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#135 - Journal Club 52

Hello Friends 👋

We are so happy to bring you a fresh episode of Journal Club, mostly because Daphna and I have both been traveling this week and making this recording happen was tough but always a pleasure to record. We spoke about human milk fortifiers, viral infections and NEC, nebulized surfactant and more.

We hope you enjoy this episode.

Have a good sunday!


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

Mani S, Hazra S, Hagan J, Sisson A, Nair J, Pammi M.Pediatrics. 2023 Jul 1;152(1):e2022060876. doi: 10.1542/peds.2022-060876.PMID: 37293714

Ackley D, Wang H, D'Angio CT, Meyers J, Young BE.J Perinatol. 2023 May;43(5):624-628. doi: 10.1038/s41372-023-01654-z. Epub 2023 Mar 29.PMID: 36991141

Sánchez PJ, Prusakov P, de Alba Romero C, Zamora-Flores E, Reyes Escamilla MC, White NO, Miller RR, Moraille R, Theile AR, Magers JK; Nationwide Children’s Hospital Neonatal Antimicrobial Stewardship Program (NEO-ASP).J Perinatol. 2023 Jun;43(6):741-745. doi: 10.1038/s41372-023-01634-3. Epub 2023 Feb 22.PMID: 36813903

Fleiss N, Gurka MJ, Burchfield DJ.J Perinatol. 2023 Jun;43(6):683-684. doi: 10.1038/s41372-023-01671-y. Epub 2023 Apr 7.PMID: 37029166 No abstract available.

Gaertner VD, Minocchieri S, Waldmann AD, Mühlbacher T, Bassler D, Rüegger CM; SUNSET study group.Arch Dis Child Fetal Neonatal Ed. 2023 May;108(3):217-223. doi: 10.1136/archdischild-2022-324519. Epub 2022 Nov 24.PMID: 36424125 Clinical Trial.

Fleishman R, McAdams RM, Carter BS, Gautham KS.J Perinatol. 2023 Jun;43(6):813-816. doi: 10.1038/s41372-022-01565-5. Epub 2022 Nov 21.PMID: 36414736 Review. No abstract available. ----

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

Ben 0:57

Welcome. Hello, everybody. Welcome back to the incubator. It is Sunday Journal Club is upon us, Daphna. How are you still from Turkey?

Daphna 1:09

It's still in Turkey. But we're doing great. I'm glad my internet connection is good. You never know. Right?

Ben 1:16

Your internet connection came through in the

Speaker 1 1:19

zoom and telemedicine you still never know. So?

Ben 1:23

Especially since it's when you need it the most that most likely to fail? Yeah. All right. All right. We have some very exciting papers today. I don't think we have any updates or any news? I don't think so. I guess we can announce that we will be at the next Society meeting. We'll have no podcast booth. So if you're planning on going, get ready, we're going to want to get your opinions on things and so you can stop by our booth.

Daphna 1:53

That's, that's actually quite big news because we love going to conferences. That's right. Very excited.

Ben 2:01

Okay. All right, then. So then I will start off this week's Journal Club. I am going to start with a paper that I meant to review the last time. It's a paper published in the Journal of parasitology. And it's called human milk derived fortifiers are linked with feed extension due to hyperglycemia in infants less than 12 150 grams, or less than 30 weeks a match the retrospective chart review.

Unknown Speaker 2:27

What a good topic.

Ben 2:28

It's a great topic. The title is awful. I feel like it's just

Daphna 2:33

I don't know what to do with the title, but it is it tells you exactly what you're going to get.

Ben 2:38

I miss those old papers where they had like puns and stuff in the title. But anyway, the title is very clear

Daphna 2:43

about that some people and I think we love puns. Very good, steady name for you coming up. So we'll get there.

Ben 2:55

All right then. So this was published in the Journal of parasitology. It's coming out of the University of Rochester. first author is Dr. Ackley. And so the background is very extensively they spent a lot of time on the background. I'm going to try to summarize this with a few bullet points. They're basically showing they're basically saying how studies have shown that infants receiving human milk derive fortifiers have less have exhibited decreased incidence of neck that exclusive human milk diets have also been associated with a shorter time to full volume feeds decreased usage of parenteral nutrition. But they're also making some comments about the severity of hypoglycemia in the NICU and how hyperglycemia is the most common cause of morbidity for high risk infants occurring in about 30 to 60% of preterm infants, especially if they're small for gestational age or if they have growth restrictions. And they're also mentioned in this study by Stiffler. And colleagues that looked at the incidence of hyperglycemia in extremely preterm infants once on full enteral feeds. And that study found that like 44% of infants who are less than 1000 grams and 23%, for kids were between 1015 100 grams had at least one incidence of blood sugar less than 45. And what they mentioned is that often because of hyperglycemia, we tend to extend the feeds, we tend to put feeds over, I don't know, 16 minutes, hour and a half, two hours, sometimes even two and a half hours. And that's not good. They're mentioning how this meta analysis by Wang and colleague concluded that having intermittent nasal gastric feeding, are allowed to reach volume for volume feeds more quickly than people who were on continuous feeds. And what they're saying is that in their unit called the Golisano Children's Hospital NICU, in Rochester, they switched in 2017, from providing bovine fortifiers to human milk derived for the fire and to babies who were either less than 30 weeks or two left and 12 150 grams until they were 33 weeks corrected. And what they say is that their providers anecdotally noted an increased incidence of hyperglycemia during routine blood group costs measurements, which lead to a lot of interventions such as feeding extension and so on. And so what they aim to do in this study is to do a retrospective review to investigate number one the prevalence of hypoglycemia, and see if it was higher in the infants receiving human milk fortification compared to those receiving bovine fortification. And number two to investigate if the prevalence of extended feed duration was higher among the babies who received human not fortification compared to bovine fortification. I thought this was an interesting study because definitely we've seen the same thing.

Daphna 5:33

Yeah, no, I totally agree. It was nice to hear and see the review about the descriptive stuff because it's definitely what we've been feeling at least.

Ben 5:44

So a bit of background about this study. Obviously, it's retrospective, but in terms of how they feed their infants, they usually start fit within 12 hours feed advancement is usually about 20 mL per kilo per day fortification is introduced when the babies are tolerating about 60 mils per kilo per day, and it's advanced to go fortification once they are at 80 mL per kilo per day. From 2015 to 2017. Infants would have received maternal breast milk and or premature formula to 24 calories and starting in November 2017. They had pasteurized donor milk and human milk derived for the fire that were introduced in their unit. The feeds are fortified with human derived fortifiers to 24 calories initially, and they have the potential to go up to 2630 calories as deemed necessary by the medical team. Typically they feed every three hours over 30 minutes. In this study, specifically, they included all the patients who were admitted to the NICU born at less than 30 weeks, or less than 12 150 grams between 2015 and 2019. They excluded babies who received insulin or beta blocker medications during the time of the review. And infants who died during the hospitalization were also excluded. They using data from 277 infants they had 51 infants who receive human milk derived fortifiers between 2017 and 2019. And these were selected as the human milk fortifier group. What they did is that they were matched to infants who would have qualified for human milk derived for the fire prior to the introduction of the of this new tool. And they found kids with at the time before the introduction had been receiving had received bovine derived fortification, and they were matched based on sex, gestational age, birth weight and the age at the time of fortification level, and the exact calorie fortification level. All matched subjects were fed ng at the time of the period recorded and that's really all I want to say about that in terms of feeding extension. What did they do so the lowest daily glucose levels were recorded as well as the presence or absence of hyperglycemia. How did they find hyperglycemia either sugar less than 60 milligrams per deciliter or a sugar less than 45 milligram per deciliter on each day that the subject received the level of calorie fortification, the wide would they extend the feeds so they had several reasons that were outlined one of them being hyperglycemia and other one being feeding intolerance and other one being cardiopulmonary events and another one just all encompassing like unclear reason, as they said, the primary outcome of their study was the incidence of ever having an episode of hyperglycemia. And the incidence of having your feeds extended beyond 45 minutes. And the secondary outcome was the reason why your fees were extended. An additional secondary outcome were the number of days of hypoglycemia or feed extension. Okay, then. So let's talk a little bit about the results. The results are very interesting. They had a total of 98 patient 49 that received human fortification 49 that received bovine fortification. The subject characteristics are presented in the paper and the two groups were similar. There showed some statistically significant difference in ethnicity between the groups. And the difference in race that was also approaching statistical significance. I thought, just for the sake of completeness, it was worth mentioning, in terms of the actual result that we are interested in human milk fortification and infants who received human milk fortification had a 3.6 times higher rate of having a blood glucose less than 60. And there was no significant difference in the rate of blood glucose less than 45 between the groups in terms of having at least one episode of hyperglycemia 39% of infants in the human milk fortifier group compared to about 24%, in the bovine fortifier group, had at least one hypoglycemic episode for a blood glucose of 60. And using a cutoff of 45. By the way, I should mention that while this difference is impressive, 39 versus 24%. It was it didn't meet statistically significance. Using a cutoff of 45. The human milk fortifier group exhibited at least one hypoglycemic event in 17% of cases versus 4% in the bovine fortification group. Again, close to significance but not significant P value 0.07. And the confidence interval is quite wide. The result that did reach statistical significance is that human milk fortified infants had a 2.9 times increased rate of having their feeds extended. And when they were evaluating the binary outcomes using these generalized equation models, feeds were extended for any reason in 55% in the human milk fortifier versus only 20% in the bovine fortified infants. Sorry, and when you're looking at this graph, I think it's figure one should I didn't register that that's okay. But the reason for the feedings being extended at no point in time or fees extended in the bovine fortification group for reasons of hyperglycemia. But feeding intolerance is about similar but not yet not so it's not statistically significant. But in 14% of cases for the bovine fortification group versus 10% In the human milk fortification group, where the feeds extended for issues of feeding intolerance. And for cardio respiratory events, the difference was like 6.1% in the human milk fortifier group compared to 2% in the bovine group, again, not statistically significant. And so the conclusions of the paper is that the data confirms this clinical anecdotal anecdotal observations that switching from a predominantly bovine derived to a predominantly human milk derived diet for premature infants is associated with an increased feed extension and the trend towards having higher incidence of hyperglycemia. I invite you to read the discussion, they do venture into trying to explaining why that could be obviously these are going to be just speculation. They do mention whether the insulin content and the difference of that between the bovine versus the human that could be could it be something they don't seem very convinced about that to be very frank, and they don't really have a good answer. But I do believe that as donor breast milk is becoming more readily available as human milk for the fires that are more readily available, we're learning new presentations of our patients. And I think I think that's interesting. I think that's interesting. And if you've experienced this, then it's refreshing to see that you're not the only one.

Daphna 12:18

Yeah, it's hard, right? And in the NICU in medicine, we're always weighing risks and benefits of all the things that we do. So often, we submit, we sometimes mistakenly, I hear this all the time, send this message to the rest of the team and two parents say baby's been hypoglycemic. The weekend hasn't been that good. But we're switching to what this new fortifier, this formula, fortifier, whatever, and that we expect those things to be better. It's hard, because we have these subtle signals, and we send these subtle messages. But the risk is still there, right to not be not using human milk. So it's interesting, but it's a reminder that those babies are at risk.

Ben 13:06

Yeah. But I also think that's something that we've encountered, which is like we see these episodes of hypoglycemia. And we know that hyperglycemia can be so many other things. And you're like, is this sepsis? Right? Am I is this baby brewing something? And I think us finding out that other institutions who are using human health fortification are also experiencing this may actually help us reduce how aggressive we can be sometimes with these humans right now, actually, this is something that we know is associated with this new way of fortifying. And maybe we save these these few extra like CBCs and Procol and CRPS these kits. So I think that was interesting.

Daphna 13:43

Yeah, I think the real question is, then what do we do with them? Right, so they're going to be hypoglycemic. So what do we do with them? So, we know that extending feeds isn't the right thing to do. But it does seem to improve the blood sugar's so

Ben 13:56

it does seem to improve and then they haven't really talked about it. I probably didn't have the sample size for that. But some so many people then just go up on calories. And I'm not sure that's the right answer. Yeah. No, time will tell or not. I wish

Daphna 14:15

Okay, thank you for that. I have an article for you. This was entitled viral infections in neonatal necrotizing enterocolitis and meta analysis, lead author, Sreenivasan Manny and senior author Mohan Palmy. So the primary Oh, this was in pediatrics sorry, that I didn't see are the primary objective was determined whether infection with viral pathogens is associated with neck in preterm and term infants separately compared with those without viral infections. And then they wanted to look at some secondary objectives about whether birth weight or any specific virus was more highly associated with His neck in the creature and the term and so this was a meta analysis. They included cohort and case control studies that examined the association of viral infections with neck reviews, case reports, letters and editorials were all excluded. And in terms of the patient population they included in neonates and infants under six months of age, admitted to the NICU, and they included infants of all gestational ages, but like I said, they do split it up and subgroup analysis. They also excluded all patients and they excluded all patients with known congenital or structural abnormalities of the GI tract. So the exposure and risk factor was obviously did they have some sort of viral enteric pathogen detected at the time of a neck diagnosis and they defined infection as isolation or molecular detection of DNA or RNA, or pathogenic virus known to affect the intestine from the infant's laboratory specimen. The control group were predetermined term limits under six months of age diagnosed with neck but not infected with a virus. And then the primary outcome measure was neck diagnosed by Bell staging criteria stage two or greater. So they screened 1102 Study abstracts 130 were selected for retrieval. And then 29 studies were initially included in review, this involved 14 separate countries, they eventually included 24 studies that provided data for the meta analysis, the those remaining five studies, didn't have a comparator group, so we're not included in the meta analysis. So in total, the studies evaluated for 1787 newborn infants for this association between 11 different viruses, and neck. Rotavirus and CMV were the most studied viruses, including 62% of studies. So the primary outcome is that viral infections significantly increase the odds of neck and odds ratio of 3.81. Though there was significant between study heterogeneity, and the association between viral infections and neck remain significant after doing two additional sensitivity analyses. So for the secondary outcomes, there was a subgroup analysis based on birth weight to the split of the participants less than 1500 grams, and those greater than 1500 grams. And for each studies, including infants less than 1500 grams, a significant association between viral infection and the occurrence of neck and an odds ratio of 3.62 was observed. And then an analysis of six studies for the infants greater than 1500, gram showed a significant association between viral infection and the occurrence of neck an odds ratio of 5.28. And then they analyze this kind of subgroup of 10 studies that combined very low birth weights and non very low birth weight infants. And they actually did not show a significant association between Barrow infection and neck. And then finally they performed another subgroup analysis based on the type of virus, the odds ratios for the viruses and their association with neck rotavirus and odds ratio 3.96 CMV, and odds ratio 3.50, norovirus, an odds ratio of 11.95, Astro virus and odds ratio of 6.32. So all the viruses studied showed a significant association between infection and neck. Not a very long paper. But I thought it was interesting, because the association is definitely there. And that's been obviously shown in many other studies. And what do we do with this information? Since the management is still pretty much the same? I just wonder if it will change our habits about even screening for viral infections, particularly the association with CMV. Right? Because that's something we could potentially treat.

Ben 19:00

Yeah, I was baffled to see the number of articles that met the inclusion criteria, you know, how we have these meta analyses in neonatology. And they ask a very basic question that like only two studies. I know like holy shit, I thought, maybe more studies. And here in this case, when I was reading this, I'm like, I never sent viral culture on the stool sample. I've never done it. I'm going to

Daphna 19:23

be I trained at a place that is known for studying neck and it just was not we talked about it, but we were still not evaluating for viral pathogens.

Ben 19:32

So what's interesting to me looking at this study is I think like you said, the kid that I'm convinced has any see doesn't make a difference whether

Speaker 1 19:42

Yeah, he's gonna stop the antibiotics. No, no,

Ben 19:45

but the kid I'm the kid that I am not sure. If I send the stool and I see that it's positive for a viral pathogen. Am I gonna start thinking, Oh, maybe. First of all, I don't even know if our lab would test the stool for viral pathogens.

Unknown Speaker 19:59

So though after a virus I,

Ben 20:03

but But I'm saying if you do have this capability and you do send this tool for viral infections, and then you get a result back and you get I don't know, you get oh yeah Rodas positive, considering, as we talked about last week with a new hair and Misty, good, considering we have no clue about the pathogenesis of neck. Are you going to say this is concerning? I'm going to start antibiotics, or are you just going to ignore it? I think that's a very interesting question. The middle,

Daphna 20:32

right, that's the you know, how many kids we rule out, quote, unquote, for neck, right? You give them their 48 hours? Some of them do. They were not quite, they weren't equate a definitive stage to stage three. They're this kind of fuzzy group. And some of them seem to do better after you roll them out for 48 hours. But are they better because they've been on antibiotics and NPO? Or a better because they didn't have neck? We don't know. But yeah, maybe this is maybe the kid who gets better as the kid you but they have this testing is the kid you watch for longer? Yeah, are not so aggressive about but I think the association with CMV is really interesting, especially given the other findings in CMV. Particularly like thrombocytopenia that we see all the time and neck or a baby who doesn't have neck but has CMV. Maybe we are more cautious with feeding that kid. Okay.

Ben 21:31

Okay, then, my turn. I'm going to go back to the Journal of parasitology. I have another article that caught my ID this week. It's coming from first author is Pablo Sanchez, the famous Pablo Sanchez from nationwide. The paper is called short curves, short course empiric antibiotic therapy for possible early onset sepsis in the NICU. I thought that was an interesting title. And in the background, Dr. Sanchez goes over the usual antibiotic stewardship. Tenants antibiotics are the most prescribed medication in the neonatal intensive care unit. Prolonged therapy has been associated with delayed initiation of breastfeeding, it has been associated with obesity down the road with recurrent wheezing with GI disorder as well as autism. And so what's prompting this study is that in 2019, they have an antimicrobial stewardship program at Nationwide that recommended reducing the empiric antibiotic therapy for possible early onset sepsis from 48 hours to 24 hours nine of their NICUs and eight of their newborn nurseries in Columbus, Ohio. What they were looking at retrospectively reviewing their blood cultures was that the median time to positivity was 13 hours with a range of nine to 21 hours. And so logically, that's what really prompted the change this if most of our cultures turned positive within 24, do we really need an extra day of antibiotics? So the objective of the study was to describe the safety of providing empiric antibiotic therapy for 24 hours compared to 48 among high risk newborns in the NICU, and they're basically going to share with us the impressions and and their experiences with this new Qi initiative. So this is a retrospective study of all newborns evaluated for possible early onset sepsis, which is defined as having concerns before 72 hours of age at six Nationwide Children's Hospital NICUs from 2018 to 2019. newborns who were suspected with early onset sepsis received either 24 hours or 48 hours of empirical antibiotic therapy with IV ampicillin and IV or im gentamicin. I think that's pretty much the standard, I think, for all of us. Now, what was interesting is that the QI initiative was really implemented rigidly where the admission order set in the EMR was changed to have the antibiotic order timeout at 24 hours. So they excluded all the infants who had antibiotic extended beyond 48 hours for treatment of positive bacterial culture, or culture negative conditions, such as pneumonia, and so on, are born infants who received antibiotic before their arrival to the nationwide NICU were also excluded. The evaluation for suspected early onset sepsis and the components of the evaluation were at the discretion of the attending neonatologist including the use of the sepsis risk calculator, so they didn't really have a rigorous hotline where everybody had to follow a certain process of evaluating for early onset sepsis. There was really the clinicians were allowed to exert their clinical judgment their early onset sepsis was defined as a positive culture for a recognized neonatal pathogen, with organisms such as CO ag negative staph Micrococcus, Bacillus species coin bacterium, propionibacterium, and very dense group streptococcus considers contaminants unless they had more than two cultures that were positive for the organism. The pertinent clinical labs and microbiology data were obtained from the EMR. program notice was present as documented in the maternal or neonatal medical records and the severity of illness was measured using the crib to score, which is, as you may know, validated risk adjusted instruments for prediction of mortality among the LBW infants. The safety endpoints were the renewal initiation of antibiotics within seven days after discontinuation of the initial course, positive bacterial culture or blood positive bacterial culture of blood or of the CSF in the seven days after antibiotic discontinuation and overall and sepsis related mortality while in the NICU. So far, so good Daphna. You're nodding. Okay, so during the eight month study period, 414 newborns were evaluated for early onset sepsis in those six NICUs of these 414 infants 47% 196 received the 24 hour rollout sepsis. 218, which is 53% received the traditional 48 hour course. The newborns who received the 24 hour course had a lower mean gestational age, but did not differ in birth weight, sex Race mode of delivery, Apgar scores at one five minutes or their crib, two scores, and they report all that in their tables. The two groups also did not differ in the rates of maternal GBS colonization, I think that's an important point. And they're rates of chorioamnionitis. The mothers of infants who received a 24 hour course however, of antibiotics therapy were more likely to have received intrapartum antibiotics and have ruptured a fetal membrane greater than 18 hours. So if anything, you could say if the rupture of membrane was longer, maybe that puts them at a bit of a disadvantage. 29 infants had antibiotic therapy continued past the 48 hour mark and being the indication included cultural negative sepsis in 10 cases, pneumonia and seven, early onset sepsis in three spontaneous perf in three prophylactically in three patients, congenital syphilis, and one and two others were like either on other or unknown, these 29 infants obviously, as we said in the methods were not included in the analysis. Infants in the 24 hour rollout group had significantly lower length of antibiotic therapy both during the initial course which by the way up like duh, but also as well as for the entire hospitalization, which I think was very interesting. So they noted that the kids who received only the 24 hour course tended to have less antibiotics given to them for the duration of their NICU stay. Infants in the 24 hour rollout group were significantly less likely to have antibiotic therapy reinitiated within seven days after discontinuation of the initial course,

Unknown Speaker 27:48

I think that's super interesting.

Ben 27:52

Otherwise, they mentioned that the two groups did not differ in the positive bacterial culture of blood or CSF in the first seven days after antibiotic discontinuation. And overall sepsis related mortality, while in the NICU were similar. So now that I've convinced you based on the data, that this might be a good idea, I'm going to start now pulling you in the other direction. So they were for

Unknown Speaker 28:13

advancing measures as Holy moly.

Ben 28:15

Yeah. Because that when I read the paper as you're reading it, like, maybe we should consider it 24 hours. And well, I'm not saying that what they're doing is not safe. I'm just saying that there's a lot of things to take into account that maybe should make you think about whether it's the right thing for your unit or not. So there were four deaths in the initial 24 hour antibiotic group. Three infants subsequently died from a sepsis related condition. We're going to talk about those one was a 25 week gestation infants who developed septic shock due to gentamicin resistant Ecoli at six days of age, a second 25 week gestational age infant had put some Rajic hydrocephalus with placement of a drain device for weeks of age to be had a decompensation the culture grew a weird bacteria, but the baby was basically allowed the natural death right, so that was quite a medically complex baby. But a third 25 week infant died secondary to necrotizing enterocolitis with basically neck totalis concomitant with urinary tract infection due to Klebsiella oxytoca at five weeks of age, and of the seven deaths in the 48 hour group, none were related to an infectious condition. I'm not done so in conclusion, the utilizing currently recommended early onset sepsis guidance and located at hospital where whose microbiology lab utilize automated continuous monitoring of blood culture systems, which means that the blood cultures are continuously monitored for growth not like every six hours somebody opens the incubator takes a look and then reports antibiotic therapy for suspected ELS can be discontinued safely within 24 hours if blood cultures are sterile and there is no sign of site specific infection. Now, with that in mind There's a very interesting editorial in the Journal of parasitology, written by some physicians from Yale. And I think they're moderating a little bit some of the findings, right? So they're mentioning a few things. And that to them doesn't mean that the data is not good, but saying that the data should be interpreted carefully. Number one, they're highlighting how most of the infant's 62% of them are infants with a gestational age above 34 weeks. And while they included every gestation, the breakdown was not similar. So they did have babies who are less than 28 weeks, but they're represented maybe 10 to 15% of the population, they had babies 29 to 33 weeks, these represented like 20 to 29% of the power of the population. And then 34 to 37, plus represented respectively, I think, 57% of the group in the 24 hour cohort, and 67% of the group in the 48 hour cohort. So they're saying, Be careful when it comes to that. And they're mentioning something about the study design. Obviously, the author's in their discussion do mention the nature of the study itself, and saying that how in and of itself, that's a limitation. But this editorial mentions how there's caveats to consider before concluding safety and adapting such practice change, such as switching to 24 hour antibiotic, for example, they're highlighting how the relative rarity of early onset sepsis in neonates, especially in full term and late preterm infants, and that's not wrong. The authors do mentioned that the number of positive blood cultures in this cohort was basically three, one in the 24 hour cohort, and two in the 48 hour cohort. And they're saying that because the incidence is so low, maybe the sample size that you need is very large to detect one true case of us. And so they're saying how here in the sample of 414 infants, we only see three positive blood culture, again, proving the paucity of infection in this population. And they're saying that it would have been nice maybe to have a power analysis reported in the paper. Now, what they're trying to say is that we should be careful about the question we are trying to answer. So if one were to attempt to answer the question of safety for these two approaches, given the author's focus on no difference with respect to safety, they were mentioning how maybe a non inferiority trial would have been the way to go, which obviously requires a massively larger amount of babies. And so I think at the end of the day, they're not so much criticizing the study, but rather saying that we should just be careful that when we're reading the paper, and we're seeing that the findings, that finding no statistical significance between two approach does not mean that the two approaches are by default. Similar. I think it's interesting how it's almost like a cognitive bias that we have, where you're like, if there's no difference, they must be the same. And it's, and I think it's nice to have this editorial to remind us that while the two approaches don't show much difference, they may not yet be considered to be the same. And I think that a big part of this is the fact that the Nationwide Children's Hospital microbiology department and infectious disease department are very well developed. And they have very good handle on how quickly their cultures are turning positive, and they have a very good, probably anti microbial gram. So that's it. So just take it with a grain of salt. And that's the end of it.

Daphna 33:28

I promise I will put everybody on 24 hour rollouts. I wonder though not all be these pretest probability is the same. So we I think we'll probably find that there's a group of babies that are safe to rule out for less time, and those babies are at less risk from the beginning. Okay, early onset sepsis, because we put a lot of babies on antibiotics but they don't all have the same risk. Criteria it's an interesting it's an interesting paper.

Ben 34:02

This episode is proudly sponsored by record me Johnson. Record me Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage including an extensive Enfamil portfolio for premature and low birth weight infants learn more at HCP dot meet

Daphna 34:22

Okay, I'm want to take us a little somewhere different. And talk about this article also in the Journal of Perinatology. Entitled narrative neonatology integrating narrative medicine into the neonatal intensive care unit lead author, Rachel Fleischman and senior author, Aiko. Gausman, who both authors are on Twitter, and it definitely if you're not following Dr. Goffman then you should be

Ben 34:47

I was gonna say I think I stumbled upon multiple tweets from Rachel Fleischman on Twitter.

Daphna 34:54

The reason that you stumbled on multiple tweets from Dr Fleischmann is because she is As a very active writer, she's an essayist and she, her topics of interest are on motherhood, perinatal ethics, life and death in the NICU pregnancy, the threads. So she's written a lot of recent articles in particular, that have gotten a lot of buzz, especially in the changing of the Dobbs rulings. So that's probably

Ben 35:28

no, I see her face now. I remember Yeah, she wrote for time, and she wrote for The New York Times, okay, great.

Daphna 35:34

And that being said, some of her more, some of her more remote articles, older articles are just as fabulous. She has a website, Rachael If you haven't taken a look there, I highly recommend it.

Ben 35:49

And my son and, and, and our friend from Neo mind, AI, the artificial intelligence, Tim Ryan McAdams, a second author of Hey, Ryan, if you're listening.

Daphna 35:59

So I'm going to, with no respect disrespect to the authors, I'm going to review the article in a little bit of a backwards manner. And first talk about really what is narrative medicine because I realize not everybody has a good handle on that. So the definition by one of the frontier for founder, five founders of Narrative Medicine, define it as a metaphor, a quote, unquote medicine practice with the narrative competence to recognize interpret, and be moved to action by the predicaments of others, aims to help clinicians attend to the stories embedded in our work and by extension, provide respectful, empathic and fulfilling medical care. So it really was a change a paradigm shift from this really medicalized way that we present patients, to including more about the patient's narrative. So learning about their lives, learning about what they do, like see things that many of us do anyways, with families, but including that as part of the medical care, not ignoring all of those important medical aspects, but just including some of the more humanistic aspects, seeing the patient as a full person, and not just as their disease process. But really, the use of Narrative Medicine is basically using close reading and reflection on texts, written by other people written by other healthcare professionals, and taking the time to just think about how those things in those narratives and those stories affect

Ben 37:39

with. So then, if I understand this correctly, because I am not familiar with the concept of Narrative Medicine, I have to be honest, but for example, if a mother loses a child to sepsis, and then has another baby, that is basically equivocal, right, and you say, this baby could be worked up could not be worked up, you taking into account the mother's the parents story of having this prior child and incorporating this into your decision is effectively, that is effectively what you were describing as Narrative Medicine. Meaning that's the Go ahead. Because you could I'm saying because you could look at the baby from a purely mathematical standpoint, as XML, I'm going to do, I'm going to decide based on one way or the other, but you could also elect to bring in the prior experiences of the parents. And so for this family, the right choice would be to put them at ease and make them feel like this is not going to be missed or something like that.

Daphna 38:30

I think that's the end goal of Narrative Medicine is to say, how do we incorporate your write the needs of this particular family, and what's going on medically with their infant, but the practice of Narrative Medicine is really sitting down and either doing reflective writing, reflective reading, to get in touch with some of those other components. The benefits in narrative medicine, like you already described, really is helping us develop empathy, helping professionals develop resilience, mitigating burnout, helping with stress reduction in medical professionals, but the true the same is probably true for patients and families, that having them do their own writing in their own stereo to storytelling, or reading the stories of others can be quite cathartic. And so they gave some descriptions of how can we actually integrate narrative medicine into the NICU. And so like they describe it can take many forms, they describe reflective writing, so means telling your own stories, including stories of your patients in a safe way, but really providing this opportunity for reflection. This in particular helps mitigate burnout. They recommend things like Narrative Medicine seminars in the same places where people usually hold their hand kinds of didactic lectures. For example, a facilitator may pick a poem or prose or some other art form, like painting and just let people talk about what they see. Another opportunity is reading patient and parent stories in neonatal intensive care. So this is a step back from our own internal reflection, but in turn reflecting on the stories of others, and then storytelling events, so it may be an opportunity for clinicians to get together and share their own stories. And again, this is this is why we started the podcast, we can share the stories and we feel I think, a little less alone in our work. And then mindful narration of clinical cases, I think this one's probably the easiest for people to do on a day to day by day basis. And it's basically just, it's basically using even with medical professionals, the type of language that we would use with parents when we do it, right. We don't just describe the baby in their acronyms, right, we talk about the baby, what's going on with the baby from a person perspective, and not just from a medical perspective. And so that's something we can add to like our daily rounds. I think it's a good read. It's an easy read. And if you're still a little bit confused, then I would check out Dr. Fleischmanns website. I think that will help.

Ben 41:28

Awesome. Okay, I have one more, maybe tomorrow, because let's see how far we go into this. The next paper I wanted to talk about was something that came out in the archives of disease in childhood. And it's called prophylactic surfactant nebulization for the early variation, variation of the preterm long a randomized clinical trial. first author's Vincent Gardner, and it's on behalf of the sunset study group. Anything nebulized we're trying, right? We're really trying to get surfactant to be nebulized and try to avoid laryngoscopy. The author's in the background, you mentioned how obviously, we know laryngoscopy, no matter what you're trying to do, whether it's insurer, Lisa or whatever, there's always a risk of vasovagal reaction can be associated with ivh. And so really, a truly non invasive approach is what we're still looking after. And so that's why we're continuing to try with nebulized surfactant. Now, in that study, what's interesting is that while they're looking at nebulas, nebulized surfactants. Their endpoint is looking at electrical impedance tomograph, which is basically a non invasive and radiation free sort of lung volume imaging. And I'm not really going to try to go into electro electrical impedance of the lung, but basically they're looking at an expiratory lung impedance, which is, for all intents and purposes, just an overall measure of FRC. So the objective of this study was to compare the effect of prophylactic nebulized surfactant immediately after birth on the X and expiratory lung impedance with standard care, which is just CPAP alone. And this was done in a cohort of preterm infants between 26 and 32 weeks. So this was a masked, parallel, prospective, randomized control trial done at the University Hospital of Zurich. And basically all infants had to be born between 26 and 31, and six weeks, the excluded babies with severe congenital malformation adversely affecting long variation or life expectancy, any baby with an a priori palliative care and genetically defined syndrome. The intervention was at every baby got delayed cord clamping for 62nd CPAP was being given via facemask. Don't text me while I'm doing the journal club?

Speaker 1 43:48

I said what did you say I didn't have to interrupt you. Anyways

Ben 43:58

no worries Okay, every baby got delayed cord clamping for 62nd continuous CPAP via Face mask and the decision to escalate care whether it was like whether it was a higher CPAP level to go to non invasive ventilation to switch the interface that was not protocolized that was at the discretion of the clinician. Now in the intervention group, they gave 206 per kilo dose of surfactant, they use protectant and it was nebulized via a customized vibrating membrane nebulizer. So if you are into naps or fact and they were using the E flow neonatal nebulizer system, I am not familiar with any of these, they have a very nice picture showing their whole setup. We'll post that on Twitter. And that nebulizer was positioned between the facemask and the ventilator circuit nebulization commenced simultaneously with the first application of positive descending pressure after birth and continued until the entire surfactant was nebulized irrespective of the mode of non invasive respiratory support. If you were randomized to the control group, it was the same setup without the nebulizer and you just received a descending positive pressure. So the primary outcome was the change in end expiratory lung impedance, which remember we said as a measure of FRC, between birth and 30 minutes, infants were excluded from the primary outcome analysis if they received additional exogenous surfactant before 30 minutes after birth, or if the data any collection, any data collection failed, they had a lot of physiological secondary outcomes, which were changes in the lung impedance and the cardio respiratory parameters. They looked at expert expiry tidal volume inspiratory time inspiratory to expiratory, time ratios, respiratory rate 10 minute intervals, and they did all that at 10 minutes intervals for the first 90 minutes after birth. And then after that, from six to 12 at 612 and 24 hours which they had clinical secondary outcomes, which included a long list of things bradycardia number of events of hypothermia, hyperthermia, respiratory failure during hospitalization, Asia diverse intubation moderate to severe bronchopulmonary dysplasia, ivh grade two or more. Any grade retinopathy surgically treated neck blood culture positive sepsis, mortality, any air leak, pulmonary hemorrhage, and so on and so forth. Alright, the list goes on. Okay, so that's the study design. Let's look at some of the results data of 35 infants were collected between 2021 and 2022. And the primary in terms of the primary outcome. So what they found was that 30 minutes after birth, the change in expiratory, lung impedance was not significantly higher in the intervention group. And they have this pretty well mapped out in the figure. So that's a bit disappointing. The secondary outcome, the end expiratory lung impedance was slightly higher in the intervention group at six and 12 hours after birth, which was mainly attributable to changes in the central lung areas, because they're able to do this mapping of the lung using this end expiratory lung impedance. Now, after correction for multiple testing, they were no changes in ventilation, ventilation distribution, mean Airway Pressure sets to fit to ratio, heart rate, as well as detailed respiratory function data between the groups. Besides an increased number of overall doses of surfactant in the intervention group, there were no significant differences in clinical secondary outcomes. And you might say that this is reassuring, but they did have to report some safety concerns. They noted two serious adverse events in the intervention group, one infant developed a pneumothorax, requiring drainage three hours after birth. And another infants had an airway obstruction with persistent bradycardia during nebulized, during the administration of nebulized surfactant requiring endotracheal suctioning and subsequent intubation. So, to be very honest with you, that was quite frightening for me to read that. I'm going to invite you to read the rest of the study. But the conclusions are that they found really no significant in the significant effect in the use of prophylactic nebulizer fact and in the delivery room and and it's expiratory lung impedance when compared to standard care. Apart from a slightly increase in expiratory lung impedance in the intervention group at six and 12 hours after birth, mostly due to improve variation in the central lung areas, they found that no further physiological benefits. After prophylactic surfactant, there's no clear were no clinically important differences in the outcomes between the groups. And maybe, if anything, the study shows that collecting this kind of data in the delivery room during stabilization is feasible. They're talking about how different interfaces, nebulizer types, and most importantly, surfactant concentration should be researched more before implementation in the future. But that's really what are you what are you? What are you think about that? No, I

Unknown Speaker 48:57

was gonna ask you, what do you think your lung guy,

Ben 49:00

what's interesting is that it feels like it's a tech problem. Yeah, it feels like quite figured it out. We know the surfactant, we know surfactant works, we just know we need to get it from point A, which is the vial to point B which is inside the lungs. If we could avoid having to do this via an institute that would be the solution, whether the way we nebulizer factor this right now is good enough. Looks like it's not. But maybe somebody is going to come up with a way where this can be given non invasively in a way that can be effective. I know if this is something you're interested, there's so many ways of giving surfactant, whether it is via insure the Elisa, the salsa, all these different modes of giving surfactants are in existence. Somehow, it doesn't seem like we have managed to figure out how to nebulizer factors. And that story of the kid that got the airway obstruction that needed like even though it's one patient, my statistical thinking goes out of the out the window and I'm like holy shit

Daphna 50:00

So the end result was intubation. Right, which, with all the other methods we have to do for every baby, so,

Ben 50:08

yeah, but you always wondered, thank God, they picked up on it, thank God, they realize that this was the issue, because I always am pretty humble when it comes out. And I'm like, I don't, I hope I would have had the wherewithal to say, oh, man, that could be the nebulizer effect. And that stuck in there. And so that's, that's just scary. I was not surprised by the small sample size, it's tedious to do what they were doing in the delivery room. So the fact that they were able to randomize 32 infants, I think that was very impressive. But then, obviously, you have all these clinical outcomes that are measured there. And you wonder whether 32 patients is really enough to actually measure any significant difference there. So that you can take with a grain of salt. But what they did in the delivery room is quite impressive. And while I am I was not very I'm not very familiar with expiratory lung impedance. I understand how it works. And I leave it up to the audience to decide if this is a good way to measure this outcome. Is this the right thing? You know what, actually, this paper was also brought up in the in the park in the archives, or the archives of disease in childhood have a monthly podcast, I think its monthly, where they go over what they call the Phantoms. And they go just over some of the more relevant articles published in their journal when they did mention this article. And they didn't highlight the same point, which is, it's interesting to us long impedance as a as an outcome measure. But I understand makes sense to me. Should they have done something else? I don't know. I really don't know. But again, people can read it and make up their mind. Yeah.

Daphna 51:35

I always wonder we haven't still really when we're slowly talking about studying any intervention. Like what like surfactant, we still haven't really defined when is the best time to give surfactants does that affect the outcomes especially, and, quote, unquote, in the delivery room is different for every unit? Right? Some units stay in the quote unquote, delivery room for a few hours, many units are moving back in five to 20 minutes. We know giving surfactant early. That's a board prep question is more effective. But I wonder if it's so close to the transition time in an otherwise mostly stable baby, if we may see more problems than if we waited a little bit?

Ben 52:28

Yeah. In their case, they were pretty preterm infants with gestational ages. I don't know if I mentioned, they were like, they were 29 weeks. 29 versus 30 weeks. So I do think it's the group that you would want to test because they're the ones that sometimes need it, but you felt silly. Just intubating them. The birth weights were around like 1100 grams, so I don't know. We're gonna let the audience make up their minds on this one.

Unknown Speaker 52:52

Yeah. Let us know what you guys think. Yeah.

Ben 52:58

Okay, we should we choose? Let me see. I do we do. We've upgraded the we've upgraded things at the incubator. We have the schedule now. I should be able to tell people a little bit what what's coming up on our radar. Next week. We'll have an interview. Oh, next week is a big one. That's why I wanted to tease it. Next week.

Daphna 53:18

Our last few interviews were big ones. And we have a couple of big ones.

Ben 53:22

Yeah, next week, I'm saying is a big interview because we are reopening the giants of neonatology series. And we have had the pleasure of chatting with the amazing Dr. Barbara Schmidt. So stay tuned next week for a great interview. But other than that said, definitely we made it on time today. Impressive of us.

Speaker 1 53:45

Yeah, every once in a while. Yeah. The outliers, what do they say a broken clock is still right.

Ben 53:52

Twice a day. All right, buddy. Have a good rest of your day, then.

Unknown Speaker 53:56

You too.

Ben 54:01

Thank you for listening to the incubator podcast. 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 NICU You can also message the show on Instagram or Twitter, at NICU podcast or through our website at WWW dot v dash 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 professional. Thank you

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