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#039 - 📑 Journal Club 19

NICU journal club the incubator podcast

Hello team! 👋

Join us this week as we discuss a variety of topics. We review a paper looking at whether supplemental vitamin D could help reduce BPD. Daphna goes over a paper from Australia assessing factors that would help successful extubation after steroids. We are looking at how altitude affects neonatal survival. There are a few HIE papers and we review an article that may have an explain why babies catch less Covid-19 than adults.

Enjoy this journal club and let us know if you have any feedback or recommendations.

Articles discussed in this week's episode are listed below (in chronological order):

Effects of early vitamin D supplementation on the prevention of bronchopulmonary dysplasia in preterm infants. Ge H, Qiao Y, Ge J, Li J, Hu K, Chen X, Cao X, Xu X, Wang W.Pediatr Pulmonol. 2022 Apr;57(4):1015-1021. doi: 10.1002/ppul.25813. Epub 2022 Jan 17.

Is a higher altitude associated with shorter survival among at-risk neonates? Dueñas-Espín I, Armijos-Acurio L, Espín E, Espinosa-Herrera F, Jimbo R, León-Cáceres Á, Nasre-Nasser R, Rivadeneira MF, Rojas-Rueda D, Ruiz-Cedeño L, Tello B, Vásconez-Romero D.PLoS One. 2021 Jul 14;16(7):e0253413. doi: 10.1371/journal.pone.0253413. eCollection 2021.

Effects of tactile stimulation on spontaneous breathing during face mask ventilation. Gaertner VD, Rüegger CM, Bassler D, O'Currain E, Kamlin COF, Hooper SB, Davis PG, Springer L.Arch Dis Child Fetal Neonatal Ed. 2022 Sep;107(5):508-512. doi: 10.1136/archdischild-2021-322989. Epub 2021 Dec 3.

Outcomes of neonatal hypoxic-ischaemic encephalopathy in centres with and without active therapeutic hypothermia: a nationwide propensity score-matched analysis.Shipley L, Mistry A, Sharkey D.Arch Dis Child Fetal Neonatal Ed. 2022 Jan;107(1):6-12. doi: 10.1136/archdischild-2020-320966. Epub 2021 May 27.

Physiological responses to cuddling babies with hypoxic-ischaemic encephalopathy during therapeutic hypothermia: an observational study. Odd D, Okano S, Ingram J, Blair PS, Billietop A, Fleming PJ, Thoresen M, Chakkarapani E.BMJ Paediatr Open. 2021 Dec;5(1):e001280. doi: 10.1136/bmjpo-2021-001280. Epub 2021 Dec 16.

Nasal expression of SARS-CoV-2 entry receptors in newborns. Heinonen S, Helve O, Andersson S, Janér C, Süvari L, Kaskinen A.Arch Dis Child Fetal Neonatal Ed. 2022 Jan;107(1):95-97. doi: 10.1136/archdischild-2020-321334. Epub 2021 May 14.


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

Daphna 0:45

Hello, everybody. Welcome back to the podcast Daphna. How you been

dizzy? about sums it up, I think just busy. But you've been busy too. It seems like everybody's just busy these days, right?

Everybody is listen, I'm gonna tell you what the French people do. We take vacation for the holiday, which this year I didn't get a chance yet to take vacation. Then people come back January 3, fourth, they work for a week. They're overwhelmed from all the stuff that's accumulated over the holiday. And then they just go on strike. And they're like, No. And, and now I get it. Now I sort of I'm in that mood right now. I'm like, No, right. I'm gonna go in the streets and protest and demand, less work and more money. More money. And you're not gonna ask for more money. But anyway, this is. So yeah, it's busy. But it's cool. Yeah, we don't want to waste too much time because we have a lot to get you. First of all, thank you to everybody who participated in the podcast end of year giveaway. Yeah. Yeah, it was fun to see everybody like trying to get the trying to get some of the prizes. This is cool that we had the opportunity to do that. And we have winners, right that we're going to announce today. So which, which? Definitely, which? Which item should I start with?

I guess let's start with the books. The we had three books instead of you know,

yeah, we had three books. So yeah, so the first book is done raffles, The Strange Case of Dr. Cooney and so the winner of that book is Lisa Viola, Twitter handle at Lisa Oh four m congratulation, Lisa. Thank you for taking part in the giveaway. Should we go to the next book Daphna? Yeah. The next book is Dr. Benjamin read Ray's book when all becomes new, and the winner of that book is Dr. Radhika Batra and she is from New Delhi India. Twitter handle is Dr. Radhika Batra. Congratulations Radhika, thank you for participating. And then the last book that we have is the good time to be born by Dr. Perry class and the winner of that is at Hopkins. Is that Anthony Hopkins? I'm assuming it's Anthony Hopkins. Twitter handle is at Auntie Hopkins. Congratulations. All right. We forget something. Oh, yes, the iPad. So the iPad winner is Dr. Hope Arnold at Hope II Arnold on Twitter, from Atlanta, Georgia. Congratulations hope well deserved. And yeah, we hope you make good use of it. Stay tuned tomorrow for if you're subscribed to our incubator and neonatology review podcast we'll announce the winner of the broad skin Martin book set. So stay tuned for that. And I think that's enough number right.

We're all caught up.

I think we're all caught up. Alright, first journal club of the year I

call it housekeeping, right?

Yeah, yeah. I need to do actual housekeeping at home, but that's a different story. Okay, so there's a bunch of interesting papers to discuss this week. I'm going to start off with this paper because I just want to get it out of the way. This paper is published in pediatric pulmonology. To pre proof it's called effects of early vitamin D supplementation on the prevention of bronchopulmonary dysplasia in preterm infants. first author is Hyun Ji, and it comes out of a group in China. The reason I'm picking this paper is obviously because the title caught our attention. And I read their conclusion right away just I sometimes I just can't help myself and I go straight to the conclusion. And the conclusions we'll see. Were very, very striking when it comes to the conclusion that we're making and I read the paper And yeah, let's just talk about that. So the goal of this paper was to see if early vitamin D supplementation in preterm infants would help prevent BPD on the basis of previous work that was published by this group that showed that vitamin D levels were lower in DBS who developed PPD, about 36 weeks. So it's a pre proof, there's a lot of, it's not easy to read. I mean, I understand this is coming from an international group. So thank you for or writing this and putting that in English. But there's a lot of stuff that needs to be clarified, in my opinion. So they looked at 124 cases 20 424 babies, their inclusion criteria were any baby born before 32 weeks of gestation, and the birth weight less than 1.5 kilos, they also had to had the diagnosis of respiratory distress syndrome, they obtained consent from the families to perform, to enroll in the trial, they excluded any babies with critically ill with with AVH, with massive pulmonary hemorrhage or with shock upon admission. And so these were the inclusion exclusion criteria, the definition of BPD, which is, as we'll see, one of their outcomes was oxygen therapy still needed after 28 days after birth. And that was considered as BPD. The Classified BPD after that they had no oxygen therapy at discharge that was considered mild, if they required less than 30%, that was considered moderate 30% or more or needing invasive mechanical ventilation that was considered severe, sort of 22,001 nih type of thing. They have a lot of explanation in terms of the trim treatments that they've given them. And they talked about the administration of surfactant, I'm going to skip all that. The they go in depth as to the different vent settings that they're using, and so on and so forth. But I don't think it's going to be worth your time to go through this right now over the podcasts, just read it when you get the chance

that it was helpful, though, that they had the intubation and extubation criteria.

I think at some point they were talking about, like using something called Google Sue. And I was like, I'm assuming that's like surfactants in China.

I know, because I couldn't find it. I couldn't I searched for it on Google.

I looked for it on Google too. And I was like, No,

I That's my guess. That's my guess. It could be repeated every day, you know, 12 hours. It's instilled

through the entire tracheal tube. So it has to be but that was cool to

test taking skills are

by process of elimination, yeah, go Sue is most likely surfactant. If you are working out of China, and you can enlighten us, please let us know on Twitter if we get it wrong. Interestingly, so the question was, how do they supplement vitamins? Right? So like, my first question is like, how do you get vitamin D. And so they provided vitamin D drops 800 units per day, given within 48 hours after birth. They last the treatment lasted for 20 days until the point in time in which they decided whether the babies had BPD. And then they just they discontinued after discharge from the NICU. Their observation indicators, which I think are what we would call primary outcomes, where the presence of BPD mechanical ventilation parameters, vitamin D level, and serum inflammatory markers at the time of admission to the NICU and 28 days. That's it for the methods, you all get the idea. So, they had about 120 babies, they had 55 babies in the control group 57 in the vitamin D group. So, the BPD occurrence in the vitamin D group, which was 12.3% was dramatically reduced when compared to controls and the found that the occurrence of mild BPD 3.5%, moderate BPD 7% and severe BPD 1.8% in the vitamin D group were and I quote remarkably lower than the control group. So that was 3.5% mild compared to 9% mild in the control 7% in the vitamin D group compared to 14.5% in the moderate group, and 1.8% in the vitamin D group compared to 5.5% in the control group. And then they just state this again quote, these data are suggestive of early supplemented with vitamin D after birth and premature infant could effectively prevent BPD occurrence so quite a very, very bold statement. Other Other notable findings that they highlight is the fact that vitamin D supplementation not surprisingly raises vitamin D serum levels in babies. They also looked at PA or to Pa co2 Using a static analyzer, they did observe the level of pod they're saying was remarkably increased by supplementation with vitamin D, relative to the control group contrarily, they observed that the levels of pH co2 in the vitamin D group was remarkably decreased in comparison to the control group. And then they looked at some inflammatory markers, as we said, and so to determine the role of vitamin D, and the inflammatory response, they looked at a bunch of things, including CRP, il six, TNF alpha, and that's it. So at baseline, they both they all had similar levels. But after 20 days of treatment, the levels of CRP, il six and TNF alpha were significantly reduced relative to baseline. So it's all sounds pretty good. But let's look a little bit at the data because they're providing so the way the way the paper is a bit disappointing is because they provide a lot of the data, but we have to put that into context. So the gestational age in weeks was I guess, I'm assuming the mean was 29 to 30 weeks. Okay. So so they were pretty big babies, the birth weights, were 1.29 in the control group, 1.24 kilos in the environment. So these are not, in my opinion, the most at risk babies of developing BPD. That was my first thought when I looked at the numbers. And not surprisingly, their rates of BPD were very low. No, they were, they were very, very low. So let's, let's look at that for a second. The other thing I do want to mention, is the fact that when you look at the administration of antenatal steroids 83% in the control group, and 81% in the vitamin D level group had no antenatal steroids, which was quite striking. I mean, if you deliver pretty precipitously that could explain I didn't really comment on that during the paper.

But it's interesting. They still had low rates, right, even though the antenatal steroid use.

Agreed. So when they're looking at the rates of, of BPD, right, so they have fixed about about 50 to 60 in each group. So 71%, in the control group had no BPD 88% in the vitamin D group had no BPD. And the difference is not really statistically significant. So most of these kids are fine, right? And so when you're looking at the number of babies with BPD, and I'm going to go down by group, if you look in the vitamin D group, they have two babies with mild four with moderate BPD, and one with severe BPD. And in the control group, the numbers are not that different. Five, it with Mayans eight with moderate, and three with severe. So it's a bit it's a bit of a letdown, I believe, just because when you look at the percentages, right, so if I go back and the way the results were framed in the results, they're saying, oh, vitamin D supplementation reduced the rates of mild BPD, from 9% to 3%, from moderate from 14 to seven, and severe from five to one point into like, Whoa, this is great. It seems like but, but it's like, it was reduced from five babies to two babies from eight babies to four and from three to one. So I'm not dismissing their efforts, they may be onto something. But on the other hand of the data is not really, I think usable when it comes to translation to the bedside right away, it would need to probably be studied on a larger scale. The other issue, in my opinion with the paper is the fact that they're not really addressing the fact that what if the babies are very small, and their vitamin D levels are really low? Is there another way to provide vitamin D other than pill? Or enteral? Right? Because if the babies are often NPO cannot really tolerate feeds, is there an alternative to providing vitamin D? So it's a super interesting idea. But I thought it was very important for us to go over this paper because the title and some of the text, I mean, I will I will read to you the I will read to you the conclusion. And that's where it's a bit misleading. And I think the pediatric pulmonology journal should try to edit a little bit some of the findings to not mislead people. But the conclusion of the abstract are, we demonstrated that early vitamin D supplementation could significantly reduce BPD incidence in preterm infants. I don't know if we can be that. That's such strong language. So. So yeah, so that's my take just if this you see this paper out there, we've reviewed it. I think this is a great, great idea. There's a lot of data on using vitamins and RGS and adults. So I think this needs to be pursued. But I don't think we can reach the conclusions that the authors have written down based on the data available.

Yeah, I agree it was strongly worded, and they did have a difference in overall BPD. But when they split out the groups, right, the classifications they it was not statistically significant. But that being said, I mean, there's definitely a A, you know, a physiologic plausibility right to vitamin D, and especially in our babies that we know are kind of at a nutritional deficit. And for most of us, we don't, right, we don't start checking vitamin D levels until maybe growth is poor, or you're at least on full feeds. And so might we be missing an opportunity to supplement earlier potentially. And I think especially vitamin D is such a hot topic right now, especially with you know, severity of COVID disease, and then the research coming out there. That I mean, it stands to reason that we, we should look at it. There also was another new paper linking excess vitamin D to to prostate cancer. So, anyways, I agree with you. I'm not sure we should change our practice yet. But I think there's a lot of things still about neonatal bone disease, and vitamin D supplementation that we we don't understand, right, we don't know when to give it or how much to give, or, you know, we have these ranges that that are not even necessarily written for preterm babies. But I am not as disappointed as you are. I think the wording was strong. Maybe something was lost, you have no,

listen, I think I think maybe some things were lost in translation, I have no issues with that. The problem was that I was so hyped I have this paper in my, in my folder since maybe Monday, and I've been on call and I'd be like, Man, we're going to start using vitamin D, this is going to be so fun. And then I read the paper and I'm like, Ah, man. So anyway, I was,

I don't think all hope is lost


your rights. And I think this group may be able to give us more of that information. And I think it's, I think we may see, even with bigger numbers and smaller babies, we may even see a bigger impact, right, because I anticipate that they'll have more vitamin D deficiency, but we'll see. I don't know.

agreed this is going to be something to continue watching. Alright, enough of vitamin D. Let's move on to the next topic.

All right, well, we're still talking about bronchopulmonary dysplasia. So this is another paper on a pediatric pulmonology factors associated with successful extubation. Following the first course of systemic dexamethasone and ventilator dependent preterm infants with or at risk of developing bronchopulmonary dysplasia, the lead author, Kristen O'Connor, and this is a study out of Australia. So what they really intended to do is see which babies you know, based on their kind of baseline characteristics with, which are more more likely to have successful extubation. So the primary outcome was that successful extubation within 14 days of starting dexamethasone and remaining excavated at least seven days, which actually I think is a really important thing that they did, because we activate a lot of babies who don't stay activated. Right. So I think that was a reasonable criteria. So they had 287 babies, this was a retrospective cohort. So of babies between 23 and almost 30 weeks, 29.6 weeks gestational age, which we're receiving their first dexamethasone course. And then the data is a little complicated, right, because they talk about the dexamethasone regimen, and unfortunately, I guess they had a variety of dexamethasone regimens, so 10 plus days of one of the following. So a starting dose of point five milligrams per kilogram per day, a starting dose of point three milligrams per kilogram per day, or the kind of official Dart protocol, with a total starting dose of point one five milligrams per kilogram per day.

I guess that's the issue with a retrospective study, they can't control too much what people were doing in terms of the steroids,

they couldn't, but they could have given us the data for the babies who got each type of steroid regimen. And they didn't get we I we didn't have that I would have liked to have seen that. But there was a group of babies who got steroids and a group of babies who did not get steroids. So compared with those that were not successfully excavated, those who were successfully excavated, were not surprisingly more mature at birth, so the gestational age was higher or had higher birth weight. So both of those predicted success at extubation on univariate analysis, and they were also heavier at the time of starting dexamethasone and they were more mature so they had a higher corrected higher post natal age and postmenstrual age and they were bigger babies and and they were more likely to be off of parenteral nutrition, so potentially less sick babies, they had less severe BPD on their chest X rays. And this I thought was interesting had an higher number of failed extubation attempts prior to their first dose of dexamethasone. For me, I don't know if that means the babies, people thought the babies would have more success, the babies, you know, looked bigger and more mature. So people tried them sooner, or they had fewer days, intubated, I don't know. But all we know is that they had a higher number of failed extubation attempts prior to their first dose of dexamethasone. And that was not successfully excavated. By 14 days after starting dexamethasone were more likely to have had a PDA and then higher mean airway pressures, higher fit requirements and using ventilation with a high high frequency. And those babies were also more likely to have been born to moms diagnosed with chorioamnionitis. So the analysis altogether, the biggest predictors, so gestational age of birth, was strongly predicted was strongly protective with each additional gestational week, leading to a 1.8 increase in the odds of successful extubation by 14 days. And then, like I said, the birth weight, the aging days, and the current weeks, were all strongly associated with successful extubation on the univariate analysis, but after adjustment for those mutual factors, they were no longer significant. But when they looked again, on the multivariable analysis, the biggest predictors were what was the Fit needed by the baby at the time? And what was the mean airway pressure, those both remain significant, even after adjusting for other prognostic indicators. So no, I don't think any of this data is surprising. I would have liked to have a little bit more information maybe. Which, again, which regimen which babies were more successful on which regimen since they had that information. But it's nice to have the information. And and the the one key factor here is that just because a baby has failed numerous times doesn't mean they're going to they're going to fail this time, I guess was my takeaway.

Yeah, I mean, I was I was surprised when I read that. Because, yeah, I mean, if you fail multiple times, daily multiple times can mean several things. In what context? Did you fail? Did you fail in the context of a course of steroids? Did you fail because of an accidental extubation. All these things do matter. But then even

that nobody you didn't, you know.

And then and then all these factors, then once they were correcting for other variables, the idea of multiple failed extubation went away. And they were left with just the factors you mentioned, gestational age, mania were pressure and fit to, I think the media were pressure. And if YouTube was not really surprising, the gestational age, I think, is something that makes sense. Because I think the bigger the baby, the more mature the baby, the more likely you are to be successful at keeping a baby excavatum. But I was, I also feel like, it doesn't change much the way we are practicing just because I still think we should assess for risk factors for BPD. early on. And there's enough data to show that early early use of steroids in babies that are at high risk of BPD or are probably very beneficial. And so I don't think that I think it means that if a baby has a higher gestational age, you're more likely to succeed, but it doesn't mean that you should wait for them to have a higher corrected gestational age to try steroids. I think that's the only clarification that I would make. Other than that. I thought it was a cool paper.

Yeah, this morning, more information. Right about okay, where to next?

All right. If you're asking me to pick I'm gonna pick this paper from plus one. The paper is called is a higher altitude associated with shorter survival among at risk neonates.

Interesting, right? I mean, it's not a problem for us, but but it is a problem for some

definitely not for us in South Florida. But, but I mean, the title just like, I mean, I saw this title come across I was like, holy moly. I would like to find out first author's I was like, huh, yeah, I

never thought of on.

I never thought about that. Yvonne Duenas. Aspen is the first author. There's a long list of author and this is a group coming out of Ecuador. So the goal of this study as the title states was to assess the association between survival among at risk neonates as measured by days as the primary outcome based on how at what kind of altitude were they born? So this was a Nash nationwide retrospective study that looked at the registered deaths in Ecuador. Of all infants that died before 28 days of life. And these were coming from all registered public and private health care facilities of which there was 126 of them. And they have this, this thing that I'm obviously not familiar with this surveillance system of neonatal mortality of the Ministry of Public Health of Ecuador. So they were able to really track those pretty well. And it sounded like kind of what we do in the US when it comes to filling out death records, right, they said that the clinician has to fill out a bunch of information that they were able to gather, and that's entered into this registry. They looked at data from January 2014 to September 2017. The main outcome was survival. And they looked at the looked at the altitude at which the center was, then they corrected for some covariates, whether it was differences intrinsically, in the different babies based on gestational age based on birth weight, and so on and so forth. And they also addressed contextual covariance, which I thought was obviously the first question everybody has, which is administrative planning areas type of health care facility, level of care, and so on. And so they also looked at something as I have to mention this, which is, like if the mother moved right from like, depending on has her gestation happened at a certain altitude, and she delivered at a different place, like they looked at all these things. I thought that was very interesting, then

that could have been, that could have had a lot of the data, right.

So I'm not gonna go too much more into the details. I mean, they looked at a bunch of clinical data, and you can look back at the paper. But basically, the study identified about 3000 neonates that passed away between January 2014, and September 2017, the median gestational age was 32 weeks at birth, the median birth weight was 14 102 grams, and the median Apgar score at five minutes was six. So in terms of the results, the highest altitude was significantly associated with shorter neonatal survival time. And they looked at that based on two different categorization. So they looked at a dichotomous type of variable. So they said, alright, what if you were born between 10 meters, and 2500 meters, by the way, I'm not going to try to convert that into anything other. Definitely, if you want to help our audience, go ahead. But I didn't do it. So do it. And then they looked at if you're born above 2500 meters, and so the survival. So considering that specific reference range, there was a 23%, and a 26%, higher hazard ratio of, of death, with altitude. And when they were looking at more divided subcategories that they were looking at whether you were being cared for between 80 and 2400 meters, then 24 to 2750 meters, and then 2750. And above the hazard ratio were 42% 57% and 17%, higher each time based on altitude. So then they ran mixed effect models, which included all the things that we talked about when it came to contextual variable, and so on and so forth. And the estimation corroborated a higher hazard ratio as altitude increased. And I recommend you guys check out figure one, where you see that basically, as the altitude goes up, depending on the head various models that they ran their hazard ratio progressively like a almost like an a dose dependent relationship. There's, we can look at the data for all the babies that they had. And and I was trying to see whether the babies that were born at higher altitudes were somehow sicker or anything, but not Not really. I mean, they have they have a bit more when it comes to maturity, prematurity. And they accounted for that, but the rest, not necessarily sometimes they will be that were born at lower altitude were sicker. So really highlighting that, that possibility that altitude has an independent as an independent risk for poor outcome. What else can I tell you? So the conclusion was that higher altitudes are independently associated that we just said with shorter survival time, as measured by days among at risk neonates, and so altitude should be considered when assessing the risk of having a negative health outcome during the neonatal period. So I kind of like these these environmental sort of studies when you look at your environment as how it affects your outcomes. What do you think about

Yeah, I will say if I'm the the paper a little statistically difficult to follow, because the raw data, the numbers weren't that different, but you know, they they put it through some, you know, the multivariate analysis and the modeling to to at count for some of those co founders. So it was hard to follow. But the graphs are really impressive. So I thought that was really cool. And they did talk about how, you know, first for some of those moms, like you mentioned that it's not just about where they deliver, right, it's not just because some of that probably has to do with what their prenatal course looks like. And they actually had a great introductory, few paragraphs about why that's important in that that's data that I had not looked at before, you know, about the differences, just in pregnancy, relating to high altitude. So I thought that was really interesting. And so anyways, that, you know, they go on to say, you know, we can't make people live somewhere else, or we can't make them deliver somewhere else. But, but it's just something to to note. And, you know, as we review papers, and we talk about research, I think it's something to consider also in the future. So I thought it was super interesting. It's not a question I had ever asked. So I was glad to see it. And

I think this is super relevant for low income countries, right? I mean, you if you don't have all the tools, I'm not saying that Ecuador is a low income countries, but I'm saying, if you are a place that doesn't have access to all the tools, you want to try to get your risks as low as possible. Right. And that could be one of them. So I thought that wasn't that that was interesting. That was an interesting paper. And you know that if you're doing Board reviewed, you know, that there's going to have, they're gonna have questions about changes in PIO, two and SATs.

Never asked the question about high altitude, but I have done many of those equations. And so I should have asked the question. That's why those equations are so important. Okay. I thought that this was such a cool paper. I'm going to talk about this one. It's in the archives, and effects of tactile stimulation on spontaneous breathing during face mask ventilation. first author, Vincent Gardner, and this is. So the author's come from a variety of places, but the study was done in Australia. And so it was actually this paper is a secondary analysis of a prospective randomized clinical trial, which is comparing the effect of two different face masks on mask leak, during PPV in the delivery room, resuscitation of infants greater than 34 weeks gestation. And so what was cool about this is they had already had all of these videos of resuscitation of infants for this other trial. And then they wanted to do this secondary analysis. So what they were looking for, is if you stimulate the baby, while you're you're giving PPV, will you have a better response basically, is what they were looking for. And so they gave us a little bit of background about how they did this. And I want to spend some time on this because I think it's super cool. I think it would be a great way to practice and to evaluate your efficacy in the delivery room, especially for you know, training programs. So they video recorded the resuscitations from above the warmer so that everybody could see the infant's body and the operator's hands. And they did a number of things. So they were looking for tactile stimulations. And so what that entails is that if somebody basically took their hands and rub the baby in any place just to stimulate it. And so they looked at overall area of stimulation by dividing, dividing up the infant's body surface into regions using the who burn charts, which I thought was a great resource. And they counted any stimulation to any specific site. And then they evaluated like, what was the total surface area that was stimulated, so they looked at total surface area, and the number of stimulations and then they used this really cool flow sensor put in, you know, between the Neo puff and the mask to measure inspiratory and expiratory flow, and they looked at flows at baseline, before and after stimulation, but obviously, during PPV, and then, compared with what the flows looked like, during stimulation, and they didn't just get the flow data, they were able to measure leak and variability of tidal volumes. So that's why I think this, this setup just in and of itself would be really valuable and studying our delivery room behavior. So they had 40 videos for different babies. And I'll give you just some cohort to So the just average decision of age was 37.2 weeks, average birth weight was 2.9 kilos. Interestingly 13%, male 65%, female, six of the babies, moms had general anesthesia. The average Apgar at one minute was three, the average after five minutes was seven, initiation of PPV. So time to initiation and PPV was 57 seconds, which I thought was notable. And in general, the average time to the end of PPV was 204 seconds. And one of the babies was oh, one sorry, five of the babies were intubated in the delivery room, and 30 of the babies were admitted to the NICU. Okay, so let's get into kind of the granular data. So the median number of stimulations before PPV, were two, which actually I thought was interesting. So it took almost a minute, the median time was almost a minute to say that again. So the median number of stimulations before PPV, were two. So they, you know, stimulated the baby twice, on average before initiating PPV. And that maybe, maybe maybe I'm just very vigorous and delivery group before initiating positive pressure ventilation.

No, but I think I think also, the way they defined individual stimulation was that if there was a, a two second break between stimulation, so like,

that's true. So you could have a very long session of stimulation,

yeah, and it would still count as one is still count as what.

So that's true. And that probably is what happens in a lot of delivery room resuscitations, right, we just keep, I feel like some

babies aren't catching a break. They're just being like,

take a breath, right. But not surprisingly, if I think about delivery room reception patients, infants were less likely to be stimulated during PPV compared to the time period before PPV. So 20 of 40 infants or 50% of the infants were stimulated during PPV compared to 98% of the infants who were stimulated before PPV. And then they were able to take the flow data from 57 of these tactile stimulation episodes. So we'll get back to that the median time between onset of PPV. And the first stimulation was 43 seconds. So that's an interesting thing to think about. That's a long time before you say, well, let's try so let's try something else, like stimulating see

Ben 37:47

that some people were very good. Like, there's like, the range is like 31 seconds. So like, you have the people who are like, NRP perfect, you know, they're like, they give 30 seconds, and then they started. And then some people went 70 seconds, and guess that's okay.

Daphna 38:00

And I you can almost see what's happening. So they talk about how many of the Mr. SOPA steps were done. And you know, stimulation is actually not in the Mr. sobo right. So 65% of infants had corrective steps for mass ventilation, before the first stimulation, so readjusting and head positioning was 65% as well suctioning and opening the mouth in 10%, and then going up on the pressure and 5%. So many more of those were done, then really stimulation during PPV. And the other thing to remember to note, which isn't surprising is that all stimulations during PPV were performed by a second person not involved in mask ventilation, which makes sense because the head of the bed you know, your both of your hands are occupied. So this gets to your appointment, how long did they stimulate, so stimulation episodes during PPV had a median duration of four seconds, which isn't that long. And 13% of the total body surface area was covered. The most common sites of stimulation were the thorax, not surprisingly, the the lateral thorax, anterior chest 40% legs 37%, arms, 30% feet 25%, back 11% and head 5%. But let's get into the data they were really really looking for. So the number of spontaneous breaths increased significantly during stimulation from a median of one breath before stimulation to three breaths during for those babies who are stimulated. Correspondingly, the respiratory rate also increased during stimulation, you know, a median of 20 breaths per minute, versus 36 breaths per minute during stimulation. The tidal volumes also increased during stimulation, so median 4.2 miles per kilo, before stimulation versus five mls per kilo during stimulation. All of these were statistically significant Another interesting factor was the variability, the title volumes was greater during stimulation, as compared to before stimulation. So 33% variability versus 51% variability during stimulation, which is something maybe we can talk about. And then importantly, the tactile stimulations did not appear to affect the leak at the level of the mask. Yeah, that's I thought maybe that was part of the very the problem with the variability was that we would see some some leak, but they didn't have a longer duration of stimulation and more surface area covered was associated with greater increase in number of spontaneous breaths. So the first thing I'll say is, I didn't actually even expect them to look at it the way they did, where they looked at kind of the babies, these the babies their own control, they looked at the baby's baseline, and then they looked at it during stimulation, I actually anticipated they would say, like, let's look at the babies that didn't get stimulated versus the babies who did. So maybe this was the right way to do it, because it may be served as their own control. But I thought it was interesting. I think, I don't didn't necessarily see any downsides to adding a little stimulation during ppb, especially while you're doing those Mr. SOPA steps. I think sometimes stimulation can be too vigorous. We overwhelm a baby. But what did you think?

I thought there was, I thought it was a cool paper. I agree. I mean, there's something I had not thought about, I think it has to do with the NRP guidelines where I'm not blaming the NRP guidelines by any means. But you know how we teach the fact that if you have primary apnea, that's more likely to respond to stimulation. And then if that doesn't work, then you're entering this phase of secondary apnea that's much less likely to respond to stimulation and more to PPV. And I think the mental leap that I've probably made before is, is that okay, so then I should stop stimulating them. And this paper is saying maybe you shouldn't? I do think so. I think that's from that standpoint, I think it's interesting. And I'm going to be honest, I have been I've been in practice for not very long, but I have had a ton of delivery room experience, every place I've been to, somehow we I was always the one in the delivery room. And I've seen a lot of stuff. And I've seen a lot of experienced delivery room nurses or nurse practitioners or even attendings that do like some CPT, you know, like they like for babies who are having difficult time transition. And that's obviously never like there's nothing in NRP that says that you should just like, and, and they're talking to you from experience saying like, yeah, if you're if you're having a problem, then you give them a bit of CBT. And they do fine. And this would go back. And so I never, I never took on the practice because it it's not really worth an RP teachers. And but I respect what others have done. And now you see this paper and you like maybe they have a point maybe, maybe they do need more stimulation beyond that initial phase. So I think that's very interesting. I do think like you said, that the fact that the babies acted as their own controls is the biggest limitation of the paper. Because technically, as time progresses, they're supposed to get better like things are the values are supposed to get better. So how much of it is due to the to the stimulations versus how much of it is due to the baby just surely transitioning? That's left to be

Yeah, and then this was in term babies, right. So different than the than the preterm baby. So, yeah.

So I thought that was a cool paper. Yeah.

Okay, listen, we're

not here to judge. We're just here to bring up the information and then people do whatever they want with it. That's right. But this was very cool. I like when people make you think about something different. Even if the data is not pretty. You can take the data right away to the bedside, it makes you think about something that you've done for ages, and you're like, oh, maybe I have something to learn from this. Absolutely. Yeah. All right. Shall we go into Hae? Sure. Let's, alright. So we have two papers. We have one about transport of HIV babies and we have one about cuddling HIV is which ones you want to take.

I thought you we're gonna do both of them. Fine, whatever you want.

No, that's okay. All right. So the first paper isn't published in archives and it's called outcomes of neonatal hypoxic ischemic encephalopathy in centers with and without active, active therapeutic hypothermia, a nationwide propensity score matched analysis. First author is Leora Laura Shipley, and this is from a center out of Nottingham in the UK. The premise of the paper is an interesting one, right? And the premise of the paper is that we are regionalizing our care, letting single centers take the brunt of the acuity and leaving smaller centers in the periphery with less services to offer lower levels of care. But they were saying when it comes to HIV, doing this could negatively impact babies because you have babies that are born within a smaller hospital that doesn't have the services available to call the babies. And then these babies need interventions right after birth, you have really the clock is ticking, you have to do stuff within the first six hours optimally. And most of these places don't have ways to start cooling, like they don't have equipment. And again, these are generalization but the framework makes sense. They wouldn't have the equipment to start for calling some regional centers may not have transport equipment to cool on transport. And so they said all the delay in bringing the baby from that center to that regional center that can provide cooling can create a significant delay in care, and could that eventually negatively impact the baby? We're talking also about the fact that most centers if they don't have the cooling equipment, would probably do passive cooling. And, and would that even help? So I thought that was a very interesting idea. Yeah, because HIV is a is usually a problem of delivery going awry. And so you would think that the smaller centers would be a prime place for something like that to happen, I mean, or somebody delivers precipitously, something happens at home and you go to the closest place you don't take, like you don't, it's not like you're you have a baby with prenatal diagnosis of congenital diaphragmatic hernia that you can plan the delivery, it's usually catastrophic. It happens and, and yeah, of fetal movement, something like so anyway. So this was a retrospective cohort study. And they looked at data from this new UK national neonatal research database. And it was prospectively collected, they looked at all infants born between 36 and 42 weeks between 2011 and 2016. primary outcome of the study was seizure free survival to the neonatal discharge. In babies with moderate to severe HIV, I think we have to mention that again, in any HIV study, this does not include mild secondary outcomes where mortality seizures anticonvulsant, use an admission temperature from time of birth to arrival at a cooling center following transfer. We're running a bit out of time, so I'm going to be I'm going to go straight to the to the to the results. So birth in a cooling center was associated with improved survival without seizures. And the difference was 35% versus 31.8%. Value 0.02. Being born in a cooling center meant fewer seizures, 60% versus 64%. And mortality was similar. And again, I mean, really mortality. I mean, to me, whenever we when matched infants from level two centers only had similar results. And birth in a cooling center was associated with a greater seizure free survival, compared with non Bowling Centers. What was interesting was when you looked at temperature, following transfer from a non cooling center to a cooling center in France arrived with a recorded optimal temperature, but only in 12.7% of cases within six hours. So it's really minimal. And so the conclusions of the paper were that almost half of the UK infants with HIV were born in a noncoding center. And this was associated with sub sub optimal hypothermic treatment and reduced seizure, seizure free survival. And so the conclusions of the paper are not that you should be delivering at a regional center, but saying, Should we rethink how we equip our non cooling centers with at least some, some equipment to manage temporarily these babies in order to improve outcomes so that these babies can make it to the regional center? Safe and sound? I thought that was a very interesting subject. And it's interesting. It's always hard to see how you're going to study this practically speaking, but I guess this database really lent itself to that data. So that that was interesting.

Yeah, I think they did as well as they could, given that it's complicated data, and, you know, coming from lots of sites, and they did a good job with this kind of propensity score matching. But I mean, I totally agree. I mean, I think cooling even though we're all trained to do it is still a high risk procedure. Right. And so if your centers not doing a lot of them, then then you know, I think the more you do, the better you are at anticipating what will go what could potentially go wrong. And so, I think we should still regionalize it, but I think the message is exactly right. So how can we reduce time to transport you know, have better concrete pathways from small are hospitals to bigger? Not necessarily but to the to the specialized care facility so that the first, you know, hour isn't spent calling around to say, you know, where's this baby gonna gonna go? Which which does happen even here in the state. So I mean,

the one thing that paper doesn't address is this paper talks really you think about the cases the paper talks about, and they are mostly like the typical HIV case. But so many times the baby is born and you don't know and you and you need to wait. And then you see how they do when like, maybe you do have to take two hours to make an assessment. And then you do call the regional center. And guess what, it's COVID and they don't have any nurses available, because they're already like, strapped because they are running thin and now they have to find people. So it is it is it is crucial, in my opinion to to bring this paper to the forefront because for these babies Time is ticking. And we're talking about long term outcomes. So So yeah, I think I think this is something that is coming out of the UK, but I think is easily applicable to the US and come from France, France to is in the same boat. So very, very valuable. Conclusion and I

yeah, I think the the thing to highlight is just that the babies didn't have to get there by six hours, but the they, we should get them to the right temperature by by six hours. And that that's something we can do you know, theoretically in transport, or, like you said, having having more equipment to outline facilities. So

and passive cooling is is fine, but it's not great. I mean, it's, it's these kids deserve better. All right. Okay, one more paper about therapeutic hypothermia, which I really enjoyed. It's in BMJ pediatrics open it's called physiologic response to cuddling babies with hypoxic ischemic encephalopathy during therapeutic hypothermia. And observational study. first author is David OD. And this is a paper out of the UK, again, the UK are being well represented this this week. So this paper talks about something that I've always thought of, which is babies have their babies have HIV in a therapeutic hypothermia. And the parents can touch these kids for like 72 hours. I mean, can touch it's not true, but they can hold their babies right there. They just have to leave the baby on the blanket right or cooling and, and so they're saying, again, another one of these paper that challenges dogma, do we is it Is that a fact like why can they hold the baby? And obviously you're worried about how their EEG is going to respond. You're worried about like their temperature changes, and so on and so forth. So this, this paper looks at, can we cuddle babies? And what are the effects on geologic parameters. This was a prospective observational study that was done between October 2019 and November 2020. right in the thick of COVID times I was very proud of the fact that this study comes out in the middle of the pandemic, which means that parents were at the bedside and they did skin to skin so good for them. Babies eligible obviously, were babies born 36 weeks or more undergoing therapeutic hypothermia admitted to the NICU for HIV. And they excluded infants who received considerable quote unquote, cardio respiratory support. Infants who had congenital anomalies, Status Epilepticus at the time of the battle, as families who lacked English proficiency to complete the questionnaires were also excluded. So these exclusion criterias are obviously something you can review and sandwich about them. And so the study procedure, I think, was called They call this the cool cuddle and I, they were the I mean, I wasn't super clear as to how they were doing this. But my understanding is that they did put the baby on the mother's chest or on the father's chest. I think certain areas of the body were in contact with the skin, but not the entire not like half of the baby's surface area.

Again, I understood it that the baby was still mostly in cooling blanket. Yep.

And all the babies had EEG monitoring, they had nears and they collected a bunch of data, obviously, both on the cardio respiratory support, they looked at blood gas measurements. And they also did some very cool things when it came to maternal postnatal depression. We looked at maternal infant bonding scales, and they looked at fathers attachment, and they looked at rates of breastfeeding after discharge. So 58 infants received therapeutic hypothermia for HIV, of which they recruited 27 babies and those 27 babies. They had 77 Zero cuddle experiences rated over a cumulative duration of 115 hours. The mean age of the first cut or the first skin to skin, whatever we want to call this was 50 hours, the second was 62 hours. And the third and the third was 72 hours, the fourth about 74 hours. So, not super early on, right. I mean, like nobody in the first six hours, obviously and probably because for good reasons. That was something that was very disappointing. Not disappointing from the authors, but like, only 18% of the cuddles were performed by the Father. So yeah, I mean, that's that's a shame. I think there was no evidence of so let me let me go over some of the results. And there was no clinical no evidence of a clinically meaningful difference in most measures between the pre cuddle during and post cuddle period. They had like very, very mild increase in rectal temperature around by 0.07 degrees centigrade. There were changes in peripheral oxygen said there were changes in peripheral oxygen saturation and entitle carbon dioxide. They had no difference in tip, peeps, and mean airway pressure fit to inspiratory time tidal volume respiratory rate between all three observational periods. They had no, they had higher co2 At the end of the cuddle, but no differences in pH and no differences in pH co2 based deficit glucose or liked it. There were changes in mean blood pressure with babies having higher mean blood pressures after the cuddle. Again, not sure what to make of that. Finally, the occurrence of seizures and sleep wake cycling and the overall ag score did not vary between the three periods. They describe some EEG changes where the upper margin and the bandwidth did change during the cuddle. But the number of seizures did not change before, during or after cuddle. And they had defined some some adverse event that if they were to happen, would have required the interruption of the cuddling. But that was never reached from discharge to eight weeks postpartum maternal postnatal depression declined, they had higher breastfeeding rate than average, in the babies who were cuddled. And mother infant bonding, bonding scales remained stable. Again, this is another case where the babies provided their own control, they didn't really have a control group. But I thought this was very interesting. Even I was expecting that the babies who underwent the cuddling procedures would do better, they would have lower, they would have better blood pressures they would have, everything would get better. But at least the fact that there was no significant changes, really, in my opinion, emphasize the fact that it's not incompatible with therapeutic hypothermia to hold your baby. Yeah, I don't know what your thoughts were Daphna.

Yeah, I mean, for me, this was this was this is what I wanted to do as my fellowship project. So I'm glad somebody, somebody was given the opportunity to do it. So because I think what we showed is that it's safe to do, right. And I think that we don't realize enough how trauma associated with a very acute admission affects parenting. And parenting certainly affects outcomes. And so I just, I think this is an important paper, I think this is such a time where we're addressing parental mental health. I too, I had hoped that this may, you know, show improved ag findings. But I think even if it doesn't, there's a lot of value to giving parents this opportunity, especially in the in the HIV population where the admission may be short. And the parents have to go through this like roller coaster, and then turn around in 10 to 14 days and take their baby home. And some of these moms also had have traumatic deliveries. So anyways, I think any control that we can give back to parents, I think is optimal. I'm hoping we'll do bigger studies, and maybe we'll see some some change in this. This didn't look at outcomes, right? It just looked at really like

that's exactly what I was hoping to see if there's any change in long term outcomes when it comes to that I doubted considering it's a it's a minimal intervention that gets not like the babies are spending that much time

and money mass at max they said two hours for a cuddle, but one of the other things they didn't see they looked at pain scores, but they didn't look at the need for sedation. So that's something that I think would be very valuable. Might we be able to use less sedation in these babies, which will be helpful for a number of reasons, one for the, you know, neurologic benefits. And to me, we see less adverse events like bradycardia and low blood pressures if we could use less sedation.

Yeah, I mean, they did collect and pass. And they did mention that babies were receiving allergies and stuff, but I didn't see any specific.

We have time for one more.

Should we should do that little COVID?

Yeah, I think I think this is short. So we'll I think we should I think it was interesting. You know, it's, it's COVID COVID COVID. This paper was again in the archives and nasal expression of SARS cov, two entry receptors in newborns. First authors cin, two he known in which I'm sure that I

found another another one bites the dust.

We're working on it you guys check us correct us this message as Tweet us, let us know so we can do better next time. So the authors are coming from Finland, and Estonia. And so what they did is they took these nasal scrape samples that had been previously collected for a different set of research studies on epithelial ion transporters. But they wanted to look at the expression of viral entry receptors between these three groups. So they looked at term newborns with gestational age 4040 plus or minus one week 11 preterm and newborns between really 28 and 32 weeks, and then 10 healthy adults. So they had 17 term babies 11 preterm babies, and like I said, 10 healthy adults aged 30 to 60 years, the samples in the babies were collected 24 hours after birth. And then they basically just looked at the MRI mRNA levels of the following entry receptors as to which is getting a lot of attention, obviously, because of COVID. But these other receptors have what as well, TM P r s s two and RP one and RP two and IGF one, our receptor were an all of them were significantly different among the term and preterm newborns, as compared to adults, and so they had less of the viral entry receptors then adults did, and this had been previously shown in children, but nobody had really looked at Babies yet. Interestingly enough, they didn't really see a difference between the term and the preterm neonates, but just that they had seen significantly less viral entry receptors than adults. And may this give a nod and indication to why thankfully, most babies stop most babies are not being infected, even when they have an exposure or a positive mom. And most babies are doing quite well, thankfully. So may this be a piece of the puzzle?

That's exactly right. I was I've, we've seen this, right, obviously, I mean, every mother on the lnd, four has COVID These days, and babies are fine. And so it's interesting to see babies going home in these vary during the time of pandemic and really not being as sick proportionately in terms of their population compared to adults and stuff. And it's kind of nice to have, like you said, a piece of the puzzle that says, well, that's that may be why they're catching it less because they have less of these receptors. Interesting. Also, that terms in preterm didn't make much of a difference. I was really expecting to see this dose dependent response where you would see like very little and preterm a bit more in terms and then higher in adults, but no pre terms and term, baby. I mean, it's a small study, there's not that many like they were the 11 preterm babies. So I guess I can't generalize too much. But it's very cool. Very cool. Study late. Yeah. Check it out.

All right, buddy. I think that's all we have time for.

That's right. See you next week, Daphna we have a bunch of cool guests coming up. And yeah, stay tuned. People. Thank you for thank you for all the engagement for all the love on Twitter. And yeah, see you next time.

Okay, bye.

Ben 1:04:39

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 podcasts, 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 BQ podcast at 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

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