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#001 - Journal Club 📑 (1)

Pilot episode (we apologize for our subpar audio on this one :)

Daphna and Ben review some compelling articles that were published in the April edition of the Journal of Perinatology.

Please follow the link to access the Journal:


The transcript of today's episode can be found below

Ben 00:00

So this is our first podcasts. It's very exciting. And today, we're going to go over some of the articles that came out in Journal of parasitology, the April edition. So should we start with last month's issue of this donor milk and exclusive breast milk study versus formula that looked at ivh and PVL?

Daphna 01:14

Well, I think we can't get away without talking about it. Obviously, you know, that I think breast milk is really important. And I think we're going to learn over time how important it is. But this, this article was a little complicated.

Ben 01:30

It was but I think it it goes with sort of what your sentiment is, which is that, yeah, EDM, breast milk and donor milk is best. And so just for the people who haven't read this paper, and it was published in the last edition of the Journal of parasitology, in March, and it comes from Dr. Caroni. And senior author is Brian Parvez. They're physicians and researchers from Westchester Medical Center in the state of New York. And what they did was really to compare sort of the evidence of the incidence of severe ivh and periventricular, leukomalacia PVL, between two groups of babies who were extremely low birth weight, and comparing whether they received human milk versus formula. And there's a lot of things going on with this study. And I think the most critical aspect of it is its design. It was not prospective, it was retrospective, and they spanned a wide timeframe from I think 2012 to 2017. And, and they went over some of the feeding protocols where the feeding protocols seemed fairly standard. I don't know what you thought about it.

Daphna 02:53

Yeah, I thought they I thought that was pretty consistent to you know, things that we've done the both of us at different institutions. But, for example, they had a wide range of the epochs had different, you know, fortification, there are different things that part of the human milk protocol that they had that were different over time.

Ben 03:18

Right. And, and I agree with you, I think they offered colostrum to every preterm baby within the first 24 hours of life, they started with like trophic feeds at around 20 mL per kilo, they went up by 20 mL per kilo. I thought that the honesty of disclosing their whole feeding protocol, it's something that is so controversial still, that it required a lot of guts I think. I think it was interesting to see also that at some point in the paper, they wrote something to the effect of the decision to hold fees was based on Nitro protocol, which takes into account gastric volume and types of residuals. And considering the, the sort of

Daphna 03:59

the discussion around residuals,

Ben 04:01

along with residuals I was like, Oh my God, that they're gonna get knocked out for this. And then so the crux of the study is that they divided their babies into two groups, some of them that were exposed to, to bovine sort of feeds and and I'm going to read it from you from the from the from the paper itself and said the Eh M, which is the exclusive human milk cohort, consisted of all infants who had no exposure to bovine proteins, and received the data of only consisting only of maternal milk and or donor milk fortified with human milk derived fortifiers and colostrum. And then they had an Nan Eh M group that consisted of infants who had any exposure to bovine protein provide milk derived human milk fortifier and or formula prior to 34 weeks. And so their findings were interesting. Looking at head imaging results, grade three, grade four ivh PVL. Well, individually, they had found no difference in the incidence of it. Ah, only, they found no difference in the incidence of PVL, only ivh mpbl was not really significant either, however ivh and or PVL, that they found significance. And so the bottom line is that in their conclusion, they wrote that exclusive human milk diet had an independent neuroprotective effect, and was associated with decreased incidence of severe ivh and opdl supporting the need for exclusive human milk in LBW infants. Obviously, there's a few. There's another modifier, I think that we should talk about is the fact that their rates of any C, were significantly different between the two groups, sort of not really unexpected, because the human milk group had 5%, instead of versus 17%, in the non human milk group. So that's sort of what they found. And yeah, I'm curious to see what what your thoughts were on this study, specifically? Because I have, there's one specific issue that really bothered me, but but I want to see what you what you had to say first?

Daphna 05:58

Well, I think, you know, the authors provided a really good path of, you know, physiology for why this would work. And we know that breast milk has, you know, some innate properties that could theoretically be protective. What I, what I really wanted to hear more about is what did what does the first week look like in their institution? You know, really, you know, how many of those babies actually get started on the first day of life? Or the second day of life? And how, what proportion of milk are they getting in the first week of like, how different was milk to non human milk in that first week of life, when we know that the majority of IBH happens. So they follow these babies, you know, through the term, you know, corrected age where the bulk of their feeding takes place. But we know the bulk of it is happens in the first week. So I would have liked to see a little bit more information about that first. And I

Ben 07:00

think you're pointing to one of the responses that was sent this this month to the journal from Praveen Kumar, who talks about specifically to saying that there's plenty of good explanation as to why breast milk could have prevented and been protected for ivh and or PDL. But the the the the reply sort of suggests they're saying that there's several studies that have demonstrated that nearly all ivh in preterm infants occur in the first 72 hours of birth. And a significant proportion of these occur as early as within the first six hours of life. And they're touching exactly on that point, which is, so what exactly happens during that time? And how much does happen, so that it actually does provide some sort of significant effect? And I think that was a very valid sort of question. Because it's true, that it's not really the author's fault. I think providing colostrum within the first 24 hours of life is standard protocol. But how much is actually being given? How much of that actually provides an effect? is a big question. Obviously,

Daphna 08:05

I think the author's touched on another part that, you know, I feel strongly about is actually getting the oral stimulation and oral feeds. And it's interesting, right? Because one of the groups the non human milk group wasn't exposed to that at all. And so how much is kind of that intervention versus the type of feeding itself? It's hard for us to parse out.

Ben 08:33

Right. And there's, there's the doctor Kumar, who, who wrote this response to the article, also add something that I thought was very pointed, which was that she would have liked the authors to provide more information on the use of practices reported to have an impact on the incidence of ADH, such as Do they give prophylactic indomethacin position of the head and so on and so forth? Especially considering that the cohort spent such a wide range of time, and that it's a retrospective could could there be differences in practices? I think those are those are important factors. And the author's did respond. And for the most part, they mentioned what you mentioned that the colostrum oral care within the first 24 hours of life does provide some protective effect against ivh. And that they they suggested that they had no changes in their practices over the five, seven year periods that they covered, which I'm more than happy to believe and they know their unit better than anybody else. There was another interesting reply to this article from from Dr. Rezac, who is somebody that I've befriended on Twitter, and who is from Saudi Arabia, if you're on Twitter, I think he's a very good follow up dual Prozac. He always sort of dissect articles in a very sort of dry manner. And he always has good insights. So he was mentioning something very interesting, which was that the author's did do some corrections, in order to evaluate the association between breast milk and ivh, and PVL, one of these being anti natal steroids. So they corrected for that, rightfully so. But then he points to the idea of whether or not it was necessary to correct for NEC, the authors did correct for the difference in the incidence of NEC between between babies who received human milk versus formula. And she was saying that's an inherent effect of the diet itself. So maybe controlling for NDC, he says, would be inappropriate, as it would partially close an indirect causal path, thereby attenuating, the observed association between hm, and ivh or PVL. And I thought that was very interesting.

Daphna 10:58

I do think there's, there's something here though, so I'd love to see the groups of babies who do have bleeding in the first week of life, and then really following what does their diet look like? And their long term developmental outcomes? I think, can is there some regenerative capacity or rehabilitative capacity of our diets on, you know, brain injury? So, you know, I think they're on the right track.

Ben 11:26

And so what was interesting was that the authors did respond to that query, saying that, obviously, had ultrasounds were done within the first week of life, and he sometimes develops later in life. And so it's difficult, it's a very difficult question to answer, obviously, whether or not to correct. He points out to some differences as well, in some of the odds ratio that had to be corrected. I think that was done. But overall, I think that was very interesting, because the conclusion of the article together is something that is not really surprising. It's something that we expected that human milk is fares better in overall outcomes, especially now in this case of ivh versus PDL. And, but the methodology of the paper obviously left a lot of questions unanswered. And I think that has to do with the wide timeframe that they chose 2012 to 2017. And the fact that it was retrospective, it's very hard to control so many variables during a large timeframe in the study that involves so many different variables. Okay, so then, I think that the next article that really we should touch on is the article that comes from your former institution, the University of Florida. This article is called comparing head ultrasounds and susceptibility weighted imaging for the detection of low grade hemorrhages in preterm infants. And it's a good article to follow up with because it's going to get us to go right back to that study from Westchester, about ivh and PVL. So did you get a chance to go over that article?

Daphna 12:55

Well, of course, how could I not review that article? But I think I think it is important to it was an important study to do, especially since so many centers are moving away from term corrected MRIs. But nobody had actually really done the work to say, you know, what is the value other than the cost analysis of the term? Correct.

Ben 13:21

And I think they points to that directly in their discussion. And they quoted the 2015 sort of choosing wisely and newborn medicine, from the AAP that recommended avoiding routine use of equivalent of term equivalent MRIs in preterm neonates, due to the insufficient evidence that this screening MRI would benefit the patient's long term outcomes. And I think that that paper directly comes to sort of contradict this recommendation, because it highlights a lot of issues with with ultrasound. So do you want to summarize this study for us before we go into the details?

Daphna 13:53

Yeah. So basically, what the team did is they took the one week, the seven day head ultrasound, and compared it to the term corrected or it's kind of 36 week had ultrasound or MRI, excuse me, that's kind of standard of care still in that institution. And what they looked for is, what was a congruence between those two imaging studies on the findings, and interestingly, they saw a few different things. And so obviously, had ultrasound was very good at detecting high grade bleeds, stage, you know, grade threes and grade fours. Not as good at detecting low grade ivh, which was later detected on the term corrected MRI. And then what we already know about head ultrasound is that it frequently misses periventricular leukomalacia, which we know impacts neuro development. Something else that they added, which I thought was interesting is that and Sometimes we can even have an overestimation of the low grade ivh. And the athletes talked about how this impacts the parental stress and the beginning of the admission, and how sometimes it's all that they can think about. And so are we adding undue stress to the parents by over estimating some of those low grade leads? I think something else they touched on, which was so interesting, they had really good discussion about kind of caregiver or our caregiver distress for having to report findings on a term corrected MRI that we didn't previously know about. And so much of that does change our practice, I think. But just because it makes us uncomfortable, or we don't know exactly what it means doesn't mean that we shouldn't be talking to parents about it. So I think they had really robust discussion. I think that given the literature that is continuing to come out about how even the lower grade bleeds, unilateral bleeds, do change outcomes for babies that, that we owe it to families to give them as much information as it's possible. I'd love to hear your thoughts. Yeah, no,

Ben 16:16

I thought I agree. I agree with everything you're saying. I think it was a very interesting study, because there's been more and more data that has come out in recent weeks and months about how low grade ivh is just not so it's just not nothing. And we used to think that to grade one or grade two meant everything was going to be fine. And for long term neurodevelopmental outcomes, there was no independent dissociation in and of itself with mild, mild ivh if really, there was nothing else going on. And many, many physicians have tailored their discussions with the family towards that, that data saying, Well, if you have a great one or a great two, then then no big deal. And that recent data has shown that no some some of these babies do develop. Cerebral Palsy have long term neurodevelopmental outcomes that are impaired. And so it has already started to change how we talk to families about grade one inquiry to now this paper highlights the fact that the head ultrasounds are just not very good at detecting mild ivh. And they had this very nice matrix that looks at sensitivity specificity, the positive and negative predictive value of head ultrasounds. And you could clearly see that for the severe types. The sensitivity specificities were always above 90, sometimes above, above 80, sometimes above way above 90%. But for low grades, it was actually very, very poor. And so it adds another level of nuance that will need to be introduced, in my opinion, when we talk to families about a normal head ultrasound. And it reminded me of this, of what this author Dr. Nassim Taleb, who wrote the book anti fragile, and talked about some of the issues associated with how we interpret data. And he always made that difference between the evidence of absence versus the absence of evidence. And I thought that was exactly what this paper was touching on, because we'll have normal head ultrasounds, and we'll be very encouraged to tell the families this is great news, all the while this may still be hiding a low grade ivh that potentially has long term implications. So we'll have to move I guess, towards what this interlab is talking about saying, Well, we have a normal head ultrasound, which means that there's the absence of evidence, but it doesn't mean that there's evidence of absence. And so I think that's that's that was that was very, very cool. And also to have that breakdown of the different babies that crossed categories between cerebellar hemorrhage, and all these other things that are being picked up on MRI. I think this was very interesting to actually get the magnitude, especially when they're represented in percentages. It's it's quite shocking.

Daphna 18:58

Yeah, I think the the part particularly actually about cerebellar hemorrhage I had underlined here is, we know that that will likely impact motor development, and so to not have that information for parents to not have them looking for that, I think can be really a significant cause of morbidity for babies. Certainly, it adds parental stress, but it does, it does give them something to look for. But I think you hit the nail on the head that we're just so hopeful, especially in a very extremely preterm infant to give the parents any kind of modicum of hope or that things are going well. And so we're so excited to say that ultrasound is normal or it's low grade. When really, I think we're also missing an opportunity to talk to parents about what does long term outcome for the preterm baby, just by nature being preterm, regardless of ivh or PVL really look like and there are some long term features that I think that we're not discussing. So I think this paper hopefully will ask people talking a little bit more about what does our anticipatory guidance for families look like?

Ben 20:12

Yeah, I think the next steps after this this type of data is being published is we should really look at how many babies actually receive and pursue therapies after discharge. Because I think for many parents, if the only issue with their baby, I guess we have to put that in quotes, the only issue with their baby is the fact that they're preterm, they may be encouraged not to pursue aggressively therapies because they feel they have a perception that their baby is doing great. And this MRI findings, I term may actually give parents an objective and tangible evidence that there's a need to actively do work with their child to actually catch up by sort of two, three years of age to full term sort of counterparts. So I think that that's, that was very interesting. Now, where this, this sort of lends us right back to the human milk study from from New York, is the fact that going back to that study, looking at at human milk versus versus formula, and ivh, and PVL, all those studies, all these markers of ivh, NPVs, were done on head ultrasound. And so it was funny that I did pick up on the fact that the PVL was measured by head ultrasound, which we know to be not very accurate. And we know that ideally, you would need an MRI, even though if you do find PVL on hand ultrasound, it's usually severe PVL. But I thought that this paper added another layer of confusion to that prior study about milk and ADH and PVL, because it just undermined the head ultrasound altogether, saying that even ne ivh may not be reliable if you're just measuring it by head ultrasound. And so I thought that was very interesting how these two studies interconnected across two different months of, of the journal apparent ontology?

Daphna 22:02

Well, I think to it, it speaks to some of the other articles we had in here that are, you know, our definitions matter are how how, how we study how we diagnose certain pathologies matters, and it changes the way we're able to study them, and how we're able to talk about them, you know, across institutions across countries. And if we're not using kind of the same standards or definition,

Ben 22:29

and it's, and it's very difficult when those those practices are evolving as the papers are being published. So we're still not all in agreement that we should get term equivalent MRIs. And yet, so that undermines all the studies that are being published where PVL is diagnosed, I'm just playing head ultrasounds. So I think it's just very interesting. And it requires the authors to do this, this thorough review of their own data down the road as the as the protocols are sort of more refined. But let's, since you're bringing the topic of research projects associated with definition, was there a specific paper you wanted to jump to? regarding that?

Daphna 23:10

Well, I thought it I thought this article on the definition of BPD was really valuable. Because when we talk about interventions when we talk about long term outcomes, and so much rides on the, you know, what are we using as the initial diagnostic criteria? And so I thought they did something that I think we all talk about a lot, we question a lot, that this team, use the kind of three most popular definitions of grading BPD. And they took their cohort of babies, and they said, Okay, using each definition, what are baby qualify for? BPD or not? And the range? I don't have written down here, something like it was like 9%. Yes. So they arranged very dramatically, dramatically, about how would you even say that this particular baby has bronchopulmonary dysplasia based on any given criteria?

Ben 24:19

So this group out of out of the New York Presbyterian Children's Hospital in New York, published this retrospective sort of review of their of their data, and trying to apply three definite three common definitions, which were the Vermont Oxford Network definition, the 2001 nih definition and the 2018 nih definition. And for those who need a refresher, the Vaughn definition really just looks at the amount of supplemental oxygen at 36 weeks and assigns an incidence of BPD depending on whether or not the baby is receiving either 21% or more. The NIH 2001 definition looks at BPD on a scoring scale where you would have mild BPD. If you're breathing in room air at 36 weeks moderate, if you're receiving less than 30%, oxygen at 36 weeks, and then severes, where you would get more than 30% on CPAP. And severe type two, if you're on mechanical ventilation, the revision to that definition done by the workshop in 2018, has a new grading system that's now grade one, two and three. And looks now more specifically at both the fraction of inspired oxygen and the the interface with which this oxygen has been delivered. So it takes into account invasive ventilation, non invasive, low flow nasal cannula, high flow, nasal cannula, hood, oxygen, and, and it's a little bit more tedious. So what they did find was when they looked at their cohort, using the van definition, they had about 9% of BPD. In their unit, looking at the 2001 definition, they had about 8%. And they had much more sort of moderate and great to BPD using that definition. And with the 2018 definition, really their their rates of BPD skyrocketed, I think to to something like 25%. And

Daphna 26:22

I think that will be true in most units. You know, we have lots of babies who may be on low oxygen, but on a, you know, high high pressures. And, you know, I think all of us kind of get that feeling is, you know, do it can I say this baby really doesn't have BPD. But I think it would be helpful, right for PSA to have a standardization, both in terms of counseling parents, but certainly in terms of research. I, you know, it's hard for us to move forward and research and do comparative, or comparisons between studies if we don't have a standardized definition. So I think people are working towards that. But we're not quite there yet.

Ben 27:08

Absolutely. And I think this goes at the core of how we assess our healthcare system in this day and age, because if we're being measured by some of the outcome metrics that include something like BPD, that is hinging dramatically on how we define it, there's going to be a huge incentive for people to use a definition that might favor their their purchase their institution. So obviously, if you look at these definitions, we all have to be in agreement as to what we want to use. Because if I'm able to choose, I can read portray the outcomes of my unit one way or another, you can have incidence of BPD, that comes closer to 5%, when according to another definition, you're closer to 30%. And the fact that the range is so wide is frightening, in my opinion, because it really doesn't allow us to compare outcomes equally. If if institutions are not willing to play the game, truthfully, and just really help in a collaborative way to share what experiences are to actually minimize the incidence and the burden of a disease that everybody is struggling with.

Daphna 28:10

Yeah, you're so right about that our, our success as physicians, or what, you know, the system that's put on us as success really undermines progress sometimes, because we're just stuck in trying to, you know, present our unit, as you know, having the lowest rates of you know, x and we don't even have really good definitions to define that. And unfortunately, it changes funding, it changes patient flow, when you know, there are some units doing really good work, who may not be recognized, because like he said, maybe they're not playing the game, or maybe they use a different definition to report for themselves internally. And so I think there's, there's value to standardization. Absolutely.

Ben 29:01

And so just So to clarify, because I may have transcribed the numbers wrong, but their outcomes depending on the definition was 9% for the Vaughn criteria 28% of the PDF with the 2001 definition of the NIH and 34% with a 2018 definition. Now, where the authors were very open in their sort of sentiment towards decision with definition is the fact that it's coming from Columbia Presbyterian, a place that is notorious for its comfort with bubble CPAP and the use of bubble CPAP. Well into sort of the 30 to the 3132 week mark, because their theory obviously is that providing this descending pressure is beneficial for long term lung development. And so obviously, when we're using the one definition, as long as you're on 21%, you're okay, but with these new definitions that really look at the mode and the interface that you're being that is being used, regardless of vfio to this has a significant can impact for an institution like Columbia, which has had a great track record of using bubble CPAP until 32 weeks. And so obviously, this creates this creates a problem.

Daphna 30:11

And I think the other thing it does is that it confuses parents, right. So it's hard for parents to decide, are they at the right institution for their certain pathology? And also, does their baby have BPD or not, depending on who they talk about, maybe at the same institution, people might give them different definitions or different ideas about where their baby is and what their risk is for long term disease. So our words matter?

Ben 30:41

Absolutely. Absolutely. And, and we all need also to realize that our current definitions are all imperfect. I think there's so many papers that have come out talking about the right way to define BPD. And some of them have shown that later, assessment points are probably better, like 40 weeks corrected age, even though many babies are gone by that time. But we do realize that the arbitrary 36 week mark is imperfect, we do realize that the clinical evaluation of using just a motor ventilation and an FYI, your two is imperfect. And I think there was another article that in this issue specifically, that looked at room air trials. And I thought that was very interesting, because that goes right back to the definition of physiologic BPD. And so let me just let me just pull this up. I am having trouble finding it. There you go roomier challenge, so that that article came out of a group from the Medical College of Wisconsin, and the Children's Hospital of Los Angeles in the University of Chicago. And so what they looked at was really, the paper is entitled Roumier challenge predicts duration of supplemental respiratory support for infants with bronchopulmonary dysplasia. And their objective was to determine whether a roomier challenge correlates with the duration of respiratory support for infants with bronchopulmonary dysplasia. And so what they did was for in a prospective fashion for babies who were less than 32 weeks, they really looked at infants who were on less than two liters or less of nasal cannula support. And they they perform the Roumier challenge where they they progressively go down on the FIU to 21% and see the baby's tolerance to being on room air. And they found that among those who pass the rumor challenge 32% were discharged on home oxygen anyway, compared to 88% of the babies who did fail 90% of those who were on positive pressure at 36 weeks. So So sorry, yeah, so 32% versus 88, and 90%. So that was that was huge. And there were a few things that they looked at the time, from 36 weeks to the stopping of the oxygen at home, they found that that was significantly different than babies who failed the Roumier challenge. And And initially, those results felt a little bit dubious, because you look at it, and you say, well, obviously, if one person passes, then they're doing pretty good. And they should be recovering sooner than the one who didn't do so well at the exact time point at the exact same time point. But then, in the discussion, they did touch on an issue that I thought was very interesting, because they said, more and more people are moving towards the quote unquote, Jensen definition of BPD, where really, we're starting to look at just the amount of support based on on leader flow and so on. And they were saying that the proposed definition by Jensen is the easiest to apply retrospectively. In our study, since all the infants receiving a room air challenge were receiving less than two liters of flow and would be classified as grade one. And they weren't making the point of saying once you're in that grade one BP definition, given by Jensen, where you are in that less than two liters, nasal cannula, it becomes difficult to tease apart of those babies who are the ones who are more vulnerable than the others. And they're saying that using the Jensen definition, our study findings would suggest that a roommate or challenge could provide additional information to distinguish respiratory outcomes. And I thought that was very interesting, because it is true if you are on on non invasive mechanical ventilation. Yes, it may not be super necessary. But of all these babies who are on the flow one liter 1.5 How do we actually differentiate these and prep these babies for a safe discharge is is interesting.

Daphna 34:32

Yeah, I also it also speaks to the differences in practice about deciding to send babies home on oxygen. So so few institutions are doing which is probably the gold standard, which is a sleep study. And so, you know, it's still begs the question, how do we make the decision about who, who really needs to go home on oxygen so the baby who really fails there We may challenge or those babies go home on oxygen. But there's probably a subset of babies who maybe don't fail, which they're showing here don't fail but still benefit from going home on a little bit of off.

Ben 35:10

And I think that's, that's so important too, because you look at the time in weeks that it took to win the babies completely off oxygen. And you compare it to the babies who did fail, the roomier challenge had to remain on oxygen for something between like 16 and 37 weeks. So I think sometimes we want to be very hopeful that even if the baby has failed the roommate challenge, we're going to get there in a few weeks. And this may be completely sort of a pipe dream, because they need much more time. And on top of that, even if they do pass the Romero challenge test, you see that their their time to actually getting off oxygen is a median of 13 weeks with a range of 12 to 21 weeks. And, and so that's also very significant. Obviously, I think this has to be taken with a grain of salt, because what are the criteria with which they're winning these babies off? Fine, but at least even in relative terms, comparing the two, these are significant number of the six significant amount of time to actually get these babies really off oxygen. And it begs the question, should we continue pushing babies to go home on no oxygen at all costs, sometimes discharging them, not as safely as they should be? And now just leave it on even though they've passed the rumor challenge test? I think that's something to take out from this study?

Daphna 36:29

Well, it speaks to how we're managing BPD in general, right? It's not just about being on the lowest amount of support that you can possibly tolerate. It's really about changing our discussions about what does their kind of quality of life look like? Can they tolerate therapy? Can they feed successfully? And I think sometimes we underestimate how much respiratory support impacts their ability to feed. And so yeah, I think I think this was a study initially where I said, Well, I'm not so surprised, but I think there are a lot of good takeaways hidden, hidden inside,

Ben 37:06

should we move on to another topic?

Daphna 37:08

Yeah, I actually thought that these kind of dovetail nicely with this a Qi. Article about standardization of the postnatal steroids.

Ben 37:22

I knew you were gonna like that article, especially since we were talking about that this week, about the use of darts versus prednisolone.

Daphna 37:30

And, and so I had a few thoughts about it. And basically, what the team did was, provide really just a workflow diagram about which baby shouldn't be receiving postnatal steroids. And really, their project was just intended to look at adherence to their, to their protocol. And they did show improvement, through their intervention about adherence to protocols. And the one thing I wanted to highlight about about this study, when we talk about Qi researchers, how do we get it done? Right, and so I think they did a very nice job, specifically outlining one of their successes was really that just in time reminder, which makes sense, right? Sometimes when you're on service, you kind of may lose track of where the baby is in their process, even where the baby is in their admission, or you have something acute going on. And, and, and any one physician or provider who's on may miss the mark, we see that all the time, right vaccines, all sorts of. And I

Ben 38:43

think it's very important because it sort of makes sense when you think about this baby that may be stuck on the little bit of of mechanical support, and you're wondering how to get them off, and so on and so forth. But it's for the babies where you may not think about it at all, the baby who is on very minimal support, but still made meet criteria for hydrocortisone treatment or the babies who are very, very sick, who you do not expect to get off a jet or an oscillator, and yet may benefit from hydrocortisone, I think being able to be reminded in those situations that you still need to do risk assessment. Even though in your head, obviously, the risk assessment is either very low or very high, it's still very important to not rely on intuition, and actually plug all the numbers in and see if you're not sort of being fooled by the data.

Daphna 39:25

I thought this too would target babies who are kind of in the, in the moderate range, right? There are some babies who are weaning, and they're doing quite well. And there's some babies who are quite sick and you're always thinking about how do I how can I optimize this baby holder the steroids, and now those babies who are on maybe moderate settings, and we may be less likely to kind of initiate a steroid therapy and a baby where it really could could help. I also think, obviously, there's a lot of debate still about what is what is the right protocol to use when we're talking about initiating on steroids. And so, you know, that's a whole different discussion we can have. But I think they also highlighted something that was very important that we lose track of and you know, is kind of a passion of mine. But the fact that our very ability in management, even in the same institution, can be very overwhelming for parents, especially these parents on the cross and the most are most chronic babies, our most vulnerable families who have been there the longest. And they start to get that little bit of ICU, itis ICU delirium, and they must feel like you know, every time somebody new is on the plan might change. And so I do think there's a lot of value to experience satisfaction.

Ben 40:45

Because families believe that we're just discombobulated group of providers, when in truth, we're not really certain of what we're all practicing, because the evidence is not cemented yet. And and there's a little bit of an ego issue where we're not really being forthcoming with family saying, Hey, we're giving steroids but we're not really sure if this is the optimal medication, the optimal duration, we're just based that on Exactly. We're basing that on some relatively weak evidence, we're never telling that to families, and then they just see the variation and interpret that sort of lack of sort of, you have communication. Absolutely.

Daphna 41:21

So I wanted to highlight that study, because I think it's a good reminder that, you know, we always looking for standardization, and how does it improve outcomes, knowing that sometimes it might not actually improve outcomes that we, you know, are being graded on by the hospital or, you know, that were that we were looking for in medicine, but it can improve the parent experience in the NICU significantly. And I liked I guess I like that. Maybe if we used more just in time reminders, either as research staff or using our EMR that we'd be able to get get more done. Absolutely.

Ben 41:58

So since we're talking about the use of postnatal steroids, let's talk about this study, looking at the supplemental use of hydrocortisone. So should I go ahead? Do you want to go ahead. So this study came out from a group that involves Duke University. Another few researchers from Baylor, some folks from the pediatrics Medical Group, and the Department of Economics at Clemson University. And this study is called the use of supplemental hydrocortisone and the management of persistent pulmonary hypertension of the newborn. I was very interested in the study based on the title and obviously hydrocortisone is such a hot topic, as we just discussed, that any any data coming out is always worth reviewing. The author's objective was really to characterize the association between hydrocodone is the reception of hydrocortisone, and in babies and hospital outcomes of infants with PPHN. So they did a cohort study of infants born at more than 34 weeks of gestational age with the phn who received inhaled nitric oxide in the first week of life between 2010 and 2016. And they looked at a number of outcomes, including death, bronchopulmonary, dysplasia, oxygen at discharge, and so on. And like with these big databases, they had 1000s and 1000s of babies. And I think their idea to look into this was was sound because there's a lot of animal models, as they described in their background that shows that the administration of hydrocortisone, improved oxygenation, decreased PD five expression and increasing cGMP. So does hydrocortisone needs to be a key player in the management of pulmonary hypertension is a very interesting question. If you're thinking of using nitric oxide, should you think of using hydrocortisone as well, this is something that I have found myself looking up and have discussed with other colleagues. So obviously, this was something of interest. Interestingly enough, there used the definition of bronchopulmonary dysplasia as receiving oxygen or respiratory support after between 28 to 34 days, but my biggest issue, obviously, was the fact that PPHN was not diagnosed more strictly. And in their definition, they said we define PPHN CDH and meconium aspiration syndrome by clinician diagnosis in the electronic medical record, which I feel like CDH usually is if you if you diagnose it, you know what's going on. The codium aspiration syndrome is also fairly reliable, but PPHN if you don't really have an echocardiogram, it's very difficult.

Daphna 44:36

Well, any I mean, even CDH, right, there's such a range, a spectrum of babies that diaphragmatic hernia that they act, they act differently,

Ben 44:44

but I and I feel like PPHN is it's such a wide spectrum because on the one hand you will have babies who will do who will get an echocardiogram and who will show signs of PPHN and then will be treated appropriately. That's fine. There's also babies who cry nicley behave as PPHN and mandap being treated empirically, I think that's fine too. And some babies may just like be tried on nitric oxide just to see if it helps. Because resources because of the time of the day it is, or because of the day of the week it is. And I feel like that's fine too. But for research purposes, that creates a huge issue. If the pathology is not clearly defined, I think it opens the door for a lot of issues with the interpretation of the data. The other issue that I had was that in their in their results section, they seem to have struggled with the volume of CDH. Baby. And so they wrote that they were unable to analyze the effect of hydrocortisone exposure in the, in the on the outcomes of interest in infants with CDH, because there was only 32 infants with th in the cohort. I think that was nice of them to report that. But obviously this leaves a lot to be wanting from this from this study. In the end. Their their main results obviously was that what they found was in their in their about 3000 database of babies 30% received hydrocortisone. And there was no difference in their reports on death bronchopulmonary dysplasia or oxygen at discharge between the babies who did receive hydrocortisone versus the ones who did not. In the babies who had meconium aspiration syndrome, hydrocortisone was associated with a decreased oxygen at discharge. And, and so that was that was the conclusion. So I have to be honest with you, I feel like it's always difficult to balance the benefits. And the drawbacks from these big database study. On the one hand, you have such a large patient population, that it's sort of so enticing to just study it. On the other hand, you can find a lot of statistically significant stuff that may not be clinically significant. And in this case, the biggest issue obviously, is how the pathologies were defined. And the volume is so big, obviously, that they couldn't have gone chart by chart to review how PPHN was diagnosed. So I'm curious to see if anybody is going to submit a letter to the editor next month to discuss how to interpret these results. Because it is it is, if anything, the study may be a little bit fluid. But at the end of the day, it's a such an important discussion to have. Because when PPHN comes up, it's such a frightening illness and pathology that you want to be able to use medicines and interventions to the maximum of their abilities and hydrocortisone is definitely in that list.

Daphna 47:32

Yeah, in our arsenal. I agree. I think there was a lot of data, which I was grateful for how much data they gave. But I still I found myself wanting more. Right, I wanted the groups to be different. I wanted them to be split by pathology. I thought it was interesting. You know that the babies were on nitric. But what about babies that weren't on nitric, you know, as a as a third independent group? And then certainly when we're talking about pulmonary hypertension, and the use of steroids, you know, we don't know what were the indications for starting the steroids for each of the babies, and certainly hypotension in and of itself as a kind of an independent risk factor for worsening of disease. And so I think it's a good start. I think we're gonna have to keep talking about it. I think there are always going to be people who will be using a lot of hydrocortisone and there are always going to be people who don't want to use it at all.

Ben 48:32

Absolutely. And they mentioned that in their discussion. The if I can find the, in our in our unadjusted cohort infants treated with hydrocortisone had a more severe clinical course, as indicated by higher VAs vasopressors, sedatives and paralytics use as well as high frequency ventilation. This is not surprising because hydrocortisone is used as a rescue therapy prior to ECMO in some centers. And I think this is exactly right. And like you're saying, we don't really know what was the motivation behind hydrocortisone? It may not have always been because of pulmonary hypertension. It may have been for other reasons. But it's almost as if the benefits of this study are going to be great because it it just it's a bit polarizing. And it's going to lead people to actually go further into that topic and cross the T's dot the i's. And so I'm looking forward to see what kind of door this opens for, for the research community. Absolutely. So we're almost getting to the end of our first episode, because it's been now for 49 minutes. So let's see, was there was there a few other papers that you had in mind

Daphna 49:38

when you now I wanted to talk about it's not what you wanted to talk about, I'm sure, but I like this that this kind of review article on functional neuroimaging. Yes. So I mean, it was really just a good review about what do we know about the pre term brains? which is not a lot really. And I think it's such a good kind of merging of disciplines. So we have neonatology, but really neonatologist are not using a lot of functional MRI. You know, very few groups are. But this is uh, you know, the neurobiologist, psychologists, there lots of disciplines that use functional MRI, routinely, in their in their research. And so, like you said, you know, right now our modalities are really head ultrasound and MRI, and is that giving us the best information for one anticipatory guidance for families, but too, for studying our interventions. And so I think that this kind of review article which basically just described some of the findings and functional neuro imaging, it's how we understand some of the deficits that we see in a premature baby, regardless of our uvH that memory tasks are particularly difficult, that they have different decreased cognitive control. So we know that the rates of attention deficit and hyperactivity disorder is increased in the preterm infant, and that a lot of these babies into school age into adulthood still have some difficulty with emotional processing. And it may help elucidate that link, that there are some more, many parents and pediatricians are concerned about preterm babies being on the autism spectrum disorder. So I think it's, it's exciting, because we just need more information about how we can help provide interventions for these babies long term, how we can educate these babies in early childhood. But also, again, some of the interventions that we're doing in the NICU every single day, this may be give us another whole nother avenue for evaluating the efficacy of this.

Ben 52:08

So this is I'm so happy that you're talking about these things, because there's a few articles in the journal this month about near infrared spectroscopy and cerebral sort of oxygen monitoring. And so there's three specific papers that we have to talk about them. There's there's the two actual studies that have looked at various aspects and uses of nears. And there's this editorial which I almost wanted to sort of hang in my room, it was so good. The first paper is called the association between early cerebral oxygenation, and there will be a mental impairment or death in premature infants. And this was a follow up study of the new Prem paper that was published. I forgot when it was published. It was published in 2018. And it looked at the use of Near Infrared Spectroscopy on baby's brain during resuscitation. And what they looked at was the relationship. This just for the sake of completeness, this this was done by the neonatal research institute that chart Mary Birch Hospital in San Diego, California. The group tried to assess the relationship between cerebral oxygenation in the first 72 hours of life and neurodevelopmental impairment at two years of age corrected. And they had taken 127 infants less than 32 weeks of gestation. They placed the nears lifted for 72 hours, and using and they basically reported something that was very interesting, they were almost a little bit too categorical with it, but they were reporting a threshold of 67%. And they're saying using a threshold cutoff for cerebral hypoxia. They noted that anybody who was below that threshold, had significant neurodevelopmental impairment. And, and long term sort of long term impairments was associated with with spending a significant amount of time below that threshold. So they said that this auto saturation threshold of 67% was quote, unquote, a predictor of death or NTI, with a statistical significance of 0.049. And so this, obviously, is a paper that deserves probably a full journal club, mostly because the initial study was very good, but their follow up rates were a bit low in this case. So I think they were only able to assess babies at two years of age, only 62% of their cohort, they were able to assess which follow up rates is always difficult. But you expect for a study to be really impactful to have at least 80% or above. So I felt like 62% was was a little bit shy of what what you would want. So that study showed that measuring brain tissue oxygenation in the first 72 hours of life is an important factor. We'll go into some of the editorial on that topic in a minute. But the other article that I thought was very interesting was this sort of This change in in it's called changes in cerebral tissue oxygenation and fractional oxygen, the retraction extraction with gestational age and postnatal maturation in preterm infants. I don't know if you had a chance to look at this. This was a study that was done from the Cleveland Clinic in Cleveland, Ohio, the George Washington University in in DC, and another center in Canada, and the pediatric newborn venison, Brigham and a woman in Boston. And so what they did was use nears to sort of create normal grams of both oxygen saturation and tissue oxygen extraction between day of life 07 1421 and 28. These were obviously intermittent measurements, but they were able to provide these graphs that were beautiful, the accuracy we can talk about, but obviously, they were beautiful. And I think this, this is the kind of data that we want to see coming out of nears. And so what they showed was that tissue, oxygen saturation, and cerebral fractional tissue oxygen extraction was not continuous. And it evolves over time. And it almost seems like the brain gets better with time and more efficient in extracting oxygen, as the baby gets older, and or as the baby is born less prematurely. And I thought that was very interesting, because it does, it does make sense that as babies do mature, they're able to effectively pour the oxygen from the vessels, it gets better and better. So I thought these were interesting studies, because nears seems to be the new hot thing. And everybody's jumping on it. But I was very surprised to see the editorial, which was not critical, but sort of was trying to moderate the excitement of all this data coming out on yours. And first of all, before I go over guitar, what were your thoughts? What What are your thoughts on nears in the NICU right now? And and what are the implications of using nears? Especially considering what you were talking about about the extra interventions that it might lead to and their impact on the infant?

Daphna 57:14

So I think that's a Pandora's box, right. But I think the data that they found was not entirely surprising, given what we know about, you know, cerebral oximetry measurements and the term and then and transition over time. I think the editorial hit on some interesting points that what so what do we do with the information? And what did we do with the trends? And do we act on them? Do we intervene? Or do we just use them as prognostic markers? And I think a hole in DNA tells you doesn't know, yet? Certainly, probably the area that this is most well studied, is in HIV. And so you know, we do have some data that the predictive values of, of having and mirrors trends and and kind of at least the short term outcomes, with it with HIV. But certainly, there's probably something to be said, similarly for the for the preterm baby. So I think it's a good start, I think we needed the data, we needed the normative values. We can't study it without having the normative data's, but I think, I think probably every journal from here on out is going to have mirrors, articles in it, because because I agree with you, I think it's our next vital sign that that people are going to try to use, I think it makes sense, especially when we talk about something like the functional imaging, brain imaging, because there are some things that we just can't see anatomically, but we know affect the tissue long term. So I think we're just going to be seeing a lot more study about cerebral oximetry. But I think what you're getting at and you and I have discussed this many times is we still as a group, as a whole don't know what to do with the information.

Ben 59:11

Right. And so that's that's sort of what the editors are alluding to, number one with the idea that every time you want to try to connect interventions done at birth, or shortly after birth to outcomes two years down the road, it's always very tedious. And they say that plainly saying it is likely but the clinical state at discharged, the results of late imaging of late brain imaging and or neuropsychological testing may overrule the predictive value of events that occurred early in the neonatal course. And that's obviously something that that needs to be taken into account. The other thing that they mentioned was kind of reduction in cerebral hypoxia actually improve clinical outcomes. I think that was something that this paper looking at this saturation in the first 72 hours of life really begs to begs an answer for. So if I do manage to get sets above 60 Seven, does that mean that I'll have better outcomes? And the answer is that we don't know. And there's, there's so many other things where we shouldn't also forget all the other interventions that we're working on that are known to improve outcome. So that's what I was happy to see also from the editor saying that many other complications of preterm births such as inflammation, nutritional insufficiency, abnormal sensory inputs may contribute. And it has been proposed that hypoxia and ischemia is not a significant contributor to the overall burden of neuro governmental deficit in this vulnerable population. So I think, because it is a new technology, because it's getting more and more attention, we're going to want to have this incorporated into the NICU, we're going to want to believe that this is the end all be all. And it's really not there yet. So they asked the questions plainly, and they said, are we ready for the routine use of cerebral oximetry in the NICU? And their answer is probably not. And I just want to read what they wrote, because they're making reference to the safe boost trial, phase three that's going to come out, which obviously is going to be great to review. But they're talking about, although better technology is coming, no quantum leaps are expected healthcare personnel availability is limited in busy NICUs. And the benefits of monitoring cerebral oximetry may depend as much on the agility of the clinical staff as on the device itself. And so even though they're mentioning that significant harm is unlikely, meaning like skin marks due to the heat and pressure, they're rarely serious. But and that was so good. They said, the mismanagement due to falsely low readings, or due to faulty reasoning, when trying to respond to cerebral hypoxia, it's possible. And I think that was so good. And they're saying in any case, adding another sensor, another cable, another screen, and another number to the already crowded neonatal intensive care environment that surrounds such small and frail newborn patients, and the parents that was for you, is likely to disturb even more, and should and we should not disturb unless necessary. So I thought that was so well put. And, and I think that we have to sometimes really put the brakes a little bit and reassess how we do all these things, especially when we're talking about what you were mentioning before functional MRI, is is what would be a better use of our time resources. Would it be functional MRI versus nears? So I think this is this idea that we have to really have a long and deep introspection into what we can do to evaluate the baby's brain is, is something that is going to be I think, the big topic of debate for the next few years.

Daphna 1:02:46

Yeah, for sure. And I think, you know, and I've looked in cerebral oximetry, quite a bit, some extensive reading on it, especially as it relates to HIV. And I think what we will find long term is that it's not the high values, it's not the low values, it's probably something about your transition from high to low, or vice versa, that that we'll see. And that's what we know about the preterm physiology, that it is transitional, it's changing every hour after birth is changing every day after birth. And there's so much that we still don't kind of understand about that transition. And I think it's, it's very well reflected and, and I use the cerebral oximetry as it stands.

Ben 1:03:28

And an absolutely, and the editors were sharing something to that if to that extent, where they reported this graph looking at some of the interventions that were done based on the readings, including changes in dopamine infusions, fluid boluses. And obviously, these are not benign. And when you're considering that these interventions are done, based on the reading on a device that we still don't fully understand that has its own limitations. I think it's very important to be cautious. Alright, I think that's the end of episode number one. Thank you, Daphna.

Daphna 1:04:04

Yeah. Thanks for joining us, everybody. We're looking forward to to digesting more neonatology. That's right.

Ben 1:04:10

Thank you very much, everybody. Thank you for listening to this week's episode of the incubator. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcast or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address, the queue You can also message the show on Instagram or Twitter at NICU podcast. Personally, I am on Twitter at Dr. Nikhil spelled Dr. NICU. And Daphna is at Dr. Dafna MD. Thanks again for listening and see you next time. This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns, please see your primary care practitioner. Thank you Hi

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