Hello friends,

We have a journal club episode packed with great content this week. We report the result of an Italian study that tried to answer the question of whether CPAP or HFNC causes more feeding intolerance in preemies. We talk about neonatologists' fatigue and fallibility, non-HIE neonatal encephalopathy, and chat with the amazing Dr. Elizabeth Sewell and Dr. Susan Cohen for our monthly EBNEO commentary. This month we discuss the recently published meta-analysis by Abdul Razak and colleagues looking at interventions to reduce severe brain injury in preterm infants. If you enjoy the episodes we release each week, please leave us a 5-star review on the Apple podcast; this helps us tremendously.

Thank you all!

Have a good Sunday.

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

Does Growth Velocity Affect Associations between Birth Weight and Neurodevelopment for Infants Born Very Preterm?

Sériès T, Guillot M, Angoa G, Pronovost E, Ndiaye ABKT, Mohamed I, Simonyan D, Lavoie PM, Synnes A, Marc I; MOBYDIck trial group.J Pediatr. 2023 Jun 1;260:113531. doi: 10.1016/j.jpeds.2023.113531. Online ahead of print.PMID: 37268036

Fatigue and fallibility: the perils of prolonged shifts for neonatologists.

McAdams RM.J Perinatol. 2023 Jul 8. doi: 10.1038/s41372-023-01718-0. Online ahead of print.PMID: 37422587 Review.

Effect of Nasal Continuous Positive Airway Pressure vs Heated Humidified High-Flow Nasal Cannula on Feeding Intolerance in Preterm Infants With Respiratory Distress Syndrome: The ENTARES Randomized Clinical Trial.

Cresi F, Maggiora E, Lista G, Dani C, Borgione SM, Spada E, Ferroglio M, Bertino E, Coscia A; ENTARES Study Group.JAMA Netw Open. 2023 Jul 3;6(7):e2323052. doi: 10.1001/jamanetworkopen.2023.23052.PMID: 37436750 Free PMC article. Clinical Trial.

Early Antibiotic Use and Neonatal Outcomes Among Preterm Infants Without Infections.

Yu W, Zhang L, Li S, Yan W, Bai R, Yang Z, Shi J, Yuan J, Yang C, Cai W, Wang Y, Zhang Y, Gu X, Cao X, Huang Y, Hong L, Zhou Q, Yang Y, Lee SK, Jiang S, Cao Y; Reduction of Infection in Neonatal Intensive Care Units Using the Evidence-based Practice for Improving Quality (REIN-EPIQ) Study Group.Pediatrics. 2023 May 1;151(5):e2022059427. doi: 10.1542/peds.2022-059427.PMID: 37042203

Characteristics, Genetic Testing, and Diagnoses of Infants with Neonatal Encephalopathy Not Due to Hypoxic Ischemic Encephalopathy: A Cohort Study.

Lenahan A, Mietzsch U, Wood TR, Callahan KP, Weiss EM, Miller DE, German K, Natarajan N, Puia-Dumitrescu M, Esposito V, Kolnik S, Law JB.J Pediatr. 2023 Jun 1;260:113533. doi: 10.1016/j.jpeds.2023.113533. Online ahead of print.PMID: 37269901

Interventions to Reduce Severe Brain Injury Risk in Preterm Neonates: A Systematic Review and Meta-analysis.

Razak A, Patel W, Durrani NUR, Pullattayil AK.JAMA Netw Open. 2023 Apr 3;6(4):e237473. doi: 10.1001/jamanetworkopen.2023.7473.PMID: 37052920 Free PMC article.

EBNEO Commentary: Interventions to reduce severe brain injury risk in preterm neonates: A systematic review and meta-analysis.

Sewell E, Cohen SS.Acta Paediatr. 2023 Jul 21. doi: 10.1111/apa.16908. Online ahead of print.PMID: 37475595 No abstract available. -----

Find some of our notes here 👇

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

[00:00:00] Ben: [00:01:00] Hello everybody. Welcome back to the incubator podcast. It is Sunday journal club time is upon us. Stefano, how are you?

[00:01:09] Daphna: I'm doing good, buddy. How are you?

[00:01:11] Ben: Very good. I'm doing very good as this episode is airing probably on my way back from Europe. And I am, uh, I'm sure it was a

[00:01:19] Daphna: hope, you hope you're doing very well.

[00:01:21] Ben: Yeah, I'm happy. I'm hoping I had a fantastic time. Um, yeah,

[00:01:27] Daphna: Are you going to bring me back some chocolates?

[00:01:30] Ben: chocolates from France. That's not our area of specialty.

[00:01:34] Ben: They have good chocolate in France.

[00:01:35] Daphna: those, um, uh, lavender candies.

[00:01:38] Ben: sure, sure. Lavender candies we do.

[00:01:40] Daphna: kidding. Right.

[00:01:41] Ben: Um, but what else is very good? We do a lot of soap, like handmade soap is something that's good. Perfumes are a very big thing. And then, um, what else do we do that's pretty, uh, reputable? Yeah, luxury goods, but I don't have to pay for that to, to start, [00:02:00] uh, gifting Louis Vuitton bag, uh, around the hospital. All right, Daphna, let's talk about Journal Club. Do I, do you want to go first? You, you should go first. You have a funny paper that you want to read from, from our buddy Ryan.

[00:02:16] Daphna: Yeah, okay. You want me... I never go first.

[00:02:18] Ben: know I want to swap things around a little bit.

[00:02:20] Daphna: Okay. Well, this paper, um, was in the Journal of Perinatology, uh, it's a perspectives piece. It's called Fatigue and, Fatigue and Fallibility, the Perils of Prolonged Shifts for Neonatologists, um, by Ryan McAdams. I think the, I think the title is very catchy, so, um, so it was a perspectives piece, um, and it basically describes the problem, um, with the sleep deprived neonatologist.

[00:02:54] Daphna: And I guess if you're not thinking like, Hey, that could be me, [00:03:00] then maybe you should. Rethink it or let us know what you're doing and you're on your team, um, if you don't ever feel sleep deprived. So, it really, uh, you know, the beginning of the article references kind of the consequences of inadequate sleep and.

[00:03:16] Daphna: Just in case people don't sit down to read the article themselves. I think this is a good place for us to talk to the community. A reminder about what those are. You know, we're doctors. We know that. We tell the parents how much, uh, their own sleep and the sleep of their babies is important. But let's talk about what happens when we don't sleep.

[00:03:36] Daphna: So we know there's increases in motor vehicle crashes. We, um, we reviewed a paper just a few months ago, um, about this in residents. Um, we know there's an increase in medical errors. We know that fatigue hinders productivity. It diminishes working memory and, um, that prolonged wakefulness impairs cognitive and physiologic performances.

[00:03:56] Daphna: Similar to alcohol intoxication. So somebody's actually done this [00:04:00] study. Being awake for 17 hours is like having a blood alcohol level of 0. 05. Being awake for 24 hours, which in our community we do not infrequently, um, is like having a blood alcohol, a blood alcohol level of 0. 1, which does exceed the legal limit in the U.

[00:04:17] Daphna: S. uh, for driving under the influence.

[00:04:20] Ben: What is it,

[00:04:21] Daphna: Um,

[00:04:22] Ben: They ask

[00:04:23] Daphna: so.

[00:04:24] Ben: you that when you're taking a license.

[00:04:25] Daphna: date.

[00:04:26] Ben: Yeah, it's one of the few things... Taking the license in the US is actually quite easy. Uh, compared

[00:04:31] Daphna: so easy.

[00:04:33] Ben: No, compared to France. Like, in France, it's like a whole year you have to, like, do all these tests and all these courses. And there's, like, a few things you must memorize, aside from when the stop sign is in front of you, you should stop.

[00:04:43] Ben: But I think 08 was a question.

[00:04:45] Daphna: The Florida legal limit is 08.

[00:04:47] Ben: There you go. Look at that. I'm not a drunk, by the way. I don't know this. I'm

[00:04:54] Daphna: So, I mean, this is a bit, this is the situation that we have. So, it [00:05:00] also erodes our circadian rhythm, which predisposes for increased risk of chronic disease and mental health problems. It increases weight gain, obesity, cardiovascular disease, stress, pain. There's an increased risk of dementia. and death. Um, uh, there's reported higher burnout and decreased professional fulfillment and, um, strained interpersonal relationships both inside and outside of work.

[00:05:26] Daphna: And then, um, they did a good job of saying, okay, so how does this pertain to neonatologist specifically? Well, we know, we're all feeling it. We have an escalating patient volume, um, a real increase in patient acuity, especially as. We're pushing the limits of viability as we're doing surgical procedures for babies that we didn't use to intervene on.

[00:05:50] Daphna: And we really have a stretched workforce. We have a decreased number of physicians for this increasing patient volume. And The other [00:06:00] pressures of academic work, education, responsibilities, and administrative responsibilities are the same or also increasing, um, without a reduction in clinical time. And it has historically been, uh, that we take prolonged shifts.

[00:06:18] Daphna: including night call. And actually the paper we reviewed a few months ago, um, talked a lot about, um, the, the consequences of night call. And they give an example, a Neo who works three 24 hour shifts a month will lose almost a year of sleep over their 30 Um, and that also has its own, obviously, consequences.

[00:06:46] Daphna: So then they say like, what, what can, what can we do about it, right? Uh, what are the potential solutions? So I'll read them and I'm sure by the time I get to the end of the list, some, some people will be rolling their eyes cause you're like, [00:07:00] obviously those are the solutions, but like, how do we get there?

[00:07:03] Daphna: Um. We, the measures are to reduce shift length, increase break frequency, promote sleep breaks, use alertness strategies, and I'll just mention what some of those are, um, some things you can do, uh, during the shifts, like micro exercise, caffeine, uh, light therapy to help stay alert. Health screening and treatment, that means going to your regular checkups.

[00:07:26] Daphna: Uh, have adequate staffing, optimize work content, that means reducing secondary load, uh, tasks that cause, uh, fatigue for us, particularly the EMR and charting. Uh, monitor actual sleep, so find out how much you're actually sleeping, um, at work and not at work, you know, changing your sleep hygiene. Providing sleeping facilities, um, for overnight call and, um, changing schedule design to optimize.

[00:07:56] Daphna: sleep. And then the countermeasures, they list both [00:08:00] the pros and cons of all of those, including why it may be difficult to implement some of those things. But really what they are advocating for is that as a community, we work together to regulate shift duration. Um, because obviously the babies need somebody on all the time and we, we're not going to be able to get rid of night call.

[00:08:24] Daphna: Um, but we Could as a community change our shift duration and some of our colleagues in other countries Certainly do this not because they don't work as hard as we do, but I think that they have recognized how important that this is To their work and to their health. So they are advocating for adopting a national shift duration guidelines Kind of like duty hours for residents, but like for attending physicians, um, which again, uh, the goal is to [00:09:00] prioritize sleep by, um, placing a reasonable cap on shift duration.

[00:09:05] Daphna: Um, really to prioritize not only our own health, but the safety, uh, of our patients. So, I underscore, we must recognize fatigue as a potential patient safety risk. So, thoughts?

[00:09:22] Ben: What is microexercising?

[00:09:25] Daphna: I use the word microexercise. I mean, do they just mean like doing small exercises? I noticed, uh, there's a new set of weights in our call room, are

[00:09:33] Ben: That's right, I'm

[00:09:34] Daphna: Ah!

[00:09:37] Ben: We have, uh, we have a pull up bar. We have now weights. Um, there, there's a yoga mat. And there are, um, there are, uh, uh, bands to, uh, yeah. Actually, it's more, yeah, just like to do resistance bands. Yeah. So there's somewhere in the call room. So I'm trying, I'm trying to, uh, to transform our

[00:09:58] Daphna: But that's exactly what they're talking about. That can, [00:10:00] that can, that is a coping strategy. It can increase your alertness during the shift. It does not necessarily improve your

[00:10:06] Ben: It's something that I was trying to do. Actually, I would

[00:10:08] Daphna: though exercise does improve your sleep,

[00:10:10] Ben: I tried to do it this morning. But then I shift, uh, You know, I'm like if in the morning after I've pre rounded in the morning and I'm waiting for my

[00:10:18] Daphna: squeeze it in.

[00:10:19] Ben: Yeah

[00:10:20] Daphna: That never

[00:10:20] Ben: This morning was not a day for it to happen Okay. Um, no other than that, I think You know,

[00:10:27] Daphna: Yeah, I think,

[00:10:27] Ben: i'm gonna i'm gonna

[00:10:29] Daphna: this, but I think it's good to remind ourselves because of the way our work shifts are, and the fact that we have really high acuity, high intensity, we need to make quick decisions, and the two are not consistent with one another.

[00:10:45] Ben: Yeah, I mean, so I think um I'm going to say yes to all the things that Ryan mentioned in the paper, and yet I'm guilty of not doing any of them. Like, I haven't seen a doctor in years. Um,

[00:10:56] Daphna: Oh yeah, this was as much to myself as it was [00:11:00] to the community.

[00:11:01] Ben: But what's interesting to me is that I, I look at the idea of like, hey, we need to change how we do our shifts. And then I am wondering if based on your census, We can start making models for different types of NICU. So for example, we have a unit that has like, I don't know, like 30 to 40 beds. And, and so I think our shifts are fine, but then I have worked in units that had 120, 130 beds, and then I've been on call as the only physician when there was a census of 95 and then you, I wonder if we should.

[00:11:33] Ben: Then maybe in those units like are we going to go to like four docs a day six hours each You know what i'm saying? Like you do a six hour shift from you You show me right, you know what i'm saying

[00:11:43] Daphna: Why a six hour shift?

[00:11:44] Ben: because it's the because of the toll that uh a shift from like I mean when we were doing these

[00:11:52] Daphna: I know,

[00:11:53] Ben: we were doing these shifts with like 95 patients on on and and you were you were coming like The [00:12:00] shift technically started at like 7 30.

[00:12:01] Ben: I would be there at 6 30. The shift ended at like 4 35 I would be there until 6 you were there much later So what i'm saying is that even if you say, okay, the shift is actually only from 7 to 5, which is like 10 hours That's not true. It's you're doing a 14 hour shift whether you like it or not

[00:12:17] Daphna: I think we forget that in

[00:12:19] Daphna: our field,

[00:12:20] Ben: And then, and then you come back the next day.

[00:12:22] Daphna: right.

[00:12:23] Ben: It's not, you're not like an ER physician

[00:12:24] Daphna: you're like me, check the chart when you get home.

[00:12:27] Ben: Oh my God. Good. Do you want to tell the audience what you do? This,

[00:12:30] Daphna: Well, I mean, I'm just in full disclosure and transparency. I'm not, I'm not, I'm not just, uh, I'm not telling people what to do, I'm saying, I'm, I have the problem myself, so I, I empathize with

[00:12:43] Ben: we get, uh, we get texts from Daphna post a sign out,

[00:12:50] Daphna: Okay, that's a bad habit, that is a bad habit, for sure.

[00:12:54] Ben: the

[00:12:54] Ben: CBC for this baby,

[00:12:55] Daphna: because I trust my colleagues implicitly,

[00:12:59] Ben: the use of

[00:12:59] Daphna: I've [00:13:00] seen the lab,

[00:13:00] Ben: The use of emojis is very judicious. There's a lot of, uh, yeah, when, when the wide eyed, uh, emoji after the CBC, it's, uh, is a, is a common one. Uh,

[00:13:13] Daphna: I'm just saying, I, I want people to feel like they're not the only ones that suffer with boundaries around work. and that it may affect their sleep.

[00:13:25] Ben: Um, yeah, no, that is true. That is true.

[00:13:28] Daphna: I don't know about these six hour shifts you're

[00:13:30] Ben: I'm thinking about that. That's something that other fields have toyed with. Maybe to do like, you have a higher census, your shift are more taxing than you go for a, uh, You go for a shorter shift duration, some things to think about. All right. We have a lot of papers to go through.

[00:13:49] Ben: We have a new video segment this, this, this week. So, um, yeah, the paper I wanted to go over is a paper that made the rounds on Twitter. It's called the effect of nasal continuous positive [00:14:00] airway pressure. Effective nasal CPAP versus heated, humidified, high flow nasal cannula on feeding intolerance in preterm infants with respiratory distress syndrome.

[00:14:09] Ben: The enteris randomized clinical trial. First author is Francesco Cresi. It's in JAMA network open and the data is coming to us out of Italy. So hello to my friends in Italy. I'm actually planning on going actually. Yeah. I'm hoping that I'm going to make it to Italy this time around. So the background is interesting, right?

[00:14:31] Ben: The authors mentioned the known coexistence really of RDS, right? With feeding intolerance and that for neonatologist, that's, that's a big challenge. You, you talk about this in the context of noninvasive respiratory support that could affect feeding intolerance through several mechanisms, right? I mean, in, you put a baby on, on noninvasive positive pressure ventilation.

[00:14:53] Ben: for RDS. And number one, the pressurized gas flows, uh, intended for RDS is transmitted to the [00:15:00] GI tract causing gaseous distension. The famous CPAP belly, right? Second, you have the gaseous distension that makes its way all the way down into the intestines and it could generate mucosal inflammation because of cytokine release.

[00:15:15] Ben: And this is sort of what's been observed, uh, during episodes of NEC and basic science experiments. You also are providing them with oxygen, which basically this oxygen enriched air mixture can induce potentially dangerous imbalances in the intestinal microbiome, microbial flora, and the pressure induced by the, um, by the CPAP and so on could affect gastric emptying, gastroesophageal reflux, and mesenteric flow.

[00:15:42] Ben: So with all. These concerns that we are all all too familiar with the question they're asking is, are, what are the comparative effects of CPAP versus high flow nasal cannula in high risk preterm infants, uh, with respiratory distress syndrome on feeding intolerance? They called it [00:16:00] throughout the paper, the heated humidified high flow nasal cannula.

[00:16:03] Ben: I'm just going to call it high flow nasal cannula. Sorry, my friend.

[00:16:06] Daphna: Yeah. H H H H F N

[00:16:09] Ben: H, H, H, F and C. I thought it was like a typo. I'm like, oh, they added two more H's. But obviously, no, that was me. Uh, the study is a randomized clinical trial that involved infants who were born between 2018 and 2021 in one of the 13 participating NICUs across Italy. And the inclusion criteria were babies who, um, were born with a gestational age between 25 and 29 weeks, uh, who were seven days of life or less.

[00:16:37] Ben: Um, who, um, were being started on some form of enteral feeding. They were taking at least, uh, 70, less than kilo per day. And they, and babies who had RDS, how did they define RDS? Basically respiratory failure that requires some form of respiratory support. Um, and surfactant was administered according to the European guidelines for the management of [00:17:00] RDS.

[00:17:00] Ben: They excluded babies who had neurological surgical disease, sepsis, chromosomal anomalies, and major malformations. And so the intervention was interesting. So they randomized babies to either receiving nasal CPAP or high flow nasal cannula. Now the initial suggested setup for the non. invasive respiratory support was CPAP between five and seven centimeters of water or a high flow nasal cannula between four and seven liters per minute.

[00:17:29] Ben: But this had to be achieved after what they called a stabilization test. So basically in the first 48 hours, they had, uh, to basically make sure that they were not going to need like intubation or anything like that. So they had to go through 48 hours. Where their SATs were between 90 and 95, that their CO2s remained around 60 or less, that their FiO2 remained below 40%, that they had like a Silverman Anderson score for RDS, um, of, uh, six or lower, and that their apnea hypopnea index of [00:18:00] two events per hour or fewer.

[00:18:01] Ben: with C PAP or high flow cannula. So they have like all that pretty well outlined. And I thought that was pretty reasonable. And then they recorded nutritional data until they reached full enteral feeds. Now, the thing that's important is that each NICU that participated had its own protocols for the clinical management of patients enrolled in the study.

[00:18:18] Ben: And so, uh, there was no real criteria for. the management of enteral nutrition and for the management of non invasive respiratory support. The advancement of feeding was really up to the clinician, but they did set an upper limit at 30 per day, right? They didn't want to cause feeding. intolerance by, on a kid that you advanced feeds by 60 or something.

[00:18:39] Ben: The infants were bolus fed by NG or OG tubes, breastfed or bottle fed, um, based on the infant's cueing and capabilities. Now, the interruption of feeding was defined, uh, by signs of feeding intolerance from an abdominal, an abnormal abdominal exam. Um, some gastric residual volume [00:19:00] measurements, uh, either over 100% of the previous feed, bilious aspirates, bloody aspirates, and then fecal aspirates, which sounds terrifying, uh, vomits or regurgitation. Abnormal stool and other cardiorespiratory events. The primary outcome of the study is the time that it took babies to reach full enteral feeds defined as an intake of 150 per day. The secondary outcomes, uh, there was a lot of them. So there are secondary nutritional outcome, which were. The median daily enteral increments, at least the one episode of feeding interruption, uh, episode of feeding interruption lasting more than 24 hours, uh, pathological residual volume, frequent vomiting or regurgitation, abdominal distention, time to reach full oral feeding and growth.

[00:19:46] Ben: Then they had secondary respiratory outcomes, uh, which were the number of days assigned to noninvasive respiratory support. Um. The number of patients who required more invasive respiratory support, whether that was mechanical ventilation and so on. The number of patients [00:20:00] who changed group, the number of patients who were weaned from respiratory support, um, and some other stuff that you can look at the paper and and see.

[00:20:08] Ben: Uh, comorbidities occurred after randomization, um, such as neck, b p d, pneumothoraces, I, vh, sepsis, P D a, uh, r o p, and length of hospitalization. and mortality were also evaluated as secondary outcome. The study was done with an intention to treat approach considering enrolled patients until discharge. So far, so good Daphna about this.

[00:20:30] Ben: Uh, so interesting paper. I think it's a, it's a very hot topic about the use of high flow nasal cannula and CPAP. Uh, no, no, no real mention, right? I mean, I know we're talking about doing a mini series on this topic, uh, for the podcast, but no mention of the interface. Like, so we don't know. Yeah, yeah, so yeah, so that was not really specified.

[00:20:49] Ben: I haven't combed through such I got discouraged to comb through the supplemental material because I downloaded it and it's in italian and I was like, I could put it through the [00:21:00] the translation, but

[00:21:02] Daphna: would have been a real commitment

[00:21:04] Ben: I know i'm procrastinating procrastinating a little bit for this For this particular journal club, so please ap, I apologize if I didn't have time to run the, uh, supplemental material through the translation algorithm to get them in English so that I could read them, so I apologize. Um, okay, so the results of the study, 475 infants were eligible, uh, for inclusion, uh, 35.4%.

[00:21:29] Ben: 168 of them were not able to undergo the stability test, and so they were excluded. Uh, they performed the stability test, you know, this 48 hours, making sure they're okay on about. 80% of them of whom passed. So that's 247. Um, and who were randomized. So basically at the end of the day, they had 122 kids in the CPAP arm, 125 kids in the high flow nasal cannula arm.

[00:21:53] Ben: All right. So 120, 225. Um, the infant's median gestational age, uh, was 28 weeks. [00:22:00] Uh, in terms of the baseline characteristics, um, some interesting things that I noted. They were a bit more C section, 70% versus 63% in the high flow group. Um, the gestational age, the birth weight were very similar. Also interesting things about like there was no real difference in in house early the babies maybe started feeds Um how much they were taking at recruitment So like when they enrolled the kids most of them were taking like 20 to 30 So so not so much and impressive data on the percentage of kids who were exclusively fed human milk 79 in the cpap group and 80% in the high flow group.

[00:22:39] Ben: Uh, same thing for surfactant therapy, 52% in one group, 56% in the other group. And that's really it. Now in terms of the primary outcome. So the estimates of full enteral feed probability showed no difference between the two groups. And we'll post that graph on Twitter. The median time to reach full enteral feed was 14 days.[00:23:00]

[00:23:00] Ben: in the CPAP group and 14 days in the high flow nasal cannula group. When they tried to stratify this data by gestational age to see if maybe smaller kids did different things compared to older, more mature kids. Um, there was no difference. So then there's interesting data. When it comes to the secondary outcome and I'm going to go through a few things So there's no there were no difference between the two groups in the risk of having at least one episode of feeding interruption There was no difference in having at least one episode of feeding interruption lasting more than 24 hours or one episode of pathologic gastric residual volume.

[00:23:36] Ben: Um, there was also no difference in having at least three episodes of vomiting or regurgitation in a day, uh, and to have a pathologic, uh, physical exam or abdominal exam, uh, and the probability of having like, uh, at least one cardiorespiratory event. Now risk and relative risk secondary, uh, of secondary nutritional outcomes are reported in the table [00:24:00] and they didn't find any difference in the mean.

[00:24:02] Ben: daily increment, uh, of, for weight based on whether the babies were on CPAP or high flow. The mean time to reach full oral feeds was similar for both nasal CPAP and high flow group. Um, that was, uh, 49 days versus 48 days. What else can I tell you? Weight growth between randomization and time to reach full enteral feeds was similar between the two groups.

[00:24:25] Ben: And, um, let's talk a little bit about now some of the respiratory stuff, because I think that was interesting and also telling us something about how we manage RDS in the NICU. So between randomization and the time to reach full feed, 83 infants, which is about 68% of the nasal CPAP group, had, to change or discontinue their assigned.

[00:24:47] Ben: That was, uh, 76 infants or 60% in the high flow nasal cannula group. So less so, which is, which is quite interesting. Now, if you, if, when they dig further into this [00:25:00] data, what they found was that at the first change of support, 17% of the infants who were treated with CPAP compared to 23% of the kids who were treated with high flow actually required more support.

[00:25:15] Ben: So when you look at them, changing, right? The high flow group are the ones who, when they change, they were more likely to need more support, which goes back to this eternal discussion of saying, are we giving enough peep with the high flow nasal cannula? What they also noted was that the change was needed at a, at a, at a mean of 7. 3 days later in the CPAP group compared with 3. 7 days in the high flow group, which means that they failed. Sooner on high flow. Does that make sense?

[00:25:50] Ben: Um, okay, a few more things and then I can, we can call it a day for this paper. Um, how quickly did they get better? That's another interesting finding. So 58% in the [00:26:00] CPAP group versus 46% in the high flow group had improvement and discontinuation of any respiratory support within a mean duration of like five days for the CPAP group and nine days for the high flow group.

[00:26:11] Ben: The number of patients who switched due to their inability to tolerate the respiratory interface was higher in the CPAP group. compared with the high flow group.

[00:26:19] Ben: So that, that discussion about the interfaces is there in the results, but they don't really go into too much more detail. Um, a few more things. There were no difference that were observed between the groups in the frequency of BPD, ROP, sepsis, and, uh, patent ductus arteriosus between the two groups. And the length of stay was actually similar between the group 64 days versus 63. 5. Um, and obviously the big limitation of the study is that while it is randomized. Very difficult to blind clinicians to, uh, to this intervention. So the conclusions are that there's no difference in feeding intolerance between infants in the nasal CPAP and High Flow nasal cannula [00:27:00] group.

[00:27:00] Ben: Although so some short term respiratory outcomes were better. with nasal CPAP. Now, the findings, according to the authors, suggest that clinicians should tailor respiratory care by choosing and switching between the two techniques on the basis of their respiratory efficacy and patient compliance, regardless of the possible effects on feeding intolerance.

[00:27:18] Ben: So I think it dispels, right? It dispels something that we've, that we've all been concerned about, which is, is that going to cause issues with feeding if I have them on CPAP, uh, with more, better PEEP delivery and so on. Um, so very interesting paper.

[00:27:32] Daphna: Yeah. Totally agree. Um, and... Yeah, it was a, as you said, a hot topic on, on Twitter. It's just a reminder that we were discussing papers all the time on Twitter, you know?

[00:27:44] Ben: Yeah.

[00:27:45] Daphna: [00:28:00] Okay, thank you for that. I had a paper that I didn't get to last time, but I wanted to. Does growth velocity affect associations between birth weight and neurodevelopment for impr infants born very preterm.

[00:28:21] Daphna: I had practiced the names before last time. Um, the lead author, Thibaut Sertier, maybe?

[00:28:32] Ben: Table. And then,

[00:28:34] Daphna: Taboo.

[00:28:35] Ben: but I'm having a,

[00:28:37] Daphna: Was I close?

[00:28:38] Ben: yeah, and I'm having a problem. My computer, my right, my click is not working, so I can't even open the paper. I was trying not to interrupt you, but every time I click, it's giving me the left, the left click. So now I'm, I have to figure this out.

[00:28:50] Daphna: The left click. That's okay. This is coming to us from the, the Moby Dick trial group, which may be the frontrunner for, for [00:29:00] best, uh, um, acronym, study acronym for the year. We didn't pick one yet for this year. So, um, as a reminder, uh, the Moby Dick trial was the maternal omega 3 supplementation to reduce bronchopulmonary dysplasia in very preterm infants.

[00:29:22] Daphna: And um, they were looking again at DHA supplementation and did it improve bronchopulmonary uh, dysplasia. Um, okay. So this is a, like a So a secondary analysis, and they wanted to look at how neonatal growth velocity affects the association between birth, weight and neurodevelopmental outcomes in infants born preterm.

[00:29:46] Daphna: So like, can they catch up? Um, uh, even if they are small to begin with. okay. Participants [00:30:00] included in the analysis, uh, were children of mothers who again participated in the Mobic trial, who survived and who were assessed with the Bailey three at 18 to 22 months. So the outcomes they used were the neurodevelopmental outcomes, again, assessed in 18 to 22 months, um, using the Bailey Cognitive and Language Composite scores.

[00:30:20] Daphna: Um, the children were. It is assessed by, um, clinicians in the neonatal follow up program clinics, uh, affiliated with the Canadian Neonatal Follow Up Network, which is. It's an amazing network that they have, um, for these infants. Um, they used, uh, a number of parameters. They looked at the birth weight z scores.

[00:30:44] Daphna: They looked at, um, a number of measurements of birth and then longitudinally. And they calculated the neonatal growth velocity. So they were looking at the growth in grams per kilo per day using the average of the birth and the end weights in [00:31:00] kilogram. Um, and. Oh,

[00:31:04] Daphna: could you hear

[00:31:05] Ben: that, yeah, that was the thunder? Holy

[00:31:08] Daphna: Yeah. It's just a Florida, Florida afternoon here.

[00:31:13] Ben: Summer

[00:31:13] Daphna: Um, yeah, that's right. But summer lasts like six months here.

[00:31:19] Ben: Yeah.

[00:31:20] Daphna: Okay. So back to where I got. So they looked at all these birth, uh, uh, growth parameters. They looked at the birth weight, they looked at the length, they looked at, uh, um, the sex gestational age, and then they looked at basically the end. Weights and and they were looking at the growth over time.

[00:31:40] Daphna: So, um, they had 479 out of the 528 surviving children from the original cohort and 80% had available cognitive scores Um, or language scores [00:32:00] at 18 to 22 months of age. So, um, this was about 360 to 370 kids who had one or the other scores. Um, children born, now I'm going to get into the details. And I'm going to try to do that slowly because there's a lot of data here.

[00:32:19] Daphna: But children born with a birth weight Z score less than the 25th percentile were more likely to have a higher neonatal morbidity count, higher rates of bronchopulmonary dysplasia and severe IVH than their higher birth weight Z score counterparts. This makes sense. The highest growth velocity, uh, was actually observed in children born with a birth weight z score less than the 25th percentile.

[00:32:44] Daphna: And this was significantly different from that of children with birth weight between the 25th and 20, 25th to 75th percentile and, uh, the greater than 75th percentile. percentile. When we looked at the developmental outcomes, the Bayley 3 [00:33:00] cognitive score for the total sample was 97. 6 with a standard deviation of 15, which was significantly different between the three birth weight z score strata.

[00:33:10] Daphna: So they looked at children born with a birth weight z score less than 25th percentile, had a lower cognitive score, a mean score of 95. 6, important compared to 97. 6, in comparison with children of a higher birth weight z score. So there was a, it was a mean 95. 6 less. for those less than the 25th percentile.

[00:33:32] Daphna: For those in the 25th to the 75th percentile, it was 96. 8. And for those children in the greater than the 75th percentile, it was 101. 3. Um, the Bailey 3 mean language score was 88. 5 in the total sample, and there was no differences within three birth weight Z score strata. So In this initial step, they looked at your initial birth weight z score and they [00:34:00] looked at your developmental outcomes and it looks like the Bayley cognitive scores improved as your birth weight z score was higher.

[00:34:11] Daphna: And then they wanted to look at this association between growth velocity and your birth weight z score. So this is where you started out, but what was your growth velocity over time and how did that impact your neurodevelopment? So they found, they used this causal mediation, uh, mediation model, and it looked like there was a positive association between birth weight z score and Bayley 3 cognitive score, which was partially mediated by neonatal growth velocity.

[00:34:39] Daphna: And so they further analyzed this by stratifying it into the three birth weight z score categories, and they observed the strongest mediation effect of growth velocity for children born with a birth weight z score less than the 25th percentile. Thus, in the total sample, there was an increase in growth [00:35:00] velocity by one, so, sorry, an increase in growth velocity by one gram per kilo per day was associated with a 1.

[00:35:06] Daphna: 1 point benefit in the cognitive score. But when they looked at it by, um, stratified by just Uh, by the birth weight group. The benefit is three fold higher in the subgroup of children born with a birth weight z score less than the 25th percentile. Um, and they had a 3. 3 point benefit in the cognitive score.

[00:35:30] Daphna: So uh, the babies with the lowest z score that had this reasonable growth velocity um, had the greatest benefit in cognitive score. They did adjust for neonatal morbidity count, um, and the growth velocity at that time was not considered a significant mediator in the relationship between birth weight c score and cognitive.

[00:35:55] Daphna: score. Then they looked at neonatal growth velocity and [00:36:00] the association between birth weight z score and the Bayley 3 language score. And again, it showed that growth velocity partially mediates the association and the strongest mediation effect of growth velocity in the association between the birth weight z score and language was again observed in children born with a birth weight z score less than 25th.

[00:36:19] Daphna: percentile, um, such that an increase in growth velocity by one gram per kilo per day was associated with a higher language score by 1. 9 points for the total cohort, but a 4. 1 point benefit in the subgroup of children born with a birth weight z score of less than 25. percentile. Um, so the, the, the overall study takeaway is that postnatal growth, unless you had significant differences in neonatal morbidities, um, the postnatal growth velocity was able to mediate the relationship between the original birth weight z score and neurodevelopmental performance.

[00:36:59] Daphna: And the effect was [00:37:00] largest for the children with the lowest Birth weight z score. So I think I ended our last journal club saying that all hope was not lost for the growth restricted baby or the very small baby and that if we could optimize their postnatal growth that we could see improvement in neurodevelopmental outcomes.

[00:37:23] Ben: I did fix my, my mouse. It works now. So I'm, I'm, I have the paper in front of me and I think this is very interesting, right? That, that, um, an adequate, um, growth trajectory can sort of mediate the long term developmental outcome. Um,

[00:37:38] Daphna: that's not always possible, right? We know that some of these small babies have a Higher risk factors for lots of the more morbidities associated with an acute mission, but

[00:37:51] Ben: and I'm wondering if, up to what point, right? Um, if, if, if the weight gain is excessive or, or right, if, if we [00:38:00] swing to the other end, uh, would we see like a, uh, a sort of Gaussian type of distribution, normal distribution, where on the one end, if it's too, too low, you would, you would get the negative aspect of neurodegenerative outcomes and then too fast, then it might be another issue.

[00:38:13] Ben: So that's, I think this is very interesting, very interesting paper.

[00:38:16] Daphna: Yeah

[00:38:18] Ben: And the Moby Dick trial is a great acronym, great acronym. I finally find that, so I have the paper in front of me and the name of the first author is Thibault Siriez. Um, which is not an easy one to pronounce.

[00:38:31] Ben: Okay.

[00:38:31] Daphna: there, especially when you correct me on the French names.

[00:38:34] Ben: why not? Okay, Daphna, let's, uh, cue the jingle and get ready for EB neo segment. Let's go.

[00:38:44] [00:39:00]

[00:39:02] Daphna: Dr. Elizabeth Sewell, Dr. Susan Cohen, thank you so much for joining the podcast today.

[00:39:08] Susan Cohen: thank

[00:39:09] ELizabeth Sewell: It's our pleasure.

[00:39:12] Daphna: So you both collaborated on the EB Neo commentary for the article, um, interventions to Reduce Severe Brain Injury Risk in Preterm Neonates, A systematic Review and Meta-Analysis. So to get us started, for those, uh, who maybe haven't had the opportunity to review the article, um, maybe you can just begin with a summary of the

[00:39:32] ELizabeth Sewell: Sure. Um, so the PICO question for this article was among infants born less than 37 weeks gestation, which perinatal interventions compared to standard care result in a reduced risk of severe brain injury before discharge. So this was a systematic review with fixed effects pairwise meta analysis used for the data synthesis.

[00:39:55] ELizabeth Sewell: It was consisted of preterm infants with a gestational age less than [00:40:00] 37 weeks. or in term and pre terminates for whom the data could be extracted. And they used a variety of data sources, including MEDLINE and BASE and all. And they searched, um, from inception through September 8th, 2022, using pre specified search terms with no language restrictions.

[00:40:19] ELizabeth Sewell: However, they were pretty strict on their study selection, so they only included randomized clinical trials that evaluated perinatal interventions chosen beforehand and reported at least one or more of the primary outcomes. Two independent authors searched the databases, evaluated the quality of studies, and assigned a score for the certainty of evidence based on Cochrane Grade B. Approach. There were three pre specified outcomes that included severe intraventricular hemorrhage, which was defined as grade 3 or 4, cystic periventricular leukomalacia, which was defined as necrosis of the white matter near the lateral ventricles, or severe brain injury, which was [00:41:00] defined as severe intraventricular hemorrhage or cystic periventricular leukomalacia. I'll let Susan now talk about the results.

[00:41:09] Susan Cohen: Well, they were able to sort of narrow down their sample size, and so they used the fixed effects pairwise meta analysis of 221 randomized control trials, and they evaluated 44 perinatal interventions. Six of them were antenatal, six were delivery room interventions, and 32 were neonatal interventions.

[00:41:31] Susan Cohen: And what this, this real Big group of like data was sort of synthesized into certain categories where they looked at the outcome measure, the certainty of evidence, the effect size, um, the risk ratio and the, you know, and the number to treat or harm. And then they were able to identify IVH in preterm [00:42:00] infants, but really six came out to the top.

[00:42:04] Susan Cohen: And two of them were really the ones with the most amount of certainty of the evidence, which were antenatal steroids and indomethacin prophylaxis. Um, they did identify one that potentially was harmful, um, which was umbilical cord milking, but the, they want to like really stress that clinicians should carefully consider interventions in the context of the certainty of evidence, the effect size, and the clinical context of specific neonatal units.

[00:42:33] Susan Cohen: And then that further studies are needed to evaluate these interventions and include potentially neurodevelopmental outcomes as another thing to consider. Then, yeah, we, we basically then took this paper and Liz and I sort of discussed the idea that, you know, the idea of adding grade, which is the certainty of evidence. When you look at a meta analysis was really quite unique in this, this paper.[00:43:00]

[00:43:02] ELizabeth Sewell: I love this paper because I think this topic is so complex and it can be really overwhelming because this has been, you know, I feel like for years we've been trying to reduce the rate of intraventricular hemorrhage in preterm infants and it's really the rate over the last couple of decades has really been quite stagnant.

[00:43:19] ELizabeth Sewell: And so I love that this paper really was the first that I'm aware of. that really tried to be comprehensive and really rigorous in terms of the methods to try to compare this for the clinician that's in their unit, really trying to do the best they can for their unit and for individual babies. So I really, um, I really, I'm sure it took a lot of work, but I really appreciate all the effort that the authors put into this, because I really think it's going to be useful to take back to the bedside.

[00:43:50] Susan Cohen: What I thought was unique of like balancing effect size and the certainty of evidence, to me, I felt like that really, because we talk a lot about like the effect size and particularly when [00:44:00] you're in this fixed effect, uh, fixed effect meta analysis. They, um, uh, weigh larger studies, you know, where the, the number of patients included sort of like skews the sort of the analysis so that their results sort of rises to the top.

[00:44:19] Susan Cohen: But then balancing it with the certainty of evidence and the heterogeneity of the studies also kind of gave sort of a little more depth to the analysis. And for me, I feel like that's really clinically relevant.

[00:44:35] Daphna: Well, I wanted to, you highlighted two of the interventions, antenatal corticosteroids and endomethicine prophylaxis. I was just going to run down what the other big hitters were. They included umbilical cord milking, volume targeted ventilation, prophylactic Thamselate administration, um, early erythropoiesis stimulating agents and high frequency oscillatory ventilation.[00:45:00]

[00:45:00] Daphna: And so, you know, I think to your point, what you were talking about, so, um, We could have a variety of levels of certainty of evidence, a variety of effect size, and number needed to treat. Many of these interventions had a large effect size or reasonably low number needed to treat, which is excellent, but they may have low certainty of evidence.

[00:45:25] Daphna: So how do you think we should evaluate these interventions?

[00:45:31] Susan Cohen: Yeah, I think that, you know, the certainty of evidence really that, that great approach allowing us to kind of look at the methodology and weighing the, the, um, rigorousness of rigorousness, uh, and the, uh, reproducibility of the studies, uh, to me, I think it, it was something I'd never thought about before, you know, because I assumed that when they did the fix, the, the meta analyses, those kind of were.[00:46:00]

[00:46:02] Susan Cohen: Sort of removed or if they were not rigorous, but then it's even those studies that are large and done well, sometimes have sort of deviations from their original studies. And so to me, I felt like the, um, the effect size, like things like we, I think Liz and I talked about like volume targeted ventilation.

[00:46:22] Susan Cohen: We were discussing like a lot of people probably use that. And it was a little shocking that the effect size was large, but the certainty of the evidence was low. And then also like antenatal steroids, where the effect size was small, but the certainty of evidence was moderate. So it added a little texture to the interpretation.

[00:46:46] ELizabeth Sewell: Well, and I think if you're thinking about how to apply this in your unit, I think volume targeted ventilation really is standard of care for a lot of units, uh, for other reasons completely unrelated, right, to intraventricular hemorrhage. And [00:47:00] so when you think about how to apply this in your unit, you may already be doing that.

[00:47:04] ELizabeth Sewell: And so you may not get as much of a bang for your buck focusing on that intervention, um, as you may for something, um, that, that is less common in your unit.

[00:47:14] Susan Cohen: I think one of the more controversial things that I thought in this study was the Indomethacin prophylaxis. Um, there's a lot of, um, spicy feelings about that.

[00:47:24] Daphna: That's a nice way to put it, yeah. Yeah, I think

[00:47:27] Susan Cohen: And so, uh, indomethacin prophylaxis, I think is one of those things that have kind of come and gone and, and in many units, um, perhaps isn't something that we utilize. And this sort of highlighted that the evidence was actually pretty moderate to strong. Um, and the certainty of the evidence, um, may warrant a second look in a certain populations.

[00:47:56] Susan Cohen: They did. Go as far as saying that, though, we have to [00:48:00] pause and say that the neurodevelopmental outcomes were not a consideration in this study, but I think Liz actually was the one that sort of wrote about this part in the commentary about how parental opinion on hearing whether or not there's a bleed in someone's head versus their neurodevelopmental outcome may be poor and how they interpret that when they're making decisions, and we don't make any decision Only by ourselves.

[00:48:27] Susan Cohen: So the partnership of sharing this information with families and other decision makers, I think, is a very important component.

[00:48:37] ELizabeth Sewell: Yeah, I always have mixed feelings on this because I trained where we did not use in a medicine and then where I practice now we originally were and now it's, it's a pretty mixed bag. And so I think, especially when you have situations where the evidence is unclear, it's probably even more important to take it back to the bedside and ask the parents.

[00:48:56] ELizabeth Sewell: You know, and really, really talk to them about their thoughts. I think the challenge [00:49:00] is, is that this happens so quickly after delivery that, that it is hard to find the right opportunity to sit down and, and, and have these discussions. But I think it's, it's really important to get their thoughts, even if there's no benefit.

[00:49:15] ELizabeth Sewell: Or proven benefit or it's controversial for neurodevelopmental outcomes. I think if you ask parents if they had we had a medicine that had the potential to decrease the risk for hemorrhage in the brain, I think we might be surprised at what some of their answers are. And so I think. Thinking about different ways to include parental and family decision makers, even if it's not for an individual patient, but kind of gathering their opinions, um, may be really influential and may be different than what we think as providers.

[00:49:50] Daphna: that's such an important point. You know, we, we're really, as a community, working to target severe IVH. And, you know, I've found [00:50:00] that even when babies have a, quote unquote, low grade of IVH. I mean, the parents are definitively affected by this news. Um, and so I wonder if you had any tips about this shared decision making around, I think what's really important to families.

[00:50:18] Daphna: You know, we, we talk about BPD and we talk about cardiac disease, but when we talk about the brain, I mean, the parents are really trying to pay attention, right? So this, um, is a very important. feature of our care, I think, to parents, um, whether or not it, it, it changes neurodevelopmental outcomes. So any just tips on working at the bedside with shared decision making, especially for some of these interventions that still carry some risk associated with them?

[00:50:47] Susan Cohen: Yeah, well, I, you know, because I, I spent two locations in our, our NICU, both in the follow up clinic, as well as in the NICU. And I, I've tried recently to like lead with what matters [00:51:00] most. Yeah, you know, and like asking that question, right, like just leading with what matters most because sometimes I can come in with my own sort of pre concocted conversation and recognize that I missed the entire boat on what a family wants to talk about and what they're fearing and maybe whatever previous experience and also asking, like, do you have any experience with prematurity?

[00:51:26] Susan Cohen: Maybe they have a lived experience with a family member or friend and that might be an influential part of the conversation. Um, so I think that to me helps with that conversation opener. And then it leads you down the path that can really sort of partner with a family where sometimes you have to get there fast.

[00:51:47] Daphna: Mm hmm. Mm

[00:51:48] ELizabeth Sewell: So we're, we are taking a little bit of a different approach at Emory, um, and instead of trying to have these rushed conversations right after delivery, um, with the help of a community partner, [00:52:00] we have formed a parent advisory group. in a lived experience advisory group to really help, um, give us some insight from families and to help us try to rank in order of importance, which interventions we should be focusing on first.

[00:52:18] ELizabeth Sewell: With the idea that, you know, one day try to do all of them. Um, but instead of just having the neonatologist and our bedside nurses and actual clinicians making the decision, we've really tried to partner so that we can make sure that we are including that voice that is a different experience that we may not have.

[00:52:38] Susan Cohen: Oh, I love that.

[00:52:39] Daphna: Yeah, I especially, that's so important, right, uh, you know, no conversation about us without us, right? We, we have to decide, um, what, we can't do all of, most units can't do all the interventions all at once, right? Because our resources are limited, our time for educating the staff is [00:53:00] limited, so we have to pick.

[00:53:02] Daphna: Um, and so I, I think that's so valuable is, is saying what's important to families, but specifically what's important to families in our unit, in our demographic, and that may change, I think, uh, across, uh, the country. So, so I,

[00:53:17] ELizabeth Sewell: I was just going to say, I agree. I think that if you, if somebody took the same set of questions that we asked and the same interventions and did it in a different hospital and a different part of the country with a different makeup of the population, I would imagine that you would get different answers and particularly around what's already strengths and weaknesses in your individual NICUs.

[00:53:37] ELizabeth Sewell: So I think, um, I think while the framework can be applicable, I think the results may actually be quite different. Thank you.

[00:53:44] Susan Cohen: And that's why I think the authors of this paper really kind of highlight that, that the each unit has to sort of bring these pieces of information together, and the effect size, and the certainty of evidence, and then the number to treat, that kind of [00:54:00] highlights that each unit has their own characteristics that might sort of influence or nuance the way that they interpret these interventions.

[00:54:09] ELizabeth Sewell: I, I agree completely. They did such a nice job. I, I actually, we didn't, we didn't talk about this earlier, but I really love the fact that they gave both relative risk and absolute risk difference. I think that, um, I think that's hard for some people to understand, but I think having both allows you to have a better conversation with the family, um, and, and each individual infant's risk is going to be different.

[00:54:31] ELizabeth Sewell: So I really love that they did that so that we can kind of tailor the conversations. But I also think that they did a nice job Susan, like you said, of really saying, here's the evidence, but it may be applied differently. And it's really important to take those conversations and your individual unit into account.

[00:54:48] ELizabeth Sewell: So,

[00:54:49] Susan Cohen: Yeah.

[00:54:51] Daphna: So we've talked a lot about the individual interventions, um, but you guys mentioned this briefly also in the commentary. Let's talk a little bit about IVH [00:55:00] bundles. So do you think that the effects of each of these interventions are additive when we put them together?

[00:55:06] Susan Cohen: I sure hope so. I

[00:55:10] Daphna: That's

[00:55:11] Susan Cohen: sure hope so. Because, right, like, the, the additive, like, especially as units start to incorporate these small baby, like, guidelines, these small baby units with, like, a focus group of physicians and nursing staff who are kind of caring for this patient population. Um, I hope that we find ways to bundle really effective aspects.

[00:55:36] Susan Cohen: of care. Um, and I was curious because there are other things that they didn't talk about like, you know, head positioning and, and various aspects of handling, um, that perhaps maybe have things to like contributions that were not measured in the study. And maybe that's where like further studies are necessary to have that robust sort of [00:56:00] data set.

[00:56:01] ELizabeth Sewell: yeah, I mean, I'm not sure that there's been an RCT on positioning and handling. Right. And so it would have been hard for them to include that kind of given the, the study design. Um, but I, Yeah. I do think that this study, if you haven't designed an intervention bundle, and you're considering. Starting that in your unit, I think the study gives you some food for thought and some ideas about where to start, where you might get the most bang for your buck, and then depending on the situation of your individual unit, you may add pieces from here, from here or there.

[00:56:36] Susan Cohen: The one thing that I was a little bit shocked about was the ethamsylate. I had to actually look it up because I had never used it before and it's a very, um, dated study. So also recognizing that current practice may not be sort of timely for some of the things that were reported in the paper. Maybe that might be a pause for me, like, I don't know.

[00:56:58] Susan Cohen: Going and looking at the [00:57:00] evidence and suggesting that, you know, right there, they said the certainty of evidence is low, even though the effect size was moderate.

[00:57:09] Daphna: Yeah, I was surprised actually how many things are being treated with ethamsylate, which I had not heard of before, um, when I had to, to look it up. So, you know, we'll, we'll see if we start to, to see, um, more information on it in our neonatal population. Um, you guys had mentioned like, uh, head positioning, which is part of the kind of 44, um, interventions they.

[00:57:35] Daphna: We're hoping to, to look at. Um, I wonder if there's anything else on that list that surprised you, um, that didn't rise to the top. Something, things that we, uh, use as kind of dogma in the NICU, um, but didn't, didn't, was not a

[00:57:53] Susan Cohen: Yeah, it wasn't like, you know, there's a lot of discussion about the jet ventilator versus, you know, high frequency. [00:58:00] Um, you can see here that high frequency had a moderate effect, but like a low certainty of evidence. And I've had that privilege of talking to the folks in certain units that have very strong feelings about mode of ventilation.

[00:58:14] Susan Cohen: And so to me, I thought that was striking that the evidence didn't really provide, um, like firm. confirmation that those, uh, those, uh, interventions were, um, you know, IBH, um, supportive or like, you know, protective. Um, what was other, there was a few other things that I thought, like, you know, also, you know, there's a lot of discussions about hemodynamics,

[00:58:40] Daphna: Mm hmm.

[00:58:41] Susan Cohen: um, the, the value of hemodynamics and then the various, um, uh, medications and treatment of Um, blood pressure, I thought, I would have thought maybe would have risen to the top, but it didn't.

[00:58:56] ELizabeth Sewell: Yeah, I mean, I think we talked so much about that and we really [00:59:00] want there to be an easy solution and there, there just isn't there. There have definitely been. Bundles that have had a particular practice protocol for hemodynamics and for blood pressure and when they use, you know, medication to treat it and when they don't and as a whole, those, some of those bundles have have reduced, you know, the, the rate of severe brain injury and certain units.

[00:59:25] ELizabeth Sewell: But I think when you implement something as a bundle, it's really hard to know which factor in that bundle really had the biggest impact. And so I really, I really. We haven't seen a lot of conclusive evidence, unfortunately.

[00:59:41] Daphna: Well, as we're nearing the end of our time together, I wonder, um, if, if, uh, you have any last minute, uh, thoughts or take home points about the, the future of neonatal neurocritical care. Um, what, you know, what should we be looking for next?

[00:59:59] Susan Cohen: [01:00:00] Wow, that, you know, that's a big topic. Um, I do think that, you know, more focused management of, you know, neurocritical care will, uh, more and more units are implementing these neurocritical care, um, teams. Um, with bringing people with multiple expertise, um, the partnerships between neurologists and neonatologists, I think is only highlighted with the fact that there's going to be a fellowship that's board certified in the coming years.

[01:00:29] Susan Cohen: I think that's going to bring a lot of important, um, focus on that. And I bet it's going to be collaborative with the hemodynamic teams that are, are, um, that are arriving too. I think that's on the horizon. Yeah.

[01:00:44] ELizabeth Sewell: Yeah, I think I get really excited about all of the quality opportunities that exist for this, and, you know, right now, neuro NICUs are really only at certain centers, and I'm really hopeful that we are going to see some of that outreach, um, so [01:01:00] that we can see a much broader impact at some other centers across the state that may not have access to neurologists, but still want to see benefits for their patients.

[01:01:11] Daphna: Amazing. Amazing. Okay, Dr. Cohen, Dr. Sewell, thank you so much for your time and sharing your expertise on the topic.

[01:01:19] Susan Cohen: thanks for having us. This was fun.

[01:01:21] ELizabeth Sewell: Thank you.

[01:01:24]

[01:01:26] Ben: Okay. That was great. Thank you for recording that, Daphna. I appreciate you manning the fort when the clinical schedule gets in the way.

[01:01:35] Daphna: My

[01:01:36] Ben: I have, um, I have. Another paper that I, uh, found in the journal Pediatrics. So the AP journal, right?

[01:01:46] Ben: The journal called Pediatrics, and it's a paper I meant to review. It's called Early Antibiotic Use and Neonatal Outcomes Among Preterm Infants Without Infections. Um, it's first author is Weiyin Yu, and it's coming out of a group [01:02:00] in China. It's, uh, part of a collaborative called Reduction of Infection in Neonatal Intensive Care Units Using the Evidence Based Practice for Improving Quality, the RAIN EPIC trial.

[01:02:13] Ben: They're mentioning a few things in the background. Just 80% of low birth weight infants, um, or very moderate preterm infants, uh, receive early antibiotic during the first week of life. Now, what they're saying is that the study on early antibiotic use to see if maybe we should moderate our use are often, uh, suffering from confounding by indication.

[01:02:35] Ben: For trainees listening to us, confounding by indication really means that the indication for treatment. is associated with the outcome of interest. So it's making it difficult to see if the treatment itself is the cause, um, of the outcome, or if it's the indication for the treatment, that's the cause. Now, infants with true infection should ideally be thoroughly excluded, um, in order to avoid that, although this may require a detailed collection of [01:03:00] various types of neonatal infections.

[01:03:02] Ben: Now, additionally, adequate adjustment or stratification of illness is also required to minimize confounding by severity of illness. And especially when it comes to the types of antibiotics that we use as well. So the group tried to explore the correlation between the use, the duration, and the types of early antibiotics and neonatal mortality and morbidity with extensive exclusion of infection related disease.

[01:03:25] Ben: Uh, they also looked at the association of early antibiotics and late antibiotic therapy on, uh, various neonatal outcomes. So this is a secondary analysis of a prospective cohort of preterm infants initially, um, established by a cluster randomized controlled study entitled reducing infection and NICUs using evidence based practice for improving quality.

[01:03:50] Ben: It took place in 25 level three NICUs from 19 provinces across China that participated. In the study babies who were included in this [01:04:00] paper were infants who were born at less than 34 weeks of gestation and who consecutively Were admitted to these participating hospital from may 2015 to april 2018 They excluded babies who had death or discharge within seven days after birth babies who had major congenital anomalies and very importantly Infection babies who had infection related morbidities within the first seven days after birth.

[01:04:26] Ben: What does that mean? That means that babies who had a positive blood culture, who had a diagnosis of clinical sepsis, or as some others call it, culture, negative sepsis, babies who had ventilator associated pneumonia, urinary tract infections. Necrotizing enterocolitis, spontaneous intestinal perforation.

[01:04:43] Ben: All these babies were excluded. They obviously also excluded any babies that had, where there were error in the data or there was any issues with the data. What is the exposure they're looking at? Uh, early antibiotic use was defined as a dichotomous variable according to the use of IV antibiotics within the [01:05:00] first seven days after birth.

[01:05:01] Ben: Importantly, their units don't use prophylactic fluconazole. Um, so that's something that they mentioned. Another interesting thing is that The types of early antibiotics were used as a categorical exposure variable. Broad spectrum antibiotics included third generation cephalosporins, fourth generation cephalosporin, carbapenems, Piperacillin and Tazobactam, vancomycin and Linezolid.

[01:05:26] Ben: All other antibiotics were considered narrow spectrum antibiotics. Each NICU has its own site guidelines regarding the use of antibiotic. However, what's interesting is that they have no national guideline. At least they had no national guideline between 2015 and 2018 for early antibiotic use among preterm infants in China.

[01:05:46] Ben: And the Chinese national guideline of mental microbial treatment does not recommend aminoglycoside. for children. So penicillin based antibiotic plus a third generation cephalosporin were considered first line antibiotic [01:06:00] for early onset infections. The primary outcome of the study was the composite outcome of death or any one of the following comorbidities BPD ROP stage three or more PVL next stage two or more after day seven of life, late onset sepsis after day seven.

[01:06:16] Ben: So, um, What are some of the results? 21, 540 infants without infection related morbidities in the first seven days of life were included in the study.

[01:06:27] Ben: The mean gestational age was 31 weeks. The mean birth weight was 1, 623 grams. Overall, 85% of infants received early antibiotics, which is quite staggering, right? When you think about it. And I don't think not blaming the group. I think if you looked at our data, if you looked at data in many other units, 85%, especially when we're talking about babies who are born preterm, probably is not far off the mark.

[01:06:54] Ben: And the median duration of early antibiotic therapy was six days. So that's [01:07:00] That's quite impressive. Now, in terms of baseline characteristic, there's a bit of an issue with the table one, I think, because if you look at the P values, which is the last column on the right, a lot of the different, there's a lot of difference between the infants who received, um, early antibiotics versus the babies who did not receive her without having early antibiotic exposure.

[01:07:18] Ben: And the problem is that the numbers are so big thousands of babies that minimal differences are found to be very significant. So for example, The mean birth weight, uh, was. Let's see in the infants without early antibiotic, right? The mean birth weight was seventeen hundred and twenty four grams The infants with early antibiotics was sixteen hundred and five grams and that's a statistically significant difference um, there were other things like that where the antenatal steroid use 65 percent in the babies without early antibiotics 68 percent in the babies with antibiotics.

[01:07:56] Ben: That's also statistically significant So there were a bunch of differences like [01:08:00] that that, um, uh, you can, uh, take a look at in the baseline characteristic. Now, in terms of the primary outcomes, um, 23. 2% of the infants developed a composite outcome of, uh, with early antibiotic use compared with only 16. 4% in the infants without early antibiotic use.

[01:08:21] Ben: Early antibiotic use was not independently associated with the composite outcome, death or individual morbidity, except for increased BPD. So they basically had a forest plot. And if you look, the primary outcome again, as, as you may have, you may recall was defined as the composite outcome of death or any one of like major neonatal morbidity.

[01:08:42] Ben: And so when they did the forest plots using various, uh, model using the crude data and two different models, the only model where Um, it, it reached significance was the one with BPD model one adjusted for perinatal baseline characteristic, as I mentioned, to try to account for some of these [01:09:00] differences and model two adjusted for illness severity infants with early antibiotics had 4. 6 times the odds of receiving late antibiotics than those without early antibiotic exposure. A total of 3, 617% received 1 to 4 days of antibiotics and 68% received 5 to 7 days of for early antibiotics. Now the limited duration of early antibiotics was not independently associated with the composite outcome of death or any individual morbidity.

[01:09:37] Ben: What's interesting is that prolonged duration was associated with increased risk of BPD but decreased risk of NEC in their, in their data. One more note that I took, there was no significant association between early antibiotic exposure and the composite outcome of death, uh, in three different gestational age group when they looked at it from the gestational standpoint. So the conclusion [01:10:00] are that among infants without infection related morbidities.

[01:10:03] Ben: So in babies that don't have positive blood culture and so on and so forth, early antibiotic use is independently associated with an increased risk of BPD and late antibiotic use. Judicious early antibiotic use, especially avoiding prolonged and broad spectrum antibiotic use. among non critical infants may improve neonatal outcome and exhibit significant impact on overall antibiotic use in the NICU.

[01:10:26] Ben: What's overall very interesting to me is one of the things that they do mention in their discussion, which is that antimicrobial stewardship on early antibiotics may not just reduce antimicrobial prescription during the first week, but because this idea that they have less use of antibiotic later on in the admission may actually be a sign that you're reducing antibiotic use during the whole hospitalization.

[01:10:45] Ben: I think that was an interesting observation, but a very interesting paper nonetheless. And I'm curious to hear what you're, what you think about that.

[01:10:52] Daphna: this discussion between Antibiotics and neck. I thought they had some interesting findings [01:11:00]

[01:11:00] Ben: Yeah.

[01:11:00] Daphna: but, and I, I think, uh, it is a good reminder about using the broad or narrow spectrum. I think, especially for those babies that we treat, this culture negative business where we don't really know what we're treating, and some of them stay on broad spectrum antibiotics for a long time.

[01:11:20] Daphna: We really have to like, commit to something,

[01:11:22] Ben: Yeah. I think the broad spectrum discussion is something that's going to be difficult because obviously they have specific guidelines that they're following over there in China that may not apply to us in the U S but I think the antibiotics are the same and our approach to antibiotics is the same.

[01:11:35] Ben: And I think without talking about the disturbance that these antibiotics create, especially when without, without having sepsis or anything like that. Um, It does set the baby up for issues down the road. So that's, I think that's very interesting. Do we have time for one more?

[01:11:53] Daphna: Not really.

[01:11:54] Ben: Can I do one more?

[01:11:56] Daphna: Sure.

[01:11:57] Ben: Because I postponed this

[01:11:58] Daphna: Alright, just squeeze it in. [01:12:00] Let's go. Come

[01:12:00] Ben: Let's go quickly. You're going to like this one. Characteristics, genetic testing, and diagnoses of infants with neonatal encephalopathy not due to hypoxic ischemic encephalopathy. A cohort study. First author is Arthur Lenahan. in the Journal of, in the Journal of, in Journal of Pediatrics. I'm going to skip the discussion, the background, I'm sorry, um, but the bottom line is that a baby that presents with neonatal encephalopathy does not automatically have HIE.

[01:12:26] Ben: And for the babies who do not have HIE, how What are the etiologies for this encephalopathy that we're noticing in the NICU that could be explained? And we do have the availability now to send exome sequencing, genome sequencing, rapid, with rapid early diagnosis. Um, and so they wanted to see. What are the clinical presentation, the type of genetic tests that are being sent and the genetic findings during initial post evaluation of infants with non HIE neonatal encephalopathy [01:13:00] admitted to a level 4 NICU.

[01:13:02] Ben: This is a retrospective study of infants who were born after 35 weeks of gestation and admitted to Seattle Children's Hospital NICU between 2015 and 2019. They included babies who met the diagnostic criteria for encephalopathy, meaning seizures, an abnormal neuro exam, an abnormal tone, apnea, abnormal movement, and, um, or dysphagia not attributed to respiratory distress or anatomic impediment.

[01:13:26] Ben: Now, they had to exclude babies who met the criteria for HIE, and so they did that by excluding babies with documentation of two or more of the following variables commonly cited in previously published literature about HIE, which include the documentation of a senile event around the time of birth, metabolic acidosis at birth identified on umbilical or initial blood gas, and or abnormal neurological examination.

[01:13:49] Ben: Infants with brain malformation and other congenital abnormalities. were included and the genetic tests that they looked at were classified as three possible categories, either [01:14:00] chromosomal, like a karyotype or microarray, they had targeted testing, like you sent for a single gene or a panel of genes or maybe methylation studies.

[01:14:09] Ben: And then finally, you had exome sequencing. , the testing modalities were not mutually exclusive. You could send, you can send both on, on the single patient, um, as often they received multiple types of tests.

[01:14:20] Ben: So, because you told me I had to go quick miss, I'm going to go quick on the results. Um.

[01:14:26] Daphna: see if you can do it.

[01:14:28] Ben: Let's see, 2,273 infants were admitted to the nicu, 18% of which presented with encephalopathy. I always like to look at this incidence. 18%. Seattle has a big center. It's a, it's a center of excellence. 18% is, is a large number.

[01:14:43] Ben: It's, and it makes you put in per, not. Not that they're not taking good care of their babies and that they have encephalopathy, but I'm saying it's, it's, it's a, it's a, it's a large right. It, it's a lot, a lot of babies that we do take care of have symptoms of encephalopathy, cuz I think this may be representative of other institutions.

[01:14:59] Ben: Um, [01:15:00] 53% were diagnosed with h i e and 47% were diagnosed with non h i e neonatal encephalopathy. And included in the study that represented 193 infants, a total. A total of 122 genetic tests were sent

[01:15:19] Ben: how many tests? Resulted in a diagnostic result. Well, 10% of chromosome tests resulted in a diagnosis 41% for targeted tests and 69% for exome sequencing. So exome sequencing is a pretty, pretty, uh, you know, just, uh, Puts an end to a lot of the discussion. The median number of tests that were sent per infant was one, um, 16 different genetic ideologies were identified.

[01:15:49] Ben: Um, they have a list there. I'm going to skip that, but the most common genetic ideologies were KC N Q2 related epilepsy. In three patients, 22Q11 spectrum disorder [01:16:00] in two patients, and Prader Willi syndrome in two patients.

[01:16:04] Ben: Interestingly enough, they got like a few of these variants of unknown significance that were identified in 21% of the chromosomal test and 25% for exome sequencing. And what they did is that when they reanalyzed the four variants of unknown significance identified by exome sequencing, It revealed, um, that one is now considered pathogenic and consistent with the clinical presentation.

[01:16:28] Ben: And so if you include the diagnosis established by the reanalysis of these variants of of non significance, the overall diagnostic rate of exome sequencing for non HIE encephalopathy, was 75%. The proportion of patients admitted for non HIE NE per year remained stable throughout the duration of the of the study, and it continued to represent between 7 to 10% of all admissions, which is not again something to overlook. The proportion of infants with any genetic testing sent did not significantly change [01:17:00] over time. So maybe we need to learn about this particular finding and do something about that. But when they looked at the numbers of babies who did get exome sequencing over time, that increased from 6% to 36%. So it seems like the availability and our threshold for sending exomes is, um, lowered over time.

[01:17:21] Ben: And we're actually more comfortable with sending a test for exome sequencing. A few more interesting findings and patients with the genetic diagnosis as inpatient were significantly more likely to have a palliative care consult than those with non diagnostic genetic testing or no testing. So getting that information during the time of hospitalization was actually quite beneficial in order to start setting these services up . Death rates for patients who had diagnostic genetic testing, non diagnostic testing and no testing were similar.

[01:17:53] Ben: Infants who did not undergo genetic testing died at a younger age than those who did. And often before the time at which [01:18:00] genetic testing was typically. sent. Um, the conclusion of the study is that for infants with non HIE encephalopathy, they have a high rate of morbidity and mortality, and they may benefit from early genetic testing, even in the absence of other exam findings.

[01:18:18] Ben: The study broadens our knowledge of the genetic conditions that underlie the non HIE encephalopathy, which may enable family and the care team To better anticipate the needs of individual infants, allow early initiation of targeted therapies, and finally facilitate informed decisions about goals of care.

[01:18:36] Ben: I think as they mentioned, future studies are obviously needed on this topic. All right. I did. I went quick. Huh? You, you,

[01:18:43] Daphna: No, that was pretty good. I, I think I was surprised at the proportion of non HIE encephalopathy. That was one. Um, and I think you, that's such a reminder that like if things aren't totally adding up that you should be [01:19:00] expanding the differential.

[01:19:02] Daphna: Um, and that we, we are, the, our ability to do this testing is just like.

[01:19:10] Daphna: growing exponentially and we just have to,

[01:19:13] Ben: Take advantage

[01:19:13] Daphna: to demand it from our institutions and we have to use it.

[01:19:17] Ben: That's right. Okay, buddy. We went over time, but thank you for allowing me to squeeze that paper in. Appreciate that.

[01:19:26] Ben: And I will see you, uh, see you, see you later. Take care.

[01:19:30] [01:20:00]