show retractions, nasal flaring when in respiratory distress. You can hear the breath and heart sounds when you auscultate using the virtual stethoscope. So basically, it offers more feedback than the mannequin that does nothing.

And obviously we have some really high fidelity mannequins which are improving kind of simulation, but they're quite expensive. So is this an alternative? And it says the virtual neonate has four preset modes. They have the normal calm state. So the neonate has normal vital signs, good muscle tone and movements, regular breathing, audible breath sounds. As a distress state, the neonate has a heart rate of less than a hundred breaths per minute, increased work of breathing with.

audible grunting, visible retractions and nasal flaring, and no breath sounds. It has an apneic state, so a heart rate of less than 100 breaths per minute is limp, no breathing effort, and has absent breath sounds. And then in the intubated state, the neonate has a breathing tube in place and has normal vital signs, has improved movements, breathing effort, and equal breath sounds bilaterally.

So they did a scenario, which was similar to the scenario you talked about in the first article. So it was kind of a quote unquote low complexity case because they're trialing this new cognitive load of the VR environment. So the main educational objective was to do the Mr. Soba corrective steps for ventilation and NRP. So, you know, the mask adjustments, repositioning the airway, suction, opening the mouth, increasing the pressure and alternate airway.

So like I mentioned, the scenario includes the resuscitation by 30 week infant experiencing respiratory distress. So the learners are expected to perform the following five steps. So recognize that the infant is in distress, start PPV, assess the effectiveness of their PPV, perform corrective steps according to Mr. Sopa, and then provide post resuscitative care. And then after the scenario was concluded, they had an in-person team member standing there that conducted a debriefing.

Daphna Barbeau (28:29.218)

And all of the participants got a QR code to do a survey about their experience. Of note, there was a required training of one hour to kind of understand the VR platform. And I think that's just important when we're thinking about if we can do this in a broad way. So the primary outcome was the participants' overall attitude towards the VR model. They used four Likert scale questions.

Then willingness to reuse the model, likelihood of recommending it, perceived realism compared to traditional models and overall usefulness rating. And then they were allowed to provide qualitative feedback through a number of free text options. The secondary outcomes looked at previous use of VR, so familiarity with VR tech, adverse effects experience during VR use, which that was really cool, and other challenges encountered. So they enrolled 38 participants over four cycles.

In 2022, most participants were female and the clinical rules included NEOs, neonatal fellows, pediatric residents, and advanced practice providers. All the participants were able to complete the in-person training and the post-training survey. So overall, the general attitude towards the VR model was very positive. So most participants, 97%, expressed a willingness to reuse the VR simulation. 95 % would recommend it to colleagues.

Most of them, 70%, found the VR experience to be more realistic than the quote unquote traditional training methods. The average usefulness rating for the VR model was a four and a half out of five on standard deviation of 0.8. And it, go ahead.

Ben Courchia MD (30:11.434)

Yeah, more realistic than the usual sort of cruddy mannequin that we have when we do these mega codes or whatever, right? Because... Sure. Sure.

Daphna Barbeau (30:18.156)

which is what most institutions have to work with, truthfully. Right. It wasn't statistically significant, but this was interesting. There was a trend where the perceived usefulness of the VR model decreased with increasing years of NICU experience. So residents and fellows rated the simulation more highly than attendings did, which I guess is not totally surprising, both from an experience standpoint and

Ben Courchia MD (30:39.542)

Hmm.

Daphna Barbeau (30:47.692)

potentially a tech standpoint. So key themes from the survey responses include realism and immersion. Participants described the VR experiences quote unquote, very realistic, noting that situations felt very real. The educational value of VR was emphasized. It was described as quote, tremendous and quote, great for critical thinking. And through the asm was evident in the comments such as this is cool and I can't wait to do it again. And participants favorably compared VR to traditional SIM.

noting that it allowed them to suspend reality, providing more realistic cues. Interestingly, most of the participants had limited prior experience with VR tech. 29 % had used VR previously, and only one participant owned a VR headset, so they were able to pick it up pretty quickly. And this was, I thought...

Very interesting. The VR related symptoms were reported in 40 % of participants. The most common symptom was eye strain, 21%, followed by motion sickness, 20%, 18 % of participants. So despite those symptoms seen in quite a few participants, it was ranked very favorably. And I wonder if those symptoms will...

go away after repeated exposures. So I thought I liked this. I thought it was cool. I think we need more simulation. We need more access to practice. So I think it's a great idea.

Ben Courchia MD (32:19.134)

Yeah, Ryan showed this to the NeoMind AI group, which by the way, you're not, if you're interested in this, then definitely check out the neo-mindai.com website. And it's a really cool sort of VR system. anyway, so I think it's kind of neat.

and I recommend you following the paper. And I think this is how we're going to do a lot of the training moving forward. At Delphi, we had a few people talk to us about trying to do low tech, high fidelity sort of simulation. I think what's interesting to me is that this will be the future. think this, which appears like super innovative right now, will end up being the future of

Daphna Barbeau (32:42.86)

Mm-hmm.

Daphna Barbeau (33:05.1)

Mm-hmm.

Ben Courchia MD (33:09.076)

resuscitation. Like right now it's...

Daphna Barbeau (33:10.23)

Yeah, and VR seems very expensive, but the alternative are these mannequins that are extraordinarily, they're cost prohibitive, right?

Ben Courchia MD (33:16.662)

They're not cheap. Yeah, they're not cheap. And I think that VR sets are going to continue to get cheaper and cheaper. I think we're seeing this with Apple's VR set, which I think many people are not getting on board with because of the fact that it's so expensive. But yeah, I think the VR set for Apple is like $3,000 or $4,000. But I think...

Daphna Barbeau (33:39.49)

much is it?

Daphna Barbeau (33:44.354)

Okay.

Ben Courchia MD (33:46.138)

And Facebook is coming out with one that is much less expensive. I think that's just like the genome sequencing. It's going to get less and less and less expensive. Yeah.

Daphna Barbeau (33:54.092)

Yeah, interesting.

All right.

Ben Courchia MD (33:59.414)

All right, do you want me to go next or you? OK. The next paper I have, and I have two more papers for today, granted that I'm recording this post call, so I'm giving myself a little bit of a break from the usual seven papers that I often take on. This is called Fetal Hemoglobin and Oxygen Requirements in Preterm Infants, an Observational Study. First author is Tommy Uliender. This is coming out of Sweden and is published in the Archives of Diseases in Childhood. Fetal and neonatal edition.

Daphna Barbeau (34:01.484)

Mm-hmm.

Daphna Barbeau (34:21.314)

Mmm.

Ben Courchia MD (34:28.967)

Now, it's a great board review paper, just because there's a lot of concepts in there that come up on the boards. so data has shown that low-circulating levels of hemoglobin, of fetal hemoglobin, hemoglobin F, during early post-natal development has been associated with neonatal mortality.

Daphna Barbeau (34:34.45)

Absolutely.

Ben Courchia MD (34:54.964)

In preterm infants, levels of fetal hemoglobin decrease gradually after birth. And in infants born at term, the percentage of hemoglobin F is less than 10 % of the total hemoglobin by the age of 16 weeks. Other data suggest a natural decline in fetal hemoglobin with a weekly rate of 16 % reaching a complete switch from fetal to adult hemoglobin, which is hemoglobin A, after 25 weeks of life.

Interestingly enough, for us in the NICU, blood sampling during the first two weeks of life correspond to a significant iatrogenic blood loss. And on average, we take about 40 ml per kilo of blood corresponding to about 58 % of the total blood volume of our infants. And as a result of these iatrogenic blood losses, the infants are exposed to frequent red blood cell transfusion. And red blood cells are usually coming from adult donors. And thus, we're actively

Daphna Barbeau (35:40.032)

Sing!

Ben Courchia MD (35:53.48)

influencing this replacement of the fetal hemoglobin with adult hemoglobin with each transfusion. Now, it's been previously shown that an early postnatal decrease in fetal hemoglobin, the percentage of hemoglobin F, is associated with the development of bronchopulmonary dysplasia in a cohort of very preterm infants. According to that study, the probability of BPD is inversely related to the mean hemoglobin F percentage during the first postnatal week with a probability of 20 %

for the development of BPD at a mean hemoglobin F of 80 % and a probability of 90 % of developing BPD when the hemoglobin F reaches levels as low as 40%. So the question the group is asking, it's threefold. They're saying, is there an association between the shift from predominantly HbF to HbA due to transfusions, et cetera, and an increased in oxygen requirement in very preterm infants during the first week of life?

And does this association between the shift in hemoglobin type and oxygen requirement remain independent of other physiological factors affecting hemoglobin oxygen affinity? The other thing they're looking at, which is why I think it's such a good point of view, problem is that what is the relationship between the fraction of inspired oxygen, the FiO2, and the AA gradient and the hemoglobin F in very preterm infants during their first week of life? So let's get into it.

The study is conducted in a single center. It's an observational cohort study that includes 440 infants born before 30 weeks of gestational age at Skane University Hospital in Lund. And they're admitted to this tertiary level neonatal intensive care unit between 2009 and 2015. The outcome they're looking at is the oxygen requirement as determined by the FIO2 and the AA gradient with

hemoglobin F percentage being the exposure variable. So let's put on our neonatology review hats and remind ourselves what is the AA gradient. The AA gradient is the thing I hate the most because it starts very simple and then the formula gets complicated. But the bottom line is that the AA gradient is the difference in the amount of oxygen between your artery and your alveolus, right? So it's how much gets to the alveolar space and how much of it you find in the artery.

Ben Courchia MD (38:12.726)

So the formula is P big A O2 minus P small a O2. And it's when we're trying to replace these things that things get tricky. So just for as a reminder, the formula is basically you're taking your FiO2. You multiply that by parentheses, your barometric pressure minus your pH 2 O. And this is all subtracted from the PaCO2 over R, which is a constant that's close to 1.

OK, moving on. The infants received supplemental oxygen to maintain a target SAT of about 91 to 95%. I think that's also very important, because if you're looking at how much FIU2 you need in a study, you want to know what kind of SATs are you trying to reach. Because if you're keeping 88 % to 91%, it's very different from trying to maintain 91 to 95%. And there's something to be said about every potential SAT range, as we don't have a clear-cut definition of what is the gold standard. In terms of red blood cell transfusion, that also was an arbitrary sort of decision, where they tried to keep

in the first week of life, the hemoglobin above 14 gram per deciliter, which granted is higher than the latest consensus from that were recently published that we reviewed on the podcast. So they're being generous in making sure they keep a nice hemoglobin. And BPD was defined as the amount of supplementary oxygen at 36 post menstrual weeks. Hemoglobin F

hemoglobin in general, pH, O2Sat and partial pressure of oxygen and partial pressure of carbon dioxide were obtained from arterial blood gases performed during the first seven days postnatally. Any venous or cap gas were excluded from the study. So very, very rigorous, simple collection. Let's get into some of the results. This is a paper that I really enjoyed. The graphs are spectacular. If you are

an investigator, please look at this paper, how graphs can make such a big difference. 440 infants are included in this observational study. The gestational age, the mean was 25.9 weeks. The mean birth weight is 876 gram. Mortality reported as death before 36 weeks was about 12%. And 379 infants then survived to reach the point of BPD diagnosis at 36 weeks. And...

Ben Courchia MD (40:37.37)

of those babies that survive, 56 % developed BPD. So it's still a big disease. I know we beat BPD to death, but there's work to be done, The total number of blood gases that they were able to analyze per postnatal day was 10,015.

In terms of evaluating the different relationships, I'm going to go through a few results. have three results that I want to share with you. So evaluating the percentage of fetal hemoglobin in relation to postnatal age, gestational age at birth and sex, it showed a decline in hemoglobin F in relation to increasing postnatal age, which was increasingly prominent as the babies were less and less mature.

So if you look at these graphs, you'll see that the degree of hemoglobin F basically has a negative slope. It goes down over the first seven days. But when they stratify these curves and look at it from 22 to 24 weeks or 25 to 27 weeks or 28 to 29 weeks, you can see that the decline is much sharper for these less and less mature infants. There was no significant difference in how sharp this decline was when you compared the different groups based on sex. So boys and girls,

similar pattern. In terms of oxygen requirements, as determined by the FIO2 and the AA gradient respectively, the oxygen requirement decreased from birth until about postnatal age three in all gestational age subgroups. And there's a clear shift, they say, that happens on postnatal age three days, from three to seven days, in which the babies with the low gestational age,

tend to have a continued decrease in their FIU2, while the babies that were more mature... I'm sorry, I'm going to say this again, I made a mistake. So the babies with the lower gestational age had a sudden increase in their FIU2 after day of life three, while the more mature infants, the one in the 28 to 29 week group, sort of saw a continued decline in their FIU2. So it's kind of... Yeah, and it's interesting to see that...

Daphna Barbeau (42:52.305)

You mean the honeymoon period?

Ben Courchia MD (42:57.082)

Maybe our 28 weaker and 29 weaker stay on this honeymoon phase. may be less pronounced, but it continues while the 27 weekers or less tend to have a literally like 90 degree turn where their curve takes an inflection point and the FiO2 goes up significantly.

Daphna Barbeau (43:01.288)

Mm-hmm.

Daphna Barbeau (43:11.775)

Yeah.

I mean, don't we feel that clinically, right? We see it all the time.

Ben Courchia MD (43:16.84)

Absolutely. Absolutely. that's then the last thing that I wanted to talk about is that when they evaluated the influence of the fetal hemoglobin on the respective determinants of oxygen requirement in relation to postnatal age, gestational age at birth, and PCO2, what they found was that the FIO2 and the AA gradient respectively were inversely associated with the percentage of hemoglobin F, and these relationships showed a strong interaction with postnatal age.

The inverse association became more apparent with increased postnatal age with an approximately 10 % reduction of FiO2 and a 16 % reduction in the AA gradient associated with an average 20 % in increased fetal hemoglobin by postnatal day 7. There's some beautiful graphs there that show you this, where you're looking at

the correlation between the percentage of hemoglobin F and you're looking at on the figure is divided into two, you have one set of graphs that look at the FIO2, one set of graphs that look at the AA gradient, but you can see that the percentage of hemoglobin F is very much correlated, especially after the postnatal age four to seven days between the percentage of hemoglobin F and the FIO2 and same thing with the AA gradient.

So I think it's a very interesting paper that shows how decreased fetal hemoglobin is associated with increased inhaled oxygen requirements during the first postnatal week and very preterm infants. This association, they say, remains strong after adjustment for other factors with a modifying influence on hemoglobin oxygen affinity. Increased oxygen exposure in the alveolar space may aggravate oxidative stress and inflammation and thus be causal in BPD development. In terms of...

The association with BPD, don't think the data was very conclusive in this particular study, measures directed at counteracting premature replacement of fetal hemoglobin may prevent neonatal morbidity. They're mentioning this ongoing multi-centered prospective randomized control trial that is currently evaluating the effect of minimizing iatrogenic blood loss in extremely preterm infants on neonatal morbidity and mortality. So I think it...

Ben Courchia MD (45:37.492)

So since a stark reminder of us drawing blood, us getting root quote unquote, I hate the word routine labs on these babies, not only just has an effect on depleting the blood stores of our babies, but also has an effect on shifting the makeup of their hemoglobin and potentially affecting their long-term outcomes in terms of some of these.

of these metrics.

Daphna Barbeau (46:09.186)

Super interesting. Well, isn't it nice when the physiology helps explain what we're seeing clinically? It's cool. Yeah.

Ben Courchia MD (46:17.494)

Love it. I that's why I spent my time reading this paper. This was a tasting.

Daphna Barbeau (46:26.903)

All right, I have a paper. I know you've been looking forward to. I've been looking forward to. It's entitled Outcomes After Intranasal Milk Therapy in Preterm Infants with Intraventricular Hemorrhage. Lead author, Alessi Gallipoli and senior author, Rebecca Hobian. This is in the Journal of Perinatology and it's out of Toronto. So it was a phase one trial. They underscored that it was not powered, right? So they were really just looking at...

safety of doing this intranasal milk therapy. They have reported on this before, both from a safety perspective and looking at post hemorrhagic ventricular dilation. So this time they wanted to look about again safety and feasibility at looking at intranasal

milk therapy, so as a way to provide basically stem cells to preterm infants with IVH. The secondary outcomes included some short-term outcomes to NICU discharge and longer neurodevelopment outcomes to 18 months corrected age compared to recent historic human milk fed controls. So wasn't a randomized control trial. They had this cohort of babies who got intranasal milk therapy and they have

a set of historical controls. They enrolled babies for the intranasal milk therapy between July 2020 and September 2021 at two tertiary NICUs in Toronto. Inclusion criteria included preterm infants born under 33 weeks gestation with any grade of IVH, they were using Papille classification.

And this had to be identified on head ultrasound in the first 10 days of age. And they needed to have a lactating parent because they only used fresh human milk. Exclusion criteria included known disorders associated with neurodevelopmental impairment, infants with planned redirection of care, choanal atresia, or other anomalies that would obviously prevent intranasal treatment.

Ben Courchia MD (48:38.654)

obviously.

Daphna Barbeau (48:40.97)

surgical conditions for which intranasal human milk was felt to be contraindicated by the clinical team, parents with lactation contraindications or who did not initiate lactation, or a lactating parent who was unable to provide fresh human milk. So unable or unwilling to pump in the NICU or have fresh human milk delivered at least once a day for three days within three hours of pumping. So they did help.

families with this. provided a courier service so that they could literally get fresh milk within three hours of pumping. But they only provided it to families who were 30 kilometers or less from the study site. So if you were farther away, you couldn't get milk soon enough, then you were excluded. So

I'll tell you a little bit about the protocol. They start with a human milk dose of 0.2 mL administered into one nostril within three hours of pumping. They just use a standard oral syringe just inserted within the Nair. And then basically if that was tolerated, the dose was increased to 0.4 mL given before and after a nursing touch time.

ideally twice a day for a total goal of 1.6 mLs per day. And this was figured out based on the stem cell concentration. They discussed that in this paper and previous papers. And then administration was started as soon as possible after recruitment. So the latest is at 10 days of age. And remember, this was only for babies with known IVH. And it continued whenever fresh milk was available through 28 days of age or transfer from the NICU, whichever came first. So they looked at the NICU, you know, some of the

major comorbidities up to NICU discharged. And then at four, eight and 12 months corrected age, they looked at some neurodevelopmental outcomes. They used the AIMS, the Alberta infant motor scale, the PFMAI, the posture and fine motor assessment of infancy. They looked at hearing and vision tests, weight, head circumference and continued human milk feeding. So was a yes or no question. Is your baby still getting human milk or not? Some parents and babies were not able to come in person because it was still during

Daphna Barbeau (50:53.986)

the height of the pandemic. And so if they weren't available, they did an ages and stages questionnaire. And then at 18 months, they had a neurologic exam and a Bayley three. Okay, the results. So they had 37 eligible preterm infants and they had, I wanted to tell you, 191 historic controls to compare.

So of the 37 treated with intranasal milk, three infants or 8 % died from causes common in preterm infants. had neck or sepsis during the study period. 14 infants had administration stop prior to 28 days. So that's a huge proportion of the babies. This included the three infants who died, three infants who had care that was withdrawn, and eight infants who were transferred to another hospital. So almost...

40 % of their babies did not make it to the 28 days. Study infants received a median of 17 days of intranasal milk treatment. 97 % received at least three days, which was the minimum target, but obviously a much lower amount of milk and stem cells. And when you looked at the historic controls, 11 % died before discharge.

groups were similar in gestational age and birth weight, and they did not have a lot of differences in NICU comorbidities. However, there were a lot more infants with severe IVH in the intervention group. So I think that's important to note, in particular grade four IVH, a lot more in the intervention group.

There was no significant difference in post hemorrhagic ventricular dilation. One infant in each group required surgical intervention. The intervention groups, the group who got milk was noted to have significantly more PVL, an odds ratio of 12, and NEC, an odds ratio of 2.27 when weighted for confounding baseline characteristics of IVH grade, birth gestational age, and sex. And then in terms of the

Daphna Barbeau (53:12.492)

Developmental outcomes, intervention infants were less likely to have fine motor delays, and they were more likely to have prolonged exposure to parental human milk after NICU discharge. There were no other significant findings when comparing the four, eight, and 12-month outcomes, and there were no statistically significant differences in the Bayley scores at 18 months. They discussed some trends, but again, nothing was statistically significant.

him. So I was disappointed, I guess, to say the least. I'm not sure they had enough babies to see what they were looking for. It wasn't a randomized controlled trial. There were way more that had severe IVH, so, you know, increase in PVL, but it didn't show what I was hoping for. That's for sure.

Ben Courchia MD (54:11.158)

Let me ask you something because my biggest... So first of all, I think it's unfortunately a study that it's hard to know what to make of the results, right? Because it's a small sample size, et cetera, et cetera. But I think that what doesn't get underscored enough is the fact that we don't really know whether this is the right way of using milk and its stem cells. And I'm very worried that these studies might come out. Let's say being pessimistic, the studies come out and the results are not positive.

Daphna Barbeau (54:31.35)

Mm. Mm-hmm.

Ben Courchia MD (54:41.206)

are we going to just put this in the closet and be like, yeah, so it doesn't work, right? When in truth, it's like, well, maybe the 0.1 or 0.2 MLs you're using and the way you're delivering, it doesn't work, but maybe there's another way that works. And I think that's what gives me a little bit, that's what depresses me a little bit. I just don't want the momentum to stop, if that makes any sense.

Daphna Barbeau (55:02.05)

Yeah, for sure. I mean, the idea is a great one. you know, I mean, play devil's advocate, there's obviously there are some concerns, right? Infectious concerns. People most commonly when we have talked about this locally have asked about CMV, things like that. But so far that hasn't come out of their research. But I think they need a much, much bigger trial before they hang this one up.

Ben Courchia MD (55:29.95)

Yeah. Okay. And it was kind of confusing, by the way, to see these long-term outcomes. Susan Hintz would cut my head off right now. But these 18 months corrected age outcome, they were not terrible. They were not terrible. And they were not...

Daphna Barbeau (55:32.929)

Your turn.

Daphna Barbeau (55:37.802)

Yeah. Wraith.

Daphna Barbeau (55:51.554)

I mean, that's a whole different discussion, right? When we talk about the long-term outcomes, in particular, some of these severe IVH, that is a blossoming discussion in the neonatal community. The outcomes are certainly, there are babies still with severe outcomes, but they're not universally severe like we had previously thought.

Ben Courchia MD (55:58.336)

Mm-hmm.

Ben Courchia MD (56:12.168)

Right. All right. We're close to, well, I mean, with our break, we're now over an hour of show. I think you have one more paper, and I think I might just save my last one for next time. So I'm going to let you go again. yeah.

Daphna Barbeau (56:30.594)

Sure, no problem. So I had this paper, Clonidine is Monotherapy for Neonatal Opioid Withdrawal Syndrome, a randomized trial. Lead author Henrietta Bada, trailing, senior author Marcos Lega’s. This is in pediatrics. This study was an intention to treat double-blind trial between 2017 and 2022. So basically babies were randomized to either clonidine or morphine.

This comes to us out of Kentucky. The primary outcomes included length of treatment, length of stay, and this post-treatment neurobehavioral status. used, sorry, let me tell you. They used the NNNS, the NICU Network Neurobehavioral Scale. So I'll talk about that in a little bit. Enrollment criteria included a gestational age of greater than or equal to 35 weeks.

Also, any prenatal opioid exposure with or without other substances from the mother reporting opioid use or positive toxicology results. Less than or equal to seven days postnatal age. Not unlikely to survive. So the baby was expected to survive. No medical condition other than NOWS. No seizures. No prenatal cocaine exposure in particular because they were using the NNNS, which really relies on tone.

The dog doesn't like the study.

Ben Courchia MD (58:00.374)

You

Daphna Barbeau (58:02.402)

Hold on a second.

Ben Courchia MD (58:08.98)

I could edit this where you can pretend to have a conversation with your dog and have your dog respond to you. And people are like, wow.

Daphna Barbeau (58:09.996)

Yeah, we're just going to have to cut this out.

Daphna Barbeau (58:17.09)

She's not well trained. She's not going to speak back to me, but I don't know what she's mad about. Do you want me to go check?

Ben Courchia MD (58:23.926)

Do you want to go take a look? I don't mind.

Ben Courchia MD (58:32.519)

No.

Daphna Barbeau (59:19.625)

Okay, I'm back.

Okay, so no medical condition other than NOWS, no seizures, no prenatal cocaine exposure, because they were using the NNNS that really relies on tone as a marker, meets treatment criteria for NOWS and obviously have informed consent. So all the infants still received non-pharmacologic intervention, swaddling, low noise, low light.

Rooming in infant massage, infants were monitored using the Finnegan scoring system. And then clonidine or morphine was started when an infant had three consecutive Finnegan scores greater than or equal to eight or two consecutive scores or greater than or equal to 12. Now, they talk a little bit about the dosage. This is something that had been studied before and babies were given medication Q three hours. They talked a little bit about the weaning.

after 24 to 48 hours of stabilization, weaning began by 10 % of the maximum dose every 24 hours. If the Finegan stores increased during weaning, the dose was increased to the previous dose and then weaning resumed after 24 to 48 hours. Now, so I told you it was about morphine versus clonidine, but if there was no improvement noted at the maximum dose, phenobarbital was added as a concomitant therapy to both arms.

at a loading dose of 10 mgs per kg and maintenance dose of 2.5 mg per kg, Q12 hours. Now this is interesting and they don't totally give you all the details in the results, but some, quote unquote, some attending physicians preferred clonidine or morphine as an adjunct. So infants were allowed to receive either morphine or clonidine as a secondary drug. And then they note...

Daphna Barbeau (01:01:14.74)

So if you weren't getting clonidine, you were able to get clonidine as the adjunct. If you weren't getting morphine, you were able to get morphine. But they note that the babies were still blinded. So I'm not sure how the physicians could pick and everybody was still blinded, but I digress. I told you a little bit about the neurobe.

Ben Courchia MD (01:01:34.644)

It makes the question, first of all, I mean, think you could be blinded from the standpoint of saying, hey, do you want therapy? Yes, no. And then if the symptoms don't improve, you can say, hey, I want an adjunct. And then they will give you what the adjunct should be. But it does feel like the titration and management would be very different whether you were on morphine alone or on adenine. So I'm not exactly sure how the day-to-day would work.

Daphna Barbeau (01:01:52.46)

Sure, that's true.

That's true. So still, let me get to the results because I'm not sure they're as you expected either. So basically, they use the NNNS. So basically, they need to get the baby in a sleep or quiet state all the way to crying. And most infants with severe withdrawal are unable to complete this assessment. So

Ben Courchia MD (01:02:01.612)

huh. Yeah, for sure.

Daphna Barbeau (01:02:26.078)

after withdrawal signs started to improve and they were weaning the doses, they had certified research nurses who were blinded to the treatment assignment performing the assessment. So all in all, they had 120 infants, 60 in the morphine group, 60 in the clonidine group. Five infants were withdrawn, two from the clonidine and three for the morphine group. Before treatment, the median of the maximum Finnegan score, so their kind of baseline Finnegan score was similar in both groups,

14.5 for clonidine and 14 for morphine. The vinaigrette sores decreased subsequently in both groups. However, by the third day of treatment, the maximum vinaigrette score was significantly lower in the morphine treated group with a median score of eight versus 11.5 in the clonidine group.

And then they show us this table that looks at the scores over time. And there were similar patterns of mean Finnegan scores over time for both treatment groups and the subgroups with monotherapy. So the babies that did not get either phenobarbital or other medication in addition. Mean Finnegan scores, I told you, were similar at treatment initiation. They had this pronounced drop by the second day of treatment. It was much lower, so much quicker decline with morphine.

However, after six days, the mean daily scores of clonidine group trended to be a little bit lower than the morphine group, but at each point time, the confidence intervals overlapped. So they kind of traded places. Duration of treatment, one of the main outcomes, the length of treatment did not differ significantly between treatments. So 17 days for clonidine and 15 days for morphine. There was also a...

no significant difference in length of stay. So for the clonidine group, 22 days, and the morphine group, 19 days. And those receiving the single therapy, so they didn't get phenobarbital or they didn't get kind of cross treatment, the length of treatment was similar for clonidine and morphine subgroups, 14 days for clonidine, 14 days for morphine. The mean total morphine dose per patient in the clonidine arm, so babies,

Daphna Barbeau (01:04:46.316)

who got clonidine, still got a lot of morphine, was 5.5 milligrams as compared to 9.1 milligrams in the morphine arm. The clonidine-treated infants who also received morphine had a mean standardization of 27.7 milligrams of total morphine dose per patient.

And then they wanted to get more details about this need for adjunct medication. So more clonidine treatment infants required adjunct therapy than the morphine treated infants. 45 % of the clonidine treated infants still required adjunct therapy as compared to 10 % in the morphine treated infants. The results were similar even when they took out the subjects that were withdrawn.

They did a number of analyses. The adjusted odds for adjunct therapy were, like I said, higher for clonidine and odds ratio of 58.85. And there was no other factor except heavier birth weight that was associated with adjunct therapy, which was interesting. For the NNS, so the neurobehavioral scores, the time to first assessment was sooner in morphine groups. Those babies were ready for the assessment sooner, three days compared to five days. The time to the last assessment was not different.

And the results were similar when comparing the monotherapy subgroups. So at the initial testing, the clonidine-treated babies scored worse on their first test, their first evaluation. The clonidine-treated babies had more arousal, hypertonicity, and stress. But between the initial and the final assessments, those babies caught up with the morphine.

with the morphine treated infants. So she showed significant improvement, less excitability, improved arousal, and regulation. So at the completion of treatment, the clonidine treated infants did as well as those who were morphine treated in the neurobehavioral performance, but the babies who got morphine got there sooner. So.

Daphna Barbeau (01:06:57.91)

Basically, Clonidine is an option as a monotherapy. It did okay, but 50 % of those babies still needed an adjunct therapy and it seems like the symptoms were potentially less well controlled. So, not what I was expecting either from this study, but.

Ben Courchia MD (01:07:18.038)

It's not, it depends. think that you nailed it on the head. It's not what you were expecting. You would have liked to see, they did great. 99 % did fine on just Clonidine. But the truth of the matter is like, if you think about it, I'm going to pose the question to the audience, if it was your child, right? And let's say, I'm going to say that in the case of now's patients, there's definitely, in my opinion, two different types of families. I've seen that there's

Daphna Barbeau (01:07:25.086)

Mm-hmm. They did great. They crushed it.

Daphna Barbeau (01:07:44.386)

Hmm.

Ben Courchia MD (01:07:47.22)

the family that's going to be at the bedside pretty much 24-7, right? The mother is going to be there. parents are going to soothe the baby and they're going to be so involved. That's type one. And then there some, unfortunately, where maybe because of social reason or anything there, they're less present. But I'm saying assuming type one, assuming that you have tremendous support from the family, wouldn't you think that this is a path that you would offer to parents to say, hey, we could try just Clonidine and see how it goes?

Daphna Barbeau (01:07:50.562)

Mm-hmm.

Daphna Barbeau (01:08:06.914)

Mm.

Daphna Barbeau (01:08:13.442)

Mm-hmm.

Ben Courchia MD (01:08:16.014)

Yeah, it's a coin flip. Maybe in 50 % of cases, we'll need to do the morphine anyway, but maybe we won't. And maybe we will avoid exposing your baby to morphine. I would say that if I am not, my medical history would say that I have no toxic habits. But if I was in a position where my child was in this predicament, I would want to avoid exposure to morphine at all costs.

Daphna Barbeau (01:08:23.106)

Mm-hmm.

Ben Courchia MD (01:08:44.52)

And if I'm willing to tolerate the maybe slightly worse than Finnegan scores early on, maybe it's something that we can offer to families with some support from the evidence of saying, well, we know it's not going to increase your length of stay. So it's not going to be more healthcare utilization. Maybe and maybe likely they'll be, we'll be back exactly where we should have been in the beginning. But if you are part of that, whatever.

51 % of kids who may not need the adjunct, then that's a, in my opinion, that's a win.

Daphna Barbeau (01:09:17.462)

Yeah, it's hard because just like all the other pathophysiology is we lump now's babies all into this one category and the now's baby who the prenatal exposure was say suboxone versus multi substance abuse versus I don't know, just one opiate use.

Those babies are not the same, right? But we're lumping them in and I'm hopeful in terms of research that we will start to differentiate those groups because I wonder if the treatments would be different by category, I guess. So.

Ben Courchia MD (01:09:59.21)

Yeah, I think so. I absolutely think so. And I think that, again, what I'm going to say may sound negative for our nurses, but it really isn't. Like, our nurses are suffering from staffing ratios and whatever. So they cannot be at the bedside 24-7. Like, our nurses have to care for a baby and move on to their next assigned patient, whether it's a one nurse for two babies if you're in a great institution, or whether it's one to three, or sometimes one to four. And so it's hard to attend to the needs of a baby in withdrawal.

Daphna Barbeau (01:10:11.916)

Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm.

Ben Courchia MD (01:10:29.166)

if you are a NICU nurse, but it's different if you're the mother of that baby and you can be there or the father of that baby, you can be there. Really solely dedicated to your baby. you can be, mean, we've worked in these institutions where you have the luxury of having private rooms. So you can put this family in a, in a dark, quiet room and, and you can, you can really manage these babies very well from a non-pharmacological standpoint. But if you are. Yeah.

Daphna Barbeau (01:10:51.362)

Well, on that we know for sure, right? If you have that opportunity, that's the way to go.

Ben Courchia MD (01:10:56.522)

Yeah, but if you are dealing with a patient that's born to a parent that's in like, I don't know, in the correctional system, unfortunately, and like you are in an open bay unit where I'm going to say this, I'm going to say this on the show, but okay, like some of our lights in our NICU don't turn off, for example.

Daphna Barbeau (01:11:04.416)

Yeah.

Daphna Barbeau (01:11:12.286)

Doug, it is my hottest button topic.

Ben Courchia MD (01:11:16.815)

So I'm saying, I pressed it at 71 minutes of recording. And you're right, but there's like, yeah, there's all these hospital codes that they say we can't lower, dim the lights or whatever. Like it's a very different situation. think it's kind of nice to have all these options in our toolbox. So let's see what happens. I think it's something I would discuss with families.

Daphna Barbeau (01:11:32.396)

Mm-hmm.

Daphna Barbeau (01:11:44.52)

And I still think we haven't found the right med. I think there's something else out there, fingers crossed.

Ben Courchia MD (01:11:51.924)

Yeah, I think better access to services for mothers who are in the situation in Italy is a

Daphna Barbeau (01:11:55.584)

Well, that's a whole other intervention.

Ben Courchia MD (01:11:59.86)

We are very, I'm going to transition to the outro of this episode then since we can, but yeah, so we're going to have, every year we try to make a point of having a few episodes or some dedicated time on the incubator for advocacy. Our great partner in this endeavor is Dr. Shadr Shaw. So he is the one keeping us on track. And so this year we're very excited to have another episode on neonatal advocacy.

Daphna Barbeau (01:12:04.268)

Okay.

Daphna Barbeau (01:12:13.154)

Hmm.

Ben Courchia MD (01:12:28.898)

So stay tuned for that. It's going to come up I would say either next week or the week after but anyway, so stay tuned for that and we're going to continue to have All the different series on the incubator podcast and some new series that are coming out in the next few weeks Most notably we're going to have dr. Nim Goldshtrom and dr. Adrian Bischoff join the team on a more permanent basis They're going to do more recurrent cardiology journal club So we're going to try to give neonatal cardiology a bit more of a presence on the podcast and we're going to have

Daphna Barbeau (01:12:57.462)

Does that mean we review less cardiology papers? that what that means?

Ben Courchia MD (01:13:02.004)

Well, am very happy that I'm maybe, you know what, the truth of the matter is that you and me, maybe we will be able to read a bit less papers. And I'm very happy that it's Nim and Adrian who's going to, we're going to break down some of these.

Daphna Barbeau (01:13:09.068)

That's right.

Yeah, I think you guys are going to love these episodes. I think they're great.

Ben Courchia MD (01:13:16.02)

Yeah, and I think too that for us it was important because I think that Daphne and I are seeing less cardiac babies as these neonatal cardiac units are coming up and Neiman and Adrian take care of these babies on a daily basis. So they have such an in-depth knowledge of how to care for them and they have tremendous experience. So that's exciting. And we have a new segment as well that's going to come up before the end of the year called Neo News. I'll let you.

Daphna Barbeau (01:13:26.164)

Emerging, yeah.

Ben Courchia MD (01:13:45.92)

I won't say more. No, it's very exciting. Neo News is coming up with a new addition to the incubator team as well. All these are exceptional, and I'm very excited to bring them to the incubator network. So stay tuned. All right, definitely this was fun. I'll talk to you later.

Daphna Barbeau (01:13:47.234)

You won't say more. Am I supposed to say more? No, it's a surprise. It's a surprise.

Daphna Barbeau (01:13:54.817)

Mm-hmm.

Daphna Barbeau (01:14:03.586)

Stay tuned.

Bye, buddy.