Hello Friends 👋

On this week's episode of Journal Club Daphna and I review the latest articles in neonatology to keep you up to date. The discussion spans the effectiveness of early ibuprofen intervention for preterm infants with patent ductus arteriosus, the benefits of breastfeeding in reducing bronchopulmonary dysplasia, and the impact of clinical chorioamnionitis on long-term neurodevelopment. They also scrutinize a study challenging the practice of placing preterm infants in polyethylene bags for thermoregulation during delayed cord clamping. The episode critiques hospital approaches to maternal marijuana use during breastfeeding, debates the association of platelet transfusions with neurodevelopmental impairment, and examines the unexpected outcomes of prophylactic Azithromycin use in infant mortality prevention. Finally, they explore a comprehensive review of managing refractory pain and sedation in infants, rounding out an episode packed with insights for the neonatal specialist. Special guests Dr. Cami Martin and Dr. Eugene How join for this month's EBNEO commentary, enriching the discussion with their expertise.

Enjoy.

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

Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. Gupta S, Subhedar NV, Bell JL, Field D, Bowler U, Hutchison E, Johnson S, Kelsall W, Pepperell J, Roberts T, Sinha S, Stanbury K, Wyllie J, Hardy P, Juszczak E; Baby-OSCAR Collaborative Group. N Engl J Med. 2024 Jan 25;390(4):314-325. doi: 10.1056/NEJMoa2305582.PMID: 38265644 Clinical Trial.

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm. Davenport PE, Wood TR, Heagerty PJ, Sola-Visner MC, Juul SE, Patel RM.JAMA Netw Open. 2024 Jan 2;7(1):e2352394. doi: 10.1001/jamanetworkopen.2023.52394.PMID: 38261320 Free

Marijuana Use and Breastfeeding: A Survey of Newborn Nurseries. Chang PW, Goyal NK, Chung EK.Pediatrics. 2024 Jan 22:e2023063682. doi: 10.1542/peds.2023-063682. Online ahead of print.PMID: 38247374

Clinical Chorioamnionitis and Neurodevelopment at 5 Years of Age in Children Born Preterm: The EPIPAGE-2 Cohort Study. Salmon Rm F, Kayem G, Maisonneuve E, Foix-L'Hélias L, Benhammou V, Kaminski M, Marchand-Martin L, Kana G, Subtil D, Lorthe Rm E, Ancel PY, Letouzey M; EPIPAGE-2 Infectious diseases working group.J Pediatr. 2024 Jan 17:113921. doi: 10.1016/j.jpeds.2024.113921. Online ahead of print.PMID: 38242316 Free article.

Challenges in management of refractory pain and sedation in infants. Oschman A, Rao K.Front Pharmacol. 2024 Jan 3;14:1259064. doi: 10.3389/fphar.2023.1259064. eCollection 2023.PMID: 38235119 Free PMC article. Review.

Azithromycin during Routine Well-Infant Visits to Prevent Death. Sié A, Ouattara M, Bountogo M, Boudo V, Ouedraogo T, Compaoré G, Dah C, Bagagnan C, Lebas E, Hu H, Rice J, Porco TC, Arnold BF, Lietman TM, Oldenburg CE.N Engl J Med. 2024 Jan 18;390(3):221-229. doi: 10.1056/NEJMoa2309495.PMID: 38231623 Clinical Trial.

Polyethylene bags before cord clamping in very preterm infants: a randomised controlled trial. Dunne EA, Ni Chathasaigh CM, Geraghty LE, O'Donnell CP, McCarthy LK.Arch Dis Child Fetal Neonatal Ed. 2024 Jan 11:fetalneonatal-2023-325808. doi: 10.1136/archdischild-2023-325808. Online ahead of print.PMID: 38212105

Early Hyperoxemia and 2-year Outcomes in Infants with Hypoxic-ischemic Encephalopathy: A Secondary Analysis of the Infant Cooling Evaluation (ICE) Trial. Badurdeen S, Cheong JLY, Donath S, Graham H, Hooper SB, Polglase GR, Jacobs S, Davis PG.J Pediatr. 2024 Jan 5:113902. doi: 10.1016/j.jpeds.2024.113902. Online ahead of print.PMID: 38185204 Free article.

Breast-feeding as protective factor against bronchopulmonary dysplasia in preterm infants. Uberos J, Sanchez-Ruiz I, Fernández-Marin E, Ruiz-López A, Cubero-Millan I, Campos-Martínez A.Br J Nutr. 2024 Jan 2:1-8. doi: 10.1017/S0007114523002982. Online ahead of print.PMID: 38163989

EBNEO commentary: Early human milk fortification in infants born extremely preterm: A randomised trial. How HS, Malhotra A, Martin C. Acta Paediatr. 2024 Jan 18. doi: 10.1111/apa.17110. Online ahead of print. PMID: 38235608 

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

 Ben Host 00:00

Hello everybody, welcome back to the incubator podcast. It is Sunday. We're doing journal club Daphna. How are you?

 Daphna Host 00:05

I'm doing great. You know I feel like we haven't done journal club in the while. It's not true. We've just had so many other things happening on the podcast that it feels like we haven't done journal club in a while.

 Ben Host 00:17

It feels like that. It feels like journal club is a distant ways away.

 Daphna Host 00:20

That's right.

 Ben Host 00:21

And yet it's not. It was, it's. We're following the schedule religiously, so, but it's a big year for the incubator, as you. As you may have noticed, we have already published two of the episodes from our new series, on global health, the global neonatal podcast, Hosted by Shelly-Ann Williams-Dakari. She's going to be assisted by her colleague, Mbozu Sipalo from Zambia.

00:45

Mbozu is not really going to be on the first few episodes she's joining us later in the year, but so so you'll hear, like me on the first one with with Shelly Ann Gabriel is on the second one, but but yeah, so so they're going to do, they're doing a phenomenal work and our first episode with Dr Kunda Kapembwa from from Zambia is really phenomenal. I think it was a great episode to begin the year with. And then this past week, as you may have noticed, the first episode of at the bench, a podcast completely dedicated to neonatal physician scientist air, its first episode,  Host ed by Dr Betsy Crouch, dr David McCulley and Dr Misty Good, and their their work is really excellent. If you are a physician scientist, if you are interested in becoming a physician scientist, then you should definitely check out their podcast and, if you're free to reach out to them, we have a beautiful website, and I'm not saying that because I I I worked on it days and days, and days so modest.

01:45

But on the about page you should see, you should see a whole list of picture at the bottom with our entire team and you can actually see the  Host s of the various podcasts and they'll be there by they'll. Each one has a bio. You can have their social media links and at the bottom of each of the individuals page there's even their email. So you can email them and you say hey, dr Misty Good, I want to work in basic science, can you help me out? But yeah, so so reach out to us. And one more series is due to come out, maybe next month, and we actually have finally a title for this series. I don't know if you saw that Daphna.

02:25

So, yeah, the. The series is called Beyond the Beeps and this is a podcast that will feature parents speaking to parents, with some presence from medical professionals when needed to maybe clarify some technical concepts, but mostly driven by an NICU parent who are talking to other NICU parents. So we're very excited about that, and this is done in collaboration with our friends at ICU Baby, a nonprofit organization here in South Florida that helps parents of babies who are hospitalized in the NICU. So we've been busy, yeah, we've been busy. And while we're doing all of this, I'm going to do a double shout out here. We have the Delphi conference in 2024, coming September 23 to 25. You can already start registering. We have discounted tickets for early, like an early bird type special. The schedule is pretty much done. We know who's speaking when we're just waiting for these speakers to send us their presentation titles. At least.

 Daphna Host 03:23

Yeah, you know, we've asked them to give talks. They've never given before, so they they have to rethink their titles.

 Ben Host 03:30

So that's right, and if you are one of the upcoming speakers at Delphi, don't forget to send us your title. And you're listening to this episode. Please send us your title.

 Daphna Host 03:40

You know who you are. But I think about the new, the new podcast. I think like I hope people get the chance to listen to all of them. Like, maybe you're like I don't know about global health, I'm not a venture researcher, or oh, that's podcast is for parents. But I think that everybody who works in the NICU is going to be able to learn something from each of these and our hope is that we all have like just a more well rounded understanding of the whole team, right?

 Ben Host 04:10

Yeah, I think. Remember, none of these podcasts are lectures, so like they're not presenting their, their discussions, that's the whole point. They're easy to listen to. So just listen to Dr Kunda's experience being the sole neonatologist in Zambia and how she arrived as the first neonatologist in the country and how she was received, I think, to me that was incredible incredible story, surprising.

04:32

I was not expecting her to describe what she described and listen to the at the bench. Listen to Betsy Crouch talk about her life as a as a physician, scientist, how she juggles going from service back to the bench, and what is the experience like at the bench. What are the things they think about, what are the, the stressors, the satisfaction points of their work? They're not going into a long list of proteins with weird names Like. This is not. This is not the gist of the episode.

 Daphna Host 05:01

No, there are lots. There are lots of pearls there, I think lots of pearls, yeah, and.

 Ben Host 05:06

And it helps us understand how our colleagues function, because we all function differently. Whether you are a physician scientist, a clinical neonatologist, a clinical researchers, you juggle things differently and I think it's interesting to see how, how right, a clinical researcher will look at something happening on rounds. We could do a study about that and like how does the, the bench, the bench scientist looks at at at rounds and family interactions? There's a great story that Betsy tells on her first episode. So anyway, I'm going to tease more than that. They're all doing a phenomenal job. I'm quite proud of the team.

 Daphna Host 05:40

Yeah, and what a big team. The team has grown so much in the last year and that's all thanks to people who keep tuning in every week.

 Ben Host 05:48

So yeah, yeah, and people who are willing to put themselves out there, willing to collaborate, dedicated people who are dedicated to education and the dissemination of evidence. So, yeah, we're excited about that and more collaboration. This week we have a journal club and we are actually going to have an EBNEO commentary for the article of the month, an article that we reviewed earlier but that Dr Cami Martin is joining us today with Dr Eugene How to discuss their commentary, published in Acta Pediatrica called. The paper is the paper by Ariel Salas called early human milk fortification and infant born extremely preterm and randomized trial. So that will come later in the show. We've burned through a lot of time but let's, let's jump into it. So you see, sometimes we procrastinate and that's kind of good because I was able to actually review a paper that came out yesterday evening.

06:43

So the New England Journal of Medicine published the results of the Oscar trial. The paper is called trial of selective early treatment of patent ductus arteriosus with ibuprofen. First author, samir Gupta. This is a study done out of the UK, so the study explores the use of ibuprofen for treating patent ductus arteriosus in preterm infants and the specific focus of this paper is on whether selective early treatment of large PDAs with ibuprofen can actually improve short-term and long-term outcomes. The research question addresses whether early treatment with ibuprofen for large PDA improves outcomes such as survival and the incidence of moderate or severe bronchopulmonary dysplasia. So this is a multi-centered study, includes 32 units in the UK. It was randomized double blind placebo control trial and the trial included extremely preterm infants.

07:36

I think when we're dealing with these PDA trials, the question you have is who are they testing this on? Well, this was babies born between 23 weeks and zero days and 28 weeks and six days, so a very, very extreme low birth weight or very premature population. And to be included you had to have a large PDA. What is a large PDA? Well, that meant that the PDA had a diameter of 1.5 millimeter or more, with pulsatile flow, and the PDA was evaluated via trans thoracic echocardiography. That was performed to assess eligibility within 72 hours after birth and again, that echo was reported was repeated I'm so sorry at three weeks of age, between days 18 and 24. Now the infants either received an early treatment with ibuprofen. That means that they received the first dose within 72 hours after birth, so quite early sometimes most, I think a lot of us would say usually in the third day is when we start worrying about the PDA.

08:35

And then the other group received the placebo and the primary outcome measure that was tested was a composite of death or moderate or severe BPD at 36 weeks post menstrual age. The BPD definition is the one by Walsh and Colleague where they actually do the oxygen reduction test. You can find out more about that in the paper. The statistical approach was to do an intention to treat and the analysis were adjusted for several factors, including PDA size, gestational age and mode of respiratory support. Interestingly enough, and we'll talk about some of there's always methodology question with these PDA trials. Obviously this is a New England Journal of Medicine paper, so you know it. The study is robust.

09:14

But I thought it was interesting that when they did their power calculation they predicted a 60% incidence of the primary outcome, which was death or severe or moderate to severe BPD in the placebo group and calculated the required sample size based on detecting a 12 percentage point absolute reduction. And I'm not pretending, like our center is the best center in the world, but I'm sure there are centers that might say, well, 60% is quite high for us, like our base rates might be lower and so we'll see you do with that as you may, but right, it's interesting, I will say this. So, in terms of the results, we have 653 infants that are randomized, 326 receive ibuprofen, 327 receive placebo, the median PDA diameter was 2.2 millimeter, and that data for the outcome analyses were available for 324 and 322 infants respectively, and what the study found was that a primary outcome event, which means that death or moderate to severe BPD, occurred in 69% of the ibuprofen group, versus 63% in the placebo group, and adjusted risk ratio of 1.09. So, no, no significant difference. The mortality rate was 13.6% in the ibuprofen group and only 10.3% in the placebo group. So, again, not statistically significant, but not even a signal going in the right direction, if you're an advocate of ibuprofen.

10:45

Moderate or severe BPD occurred in 64% of the ibuprofen group, compared to 59% of the placebo group, and then there were, I think, one or two serious adverse events that were possibly related to ibuprofen. I think what's interesting to mention as well is this possibility of open label treatment for any indication of the PDA, and in the study, the percentage of infants who received any open label treatment, including surgical ligation, was 14% in the ibuprofen group, compared to 29.8% in the placebo group, and so then you wonder what does that mean for the study? So another point that I think many people will discuss when it comes to that paper, which again goes back to the point of it is a very well designed study, and obviously these are the little odds and ends that people will pick on, because the rest looks pretty good. The study concludes that the risk of death or moderate or severe BPD at 36 weeks is not significantly lower among infants who received early treatment with ibuprofen compared to those who received a placebo.

 Daphna Host 11:53

What do you think?

 Ben Host 11:55

I'm not surprised by the data, and I mean it's always. I mean these trials. You always ask the questions would we do like, would we want to treat PDAs very, very early, within 72 hours, and so on? I Don't know. I still. There's a lot of people have a lot of thought.

 Daphna Host 12:15

I'm going to be humble and not yeah, there there are plenty of big opinions on the topic. So I think if people want to get the full range, they should just follow it on Twitter.

 Ben Host 12:27

Absolutely. I mean, there were a lot, of, a lot of interesting discussions about that at hot topics this year and I think when I was speaking to Gabriel Altit on the French podcast about some of these, about some of these results and some of these slides yeah, these he's also not a big advocate of ibuprofen for PDA, and I think what's interesting, I think, if I remember correctly, is that when I forget I forget who presented on the PDA at hot topics, but when talking about in the methods, in our ibuprofen and they said that the evidence shows it's harmful and that it's not indicated outside of our cities. So, like I said, I mean I'm hearing about this. Obviously people are familiar with the preliminary data, so I'm not surprised, but it's interesting to see how, in the medicine, ibuprofen nor falling by the wayside and trans catheter closure is becoming something that's might be more and more used. Anyway, that's, that's my. These are my thoughts.

 Daphna Host 13:26

Okay. Well, thank you for tackling that last minute entry to the journal fuck arena. Okay, I'll go yeah.

13:36

There was this paper breastfeeding as protective factor against bronchopulmonary dysplasia and preterm infants. This was in the British Journal of Nutrition, jose Uberos, out of Spain. This was a retrospective study To look at the intake of mother's own milk, donor human milk or preterm formula in the first two weeks of postnatal life of these very low birth weight infants. This was done between 2008 and 2021. So that's a big time span, I'll just say. But anyways, the inclusion criteria were newborns weighing less than 1500 grams admitted to the neonatal intensive care unit, invents who died in the first 28 days, those transferred were excluded and then, obviously, if there was no data on BPD, since BPD and degree of BPD were the outcomes of interest. They did talk a little bit about their feeding progression. They start with two ML's and they increase by 20 to 25 ml per kilo per day. They use mom's own milk or donor human milk until until week 32, gestational age, 32 post menstrual age, I'm sorry after which time the infant was transitioned to premature formula and they used a human milk fortifier once the infant reaches 80 ml per kilo. They monitored numerous morbidities BPD, which they defined as FiO2 greater than 21% at 36 weeks post menstrual age. Sepsis, the crib score, which is a measure of Illness severity, pda and neck. So they had 566 newborns, 74 died and three excluded for lack of data. The overall group had a rate of BPD of 39.8%. But again, remember, this cohort started in what did I say, 2008? Yeah, and they obviously showed trends over time. There was a downward trend from 2008 to 2021 52% in 2008 down to 35% in 2021, and of the 566 newborns, 195 had BPD and the remaining close to 300 without BPD. So on average for the cohort, the gestational age was 29.6 weeks of gestation, birth weight was 1241 grams, 48% were female, and then they started getting into this BPD data. So the results of the univariate analysis showed an inverse association of birth weight, gestational age and apgar score with BPD. None of that is surprising, no, and on the other hand, the bivariate analysis shows that the factors associated with BPD were history of chorioamnionitis, male gender, history of neck greater than an equal stage 2, history of late sepsis, pda, the need for oxygen therapy and mechanical ventilation Also not surprising.

16:34

Then they get into some more minutiae. So the enteral  fluid intake in the first week of life was significantly lower in neonates with BPD, such that the Infants who developed BPD had received significantly greater volume of parental nutrition. So not total fluid volume but looking at the degree of how much enteral  nutrition versus parental nutrition. So the babies who developed BPD had less enteral  nutrition. A Statistically significant portion of newborns who developed BPD had not received mothers own milk nutrition in the first few weeks of life. This was 61 versus 66 percent, but still statistically significant. And in regards to fortification, 50% of all newborns received milk Fortification and among these there were no significant differences between those with or without BPD. But the percentage of newborns who received donor human milk during the second week of life Was lower among those who developed BPD, 9.3 versus 21.8. And at 36 weeks post-menstrual age 46.5 percent of infants without BPD were breastfed compared to 52.3 percent of infants with BPD, with no significant differences between the groups.

17:56

The regression models were adjusted then for chorioamnionitis and gestational age and the analysis showed that the administration of moms owned milk and the first and second weeks of life is associated with lower odds of BPD and then even by degree of BPD, significantly for both mild BPD and for severe BPD.

18:17

So the results also looked at the trajectory of growth over time. So they were interested in how much weight gain was achieved by those very low birth weight infants and Relationships to severe BPD. So the results showed less weight gain in very low birth weight and severe BPD infants. So this appears to be a consequence of greater respiratory efforts and greater energy expenditure, such that there was a significant association between quartile one of the change in weight Z score from birth to week 36, post-menstrual age, and Severe BPD, with an odds ratio of 17.6. So those babies who had severe BPD, they were much more likely to be in the lowest quartile for change in Weight Z score from birth to 36 weeks. So they gained the least amount of weight between birth and 36 weeks, much more likely to develop severe BPD. So I thought it was interesting. I don't think any of the results are surprising.

 Ben Host 19:25

Why did you pick that paper?

 Daphna Host 19:27

I think two things okay. Well, one, I won. I think breast milk is magic, so obviously I picked that paper, but I actually think, I actually think it speaks, I Mean to the overall nutritional status. Right, it's really those. The babies who had the highest risk Were the ones who didn't get mom's milk and the ones who did not grow well, but there are many reasons why they may not grow well.

 Ben Host 19:54

Yeah, I mean obviously that that goes back to the retrospective nature of the study. Yeah, but I do think, right, it puts the finger on this, on this idea that, like you said, has been described before that Reduce the amount of inflammation as much as possible, and less TPN and mother's own milk Are probably less pro-inflammatory, so so I think that makes sense and it's a good reminder to be able to see this. I can. I kind of like the fact that they had what is it? 13 years worth of data. That's kind of nice.

 Daphna Host 20:21

So yeah, and I think it's so interesting when parents say you know what's my baby's risk for X? But it's all this inflammation is like additive. You know, yeah, if you have chorio and then you have a sepsis or a neck or a man, you're on a bunch of oxygen and you didn't get breast milk. I mean, it's hard to add up sometimes all of the factors.

 Ben Host 20:41

Absolutely, absolutely. Well. Since you're talking about chorio, I'm going to bring up another report from the EpiPage to cohort. This was something published in the journal of Pediatrics and it's called clinical chorioamnionitis and neurodevelopment at five years of age in children born preterm. The AP patch cohort study. First author is Dr Salon and colleagues, and this is obviously coming from the AP patch study, so out of France.

21:11

Now this study basically examines the the potential association between clinical chorio and neurodevelopmental disorder, and they basically did a secondary analysis that used the data from the AP patch to cohort and they looked at infants that were born between 22 weeks and 34 weeks of gestation in 25 out of 26 French regions in 2011. Now, children born alive between 24 plus and 34 plus six weeks of gestation from singleton or twin pregnancy, after preterm labor or after pre-term pre-mature rupture membrane were included. Children with certain conditions like severe congenital malformation or prenatal infections and etc. Were excluded. And the way the diagnosed clinical chorioamnionitis is by using something called the Gibbs criteria, which basically included maternal fever before labor with the addition of other factors like maternal tachycardia, leukocytosis and so on. Now I'm not I mean again, I just want to go through the paper because I think the finding is interesting. They had 2,927 children alive at the age of five. Three percent of those were born in the context of clinical chorioamnionitis and the study found no significant differences in severe neonatal morbidities between children born with or without clinical chorio. Now, of the children who survived to five years, 1726 had a complete neurodevelopmental assessment and there was no association found between clinical chorioamnionitis and moderate to severe neurodevelopmental disorder, cerebral palsy, cognitive impairment or behavioral difficulty.

22:58

You can go back and look. Like I said, I'm going to just mention this paper because the way they assessed the neurodevelopment at five years was very comprehensive. It involved parent interview, parent reports, it involved a neurological exam. It involved a lot of different things, but it's not just like right, it goes beyond the Bayley, so it's not like they gave a Bayley and so on. And so the study concluded that antenatal exposure to clinical chorio was not associated with neurodevelopmental disorders at five years for infants that were born between 24 and 34 weeks of gestation. Obviously, there's a lot of limitation to this study. I think the last to follow up at five years was 40 percent, which okay, I mean I'm not going to hold them accountable to that, but it's still a significant number, but otherwise I thought that was an interesting study.

 Daphna Host 23:46

Yeah, see, I think it's surprising, based on what we just said about inflammation.

 Ben Host 23:52

Yeah, absolutely, and I think it also goes back to show how maybe some things taper over time and obviously I think it'd be interesting to look more at these infants specifically. What kind of other pathologies did they have, and so on and so forth. One more paper before we bring on Cami and Eugene that I wanted to mention was also maybe a plug as well for our friend, dr Emma Dunn. This is a paper that came out in the archives of disease in childhood and it's called polyethylene bags. Before court clamping in very preterm infants a randomized control trial. So Emma was on the show for our series on thermal regulation that came out towards the end of last year. You should definitely check this series out. She was a great guest. We had other guests as well, from Europe. She was one of them and we had guests from the US and it was very interesting, and she spoke about this paper that we're going to talk about today. So I'm just going to review it quickly and it mentions, obviously, the concept of hypothermia, which is something we're trying to avoid in the NICU, and how we are really moving towards a paradigm in which everybody's doing delayed court clamping, and we know that delaying court clamping could potentially increase the risk of hypothermia. So what the study investigated was whether placing very preterm infants in a polyethylene bag before you clamp the cord, as opposed to after, would that result in having a temperature within the normal range on NICU admission? So they're still doing delayed court clamping, but as soon as the baby's out, they put them in the polyethylene bag.

25:27

This was randomized, a randomized control trial done at the National Maternity Hospital in Dublin in Ireland, and babies who were born there in born infants before 32 weeks of gestation were eligible and they were randomly assigned to either have the polyethylene bag either before or after court clamping. The primary outcome that they measured was rectal temperature within the normal range on admission to the NICU, and the temperature was checked rectally. In case people are going to say well, how do they check the temperature? The results of the study that took place from July 2020 to September 2022 show that they were able to enroll almost 200 infants 198 to be specific. 99 were assigned to the before clamping and 99 to the after clamping, and the proportion of infants with normal temperature on the NICU admission was actually similar between both groups and it was not as high as you may think 55% versus 56%, so still quite a significant number of hypothermia. And then, similarly, the proportion of babies with temperature outside the normal range were comparable than between the groups. The conclusion of the paper are that placing very prudent infants in the polyethylene bag before did not really increase the proportion of infants with normal temperature upon NICU admission.

26:41

And there are many things obviously that could be asked. My thoughts are well, should they check on the admission to the NICU, should they check sooner, or should there be that maybe some of these babies were able to be rewarmed between the resuscitation table or different bags, different materials? So all that stuff leads to a lot of interesting questions. If you want to learn more about how the investigators are thinking about this process, go check out the episode of the podcast with Emma Dunn and I will tell you which number that is in a second. What do you think? Daphna?

 Daphna Host 27:14

Sorry, I could have been looking that up. I was just 162. That's fine I was just going to discuss I was thinking about. What I was thinking was about that mini series. We had a lot of fun about doing that mini series. We learned a lot, I think, actually, and how fortunate we are in our high-tech species that sometimes we don't even think about the thermoregulation, anyway, all right.

 Ben Host 27:41

We're going to take a quick ad break and then we'll come back for the EBNEO commentary. This episode is proudly sponsored by Reckitt Mead Johnson. Reckitt Mead Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive female portfolio for premature and low-birthweight infants. To learn more, visit hcpmeadjohnsoncom.

 Daphna Host 28:31

Dr Martin, Dr Hao, thank you so much for joining us today. We're so excited to hear your review.

 Eugene How Host 28:37

Oh, thanks for having us.

 Cami Martin Host 28:39

Yeah, absolutely yeah, Eugene.

 Daphna Host 28:42

I'll bring you the paper, so I'll just the title of the paper Early Human Milk Fortification in Infants Born Extremely Preterm a Randomized Trial in Pediatrics of September of this year.

 Eugene How Host 28:58

Yeah.

 Daphna Host 28:59

So, Eugene, tell us a little bit about it.

 Eugene How Host 29:01

Yeah, so this is a very exciting study that just recently came out in the pediatric journal and I had the pleasure of reviewing this paper in my own journal club in Melbourne, so I thought it's a very good and exciting paper to present. So, as you mentioned, the title was the study was looking at Early Human Milk Fortification in Extreme Premature Babies and just a bit of background. So I think the important settings for this study is that it has always been quite a challenging aspect in terms of neonatal medicine to ensure optimal nutrition in extreme premature babies and, I guess, quite early on. There's a difference between parenteral  nutrition and Enteronutrition and we have quite a few studies as well that has looked into parenteral  nutrition. But for this study, early fortification of Enteronutrition is quite a novel study in comparison to other studies and I guess from all the neonatologist's centers I think what happens is the optimal goal is to provide a condition that will help the extreme premature new needs to gain optimal growth. But we are also still quite limited in our understanding of what is the best approach to provide that for all the extreme premature new needs. And as more evidence gets established for early introduction of breast milk, the next challenge will be to ensure what is the optimal calories and also optimal nutrition for optimal growth. And I think this study is in a sense the good.

31:01

The positive aspect of this study is instead of just looking at overall weight and anthropometric measures it also looked at the lean mass at accretion of all the premature babies. So that is kind of a background and setting for this study. I'll go to kind of a Pico background for this paper. So the question posted was in extreme premature new needs, so less than 28 weeks old, does the human milk fortification with human derived human milk fortifier result in an increase in fat-free mass when compared to infants who receive non-fortified breast milk in early stages of life? So kind of. So their population was the extreme premature babies and the intervention will be from day to onwards at addition of human milk fortifier and the control for this study was the population of new needs who doesn't get any fortified breast milk and outcomes.

32:12

Primary outcome that they look at was using P-part, so the at this placement pratysmography to look at fat-free mass for each and, looking at the studies, a few other aspects. So they had they use computer generated random blocks to randomize the population. So they had quite a balanced number for both groups. And the other aspects that we noted was quite strong for this study was that there was blinding in both the clinicians, parents and also the evaluators, and in terms of follow up period was up to 36 weeks or post discharge from hospital.

32:59

And in terms of the setting, it was a single study setting, so it was based in the Neonatal Unit in Birmingham Hospital and the timeline that study was conducted was between August 2020 to October 2022, which we I thought was quite interesting. It was during the COVID period as well, so it must be a bit challenging to set things in motion and I guess we already went through the outcomes. But there was also quite a few secondary outcomes that they look at in terms of significant weight loss, weight gain velocity and also rest of the anthropometric measurements. So I guess that is kind of a background and design of the study.

 Daphna Host 33:45

Excellent, excellent. Well, tell us a little bit about what they found, then let's get into the results.

 Eugene How Host 33:50

Yeah. So in terms of the primary outcome, unfortunately they didn't find any different statistical significant difference between the Z score in terms of the fat free mass for age. But in terms of secondary outcome they did observe that there was higher length gain velocity in the intervention group. There was also declines in, so the declines in terms of height circumference for each Z score was less pronounced in the intervention group. So these two anthropometric measures kind of just it's a positive finding in terms of the secondary outcome. The other important thing to note in the secondary outcome was that they noted the risk of spontaneous intestinal perforation and neck and depth was not statistically different between groups. But they did say that in terms of the numbers was a little bit too small to confidently say that.

 Daphna Host 34:56

Yeah, no, I thank you for reviewing that and certainly I know I imagine the first question people have is what were those adverse events, what are the balancing measures? And, like you said, they looked at neck sip, death and the combined outcome of neck sip and death and, I think, some of the really other interesting features. I think I'm imagining how this would go in my unit. The discussion around this paper and the cohort was pretty small and pretty early, so I think that's really important. They had these 230 extremely preterm infants the mean birth weight was 795 grams and the median gestational age was 26 weeks and of sorry, the 230 were assessed for eligibility, they included 150 in the final analysis, but of the 150, 31 had a gestational age of 23 weeks or less. So that's the our tiny, you know, our tiniest babies. So I think that's a pretty impressive group to study. I think it's the group that we're all worried about. Cami, dr Martin, your thoughts on the paper.

 Cami Martin Host 36:13

Yeah, no, I agree with you. You know kudos to Dr Salas that clinical trials are never easy. And during the COVID pandemic and recruiting the small babies, which is important because many of our nutritional studies are a little bit in the older birth weight and older gestational age babies, and as we advance our care in the more and more immature babies, what does the nutrition look like for them? And it may very well be different and we anticipate that it's different as we go along the developmental age spectrum in birth gestational age. So lots of, lots of great contributions there by this group and thank you, Eugene, for your overall summary. Yeah, I think in general, the strengths and you know, are the fact that what we just said, plus it was blinded and randomized, the limitations a little bit single center, and the smaller overall cohort size. But love the fact that he went after fat free mass because as we also get better and better at understanding body composition and getting the ideas that or the conclusions, that matters and sort of their long term outcomes, the question I'm always wanting for is well, what do I need to do? What are the guiding principles to help drive that body composition to the proportions that you want to attain for their overall health. But I think the that guidance is a little bit lacking. Like what does that mean in the in the sense of energy delivery and protein delivery and carbohydrates. So I love the fact that he went beyond the traditional growth measures and say, okay, is this going to impact fat free mass? Because an answer to that now. Now it evolves into a specific guidance around that with the endpoint of body composition.

38:00

So love the fact that he he really wanted to explore that and see and see what it meant. He didn't see a difference. He saw some other gains and and as with any good study, always brings up these other things that I wish I had known about or or could look into further. So, for example, you know the absence of a bovine human milk fortifier, I think is you know, is that a missed opportunity or not? You know he did start early, at two days, but his control group waited until full-enteral  feedings.

38:33

I think a lot of units have moved to an earlier fortification strategy, so to me it reinforces that earlier fortification before getting to full-enteral feeds matters. But it would have been nice to have a little bit of a direct comparison to a strategy that didn't wait till the end and and in full-enteral feedings. So lots of good ideas and the implementation of the study and the endpoint. And you know, obviously still more to come. And I would say the final thing in the still more to come category is there the Z scores were still declining and so there there's still so much we don't understand in supporting growth and and what that means to outcomes. So you look and see, even with this early fortification, we're still seeing declining Z scores in our anthropometrics.

 Daphna Host 39:26

And maybe you can talk a little bit to you know why. Why is early enteral nutrition so important? Why? Why does this early fat-free mass, what's the big deal Right? Why? Why do we need to? To secure this in our babies as early as possible? And, like you said, you know it's a it's we're. We're all trying to reach that goal of not having these declining Z scores, but what does it mean for babies long-term?

 Eugene How Host 39:55

Previously, when we were aiming just for weight gain, it was an accretion of fat plus lean mass, which previous studies have shown that that can increase negative impacts in the day, so they can have higher proportion of diabetes hypertension. And the lean mass that was measured help us to understand the lean mass gain in like brain function, so that will be important to assess as well, not just at term, but also a long-term outcome in terms of higher executive functions. So that's why our aim has always been to help extreme premature babies to gain lean mass rather than just fat mass.

 Cami Martin Host 40:42

Yeah, yeah, no, I think that's perfect for that part and I'll say the perspective I've always taken is that, you know, nutrition is a nutritional for proven mature infants is a nutritional emergency and in a nutritional emergency in the peri natal, you know, right after the early postnatal period and through, you know, two, two weeks, in a month of age, there's plenty of studies that showed that your, your total energy delivery, your protein delivery, you know lipid delivery, when they look at those studies, those are directly related to the incidence of short and long-term outcomes and so you don't want to delay, you don't want to know that you'll eventually get there but it may be a month or more than that.

41:24

The studies, I think, to support this concept of an early nutritional delivery within the first couple of weeks, that it matters what your total attainment is in macro nutrients into the babies outcomes, and that's not to say you know, and that's separate, right, that's a separate discussion from all the other developmental things you're doing in augmenting postnatal and testable adaptation, just by providing nutrition. So this wasn't a study about delay, but you don't want to delay for that. But you also want to attain certain metrics that we know have been shown to improve outcomes and that's early, that's within the first couple of weeks. And the other thing I loved about this study and the way he set it up is it was a two-week question. It was an intervention that was a two-week and can changing that first two weeks from their standard of care matter, and so that's how I view you know why it is why these questions are important in studying these early postnatal periods.

 Daphna Host 42:28

And I think the community has accepted that right, that we can move a little bit faster with the feeds. But I wonder there's still some units, including my own unit, or we're still trying to get to this last benchmark, let's say. So what do you think units will need to feel comfortable incorporating kind of this new step, this early fortification. It seems like it's previously been thought that the baby has to prove somehow that they can tolerate some volume of feed before fortification. So what else do you think we need in the literature to help support this so that it may become standard of care?

 Cami Martin Host 43:16

Yeah, I think that's a layered question. The first one is how early to begin that you feel comfortable with, and it is the reporting off of experience. It doesn't necessarily have to be a clinical trial per se. I think there's a lot of value when there's a practice change and people report on their practice change. And I've seen over my time in neonatology where it was until you got to 150 mLs per kilo per day before you added one fourth higher or additional calorie and that systematically went from 120 to 100 to 80 to 60. And then I know recently I saw papers regarding 40. And so I think it's having those conversations with your group and your team and looking constantly, reevaluating the nutritional data and showing examples of centers whether it's within trials or cohort experiences and practice experiences that this has been done and is being done without any demonstrable harm and moving towards that. But it is also, I think you need to set up systems within your division where you also reassure your faculty. Let's do this but let's measure it, let's decide on what those balancing measures are and let's report on that practice in our practice, because I think also what may work in one unit may not necessarily be the same practice or what works in another. So I think that buy-in is that process of reviewing the literature, encouraging people to report on the literature, do the trials, come to a consensus and move your practices steadily, with your own internal monitoring of that change of practices, including those balancing measures. And there's comfort, right, there's comfort in a nutritional protocol and a consensus where you build that confidence to make those decisions at the bedside that it is okay. This is something we've vetted as a group, this is something we're comfortable with, this is something we're measuring and if it's not good, we'll know. And so I think that's one of the first major steps in doing that.

45:24

The second question is the another layer. Is this about the human and the bovine? Should it be different in your level of comfort? Does it matter what you're using? Is that fortification or not?

45:38

And I think for that we just need really good quality studies where that intervention is specifically looked at, where everything else is controlled for your base diets, control for the diet used to supplement, volume is controlled for and you're really trying to isolate the effect of the type of fortification. And does the type of fortification matter about when you start? And we really don't have that data. I don't think we have the data that suggests one is better than the other, and we definitely don't have the data whether they can both be used, or I guess we have some human milk data. We don't have the data, I think, of bovine starting immediately at day two. Maybe we'll see a difference. I'm not sure that. I think should be. Just hopefully folks who are in this space will continue to push forward in doing and setting up those trials, but setting it up a way so we can answer that question and trying to isolate the effect of that intervention.

 Daphna Host 46:33

I love that. I love that. I thank you both so much for your dedication to nutrition and for coming on to talk to us. Any closing thoughts about the article and what that means for the future of our little babies.

 Cami Martin Host 46:46

I think it reinforces that. Early fortification is an important one, whether it has to be on day two or sometime before you go to fall into a fees, but it supports that fortification to provide more energy and more protein has the short-term outcomes, at least in general anthropometrics, I think more needs to come regarding body composition and what interventions to promote sort of that optimal body composition. And I think and finally it's also just sort of we have to think of better and better tools constantly, of how we measure nutritional efficacy in more in real time, so we don't rely on having to in the same thing with neurodevelopment, so we don't have to wait till the end of a stay or two years out before we have an understanding of what we did in the first two weeks mattered or not. So I look forward to all the smart folks that are looking at what are the earlier biomarkers of nutritional efficacy so we can link them closer to our practices and guide a little bit more precisely what we're doing at the bedside. Can Eugene any last?

 Daphna Host 47:55

thoughts.

 Eugene How Host 47:56

I don't know. Yeah, I agree with what Cammy was saying and my own thoughts during the earlier discussion was that I guess it can be quite different comparing North America with Australia. But even in our own setting I was just telling Cammy that the availability of donor meal is quite different across the states in Australia. So in Melbourne, which is in the state of Victoria, we only have one donor center that we rely on, whereby another state, new South Wales, where Sydney is, they have multiple donor center that different hospital get their supply from. So I guess for a local Australian perspective that will be the next challenge to make sure that maternal donor meal is readily available and that can ensure that the different unit to unit can start early fortification for all the babies as early as possible.

 Daphna Host 48:56

Well, I'll tell you that's a hot topic here in the states for us as well, actually. So lots of legislation moving towards better access to donor milk. So we support you in the struggle to get that for your babies. I wish you the best of luck in that. Maybe you'll be able to do it before we will. But thank you both for your time. Have a great day.

 Cami Martin Host 49:22

Thank you for inviting us Always great to see you, Devin.

 Eugene How Host 49:25

Thank you for having us.

 Daphna Host 49:27

Our pleasure, our pleasure. Okay, we're back. I really enjoy what we have. Ebenio commentaries I love having more people in the studio.

 Ben Host 49:43

By the way, I had a meeting this week with the Ebenio team. If you are interested in doing an Ebenio commentary, they're always looking for people who are interested in doing reviews and they'll be paired up with a great mentor so you can reach out to Ebenio on the web. They're very accessible, but if you have any issues, just shoot us an email and we'll put you in touch with them as well, if that's something you're interested in doing. These commentaries are getting published, by the way.

 Daphna Host 50:04

That's what I was going to say. If they're not familiar with it, it's not just coming on the podcast, it's really getting a publication on the commentary. It's a very neat opportunity. I had this paper Early Hyperoxemia and Two Year Outcomes and Infants with Hypoxic ischemic Encephalopathy. This is a secondary analysis of the ICE trial. Lead author of this paper is Shiraz Badordi. This is in the journal Pediatrics that's coming to us from Australia. It was a retrospective I said secondary analysis of the ICE trial, which is a randomized control trial performed in 28 NICUs across Australia, new Zealand, Canada and the US. Now, as a reminder, this is between years 2001 and 2007.

50:46

So one of the early trials of therapeutic hypothermia where children were actually randomized to therapeutic hypothermia or normothermia, which we don't do anymore. Obviously, the inclusion criteria were newborns greater than 35 weeks with evidence of moderate to severe encephalopathy and of peripartum hypoxia ischemia. They were looking specifically at the babies from this cohort that had a PAO2 measurement within two hours after birth. So babies were excluded if they didn't have that measurement, if they were cooled after six hours but were part of the cooling group. Birth weight less than two kilos. Genetic anomalies, refractory hypotension and acidosis are requiring 80% greater than 80% FIO2. So basically what they did is they looked at the whole cohort of infants. They looked at which babies had PAO2s. They looked at PAO2s as kind of a spectrum and then they used a scatterplot smoothing curve to describe this unadjusted relationship between PAO2 and the probability of death or disability. And then they split the group, they dichotomize the group, the data, into those babies who had normoxemia, so between PAO2 of 40 to 99, and those who had hyperoxemia, a PAO2 really greater than 100, but 100 to 500 because they did exclude those outliers that had much, very, very high levels. So in all they had 221 infants enrolled in the ICE trial. 55% of those infants had a PAO2 measure, so a total of 116 were included.

52:24

In the final analysis, 52% of that group received therapeutic hypothermia, 30% of infants died and death or major sensory neural disability occurred at 57%. I let that sit in for a while because, as a reminder, this includes babies who were cooled and babies who were not cooled and just as a, I think, a reminder of how far we've come in being able to treat HIE. So in the unadjusted analysis, infants near the normoxemic range of PAO2, so the 40 to 99 group had the lowest probability of death or disability in comparison to both the hypoxemic and the hyperoxemic infants. The probability of death or disability actually plateaued at about a PAO2 of greater than 200. And then, like I said, they excluded the extreme outliers, those with PAO2 is greater than 500, but the proportion with death or disability among hyperoxemic infants so those between 100 and 500, infants was 40 out of 58.69, which was higher than the proportion among normoxemic infants 20 out of 42%. So a relative risk of 1.66.

53:42

Then they adjusted for the apgar scar, the time to first breath, chest compression duration, arterial PCO2, the need for adrenaline during resuscitation and hyperoxemia was still associated with an increased risk of death or disability and adjusted risk ratio of 1.61. Then they included cooling and severity of encephalopathy and the adjusted risk ratios 1.58, but with a p-value of 0.06. So that did not reach statistically significant, statistical significance. But I think it's an interesting discussion when we think about how do we really optimize? You know we've got babies who are cooling how can we really optimize them? These are babies that are at risk for pulmonary hypertension. So sometimes we're pretty liberal with oxygen, but are we doing them a real disservice, especially as we're learning more and more about the downsides of having too much oxygen, obviously on all the organ systems.

 Ben Host 54:40

It just shows how complex these babies are. Like everything has to be perfect. Like the sugar like, every paper that's come out is coming out Normal, x Everything has to be normal. Like the CO2 too high is no good, co2 too low is no good, sugar too high is no good, sugar too low is no good, and same thing with PO2. So I'm not surprised that this is falling along the same path. And yeah, that's tough. That's tough, no pressure.

 Daphna Host 55:03

No, I know.

 Ben Host 55:04

I have a few more papers that I wanted to review, maybe two more. One of them came out in pediatrics. It was called Marijuana Use and Press Feeding a survey of newborn nursery. Pearl Chang is the first author. I thought this was interesting. I was looking forward to this paper. Every division has a discussion about this, I think every week. What are we supposed to do? So the introduction, I think, doesn't tell us things we don't know, except that marijuana is the most common federally illicit substance used during pregnancy. By the way, my wife and I never had cable at home, so all we have is just like our French TV thing.

 Daphna Host 55:38

I'll let you say that again for people that you actually just got a TV in your house.

 Ben Host 55:43

Yeah, that's right. That's why he's so smart people he has no TV at home and we were watching the news and there was this lady advertising for marijuana during pregnancy. I don't know if you've seen this. I was like this is insane.

 Daphna Host 55:56

We'll take it for a hyperemesis. Sure, I'm not condoning it, I'm just saying.

 Ben Host 56:01

I mean, people do whatever they want, but for me, for it to be on TV at like 8 pm at night I was like holy moly. But the study here aimed to describe hospital practices and their nursery director knowledge and attitudes regarding marijuana use and breastfeeding, and to assess the association between breastfeeding restrictions and provider knowledge, geographic, region and state marijuana legalization status. So basically, the methods is not very interesting. It's a survey 31 questions. It's sent electronically to 110 US hospital members of the Academic Pediatric Association. Better outcome through research for newborns, the born network, and they basically did descriptive statistics that were used to analyze the survey response. Of these 110 nursery representatives, 63%, across 38 states, completed the survey. Most sites were university-affiliated 72% of them and teaching hospitals 94% of them. So the majority of directors were general pediatricians and or hospitalists and 87% of cases who were more than 10 years post-training in 70% of cases.

57:05

Most participating sites at the time of the study were located in states where marijuana use was legal 39% for medical use, 42% for medical and recreational use. Now, in terms of, do they even test for it? Because that's something that even we're wondering now. Do we even need to test? 63% said that if they get a history of marijuana use. They will be used as an indication for testing, so if a parent is closed, then they'll do the testing. In terms of the confidence of the directors, 81% of them said they were quote unquote confident in their knowledge of marijuana's effect on health, and the large majority of directors knew that marijuana could cause poor judgment, impaired driving and that it's stored in fat tissue and can be found in breast milk of mothers who are using marijuana. Most directors 96% of them reported that marijuana use while breastfeeding is somewhat or very harmful, and that was in 70% and 26% respectively. In terms of do they withhold breastfeeding 16% of hospitals universally or selectively restrict breastfeeding for mothers with a positive cannabinoid screen at delivery. Most hospitals consult social work 76% of them and more than one third 36% referred to child welfare services, which I think probably used to be much higher before the legalization wave sort of started happening.

58:29

Two more things that I thought were interesting there was no consistent statistical association found between breastfeeding restriction and provider marijuana knowledge, geographic, region or state marijuana legalization status. So I think that's where we're struggling. I think we need to be more in sync with what's happening outside the walls of the hospital and find something that makes sense and to give you an idea of how sometimes out of touch we could be. Resources for marijuana cessation only 30% of directors reported that resources for marijuana cessation are provided for mothers with positive marijuana drug screens, pointing to a potential area for improvement. We don't even do that, so I thought that was sad, but interesting.

59:12

The conclusion are that there's obviously significant variability in breastfeeding support practices for mothers with perinatal marijuana use among the newborn clinicians in this network, and that the study concludes that more standardized, ethical and family-centered approaches are needed to ensure health care equity and calls for further studies to establish evidence-based practices. I am not even going to touch about the door. They're widely swinging open, saying that how does these practices? They don't give us much insights, so I don't have much to report. But they're saying how do these insights that we're gathering now where we feel like we know a lot, but our practices are not really in sync with what we know? We're not really offering cessation, we're still calling welfare services and so on. How does that work? When it comes to aggravating systemic differences in our society, absolutely true, but they don't explore that. But the door is left wide open.

 Daphna Host 01:00:05

So they don't tell us what to do.

 Ben Host 01:00:08

No, no, that was not the point of the paper as well, to their credit.

01:00:11

But yeah, clearly this begs the question, so, yeah, so that was one of the other interesting things.

01:00:16

I'm just going to mention this paper that has our friend Ravi Patel on it, from JAMA Network Open, called Play to Transfusion and Death or neurodevelopmental Impairment in Children Born Extremely Preterm.

01:00:25

First author is Patricia Davenport, and this is a study that looked at the association between play to transfusion exposure with death or severe neurodevelopmental impairment at two years of age, and that's done in the cohort of babies who were in the PEANUT trial, the preterm erythropoietin neuroprotection trial, and it showed what other studies had showed that those platelets are really not good for our babies and that maybe, if you have not adopted the new maybe guidelines or the new evidence regarding more restrictive transfusion thresholds, you might want to consider this because basically, the study showed that when looking at the primary composite outcome of death or severe NDI, it was present in 46% of infants who were exposed to platelets, compared to 14% of the non-exposed infants, and so it is associated, there's this association, and that it's retrospective, obviously, because it's using this other data and they could be confounding by indication and so on, but regardless it's falling in line with platelets. Not really good.

 Daphna Host 01:01:28

And it wasn't even close.

 Ben Host 01:01:31

Last thing that I'm just going to quickly mention In the New England there's a paper called Azithromycin during routine well infant visit to prevent death. The title grab me. This is from Dr Ali Sied from Burkina Faso, in Africa. This study is based on other studies that have shown that distribution of Azithromycin to children age one to 59 months reduced childhood mortality in some sub-Saharan Africa region, and so they're trying to answer the question of what is the effectiveness of Azithromycin if we give it during routine health care visits and trying to prevent infant mortality. They enrolled kids five to 12 weeks old. They gave them a single dose of Azithromycin 20 mx per kilo body weight versus a placebo, and they looked at death before six months of age. They enrolled a lot of patients from 2019 to 2022. That was about 33,000 kids, and the results were not really significant 82 deaths in the Azithromycin group compared to 75 in the placebo group at six months of age.

01:02:32

So this idea that preemptive empiric Azithromycin for small children in sub-Saharan Africa might actually reduce mortality does not seem to have much evidence to support it. The administration of Azithro, they conclude, to infants through existing health care system in Burkina Faso did not prevent death, and this study contrasts previous studies that have shown the benefit of community-wide Azithromycin distribution. And so they say that maybe by doing a mass distribution maybe you're treating a few people that might need to be treated, but when you actually randomize people and you have right when it's, I have a feeling that if in med school I'm going to use this study to teach medical students about study methodology, Because when you give it to everybody you say, oh, there's a reduction. It's like, yeah, but you're giving it to everybody and some people might need it, but when you randomize them placebo versus treatment, that's gone. I think that's very cool. But in case this comes across your timeline you'd like to mention, we give Azithromycin to everybody and this is in Sub-Saharan Africa, so not really in where we're practicing Daphne and I. But yeah, interesting.

 Daphna Host 01:03:37

I'm still kind of disappointed.

 Ben Host 01:03:39

There's no way that when you give something empirically to everyone with no indication, it's an antibiotic. It's not. There's no way. I never have faith in those.

 Daphna Host 01:03:49

I know, but they didn't just pull it out of nowhere.

 Ben Host 01:03:51

There was a signal there there's a signal versus the noise.

 Daphna Host 01:03:54

That's the whole, yeah, okay. Well, I only had one other thing I wanted to touch on. This was a review article. We just like to point out sometimes when it's interesting review articles are out, and we had a listener who also was interested in this article. Thank you, jacqueline Ashba from Children's Mercy Hospital.

01:04:19

But this paper was in frontiers in pharmacology lead author, alexandra Oshman. It's about challenges and management of refractory pain and sedation and infants. I mean full disclosure. Obviously this is an area of interest for me, but I think the review is valuable in understanding how little we know about pain and sedation for babies.

01:04:42

But they also did a phenomenal job of kind of collecting any guideline that exists, like from the committee on fetus and newborn, the section on anesthesiology and pain medicine, and putting all of that information together so that people had kind of a one-stop shop to look up all this information. I think the take home points for me are one, that this is still an area prime for research, for trainees and early career NEOs. Two, that we're not very good at using the pain, sedation and withdrawal scales, but they do exist. So definitely to take a look at that. And I think they did a really nice job at outlining delirium, which is not something we talk about a lot in the NICU, but it exists and sometimes, when you think about it, you will find it. So I definitely recommend that people take a look at that and rethink maybe their unit policies on pain and sedation.

01:05:47

Or rethink, or outline or have a policy.

 Ben Host 01:05:53

Yeah, many people actually reach out and say, hey, what's your pain protocol, and so on. So I think that's the first step and this is a great tool to build a guideline on, because it does the work of going around and capturing all these other resources and all these other sources. So you're going to have a lot to work with with that paper alone. So thank you to that listener for sending us this article. Ok, Daphna is telling me wrap it up.

 Daphna Host 01:06:20

You're not supposed to tell the people? For what did I develop all these hand signals?

 Ben Host 01:06:25

Daphna could be the creator. If you are a fan of the office, you would have come up with woof. If people are familiar with where a message come on every single platform that you own, that's something that you could have come up with. In any case, that's it for us, for Journal Club, and thank you for listening, and we will see you this week. I'm going to tell the audience what we have scheduled for this week. So we have this Wednesday. We're not going to have any episodes because this will be the beginning of the Beyond the Beeps next month, and so we will see you in a week with an interview with the great team from the BPD Collaborative. So stay tuned for that. A great interview, Daphna. Have a good Sunday. Bye.

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