Hello Friends 👋

This week we have a number of interesting articles. We are discussing the long-term effects of antenatal steroids, how resuscitating 22-23 weekers may not make you better at managing more mature infants, the effects of supplemental zinc and much more. We also reviewed an article by Dr. Sam Gentle et al looking at NIMV days and effects on BPD, death and growth. The methodology was super interesting and Dr. Gentle joined us to talk more abou his study.

We hope you enjoy this episode.

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

Evaluation of Long-term Outcomes Associated With Preterm Exposure to Antenatal Corticosteroids: A Systematic Review and Meta-analysis.Ninan K, Liyanage SK, Murphy KE, Asztalos EV, McDonald SD.JAMA Pediatr. 2022 Jun 1;176(6):e220483. doi: 10.1001/jamapediatrics.2022.0483. Epub 2022 Jun 6.

Safety and Efficacy of Nafcillin for Empiric Therapy of Late-Onset Sepsis in the NICU. Magers J, Prusakov P, Speaks S, Conroy S, Sánchez PJ.Pediatrics. 2022 May 1;149(5):e2021052360. doi: 10.1542/peds.2021-052360.

Effect of enteral zinc supplementation on growth and neurodevelopment of preterm infants: a systematic review and meta-analysis.Alshaikh B, Abo Zeed M, Yusuf K, Guin M, Fenton T.J Perinatol. 2022 Apr;42(4):430-439. doi: 10.1038/s41372-021-01094-7. Epub 2021 May 18.

Duration of noninvasive respiratory support and risk for bronchopulmonary dysplasia or death. Gentle SJ, Carper B, Laughon MM, Jensen EA, Williams A, Travers CP, Ambalavanan N, Lal CV, Carlo WA.J Perinatol. 2022 Apr;42(4):454-460. doi: 10.1038/s41372-021-01269-2. Epub 2022 Jan 15.

Does active treatment in infants born at 22-23 weeks correlate with outcomes of more mature infants at the same hospital? An analysis of California NICU data, 2015-2019. Bane S, Rysavy MA, Carmichael SL, Lu T, Bennett M, Lee HC.J Perinatol. 2022 Oct;42(10):1301-1305. doi: 10.1038/s41372-022-01381-x. Epub 2022 Mar 31.

Erythropoietin for preventing bronchopulmonary dysplasia in preterm infants: A systematic review and meta-analysis.

Li J, Zhang J, Hao Q, Chen H, Cheng X.Pediatr Pulmonol. 2022 Apr;57(4):1051-1063. doi: 10.1002/ppul.25837. Epub 2022 Jan 28.

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

Ben 0:00

Hello, everybody. Welcome back to the podcast. Daphna Journal Club. Went already Yeah. It's been a long week. No, it's been a very long week. We've been alternating coverage of the NICU and yeah, it's it's been tough there to record this week. But it's all good. We started the we opened our neonatal network this week. Very exciting. If you haven't joined our group on the rounds that come follow, go to our website, the incubator, the dash incubator, that org and follow the instructions, we're going to give out some red cube licenses, we're going to give out some other giveaways and grants and it's going to be a great research community. So join us.

Daphna 1:45

Yeah, and I mean, we want people to be brave and start talking to each other.

Ben 1:50

Yeah. We're gonna break the ice, you know,

Daphna 1:54

whatever you feel like.

Ben 1:58

We have a lot of interesting articles. We sure do. Yeah. Do you want to get started? Fine.

Daphna 2:06

I will. My first article today is evaluation of long term outcomes associated with preterm exposure to antenatal corticosteroids, a systematic review and meta analysis. Lead author, Karen Neenan. This is in JAMA Pediatrics. And so the question was really looking at antenatal steroids and do they affect long term developmental outcomes? And is this really different for the baby that's born preterm versus late preterm versus term? Which is actually kind of an interesting question, because there was some concerning findings like in animal animal data, that antenatal steroids might affect long term outcomes. So this was a systematic review and meta analysis, the team reviewed randomized clinical trials, quasi randomized clinical trials and observational studies performed in the year 2000 Or later, that assess long term neurodevelopmental, psychological, and some other outcomes at one year or older. And those who had pre term exposure to antenatal steroids. The real exclusion criteria was other types of public publications and if they were before the year 2000. So the primary outcome was any adverse any quote unquote, adverse neurodevelopmental and or psychological disorder. But those were really defined by each author or group of authors for individual studies. And then there were a boatload of secondary outcomes, visual impairment, auditory impairment, psychological developmental disorders, which included disorders of speech and language, Autism Spectrum Disorder, attention deficit hyperactivity disorder, conduct disorders. or basically any mix disorder of conduct and emotions, mood disorders, stress disorders, sleep, depression, anxiety disorders, cerebral palsy, abnormal findings on the Bailey, they looked at intellectual disability and long term anthropometric data. And then they looked at cardio, respiratory, endocrine and metabolic outcomes and survival in childhood and adulthood. So the reason there's so many different kinds of outcomes is because this was many studies who obviously had their own outcomes listed. So the overall results the baseline data is that it was a total of 30 studies involving more than 1.2 5 million children who were at least one year of age when the outcomes were measured. And then about the primary outcomes, which again, really looked at, again, composite To have adverse neurodevelopmental and or psychological disorder. So 10 of the 30 Studies measured outcomes for children with preterm birth who were exposed to a single course of antenatal steroids. So, it was defined that they only got their, you know, one course of VEDA methadone and no rescue. And so these 10 studies looked at babies who were fetuses, babies who were fetuses who were either exposed to corticosteroids versus non exposure, and they were not associated with significant reductions in odds of visual impairment, auditory impairment, or moderate or severe cerebral palsy. That was all comers. But for children with extremely premature birth exposure versus non exposure was associated with a significantly decreased odds of neurodevelopmental impairment, cerebral palsy and other adjusted adverse neurodevelopmental and or psychological outcomes individually. And this exposure to a single course of beta methadone versus the non exposure was significantly associated with higher adjusted odds of non impairment, which was defined as composite absence, the cerebral palsy, blindness, deafness and or neurodevelopmental delay. So you can see that the difference there was a difference for these extremely preterm babies. And then they looked at the other 20 of the 30 and included studies that had long term outcomes for children who were exposed to an unspecified number of courses of antenatal series. So the interesting thing is, this could still have been one course, but they just didn't specify, so maybe they got one course, some of them got two courses, but it wasn't specified, but they found slightly different findings. So an unspecified number of courses of steroids versus non exposure was associated with increases in risk for eight of 12 adverse adjusted secondary neurodiverse developmental and or psychological outcomes in children with preterm and full birth, so all births had that finding. And then 16 of the 20 studies that looked at unspecified number of versus unexposed steroids in specifically preterm infants found that for children with preterm birth exposure to antenatal corticosteroids was not associated with significant reductions in the risk of neurodevelopmental neurodevelopmental impairment or hearing impairment, and no significant associations were observed in other adjusted adverse or beneficial outcomes. Two of the 20 studies looked at children with full term birth after preterm exposure, and found that exposure to an unspecified number of courses of antenatal steroids was associated with higher risks of any mental or behavioral disorder and with a composite outcome of audio MeTree testing visual testing, or suspected neurocognitive disorder. And same thing for children with full term birth exposure was associated with significant increases in risk for five other adverse neurodevelopmental or psychological outcome. That's crazy. Yeah, so different. They did talk briefly about some of the secondary outcomes. For a single course of antenatal steroids. They was no really major difference in body weight or head circumference. So one study found a significantly higher proportion of children with asthma and allergic disease among those who were exposed to a single course of antenatal corticosteroids but they don't specify preterm preterm birth, it's for all comers. And for the secondary outcomes, no studies reported on outcomes of unspecified number of courses for some of those findings. So really, the study takeaways are that in this big review, involving more than 1.2 5 million children exposure to a single course of anti natal steroids was associated with a significant decrease in the adjusted odds of neurodevelopmental impairment in children with extremely preterm birth. But in children with late preterm and full term birth, antenatal steroid exposure, was associated with increased adjusted risk of neurocognitive and psychological impairment. So, and that included babies who got pre natal steroids when they were preterm and delivered at term, which is, which is interesting because sometimes we don't know if they're going to come or not come and we get the steroids. So the limitations to the study, obviously, there are lots of overlapping outcomes. And not all of the studies looked at the same outcomes. They all had some component of neurodevelopmental testing, but not always the same one And there's not was not enough information unless you go to obviously each article separately about the timing of steroids like when they were given during pregnancy or the balancing measures. And some of the studies may not have looked at neurodevelopmental or psychological outcomes as a primary outcome. So they may not have been powered for that specifically. But the question is an interesting one, especially as we're giving more courses.

Ben 10:30

So can I ask you to clarify something you said that when you mentioned the outcomes for full term births, those were children, obviously, who received antenatal steroids when mothers presented in preterm? Right. Whatever situation?

Daphna 10:46

Yeah. Yeah. It's not like they were giving steroids to 40 weekers.

Ben 10:50

Yeah, because the article is not super clear when it comes to that, just because when you if you just glance over it, it may seem like, oh, some mothers receive steroids when they showed up at like, 37 weeks, but that's not what they're talking about.

Daphna 11:02

Right. Right. Yeah. So because we don't know, sometimes we give the steroids and they don't deliver,

Ben 11:08

and they don't deliver. Now, what I'm curious, what do you think? What do you think of this study?

Daphna 11:16

You know, I mean, I imagine that the differences in outcomes are because the, you know, the extremely preterm baby who doesn't get steroids is that much higher risk for all of the associated comorbidities. So I think that's where the biggest differences is the extremely preterm baby who gets steroids versus a baby who doesn't get steroids. And I don't think we can take the risk of not giving steroids in the face of concern for preterm labor. So yeah,

Ben 11:47

that's interesting. I'm wondering, I mean, that's something that the study doesn't really address. But there's a reason why these these these pregnant mothers receive steroids, right. They showed up, they showed up with a complaint? And could that in and of itself be a risk factor for long term outcomes? We don't know that right, that the study doesn't

Daphna 12:08

look especially I mean, like, probably the most common one right now for sure for us is, is preeclampsia or at least Pah. And so I mean, we know that has an effect on, you know, long term outcomes and growth and brain growth. And, and how many of those moms come in there threatened to deliver and then they don't, you know, but it's,

Ben 12:31

it's a big, it's a big deal to study. I mean, it asks, I mean, I am wondering, what's going to come out of this study, to be honest, I don't pretend like I have the answer. And I don't pretend like I. And I don't pretend like I have a feeling as to who we're gonna give steroids to. And it's a little bit of this usual, this is an OB issue, right? I mean, we're not really going to be asked

Daphna 12:55

whether it's not true.

Ben 13:00

I mean, when did you ask you ask? It's crazy, right? I mean, I think it's like the likelihood of delivery. I mean, if you asked me, it depends on the likelihood of delivery. But that's where I wanted to get to, I think I the going to develop algorithms that are going to stratify and say, Well, if you if you show up in preterm labor, are we going to watch you for a couple of hours and see and then decide, or are we just gonna try to because right now, I feel that it's about get those steroids in as quickly as possible so that maybe we can get to those number two before the baby comes out. Maybe that's going to change. It's super interesting. It's one of these papers doesn't provide a lot of answers more like a ton of questions. But we'll see.

Daphna 13:44

Yeah, I'm really interested in I mean, admittedly, I did not look into this before we started. But I'd like to see a good study on neurodevelopmental outcomes on babies who got you know, for sure, the rescue a rescue, right. So you got your dose, and then you got your rescue because we're doing way more of those now. Because you ended up delivering it 36 weeks, but you had enough time to get a rescue. And then that that outcome. I think a study just looking at that would be interesting. Okay, we can keep talking about this all night, but we we must continue.

Ben 14:22

It is nighttime people. Sorry.

Speaker 1 14:25

Maybe not when you're listening, but it is night when we're recording to

Ben 14:31

the sock. So the next paper I wanted to talk about was a paper published in pediatrics. It's called safety and efficacy of nafcillin for empiric therapy of late onset sepsis in the NICU. The first author is Jacqueline makers are pronouncing this correctly. And there's a bunch of people that we know in that paper, Pavel Prusa cough is also on there. The famous Pablo Sanchez is the trailing author, and this is coming out of nationwide children So what's what's the premise of this of this paper? There's no real question. But the authors really wanted to report their experience with a guideline that they implemented in their unit of nafcillin. Instead of vancomycin for late onset sepsis guideline and assess the safety of the practice, the hypothesis is that vancomycin, the reducing the use of vancomycin can be done safely in the NICU. And the the people at Nationwide beginning in 2014, started this big, neonatal anti migrant made antimicrobial stewardship stewardship program that recommended the use of nafcillin instead of vancomycin in combination with gentamicin for empirical therapy of possible late onset sepsis in infants, and it's very important without a history of Mersa colonization. So if babies were colonized with Mersa, which I'm assuming they must be checking, I mean, nationwide is a huge, huge unit. So maybe they are checking Mersa colonization. And if they were not really Mersa, colonized, then then they will, they will offer this new this new regimen. So this was a retrospective review of all infants who received nafcillin vancomycin, or both for empirical treatment of possible late onset sepsis at three Nationwide Children's Hospital NICUs, in Columbus, Ohio, from 2013 to 2014. And from 2017, to 2019. So the 2013 to 2014. We presented the pre intervention cohort, the 2017 to 2019, the post intervention cohort, the inclusion criteria were infants without a history of Mersa colonization or infection, and who were evaluated for late onset sepsis at more than 72 hours of age, and who received antimicrobial treatment with nafcillin rather than vancomycin irrespective of clinical or laboratory parameters, such as the presence of the central line hypotension, or any abnormal acute phase reactant. Obviously, the excluded any baby that was colonized with Mersa. Infants with necrotizing enterocolitis, or spontaneous intestinal perforation were excluded from the analysis because their initial antibiotic therapy per their protocol involves ampicillin and sulbactam in combination with gentamicin. So that was not really a group that was interesting to look at, because they were not really receiving they would not have received nafcillin. So a few. A few other details about this protocol, which obviously is important when we're reviewing the study is that the trigger to evaluate for sepsis was left at the discretion of the attending neonatologist, so there was no real criteria that triggered the initiation of a late onset sepsis workup, as were the decision regarding the duration of the antimicrobial agent, so they didn't really have a cut off as to when they had to stop the antibiotics and so on and so forth. A proven infection. So late onset sepsis was defined as the isolation of a pathogen from the blood or CSF obtained at more than 72 hours of age. But along with clinical symptoms, a possible infection was defined as clinical symptoms with an accompanying blood culture that was either sterile or yielded a possible contaminant, but the infant was treated for more than 48 hours by the attending physician. If the antibiotic therapy was provided for less than 48 hours, then this was considered a rollout sepsis, so I thought it was very, very intelligent. Less than 48 hours it was rollout, if you gave more than 48 hours, then you were automatically into a sepsis. And then they had proven versus possible. So that's pretty clear. So the primary outcome of the study was the duration of culture positivity, as determined by the day's to culture sterilization, recurrent infection with the same previously identified identified pathogen in the 14 days after antibodies were discontinued, or, and mortality. So really looking at is nafcillin really weak when it comes to either treating your infection or making partially treating the infection. Some other outcomes. They looked at infection related in hospital mortality for all sepsis, evaluations by review of the documentation, the EMR or autopsy, whatever was available. So let's see what some of their results showed. So they had 366 infants, which basically amounted to 516 sepsis evaluation nafcillin was given in 57% of infants that was 209 cases, or 54% of sepsis evaluation that was 277 sepsis evaluations compared to 43% of infants who received vancomycin or 46% of sepsis evaluation for vancomycin. The median gestational age of these babies were 28 weeks birth weight, about 1000 grams, and 10% of the cohort died during the hospitalization. The number of infants who had a central venous catheter at the time of the first sepsis evaluation was not different between the pre intervention and the post intervention period, I think that was a very critical thing to to mention, considering the likelihood of how central line clubs he can actually be a factor in those scenarios. There were more Mersa colonization in the post intervention period. So and that was 18% versus 11%. And so these kids obviously were excluded and received vancomycin. So let's look at the primary outcome. So the pre intervention 16% of infants receive nafcillin as a first dose for late onset sepsis, versus 75% in post intervention period, and that really is a testament to when you have a quality improvement project and you're changing like you can really affect how your unit is functioning. The difference in the percentage of infants receiving nafcillin in the post intervention period was 59.5%. Compared with the pre intervention period of the total 516 sepsis evaluation 78% resulted in discontinuation of antibiotic therapy within 48 hours of initiation. So most of them did not yield the a true infection. During both time periods, the majority of pathogen detected in the blood work gram positive bacteria, mostly cons. I don't know what to think of that. 13 gram negative bacteria were identified during the study period, but but patients were not continued on nafcillin or vancomycin except for two of the 40 cons blood isolates. 58% were assessed as causing a proven infection that was 23 cases. Whereas 91% 30 out of 33 of isolates that had undergone susceptibility testing were resistant to methicillin of the 16 bloodstream infection due to Staph aureus 81% were susceptible to nafcillin. During the course of the sepsis episode, 15 infants who received nafcillin empirically were treated subsequently with vancomycin seven, that's 47% of these infants had proven infection with cons, whereas 33% received prolonged therapy without an identified pathogen. Two of them had nafcillin change to vancomycin because of a lack of clinical improvement, though the blood culture detected Pseudomonas aeruginosa in one infant and Klebsiella, pneumonia and the other. One additional patient had bacteremia with strep pneumo and receive the treatment course of vancomycin. How many infants had antibiotic therapy restarted within the two week period that they had looked at so only two infants had antibiotic therapy restarted within 14 days of discontinuation of the initial therapy for recurrence of the same infection. Both had received vancomycin therapy. So that's pretty impressive. That never happened with the babies who receive nafcillin. No infants receiving them so empirically, or for definitive treatment had antibiotic therapy restarted or recurrence of the same infection in the ensuing 14 days after discontinuation of the initial antibiotic therapy. Looking at some other outcomes in hospital mortality during the two study period was 10%, and did not differ before and after the implementation of the vancomycin reduction guideline. There also was no difference in mortality among infants who received empirical nafcillin or vancomycin. So the study takeaways are that nafcillin is safe, effective, and it could be an alternative to vancomycin for Imperial political treatment of late onset sepsis among high risk infants in the NICU, who don't have a history of Mersa infection or colonization.

And they're recommending a prudent and judicious use of vancomycin as a global public health imperative in our NICU. Some of the limitation, obviously, is that this is a retrospective review of data that the intervention period were quite long in time. So there's many other interventions that were rolled out around the same times and could have impacted the outcomes. And they also have this policy of drawing only one blood culture which could be hard in terms of determining which one's a contaminant not versus not a contaminant. So there are obviously some limitations. But I think that was a very interesting study as we're trying to reduce our use of vancomycin, I mean, you and I have seen babies growing vancomycin resistant organism already. So there's definitely an emergent need to change our practice and I think enough so in might provide that. I mean, just paper provides a very interesting solution. What were your thoughts?

Daphna 25:05

Yeah, I mean, it's, it's always complicated, right, but because for most baby one for most babies that we do SubSys workup on, it doesn't matter because we ended up stopping it right? That's the majority of babies. And for most babies, it is good enough coverage, unless you're the unless you're the baby with first. And not all units are testing for Mersa, right. And we know it spreads in units, we know, providers bring it in, we know parents bring it in. So it's hard. It's hard. It's tough. I mean, it would be great. If we can all agree together, it's a safe thing to do. And we can decrease our antibiotic resistance. But

Ben 25:53

I think you're putting your finger on one very important cue, which is, does that mean we have to do Mersa colonization screens in our units? And that's and that's sometimes a recipe for disaster because it leads to a lot of isolation courting, and, and the significance of that is debated in the literature, should you then try to treat those kids who are colonized? There's also lots of articles that have looked at that?

Daphna 26:14

Yes, once you know, then you will have this whole new gamut of brackets like

Ben 26:19

Pandora's box, right? Sometimes you may want to leave it close. And so this paper does not answer this question. Because if nafcillin had to be given in kids who potentially could have Mersa when you don't have that initial information of colonization, it's very scary. Yeah.

Daphna 26:37

But okay, shall we?

Ben 26:39

Yeah, keep going.

Daphna 26:41

Keep rolling. So I wanted to look at this effective antral zinc supplementation on growth, and neurodevelopmental growth and neuro development of preterm infants, a systematic review and meta analysis, and lead author Bell owl, I'll shy and this is for the journal Perinatology. And so they really wanted to look at the about the to evaluate the effect of enteral zinc supplementation on growth and neurodevelopmental outcomes of preterm infants. And this is an important question since growth is an ongoing problem for NICU infants and zinc deficiency is certainly known to affect postnatal growth. So this study design is a systematic review and meta analysis of randomized controlled trials examining growth and neuro developmental outcomes after zinc supplementation in preterm infants. So they use the typical practice for doing a meta analysis data extracted was performed by two separate reviewers, they were looking at the primary outcome of growth measured by the change in z score between the start of zinc supplementation and the next set of measurements and then, neurodevelopmental outcomes which were defined, again, differently by each trial. They did list a number of secondary outcomes, which again, were different in every trial, but mortality BPD, neck ROP, late onset sepsis, PVL, all the all the three level three letter acronyms and laboratory findings such as hemoglobins, and alkaline phosphatase. So this was kind of a manageable meta analysis after all, because, well, I mean, for me as the reader, not for someone who had to do it, but the total total that had eight randomized control trials, including 742 preterm infants. So for the primary outcome, there was evidence of statistical unimportant heterogeneity between the studies. And the pooled estimate of the mean difference in weight Z scores at three to six months between zinc and placebo groups using random effect model was point five in the z score. And then they looked at the mean difference in weight Z scores, and the pooled estimate of the mean difference in weight Z score was point three, eight, the pooled estimate of the mean difference in length was 1.12. There was no difference in the pooled estimate of the mean difference in head circumference. And so, thus, zinc was favored in nearly all of the studies. The effect of zinc supplementation on weight was significantly higher in studies providing greater than three MCs per kid per day of zinc as compared to those providing less than three minutes per kid per day of zinc. And it was greater in the studies where the infants in the control group did not receive any zinc through formula or human milk fortifiers. So what that means is they basically had no additional zinc whatsoever. So in those studies, where the control group was nosing compared to yes zinc, the difference was much greater. Zinc supplementation was also associated with significantly larger head circumference studies that specific so, remember taken all together, there were no major difference in head circumference. But in the studies and including SGA infants compared with studies including, you know, appropriate for gestational age infants, so the SGA babies were affected more by zinc supplementation. secondary outcomes, so three of the eight studies reported neurodevelopmental outcomes at varying time points. They revealed significant improvement in communication gross and fine motor skills, problem solving and social interaction, and infancy receives zinc supplementation. In contrast, One study reported significant increase in motor developmental scores but not total developmental scores. One study found that zinc supplementation in preterm breastfed infants improved alertness and attention pattern 40 weeks postmenstrual age and decreased hyper excitability at three months. So the overall pool data suggested that zinc supplementation was associated with higher motor developmental scores, but not necessarily the total nerd about neuro divan, neuro developmental scores. Multiple times today, mortality was reported in three studies, the overall pooled risk ratio for mortality showed a significant decrease in mortality risk ratio point by four. None of the included studies reported adverse outcomes from using zinc supplementation. One other study reported significantly lower incidence of neck and number of patients. So lower number of patients with greater than one greater than one or equal to one major neonatal morbidities in infants who received zinc supplementation. So the only thing I wanted to mention when I was thinking about this as like, okay, so that sounds great. So when we're how do we supplement zinc, you know, in our unit. So interestingly, zinc supplementation was initiated at 34 to 36 weeks in all the studies except for one. So I mean, this wasn't even in the very tiny baby. I mean, they didn't even start supplementing until very, very late in the in the admission. Obviously, there's not a lot of information about how long this link was continued for. So that's something to note. So study takeaways. Zinc may mediate improved growth and neurodevelopmental outcomes. The strengths were that it was a randomized, it was a meta analysis of randomized controlled trials, the limitations, again, lots of variability, the trials were not necessarily blinded, all the trials did not have the same outcome measures, like I said, the zinc starts very late in the admission, and it's not clear how long these babies were

Ben 32:56

supplemented for we do we do six weeks ourselves, right?

Daphna 32:59

We do. But we do that in specific babies where especially linear growth is affected. I think that's supported by this study, because that's probably that's the outcome that was most improved by zinc supplementation. But we we do that course, even, you know, before 34 to 36 weeks. So will this change my practice? I mean, I think it makes me feel like I should have a lower threshold to test slash, you know, treat for zinc deficiency. But, yeah,

Ben 33:32

I was interested because the the paper says that the linear growth has dramatically improved based on zinc. But we don't really have too much right, the conclusion that we don't have too much data on long term outcomes, right to me. There's no way that you've improved linear growth in a child. And long term outcomes are going to be worse, right? I mean, I just can't imagine. Yeah,

Daphna 33:53

I mean, they'll at least be the same, right? Theoretically, you're right.

Ben 33:57

But I'm saying, Oh, this baby that has had much better linear growth over earlier time is now suddenly having Moto and cons. Like I can't, I can't foresee that. So I'm interested to see what's going to come out and if people are going to look at this study and try to look at long term outcomes of zinc supplementation. But that's, that's, that's interesting.

Daphna 34:18

Yeah. Yeah. And maybe, and I'd like to see some studies of early zinc supplementation. So

Ben 34:26

like, when what do you want like week one? No, not

Daphna 34:29

Week One. Week one, this should be on full feeds at least.

Ben 34:36

Week two, then we'll see. Okay,

Daphna 34:42

you can go ahead and flood our inboxes with zinc.

Ben 34:46

So the one thing I will say is that there is zinc in a lot of the formula supplements that are being given. I mean, that's one of the reasons why. I mean, we are developed. Yeah.

Daphna 34:56

Well, and that's why they made that point that in the studies were the kids had feeds that were very low in zinc. That was the biggest difference, because I mean, they were zinc, probably really truly deficient as compared to the studies where the babies were fed with zinc rich things, or the zinc difference was not that great. And you know, I mean, I'm sure you're finding zinc in all the things with your new app.

Ben 35:25

Yeah. Yeah. So the the new the app is going to be released very soon. It's coming soon. But anyway, but yeah, there's so many supplements that have tons of zinc. And then when when you think a kid maybe zinc deficient, then you put them and you enter all the their, their their diet, their nutritional values, and you say, well, they're getting tons of zinc. So maybe there's no need to supplement for these kids as much as I think they would have needed anyway. All right. I'm taking you to pediatric pulmonology. Next, okay, let's go it actually, now we're going to, it's, I'm afraid that we're not going to have time to do to do this. So I want to take you to the to the Journal of parasitology. And I want to talk about this paper, duration of non invasive respiratory support, and risk of bronchopulmonary dysplasia or death. The first author is Samuel gentle. There's a bunch of very famous people on that paper as well. Eric Jensen wildly Carlo. And the study comes out

Speaker 1 36:22

of data. It was star studded Yes, definitely.

Ben 36:25

And this study is data from the neonatal Research Network. But the people who conducted the analysis were from the University of Alabama in Birmingham. So the cool thing about this paper is that it's quite unusual in its methodology. And for that reason, the first author is Sam gentle is going to be on with us in a few minutes. And he'll tell us a little bit about the study. But I wanted to give people a bit of an overview before he got into the nitty gritty. They asked a question that was very interesting to me, which is that we know that keeping babies on invasive mechanical ventilation is bad for BPD. And we and we and there's conflicting data as to, should we keep babies on non-invasive for extended periods of time? Or should we wean them to remember as soon as possible. And there's some data out there, right, that says that babies maybe should be kept on like a little bit of CPAP until 32 weeks for to promote long growth. But it's unclear as to if we increase the duration of non invasive support will that what will that will that do to BPD death and growth. Now, they looked at data from the neonatal Research Network, as we said, and that was a retrospective study of data that's collected prospectively, obviously, from 2011 to 2018. And I want to go a little bit into some of the costs of the study methodology because of that's something Dr. Gentle is not really going to get into with us right now. But the included babies were born at less than 29 weeks of gestation, and on non invasive respiratory support on postnatal day seven, defined as either nasal cannula, oxy hoods, CPAP, or nimap, documented as the highest mode of support. If on postnatal day seven, the infants were exposed to conventional or high frequency ventilation, they were off respiratory support, or obviously had died, they were obviously excluded. The primary outcome of the study was BPD, or deaf, defined by 36 weeks postmenstrual. HPPD, was defined as moderate or severe BPD at 36 weeks as treatment with supplemental oxygen, pretty much based on the 2001 in age definition. And they had a bunch of secondary outcomes BPD alone, death alone growth failure, postmenstrual age at discharge, growth failure, defined as a weight less than 10% out of 36 weeks using age specific growth curves. So what you'll see in the in the methodology is that in the statistics section, you can't really miss it, they have two possible way of analyzing the data that they're going to use. One of them is called instrumental variable analysis. And the other one is called the generalized propensity score matching, which you're probably very familiar with generalized propensity score matching, but the instrumental variable analysis was something that was very interesting. And I'm not going to get into what each one is because that's what Samsung was going to get into with us. But basically, their data covered 6268 infants that were analyzed for the primary outcome of BPD, or death. Most of these infants were either on nasal ventilation or CPAP. On postnatal day seven, that was about 80% of the cohort 36% developed the BPP BPD or died and the mean duration of non invasive support was 18 days. And what was interesting was that the depending on how you look at the data through either the instrumental variable analysis you they did not see an association between the duration of non invasive support and BPD. But when you looked at General propensity score matching, that changed. And so within the same paper, you have two conflicting sets of results. And that really, if you're reading the paper attentively, will give you pause for concern, because you're like, so what am I supposed to be taking away here? But I think the reason why that was needed was very interesting. And I guess, maybe we should let maybe Doctor gentle explain some of that stuff himself. So Dr. Sam, gentle, thank you so much for being on the show and for coming to talk to us about about your your recent publication.

Speaker 3 40:34

Yeah, absolutely. longtime fan, so happy to speak with you too.

Ben 40:39

That's awesome. We're big fans of your paper. I think we've reviewed a couple over the past few months. So keep it up. And so I wanted to for the people who haven't read the study, I think I think the study called duration of non invasive respiratory support and risk of bronchopulmonary dysplasia or death is a very interesting study, because it asks a question of, does this being a non invasive respiratory support for a long time really decrease your BPD free survival, or even increase your rate of death? And I wanted to know if you could walk the audience through what this how you run your study? And what do you think the main takeaways are?

Speaker 3 41:20

Sure, I think this is a very common clinical quandary in the units, one that I think I've faced four or five times this week, for instance, it when do you stop non invasive respiratory support? I think there's a lot of interest center and interest center variation, do you stop once babies upon RDS resolution or evolving BPD resolution? Or is it something that you extend for a set duration of time as a kind of central practice? And it's a tricky observational analysis to perform? Because it's the extension of database of restaurants port A, is it confounded by illness severity? So are you just extending the duration of support because these infants are sicker? Or is there a central practices in other words, extending to what a commonly heard that 30 to 32 weeks postmenstrual age or some sort of pre specified weight cut off? In those events? Would that actually provide any respiratory benefit in extending positive pressure exposure to those infants. So that was the kind of what we were challenged by in terms of the confounding by illness severity. So we took upon ourselves to go through a couple of different adjustment, analytical lenses. And those that we chose were instrumental variable analysis and generalized propensity score matching, and they kind of adjust for different things. I think, you know, the, we also were considering using the more traditional approach logistic regression. But again, thinking that this may not adjust sufficiently for some other maybe non included confounders so that I could get dig deeper into that analytical approach. If seen, that was what we were kind of chewing on.

Ben 43:04

I think that's yeah, so the data looks at retrospect is retrospective review of data from the neonatal Research Network. And you're looking at at survival. You're looking at BPD, at 36 weeks, I think you're using the 2001 nih definition because I think the data was collected before the data was collected before 2019. So I mean, I assume that this was the reason. But the interesting part of the paper obviously, is this is a statistical statistical approach, where you're basically using something called instrumental variable analysis to analyze whether the duration of exposure to non invasive respiratory support may be related to center specific practices rather than disease severity. And that sounds really cool. Like, can you can you tell us a little bit how does that work? Yeah, tell

Daphna 43:53

us more.

Speaker 3 43:56

Yeah, we tried to be a little bit overly descriptive, maybe in the Methods section, knowing that folks may not be as familiar with these approaches. I certainly wasn't that familiar with these approaches prior to this analysis, honestly, but RTI, who was invaluable in kind of approaching these challenging clinical questions, and this was their input in terms of how to analytically approach this. So the instrumental variable analysis piece, like you were mentioning, is a duration of exposure linked to center specific practices. And as I was mentioning before, it's non invasive respiratory support stopped at this sort of predefined time point and based upon resolution of rds are evolving BPD. And so the instrument again, instrumental variable, variable analysis is what was the average days at a patient's center. So this would reflect physician practices, but not necessarily patient illness severity. And so that's the kind of adjustment approach for that piece of art. And so we chose that one analytical lens and then the other one was the generalized propensity score matching and this When will be, I think will resonate or at least feel more familiar. It's it's kind of a candle logistic regression in some ways, but it adjusts more for confounding by illness severity, and adjusting for covariates across different treatment levels. So this will use kind of more traditional covariates, like gestational age, birth weight, if I do two things that you would think would influence the overall duration of exposure. But within generalized propensity score matching, rather than, you know, an odds ratio, or an adjusted odds ratio, it looks at, um, kind of two different metrics. And that's the average marginal effect. So that it expresses on average, if you add more non invasive respiratory support days or more percentage of time of the hospitalization, does that impact outcomes and outcomes being BPD death are a composite of the two. And then the other component is the marginal effect at the mean. And that estimates, the change in probability for extending respiratory support beyond the mean level in the sample. So that was useful job explaining those two things.

Daphna 46:08

makes way more sense when you say it.

Ben 46:13

Very helpful. And so what was interesting was that in the so in the results section, you walk the reader through the data through these different lenses. And what what I found to be very interesting is that depending on how you looked at the data, and the association between non invasive ventilation days, and BPD, PPD or death really changed, depending on whether you were looking at this when you were looking at the marginal effects of the means, or whether you were looking at the quantiles. And even in the other outcomes, when you started looking at categories of days, if if a BB had been on zero to one day, or one to seven days, or seven to 14 days, and the data really changed, depending on how you looked at it. And I think, How can you tell us a little bit as a researcher when you when you go through this, and you can really pull the data in different directions? How do you present the information in a way that is not really biased?

Speaker 3 47:13

Yeah, no, I think it's what's tough about this manuscript is coming up. Coming up with a cohesive takeaway, like you're mentioning, the instrumental variable analysis has a different conclusion, honestly, from the propensity score matching analysis, the instrumental variable analysis, again, that's the how to center practices sort of influenced duration, that was non significant for for these outcomes. But if you look at the propensity score matching, where, specifically by the marginal effect at the mean, so if you're looking at the whole sample, you look at the mean duration of non invasive respiratory support, which was about 18 days, it's, and let's say you expose babies more for a longer period of time, that was actually positively associated with BPD, or death. So further, extending the exposure for the composite outcome, increase the composite outcome, but interestingly, for death alone, it decreased death. So there's a lot of inconsistencies. I would say, if you look at table tunes, specifically between these different analytical techniques, and I will say that this wasn't published, but we looked at logistic regression as well. And that was actually similarly associated, like the longer duration of exposure, increased risk for BPD or death. And in terms of back to my, you know, what's the cohesive takeaway to me is that extending non invasive respiratory support based on these analysis, these analyses is not necessarily something that I think from, again, observational data, lower level of evidence compared to some randomized studies that have looked at extended CPAP. Or I'm stopping it upon reaching stability criteria, which may vary by study. But but our analyses did not suggest that there's extending CPAP for a pre specified duration of time with benefits babies. Although I've seen, again, kind of growing trends for extending non non invasive respiratory support to these sort of pre specified time points. I think I've walked around and Vermont Oxford Network, the Annual Quality Congress, and I've seen a number of different initiatives that are this extension of non invasive respiratory support, but I'm not sure that there's sufficient evidence for that, that practice.

Ben 49:24

So I was I was not really at our center, we we tend to like to keep babies at least once on some CPAP until 32 weeks, based on the evidence that is quoted in the paper for for long term outcomes, and then coming at the end, I kind of I fell in love with the instrumental variable analysis because I think it pointed out exactly what the issue was where these babies are being continued on CPAP. But we don't really know why and where they even you mentioned that I think also in the discussion where it's like, has as an ad has anybody even tried to win them? We wouldn't know From the data itself, so I was I was happy that you use the the outcomes that you gathered from the instrumental variable analysis and said that no, the association was not really found. When, in truth, even in the paper, some of the data from the propensity score matching, and even those, those dose response curves were were frightening.

Speaker 3 50:25

I hope what frightens you less though is the if you look at the kind of higher end of the dose response curves are far fewer babies and the far right component of that. So I focus on the left

Ben 50:36

half of I

Unknown Speaker 50:41

don't want that to scare you.

Daphna 50:44

More of a, like an ethical question, right? When we're reporting statistics in, in our work, right, so you have all the data, everybody always has their their data, and you have the opportunity to release or not release right data that you have, that happens all the time. So what made you guys write about all the data, right, and put out all of the perspectives, which I really value? I think that's really important. I think I'm hopeful everybody will do it. But sure, that's the case.

Speaker 3 51:17

Yeah, no, I think we were, again, fairly conflicted in terms of what would be the alternate central analysis, you know, in again, we kind of presented to what we call, we consider fairly equivalent analyses. But I've seen similar propensity score related analyses of for instance, there's Dr. Greenberg did a paper on furosemide exposure and BPD, using similar propensity score. So are babies getting more lasix exposure because they're sicker? Or is it sort of a center practice the same quandary? Right? So it's more exposure beneficial? Or is it more just related to illness severity, but in terms of providing all the data, I think, you know, we want it to provide as much transparency in terms of what we collected. And in showing some of the trends and the tables, when you we kind of do those sorts of stratified buckets of durations of severity, like you were mentioning, one week versus two weeks versus three weeks, because we thought each component had relevant takeaways. So I think some of those tables, but let's say your center is kind of wrestling over oh, well, Shoot, maybe we should stop at two weeks of exposure? Well, you know, if you look at that kind of dose response from those tables, it's not as though those babies have overall greater benefits from from death of BPD. So we thought that table would, for instance, be fairly clinically relevant, because this duration of exposure is this a benefit. But we also wanted to have analyses that adjusted for again, the illness severity, which we thought was the biggest burden upon us was adjusting for illness severity, and taking into account center specific practices. So I think each analytical language angle provided different narratives. And but I thought they answered different questions that were all kind of similarly important, as you're chewing on, should I take this baby off non invasive respiratory support?

Ben 53:12

Yeah, I mean, that paper is like a stick of dynamite. You know, it's like you can you can have people arguing both sides of the argument with the same data. This is this is going to be right. But yes, Sam, thank you. Thank you so much for coming on and for and for sharing with us the findings of the study and walking us through some of the methodology. I think it's a fantastic paper. And I think it's going to give a lot of fodder to the discussion as to how long do we keep these babies on an IND CPAP, or even high flow nasal cannula. So great work. Thank you. Thank you so very much.

Speaker 3 53:44

Appreciate. It was a pleasure talking with you both and keep going with the podcast. And again, we're doing Thank you very much.

Daphna 53:51

We love what you're doing. Right.

Ben 53:55

All right. Thank you to Dr. Gentle for going over that with us. Daphna, do we have any more papers to go over today. Of course, let's go.

Daphna 54:06

I have some papers, but we will do what we can. I had this other article. Does active treatment in infants born at 22 to 23 weeks correlate with outcomes of more mature infants at the same hospital and analysis and analysis of California Nikki data 2015 to 2019. Lead author, shall Molly bean. This is a journal apparent etiology. So the group wanted to investigate whether hospital rates have active treatments Who do you resuscitate or not? Basically, for infants born at 22 to 23 weeks and if you resuscitate more of these extremely preterm babies and hospitals that that resuscitate less extremely preterm babies, is does that improve your survival of infants that are born a little that leader like 24 to 27, that question. Yes. So if you,

Ben 55:04

if you if you if you resist the 22 weekers, Are you better now at 25? weekers? Right. Yeah,

Daphna 55:08

it's a reasonable question. So basically, for lack of it, does practice make better for, for lack of a better terminology. So is it a valid question? And, yes, I mean, we're learning so much about the and, you know, extremely preterm infant. In a way, we've always advanced medicine by practice. But again, at what cost. But of note, especially when it comes to these, Perry variable age, there is huge variation across the state of California and a large variation across the country worldwide in outcomes of the very preterm infants and of the moderately preterm infants. So, study design, this is actually this is a retrospective chart review. And it's a it's a type of cohort study. So the inclusion criteria is all live born infants at 22 to 27 weeks gestation, delivered at CPQ. CC. And again, that's the California Collaborative member hospitals during 2015 to 2019. And all the infants were born at hospitals was greater than or equal to total, greater than or equal to 10. Total births, between gestational age are 22 to 27, over the study period, so they had to have at least 10 of those births to be included in the analysis. And they had 8802 infants at 122 hospitals. And then to look at hospital level analysis only hospitals with greater than or equal to five births at the 22 to 23 weeks gestation, specifically were included, that's 88 hospitals. This exclusion criteria were severe congenital malformations, and they did not include any out born infants to these hospitals. As we know, you know, transport being outworn is an in and of itself a big risk factor for morbidity and mortality. So the inner the primary exposure was basically the hospital the whole total hospital rate, so does your hospital do a lot of resuscitation of 22 to 23 weekers. And again, active treatment was defined if infant had received any of the following interventions, intubation CPAP non invasive positive pressure ventilation. For infants that survived greater than 12 hours, epinephrine or cardiac compressions in the delivery room, and hospital rates were computed as the proportion of infants born at 22 to 23 weeks at the hospital during the study period who received active treatment, the primary outcome so the study outcome was, again the hospital rate of survival to discharge and the secondary outcomes, they looked at survival without any of the following major morbidities severe retinopathy of prematurity, chronic lung disease defined as Oh to 36 weeks or discharge at 34 to 35 weeks with supplemental oxygen neck with the either diagnosed surgery or post mortem examination or clinically using the following criteria bilious gastric aspirin or emesis, abdominal distension, bloody stools and then the radiographic findings, Neva ptosis, portal venous gas Nemo peritoneum, I looked at nosocomial infections, severe ivh and cystic PVL. So the baseline characteristics for these 8802 infants were that they had 1600 infants born at 22 to 23 weeks, that's 18% 3045 at 24 to 25 weeks 34% and 4154 26 to 27 weeks 47%. The hospital rates of active treatment for infants aged 22 to 23 weeks ranged from zero to 100% with a median rate of 57%. So big, big variability. So the prime have a primary outcome. So without adjusting for differences in the patient characteristics among hospitals, the hospital level of active treatment was highly correlated with survival in the 22 to 23 Weak cohort, so the more often you resuscitated 22 to 23 weekers, the more likely they were to survive an RF point six nine and modestly correlated with survival without morbidity or equals point to one. Levels of active treatment in the 22 to 23 week cohort were not correlated with any hospital level infant outcomes in either the 24 to 25 weeks of gestation cohort or For 26 to 27 week cohort, which is super interesting, crazy. Similarly, active treatment was highly correlated with the rate of cesarean section that's not surprising in antenatal care and 22 to 23 weeks infants, but not in either of the older cohorts. And then they looked at models adjusting for those differences that they found in patient characteristics or multivariate variable analysis. And a 10% increase in rate and active treatment was associated with an increase in survival for the 22 to 23 week population adjusted odds ratio of 1.22, but was not associated with an increase in survival for the 25 to 24 to 25 week group, odds ratio of one or the 26 to 27 week population, odds ratio one, no association between the active treatment and survival without morbidities were observed for any of the populations and excluding antenatal steroids from the model actually had no effect on the relationship between postnatal active treatment rate and infant count outcomes, which is also very interesting. So the study takeaways are that in this retrospective cohort study in California, they found that if you reset sedated more 22 to 23 weekers. They, it did not improve your outcomes in the 24 to 27 weeks of gestation, but it did improve your outcomes in the 22 to 23 week population. So strengths was multicenter huge data set limitations were that it was a retrospective chart review, it's really the best we can do for this kind of data, I would have liked to have seen more baseline characteristics included in in this paper proper. It won't change my practice, because we get what we get. But it it I guess it made me feel better that the low volume hospitals aren't necessarily performing worse in those moderately preterm groups. I think it also shows that those 22 to 23 weekers are just a whole different type of patient than the 24 to 27 weekers.

Ben 1:02:11

But yeah, I mean, that's that's that's what I was wondering, why do we think they're that different that because

Daphna 1:02:18

recently, I expected that you would, it would correlate? Yeah.

Ben 1:02:23

Yeah. I mean, I think if you're able to manage these 22 to 23, weekers, then your outcomes for 24, or 25, should be much better.

Daphna 1:02:30

I do wonder, too, it's hard to study the variability in when and why we get 22 and 23, weekers. Right. Some of them are preterm labor, right? They just, they're there, they showed up. So we we had them, and some of them are, you know, decisions about moms, and, you know, cesarean delivery for maternal indication. So there's variability in that too. And so is it better to wait until they're they're a little more mature but in extremis, or to get them a little earlier, but not in extremis? It's, it's, I don't want to be an OB. I tell you what,

Ben 1:03:13

I wanted to go over some of these odds ratio as well. Yeah, cuz, I mean, we've been talking a lot about it. I mean, most of the papers we talked about today had an odds ratio. And I know we talked about this on the New York neonatology review podcast, just for the people who don't recall, right? If you have an odds ratio of one means that the odds are the same between one intervention and control. And then if you have odds greater than one, then your likelihood by being exposed to whatever you're testing is greater than the control and then less than one, it means that your likelihood of getting the outcome by being exposed to whatever is lower than the control. So in case this was confusing, I'm sorry, we should have maybe brought this up again, sooner, but we should all know this. So but I feel like in this in this article, like you end up scratching your head, right? It's like, how is how is that? That it's not a linear relationship? It's very interesting anyway. Okay. It's a very interesting paper. Yeah, it's interesting. It's interesting. It's a very interesting study, because you tend to think, Okay, if we take on this mantle, then maybe we'll be better a better center overall. But that's that's not necessarily true. All right. Yeah. I have one more paper and then we can probably,

Daphna 1:04:28

yeah, we will be out of time, I think.

Ben 1:04:31

Yeah, I wanted to just mention this paper that I saw in pediatric pulmonology, called the erythropoietin for preventing bronchopulmonary dysplasia in preterm infants a systematic review and

Daphna 1:04:40

I know you're trying to make EBO prevent everything.

Ben 1:04:43

No, exactly, not. But I'm thinking every time something comes out with EPO, I'm gonna get an email saying like, Oh, like now is going to prevent BPD. This was from first to third Jing Li from Jiang Zhao in the Henan province of China. The idea is that So people may exert protective effects against PPD. And the idea is, you know, there's something called transfusion related lung injury. If you prevent more, if you prevent transfusion, maybe you can prevent more lung injury because of it. So the idea was sound. And they did a meta analysis, looking at the published clinical randomized controlled trial or quasi randomized control trial. Interestingly enough, only written in English. It was very peculiar, because they saw the the study out of China was like, how am I going to get to see some interesting data that I could not read? But no, it was only paper submission English. They looked at infants that were less than 34 weeks, and that received either IV or sub q equal initiated less than a at less than eight days of age, in the neonatal period. So they looked at the primary outcome of BPD. And they had a physiologic definition, and they had general BPD definition. They looked at Oxygen dependence. In days, they looked at the numbers of number of infants requiring mechanical ventilation, and they looked at some secondary outcomes necrotizing enterocolitis, sepsis, death before discharge, or repeat the baseline characteristics, they looked at 400 studies, they evaluated all these papers, and 14 of these studies were included in the analysis which amounts to about 3200 infants. The studies were published, published between the year 2020 20. In terms of the primary outcome, they should no significant effect of equal on BPD at 36 weeks with high quality evidence, and the physiologic definition of BPD at 28 days, that was low quality evidence. The meta analysis showed no significant effect of people on any kind of oxygen dependent of oxygen dependence days. And for our cities that did the number of infants requiring mechanical ventilation, it could not demonstrate a significant reduction in infants requiring invasive ventilation. Now, in the secondary outcome, this is where all the discussion is going to happen. 14 RCTs that reported the race of next show that it will significantly decrease the incidence of any stage NEC subgroup analysis or that only IV po significantly reduced any stage NEC. Meta analysis of the data from five randomized controlled trials showed no significant effect of equal on stage two or higher NEC. Some of the trials show that IV po significantly reduced the risk of sepsis. And then finally, that the incidence of ROP reported in various RCTs was comparable in the ICO and control group neonate except for significantly increased incidence of ROP when eople was administered subcutaneous. So the takeaways are that equal does not affect the development of BPD in preterm infants. And there's all these questions that are going to come up about NEC and ROP. Now the only thing I want to say is that there's a few limitations. Obviously, we don't have a control of the equal doses that were given across these trial, the duration is variable as well. And only when it comes to the NEC, it's important to realize that only one of the studies that they looked at in their meta analysis used NEC does it use neck as a primary outcome? And all the studies that were mentioned, this paper were present in the most recent Cochrane review on on EPO, and and the effect on on ROP has been shown not to be really significant when all these studies are put together. So again, more adding more fodder to the fire of should we be more careful with people. But yeah,

Daphna 1:08:45

well, what my question is, is these differences in IV versus subcutaneous SIBO. Because, you know, in our unit, we go back and forth, or we start with IV and then we switch to sub q. But I thought that was interesting, too, to look at the differences. Some of the studies had differences depending on administration route,

Ben 1:09:08

right. So the one thing that was not really accounted for by the authors about this topic specifically is whether I mean, for example, in our protocol, we move to a sub q injection format, when you reach us, when you lose your IV basically, right, as long as you have an IV, we want to inject eco sub q. So the question is, does that make a difference? Meaning, because right, if you're NPO and Ico is being given to you IV, then you're less likely to have that because you're not being fed. Technically, but if Ico is being given to you sub q, that was I mean, that was

Daphna 1:09:43

a brave, brave, brave statement.

Ben 1:09:47

Very brave. But you know, if have you called the surgeon for neck and the first question has they asked you is like, is this BB feeding, right? They're asking you, right, it's so it's, what I'm saying is you When you're talking about sub q being more of an issue, the question becomes is the is it the chicken or the egg? Is it that the baby is higher at risk of neck? Because the baby is now on four feeds no longer has an IV and now the EPO has to be given sub q? Or is it really what I'm saying?

Daphna 1:10:15

Yeah, and I mean, our I guess our their units that are keeping an IV is just to give EBO.

Ben 1:10:22

That feels that feels a bit of like an overkill, I would say we have, we have looked carefully at painful pricks and making sure that we don't extend our report course past a certain time point to minimize the subcutaneous injections. And we try to give it IV as much as possible as long as an IV access is available. So yeah, but all our babies who are on for feeds have no IVs, get it sub q. And they're probably the most at risk of developing neck because they're being fully fed. So who knows?

Daphna 1:10:54

Very interesting.

Ben 1:10:55

Yeah. But it doesn't increase. It doesn't reduce BPD. It does. doesn't reduce. Okay, I think that's it for us stuff now. Anything? Yeah, you wanted to share? We're not going to PS people have been asking us whether we

Daphna 1:11:11

will I will I have I have FOMO if you're missing out, and it's not a fear I'm missing. I feel like we're like, we'd like to be there, obviously. But we have an excited the Incubator has an exciting trip coming up, and somebody had to watch the unit. This

Ben 1:11:29

incubator is holding up the unit. But we will I'm realizing that we should probably speak to some of the PSP over next year and try to make something happen. We should have like a social hour or something, something that could be fun at PS next year.

Daphna 1:11:40

Yeah. You know, we've been thinking about that for some time. So I'd love to have an incubator social.

Ben 1:11:46

Yeah. But this year, this year, we've had a lot of conflicting stuff. Like I just came back from the conference. We're going to another conference very soon. So it's just not feasible. But next year, next year sounds like maybe something maybe like, you know, have a meet up as those.

Daphna 1:12:02

Yeah, we look at some things in mind. We got some fun things in mind, but we hope everybody had a great trip and learned a lot and have a safe trip home and we're still recording.