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#056 - Journal Club 27

NICU journal club the incubator podcast

Hello Friends 🫠

It has been a long week at the incubator... Daphna and I have both been on service and otherwise busy with the launch of the Neonatal Network (N2). This meant another late night recording 😵‍💫. But the papers this week were so interesting that we had a great time discussing this latest evidence. We reviewed the recently published article in the New England Journal of Medicine describing how using high flow nasal cannula during an intubation attempt could significantly increase the success rates of a first attempt. Daphna reviewed a paper from the Journal of Pediatrics that thoroughly reviewed the impact of oxygenation factors on the development of ROP in preterm infants. Some interesting data there. We also reviewed a JAMA Peds article from China 🇨🇳 that compared the use of nasal CPAP vs nasal IMV and nasal high frequency ventilation. This is something we are still no very familiar with so it was interesting to see how it compares to other modalities we are familiar with. We referenced a blog post from our friend Michael Narvey on nHFO that you can check out here: We also reviewed an article from Holland 🇳🇱 comparing open bay nicu setup and single room on short term morbidity and mortality. Finally, one last paper from Australia 🇦🇺 / New Zealand 🇳🇿 looking at the collective use of non invasive ventilation in term infants.... some very interesting findings.

We hope you enjoy this episode!

Cheers ✌️


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

Nasal High-Flow Therapy during Neonatal Endotracheal Intubation. Hodgson KA, Owen LS, Kamlin COF, Roberts CT, Newman SE, Francis KL, Donath SM, Davis PG, Manley BJ.N Engl J Med. 2022 Apr 28;386(17):1627-1637. doi: 10.1056/NEJMoa2116735.

Oxygenation Factors Associated with Retinopathy of Prematurity in Infants of Extremely Low Birth Weight.Srivatsa B, Hagan JL, Clark RH, Kupke KG.J Pediatr. 2022 Aug;247:46-52.e4. doi: 10.1016/j.jpeds.2022.03.057. Epub 2022 Apr 12.

Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation as Postextubation Support for Preterm Neonates in China: A Randomized Clinical Trial. Zhu X, Qi H, Feng Z, Shi Y, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group.JAMA Pediatr. 2022 Jun 1;176(6):551-559. doi: 10.1001/jamapediatrics.2022.0710.

Jansen S, Berkhout RJM, Te Pas AB, Steggerda SJ, de Vries LS, Schalij-Delfos N, van der Hoeven A, Lopriore E, Bekker V.Arch Dis Child Fetal Neonatal Ed. 2022 Nov;107(6):611-616. doi: 10.1136/archdischild-2021-323310. Epub 2022 Apr 20.

Trends in the use of non-invasive respiratory support for term infants in tertiary neonatal units in Australia and New Zealand. Manley BJ, Buckmaster AG, Travadi J, Owen LS, Roberts CT, Wright IMR, Davis PG, Arnolda G; and the Australian and New Zealand Neonatal network (ANZNN).Arch Dis Child Fetal Neonatal Ed. 2022 Nov;107(6):572-576. doi: 10.1136/archdischild-2021-323581. Epub 2022 Apr 11.


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

Ben 0:58

Welcome. Hello, everybody. Welcome back to the podcast. It's Journal Club Sunday, Daphna. How are you?

Daphna 1:05

I'm good. I'm good. We've got some neat articles.

Ben 1:09

We've got some neat articles, we have some I wanted to shares. I wanted to share some of the news with the audience of the fact that it appears as if we are going to be able to offer CME credits for the podcast. So stay tuned. We will, we're basically approved by the university. And we just have to figure out a way to dispense those CME credits. We're not sure yet how it's going to work, whether you're going to text a number, a number to a phone number, and or if you're going to just go online, I'm not sure. Well, if we're figuring it all

Daphna 1:44

figured out. One way, one way or another.

Ben 1:49

Yeah. We're going to have more giveaways coming up this week on your neural network, I think we're gonna start giving out some licenses to GraphPad prism, which is a statistical software, which is kind of nice. So if you haven't yet logged in or registered, the time is now.

Daphna 2:10

I mean, a lot of people registered in the first week, but people are being shy, I think.

Ben 2:17

I think that's fine. The grant applications for research are coming up June 1. So stay tuned. We're also working on providing IRB support. I actually put a poll this week this morning, on the network, not this morning, I guess, because this is airing on Sunday. But I put in a poll asking people whether that was something they were interested in, because I feel like this is something that often comes into way if you're at a smaller institution. So we'll see.

Daphna 2:46

We're just trying to get people what they need.

Ben 2:49

Yeah, I mean, that's the goal slowly, but surely, we want to become the place where if you need anything for research purposes, we're going to be able to provide it and we're starting off with statistical support library management, and grant support. Okay, so let's begin.

Daphna 3:07

My, the, my chief at the division always used to say that if, if we don't begin, however, will we finish?

Ben 3:18

That's correct. Right. That's what what's his name? Jimmy Turner always says right? So start by starting step by step. Okay, so the first paper we should be talking about today is published in the New England Journal of Medicine. It's been the talk of the town. It's called nasal High Flow therapy during neonatal endotracheal intubation. first author is Kate Hudson Hudson. And the last author is Brett Manley, who's a Twitter friend of ours, that data is coming from Melbourne, Australia. They're very prolific over there. And you know, he's Australians, they're setting the pace. So what is I thought the background for this study was very interesting, right? They're saying the rates of successful intubation on the first attempt are low. And they're reporting data suggesting that it's about like 50% success. And they're even quoting some reports saying that the success rate on the first attempt is less than 25%. Their data from the lead site in the study showed that success rate of about 30% on the first attempt, so they're really painting a picture where there's really something that needs to be done. And beyond the success rate, they were talking about the fact that the duration of an intubation is often longer than what is usually recommended. And the final point that they're making, which I think is very interesting, and it's something that we've talked with one of our upcoming guests, is the fact that we're doing less and less intubations. And so as we are doing less Have these procedures, and we need to be just as successful. We need to put the circumstances and the contexts to succeed on the first attempt.

Daphna 5:11

Yeah, and I mean, the data is really clear that level of training and number of opportunities makes a difference in terms of successful first attempts.

Ben 5:23

Absolutely. And I feel almost fortunate that I was training in the era where we suctioned endotracheal suction on every meconium delivery almost, that got me like a ton of intubation. So, that's no longer there, and we're better at preventing self extubation. So, so the question the paper was asking was, what if we started using high flow nasal cannula so you would put like the the cannula on the baby's nose during the intubation to provide supportive humidified descending airway pressure? And that's a very interesting idea, right? I mean, you may have done this before, right. If you have a baby that's on high flow that's not doing well. You're about to intubate. Many times people will just leave the cannula in, right. I also know of friends of mine at Columbia Presbyterian where they use to Jerry Rig, like an inlet of oxygen or have oxygen flow to the blade so that as they're intubating, they're providing some flow. So yeah, I mean, this, I'm saying all these things to say that this is an idea that's been out there. So it's it's kind of nice that this is finally getting studied. Yeah, yeah. So the data comes from two centers, the Royal Women's Hospital and Monash Children's Hospital in Australia. It's a randomized controlled trial comparing High Flow nasal cannula versus no support during endotracheal intubation. They included any infants undergoing endotracheal intubation in the delivery room or in the NICU. They excluded babies who underwent nasal intubation, babies who had heart rates below 120 beats per minute. Immediate mean, heart rate below 120 Like immediately before, randomization obviously, meaning if they had like some hemodynamic instability, any contraindication to high flow nasal cannula such as like Congenital Diaphragmatic Hernia and nasal anomalies. If the baby's had any sciatic heart disease, or if there was any suspected suspicion of COVID-19, in either the baby or the mother, which feels like almost everybody these days, randomization happened before the first intubation attempt. There's some important design information that I wanted to highlight in this study, because I think that the they thought carefully about it, and I think we should commend them for that. So the pre intubation FIU to the use of preoxygenation the use of video laryngoscopy, the commencement duration, and termination of the intubation, all that stuff was left to the discretion of the clinician or the provider leading the procedure. Except for deliveries that happened in the delivery room or other innovations were pre medicated with atropine, fentanyl and suxamethonium. I mean, I don't know I usually say sucks. And that was standard practice at both centers. The high flow nasal cannula, it was applied prior to the intubation. It's not really taped, taped to the face and the flow was set was set at eight liters per minute. So that's, you can have a discussion about that. That's a lot of flow. And yeah, but anyway, there's very good videos on the on the site on the New England Journal medicine, New England Journal of Medicine website, that you can actually see how the procedure was done. The FY two was set at the concentration being delivered before laryngoscopy and was increased to 100% if the O two sets fell below 90%. So something that I don't think is unreasonable, but something that is not common practice I believe. At the end of the successful intubation, hydrotherapy was discontinued. So far, so good. Okay, good. So what was the primary outcome of this study? The primary outcome was successful intubation on the first attempt without physiological instability in the infant that has a lot of words in it. So what did they define as an intubation? The intubation is the an intubation attempt was defined as the insertion of the laryngoscope blade beyond the infant's lips until its removal from the infant's mouth. So as soon as you put that blade in, it's it counts.

Daphna 9:50

But that's different than how many times you put the tube in.

Ben 9:53

I know but that's why that's why I wanted to clarify right because you may think you just look and then until you try to pass the tube that's not No, as soon as the laryngoscope blade gets into the baby's mouth, the first attempt has begun, which I think is good, right because she makes a successful intubation was defined as the completion of the intubation attempt with correct placement of the ET tube, as confirmed by the detection of expired carbon dioxide with a colorimetric detector so like the the color change thing that goes from purple to yellow sorry about that physiologic instability was defined as the saturation with an absolute decrease in oxygen saturation of more than 20% from the immediate pre laryngoscopy baseline for any duration, or bradycardia, defined as a heart rate of less than 100 beats per minute during the first intubation attempt. So I thought they were they were very, very good at defining secondary outcomes included median oxygen saturation during the intubation, the time to the time to and duration of the desaturation the duration and the number of intubation attempts, some pre specified adverse events that included cardiac compressions epinephrine, pneumothoraces, and so on. They wanted to detect a, an improvement in successful in intubation, without instability from 30 to 50%, with a 90% power, so that requires about 123 intubation. And the thing that was important to know is that this was done the primary analysis was done as an end on an intention to treat analysis. Right once randomized, always analyzed. That's the way I remember intention to treat. Yeah, like that. Okay, so what were the results, so they enrolled patients from November 2018 to April 2021. The final number of patients that they enrolled was 202 Elephants making up 251 integrations. There was 124 integrations in the high flow group 127. In the control, the median postmenstrual, age was about 28 weeks, the median weight was 920 grams, and the median age at randomization was 10 hours. So for the primary outcome, successful intubation on the first attempt without physiologic instability in the infant was achieved in 50%. In the high flow nasal cannula group, compared to 31.5% in the standard care group, confidence interval six to 29, the number needed to treat was six. So that's that's, that's, you know, that's pretty impressive results. The secondary outcomes,

Daphna 12:33

it's, it's less than the number needed to treat for like therapeutic hypothermia. That's

Ben 12:38

something Yep. The secondary outcomes the median oxygen saturation during the first intubation attempt was 93.5% in the high flow group, compared to 88.5 in the standard group. This following results I'm about to say is not statistically significant, but was interesting among the infants with an episode of oxygen saturation, the mean time to the saturation was longer in the high flow nasal cannula group 44 seconds, compared to the standard group 35 seconds, which means that when you had the high flow even if you had to reach the saturation that would take longer, so it buys you more time. But that was not statistically significant confidence interval went from like 0.2 to 17. The median number of intubation attempt during the median salary the median number of intubation attempts, the duration of the first and any subsequent intubation attempts, the percentage of intubations that were, so fatal intubation and the percentage of intubation in which a serious adverse event occurred, were all similar between the two groups. So the conclusion of the paper is that the use of high flow therapy during oral endotracheal intubation led to a greater likelihood of successful intubation on the first attempt without physiologic instability. Now, I think this is a very, very interesting paper, as we've mentioned earlier, I think to me, as neonatology fellows get less and less experienced intubating neonates and not not their fault, we're just much better when we're no longer performing these routine endotracheal suctioning in meconium aspiration. We're much better at managing babies. I'm not an invasive ventilation. We'll actually talk about that later in the show. And then you have all these other things, right? We have Lisa, we have salsa, we have all these other new methods of delivering surfactant that used to be done through an ET tube that now no longer requiring the tube. I think in this context, it's important to me that this study shows a way to create a protocol around intubation that leads to a very safe and successful procedure. And I think I think practices are going to change right away. I think this is a paper that you use, and you change your practices. Now. I think there's still going to be some some cocky egotistic people maybe like myself, we're going to say I got it. I got the first intubation, but I still think that All protocols should be adjusted based on this paper. What What were your thoughts?

Daphna 15:05

Yeah, I mean, what's the downside? Right. So. So if you can't see downside, and may and maybe people will report back to us with the downside is then, then I think you should do I think you should do it. I think we owe it to babies to give them the best first attempt every time.

Ben 15:27

Yeah. So I think the downside is, like I said, if you have a baby that you recently that you're that is on high, I mean, my, my thought processes, how much time to set up the hybrid? Sure, it's emergent. So you usually ask your therapist, hey, we're going to set up for intubation, get the tube, get this, get that. But if the baby is not already on high flow, you also have to set up the high flow that takes more time, the logistics of the whole procedure may be an issue. But I do feel like if the baby has the high flow on or if the cannulas are there, that's that's, that's a no brainer. Yeah, the question then becomes if you're delivering bubble CPAP, through some prongs, to you switch to high flow for the procedure, or you just leave the bubble CPAP on my my thought would be just leave it on, don't switch it right. Especially if they're like OptiFLOW, or RAM cannula, where you have some leaks anyway,

Daphna 16:22

it's interesting that they chose high flow over CPAP. Because there are so many babies say the RDS baby the late preterm, or who is potentially likely to need an intubation for surfactant, maybe in and out serve. Who's already on CPAP. So I don't know, maybe that's the next iteration. The next group of babies.

Ben 16:46

Right, right, I think, yep. I think, to me, the fact that they're using eight liters of high flow, I wouldn't say it's right. And and we could have a discussion about how much flow is equivalent to CPAP. The bottom line is that it's very variable. But eight liters is a yes. It's a shitload of.

Daphna 17:07

Yeah. And I mean, depending on your interface, it may be more flow than the feedback. So yeah,

Ben 17:14

I really liked this paper. They have great videos. I think it's important for articles and journals to include more media in their papers. I think enough with just words like, like Dr. Jensen said, popping pictures and figures and graphs, like, like, most of these papers are no longer getting printed, right? I mean, most of the stuff is being done online. So there's no, there's no, it's no real estate issue. They're just like, just give us more. But yeah, that's it.

Daphna 17:44

Okay. I like that. Well, I guess in the respiratory vein. I wanted to review this paper from the Journal of Pediatrics, oxygenation, factors associated with retinopathy of prematurity and extremely low birth weight infants, lead author Bharath through Bazza, and this is coming to us from Atlanta, Georgia. So what's the question? They really wanted to study characteristics of oxygenation in the first two postnatal months, and the correlation of those features with the occurrence and severity of retinopathy of prematurity. So, why does it matter? Right, so we just had on the board review podcast, retinopathy of prematurity, and there's still lots of things we don't understand about retinopathy of prematurity, we know it has something to do with high oxygen, but really, when, when, when and how much is still up for discussion and for study. So this study is actually part of another study where they described an oxygen monitoring strategy to look at basically, episodes of hyperoxia, hypo toxemia. And then looking at was it hyperoxia? Maybe because the babies were in ambient air 21% And they were high setting, or was it hypoxemia? Because we were giving them too much supplemental oxygen. They also were studying something called the titration index, which really looked at basically how often were the nurses titrating the oxygen to follow the baby. And so this is part of that study, looking really specifically at the ROP outcomes.

Ben 19:41

And was it right if I remember correctly, hyperoxia was like if you were setting above 95

Daphna 19:47

Yeah, that's exactly right. So hypoxemia was defined as above 95% And then again, either ambient air or I intragenic which means you were getting supplemental oxygen and hypo hypoxemia was below 90%. And then they classified hypoxemia as mild 85 89%, moderate 80 to 84% and severe below 80%, which I felt was appropriate. So this was a retrospective observational study. So basically what they did is they analyze simultaneous FII oh two and auctions and chasse raishin data at one minute intervals while babies were on a ventilator on CPAP or on high flow nasal cannula above two liters per minute. And then they took the raw data and they looked at these measures of oxygen lability. So they looked like I said, hyperoxia hypoxemia. The swings between hyper and hypo hypoxemia. And those are measures of the oxygen lability as they called it, and then they looked at the titration index, again, was a measure of oxygen titration performed by the bedside nurse. Well, staff, I guess anybody could have been titrating at that time. inclusion criteria, extremely low birth weight infants, so babies less than 1000 grams, born between January 2016 and December 2020, and admitted to this level three NICU, who had this oxygenation data for at least 45 of the first 60 days were eligible. Babies excluded were those who lacked fit data, who had FAO two data available for less than 45 days, or those babies who did not survive two eye examination. And then the primary outcome was development of ROP. So mild ROP was stage one and stage two and did not require treatment. Severe ROP was eventually developed stage three ROP, who may or may not have required treatment and in this cohort, they didn't have any stage four or stage five which as you'll recall, are partial or complete retinal detachments, so that's good. So their baseline characteristics so they had 101 infants who met the study inclusion criteria 53 of whom did not develop ROP 33 Develop mild ROP and 17 developed severe ROP, there were six infants treated with either Bevacizumab or laser therapy. And the groups did demonstrate significant differences in several respects. And this is pretty consistent with other literature severe O P was associated with a lower birth weight, a lower gestational age of birth, a lower percentage of black infants a higher percentage of weight events, a higher percentage of Hispanic ethnicity, a lower five minute Apgar score and hold

Ben 22:43

on hold on what is what is that about the ethnicity feels like you You named everybody?

Daphna 22:48

I guess.

Ben 22:50

Okay, severe ROP

Daphna 22:51

as compared to not having ROP. Okay. That's the comparison. So there were they were less babies who were black and Hispanic who developed severe OPI more babies. Right? Okay, you got it you with me? Okay, yeah. Lower five minute Apgar score and a higher number of ventilator days. Okay, primary outcomes. So the daily mean fit percentages were significantly higher for those patients with severe ROP compared to those without ROP, which is not surprising. They also looked at FAO two measurements over time. So the mean f IoT percentage fell for all three groups during the first five days, rose to peak at nine to 17 days, then gradually fell over the next several weeks. The mean oxygen saturation fell from a peak at four to five days to a Nadir and 19 to 2060s and gradually rose to a second peak at 55 to 58 days. Which is interesting because that's kind of what it feels like in the unit. The unadjusted daily mean titration index. So again, how often were people titrating the FY oh two at bedside were significantly higher for patients in both the mild and the severe ROP groups compared with a group without ROP. And they were, again, significantly higher for patients in the group of severe ROP compared with a group without ROP. Patients in the severe ROP group had a significantly lower mean percentage of time in ambient air hypoxemia compared with patients in the group without ROP, so they were less likely to have hyperoxia Without supplemental oxygen. I mean just a daily mean percentage of time and I estrogenic hypoxemia meaning they were getting supplemental fit that put them in that greater than 95% range. significantly higher for patients in the severe ROP group compared with those without ROP. And overall patients in the severe opioid group had significantly higher daily hypoxemia index means over time compared with those without ROP. In addition, patients with severe ROP had significantly more hypo hypoxemic episodes over time than patients without ROP and the number of hypoxemic episodes increased steadily over the first few weeks peaking at three weeks for the group without ROP and the group with mild ROP, peaking at four to five weeks for the group of severe Opie and then gradually fell for all groups. The adjusted daily mean percentage of time in mild hypoxemia was significantly higher. For patients with severe ROP than those without ROP. The mean percentage of time in moderate hypoxemia was significantly higher for patients with severe O P compared to those without ROP and the daily mean percentage of time and severe hypoxemia. So the lowest group significant also significantly higher for patients with severe Opie. Interestingly, there were no statistically significant differences in the number of rapid hypoxemia to hypoxemia. Or vice versa swings between the three groups, which is actually something that people question is Is it the frequency of kind of the volatility variability of our oxygen saturation? So the study takeaways are really that infants with severe OPI were exposed to higher levels of fit during the first five weeks of birth they tended to be smaller and more premature and sicker from a respiratory standpoint. ambient air and eye intragenic hyper toxemia were commonly observed and ambient air exposure to ambient air hypoxemia was negatively associated with you severe ROP but I estrogenic hypoxemia was positively associated with severe ROP and then severe ROP was associated with an increased duration and number of episodes of hypoxemia. So, I mean, nothing was surprising about this. But I it was interesting, you know, people ask that question all the time, specifically about babies who are high satting. But who are on Ambien air. So it was, I think, an insurance an interesting paper to address specifically that question.

Ben 27:30

Yeah, I this paper I thought it was going to be a doozy right? I was like, alright, it's going to tell us the same thing. If you with the kids who are deciding more often they're going to have more ROP, they're gonna require morose etc. First of all, the graphs at the end are pretty much because we often are told and taught right that the babies have these very high setting periods in the first week of life. And after the seventh it starts going down. So they've basically plotted the SATs and the f5 to have all these kids, the babies 60 days. So you can even if you're not interested, like there, there's a trend in how saturations

Daphna 28:12

behave. So you can basically predict, you know what, yeah,

Ben 28:17

I mean, for most babies, if you're giving a talk about like, how does the auto sad behaves in preterm infants, I think these are great graphs to pull for your presentation. The thing that was killing me was, I was reading through the paper and I thought, Alright, so this is a case for automatic adjustment of fit to you. You just that's the whole point, right? You if they need, if they need the O's to maintain saturation within range, then then they may get ROP and that sucks. But on the other hand, they cannot die. So that's it. But the thing that killed me was if you look back, you mentioned that the babies who had more ROP had more frequent FIU titration adjustments. And I was like, What is that supposed to mean? Because then that means that the automatic fit adjustment, as it makes these adjustments continuously. Is that one of the reasons why we're gonna not see that much of an improvement in rates of ROP or survival? I don't know. I thought that was that was very interesting.

Daphna 29:21

I think the one thing that they weren't not able to capture, and maybe they do in the other papers, but what does titration look like? Right? So when the baby's down, and you jack them up to 100. And then they sit there for a while and then you're like, Oh, I'll bring it back down a few time or? Okay, I'll put the baby right back to where they were. So, you know, I think there's so much variability and what does titration mean? And how, you know, are we How often do we overshoot on titration which is like a lot, a lot and so, I still think there's definitely a place for Where this automated oxygen nation? closed loop system. So,

Ben 30:06

all right. Okay, it's,

Daphna 30:10

we've done I know we did two papers.

Ben 30:12

Alright, so I'm going next to Jama peds. This is a paper that caught also some attention on Twitter. It's called non invasive high frequency oscillatory ventilation versus nasal continuous positive airway pressure versus nasal intermittent positive pressure ventilation, as post extubation support for preterm neonates in China. A randomized clinical trial.

Daphna 30:34

A mouthful. Yeah, I mean, yeah. But you need to know what the paper is about.

Ben 30:40

I think you've got the conclusion right there. You know, it's a bit like when you watch the trailer for the movies, and it's the whole story.

Daphna 30:47

All the good stuff is in the

Ben 30:50

first author is Jing Wang Zhu. From the nasal isolation post extubation study group than a zone group. It's out of China said it's the chocolate piece. So nasal highfrequency. If you're like me, it's still very much of a foreign concept. I have never used nasal highfrequency. I want to give a shout out to our friend Michael nervy, who had written a blog post in 2015. That I had to like, dig back up, where he talks about these are high frequency and so you should we'll link that in the show. And you can you can take a look. The question that the group asked was, in preterm infants with nasal high frequency be more efficacious than nasal CPAP or nasal IMV, in reducing the need for reintegration after extubation or until NICU discharge. So they conducted this multicenter study in 69 tertiary referral NICUs. In China, they looked at babies with a gestational age between 25 and 32 and six weeks the neonates neonates received any form of IMV. And they had to be a post conceptual age younger than 36 weeks. The last inclusion criteria was whether they met an extubation readiness criteria and those that was defined in the paper. So the extubation readiness criteria for this group was that the infant had received loading and maintenance dose of caffeine so that they were optimized, they had a pH of 7.2, or greater a ph co2 of 60, or lower on an ABG or a CBG. No venous gases. The the media with pressure between seven and nine centimeters of water then fit between below 30% 30% or less actually, and sufficient spontaneous breathing effort as per clinical evaluation. So it didn't really come into much more than that. They excluded any babies with major congenital anomalies or chromosomal anomalies, neuromuscular disease, upper respiratory tract anomalies, surgical conditions, great for ivh. Before the first activation, obviously, a birth weight less than 600 grams. I thought that was interesting. It was very specific, oh, let's let's that that comes out of nowhere. But maybe because of interphase, I'm not sure suspected congenital lung malformation, lung diseases or pulmonary hypoplasia. There was something else that bothered me that I have to mention. It just bothered me. It said in the methods, a race and ethnicity data were not collected. All the participants were Chinese newborns, as like that. That's that doesn't make sense. But listen, it's just yeah, I think I think there's more to demographics than this. And, and, and we've talked about this, there's a lot of data that we could collect on parents to understand their situation in the NICU. So yeah, that was a bit of a letdown. So babies who were about to get excavated, were randomized to either and I am the nasal CPAP, or a nasal highfrequency. Right. If a baby was reintegrated, they were then reactivated to the same modality again, right. So if they excavated a baby to nasal high frequency, and that failed, they re intubated. And if they had to reactivate, then they went right back to the same mode that they were on before the nasal highfrequency. All modalities were delivered to

Daphna 34:20

you. That's a commitment to the treatment arm.

Ben 34:23

I would be upset if I was a parent. Right?

Daphna 34:26

It didn't work for them back on it.

Ben 34:29

But but it makes sense, right? I mean, it's Yeah, yeah. So the last thing is that all the modalities were delivered via short by nasal prongs. So what was the primary outcome? There were three of them. There was total duration of IMV. During the NICU stay, the need for reintegration and they had pre specified reintegration criteria and the number the number of ventilator ventilatory free So like off the ventilator, I'm sorry, I'm slurring my speech. It's late at night and secondary outcome was some efficacy and safety endpoints and you can look that up. So the power, they wanted to see if they could effectuate a 20% reduction in mechanical ventilation duration. And so for that they needed 14 140 infants. This was also done on an intention to treat analysis once randomized, always. So the results, so they needed 1440 infants. So they got 1440 infants, they had 480 infants in each group, for under 90 in the CPAP and Imp and the high frequency postmenstrual age was 29 weeks, maybe the median weight was 920 grams 60% were boys, and the median age at intervention was less than four days. So let's look at some of these outcomes for the primary outcome. No difference in IMV duration between nasal CPAP and nasal IMV. The duration of IMV was longer in the NITV, the non invasive positive pressure ventilation or an IV and nasal CPAP group then in the nasal high frequency group. The frequency rates of reintegration and reintegration within 48 hours from extubation were different between the study groups and significantly higher in the nasal CPAP versus nasal high frequency group 12.5% versus 7.5% and versus the NITV group. So, the risk difference there was 8.1% versus 2.9%. In the although no difference was observed between the NI PPV and the nasal high frequency group. Ventilator free days offered differed between the study groups and were significantly fewer in the nasal CPAP group than in the NI PPV group. Looking at some of these secondary outcomes, secondary efficacy outcomes did not differ between the study groups except for postnatal corticosteroids and the duration of study intervention. postnatal corticosteroids were used less in the nasal highfrequency group than in the CPAP group, the risk difference was 7.3%. Whereas the duration of the study intervention was shorter in the nasal high frequency group than in the NI PPV group. The median difference was minus one with a range of minus three to zero days. Similarly, the study groups did not differ significantly in secondary safety outcome except for weekly weight gain, which was higher in neonates who were treated with nasal high frequency than those who received nasal CPAP. So their conclusion is that nasal high frequency if used after extubation, and until NICU discharge slightly reduced the duration of intermittent mechanical ventilation in preterm neonates, whereas both nasal highfrequency N ni, ni m v or ni PPV had a lower risk of reintegration than nasal CPAP. These three respiratory support techniques were equally safe. I think this is interesting. I don't even know if I mean, we don't have to be very honest with you. We don't have these or high frequencies, technology in our in our NICU. But I always have an issue of people comparing nMV Nava I'm sorry, NIV, Nava, or nasal high frequency with nasal CPAP. Right. I mean, as soon as you enter a rate, it's not really fair game. But those that data was pretty interesting. Now, the one thing that I wanted to mention was that there's a lot of significance, right. But I don't know clinically whether the data that we presented today was so striking that it will require a change right away. So for example, when we're looking at the primary outcomes, again, the total duration of invasive mechanical ventilation was 7.8 days in the CPAP group 7.3 in the Nim, D group and 6.2 in the nasal high frequency. So I understand it's different, but it's not a massive, massive difference. When we're looking at ventilator vent, ventilator free days, in the median of that was 32 days in the CPAP. Group 35 in the aipp. Group 34 in the nasal highfrequency. So, the data is

Daphna 39:39

statistically significant. Is it clinically?

Ben 39:42

So that's the question people have mentioned that on Twitter as well. And, and for for me, I'm always thinking I'm very self centered. So I'm thinking am I going to use this, but the bottom line is, it requires a lot. It's going to require a lot for me to get this into the NICU right that we have to like, call the company Get this technology. And then when you're looking at the data, it's like, ah, is it really worth it? I mean, am I not going to get by with NIF Nava or even even an IV? So, yeah, I think this is anytime something like this comes out in JAMA peas, we kind of have to review it. But yeah. It's not an earth shattering paper. Unlike the high flow nasal cannula paper where I think practices might need to get adjusted tomorrow, you have time?

Daphna 40:25

Well, I mean, it's still good to have the information, right, just because it wasn't just because you won't change your practice. Now you know, that you

Ben 40:35

do, I think, I think it's, to me, the key to successful respiratory management is being like a restaurant and having lots of options, because every baby responds differently. Some babies like nervous some babies like CPAP, some babies like high flow, it really is something that has to be tailored to the infant. So I think if this is something you can have in your unit, and you can offer to your patient population, I think that's fantastic. And I think the data shows that it's safe, and it's just as effective if not better. So yeah, but if there's a cost associated to bringing that into the unit, that's you're going to have to be cast.

Daphna 41:13

Yeah. You know, lots of people would disagree with your statement about your menu of respiratory options.

Ben 41:21

I am willing to fight people on this.

Daphna 41:25

I'll just leave it at that. I'll just leave it at that. You know, I care about individual individualized medicine. But there are I think lots of people who feel like you can have one system and use it very

Ben 41:35

well, for sure, for sure. But I do think that if you know how to use all these different systems very well, and you can offer them you will have so many more options that your outcomes I think are going to be the better for it. Because you're again, some babies do well on an IMV some babies need never nervous some babies just do well on CPAP. And having all these tools at your disposal makes a huge, huge difference. So yeah, come at me.

Daphna 42:01

Literally on Twitter at him, okay.

Maybe not this week, be able to respond this week. But I'm gonna review this article from archives of disease child fetal and neonatal edition. And the title is comparison of neonatal morbidity and mortality between single room and openbay care, a retrospective cohort study, lead author Sophie Jansen, this is coming from the Netherlands. So the question is, Are there risks with the other major neonatal morbidities associated with the move to single family rooms? And obviously, this is an interesting question because many centers are moving towards single family rooms in an effort to enhance family centered care. And several studies have shown beneficial effects of the transformation of private rooms, including things like shorten like this day earlier transition to full feeds, increased breastfeeding rates, and improved overall neurodevelopmental outcomes at 18 months of age. Some of the unfavorable effects that had been reported are higher workloads for like the nursing staff, lower infant language scores at two years of age. And actually some study showed surprisingly, increased maternal stress. So this study wanted to look at not those features, but really was it linked to the other common neonatal morbidities. So this was a retrospective cohort study of two epochs before and after the building of single family rooms in the same unit. The inclusion criteria were preterm neonates born at a generally gestational age of less than 32 weeks and admitted to the NICU between May 2015 and may 2019. exclusion criteria were neonates born on the day of the unit transition. Those admitted to both unit types so that they were like transfers, like from our unit from one unit type to the other. And then neonates with an admission duration less than 24 hours and those infants born less than 24 weeks were also excluded. The primary outcome was really the baseline characteristics, including respiratory support needs, and the major neonatal morbidities and mortalities included were the Nate the major neonatal morbidities included were a symptomatic treated PDA spontaneous intestinal perforation bronchopulmonary dysplasia, retinopathy of prematurity intraventricular, hemorrhage cystic PVL pneumothorax hypermobility, requiring phototherapy inotropic support, blood red blood cell and platelet transfusion needs subclinical seizures, and then looked at in hospital mortality. They did not look at knacker late onset sepsis, since they felt like this had been well evaluated in other studies. So they were looking at a lot of things to see if being in a single bay unit or the single family room type unit made any difference. So overall, they had 356 Babies admitted to the open day and 343 to the single room unit. Differences between the two groups included a higher number of multiples admitted to single family room. And differences between the two groups included a higher number of multiples admitted to single family rooms, and more neonates admitted to the single room unit required surfactin interestingly, and that there are no further differences in baseline characteristics between the cohorts. Overall, neonates in the single room unit cohort had a non it's confusing because in openbay, sounds like a single room but single room unit just to clarify means like an individual patient room. neonates in the single room unit cohort had a non significant but greater rate of ROP stage two versus a babies in the openbay. Unit. The openbay unit cohort had more platelet transfusions. But otherwise there were no differences found between the cohorts with respect to the rates of symptomatic treated PDA SIP pneumothorax BPD ivh cystic PVL hyperbilirubinemia inotropic, support a blood transfusions subclinical seizures or in hospital mortality. Yeah,

Ben 46:42

and to be fair, like the number of transfusion was like one right? It was

Daphna 46:47

very different one versus two. So that's right. That's right. After adjustment for gestational age, sex antenatal steroid therapy and low five minute Apgar lesson seven single room care was independently associated with a decreased risk of

Ben 47:04

severe, so significant evatik

Daphna 47:06

hemodynamically significant is significant PDA. single room care was independently associated with a decreased risk of hemodynamically significant PDA, the adjusted odds ratio of 0.5. So in general, no significant differences in neonatal morbidity or mortality was observed between neonates admitted to a single room versus open bay, NICU, small differences in platelet transfusions, small differences in ROP grade stage greater than or equal to two. And our significant PDA I don't know what to make of some of that information.

Ben 47:54

Yeah, I think I think I'm sorry, I thought you were done.

Daphna 47:59

No, go ahead.

Ben 48:00

No, I was gonna say it's like what we discussed with Christie Waterberg writes, like, I'm gonna read this data, you could say, well, there's no difference. We're going to stick with our open bay unit, right? There's no difference. Are you going to say? Well, you see, those kids are not getting forgotten in their single rooms, right? I mean, that's the other argument you hear. It's like, Oh, there's the single rooms and the kids are behind closed doors. And we just respond to the alarms if we respond to the alarms. So I think you can make the case for both single bed, single room and open bay. And to me, it's it's much more complicated than that. I think we've talked about fight care. And we've talked about going back to a situation where the mom and the baby are in the same room. And that's Yeah, I think we're just letting other philosophies permeate to the NICU. And maybe the NICU has to think outside the box a little bit. And I think TRICARE does that.

Daphna 48:58

Yeah, no, I think that's I think that's one of the main potential confounders maybe of the study at you know, there are two different epochs, obviously. And if you are making a change to single family rooms, I mean, theoretically, you may be making a lot of other changes in a unit, both cultural changes, logistical changes, technology changes. So

Ben 49:24

that's always the end. That's always also the issue with that type of design, right? Because it's not two units running at the same time. It's a historical cohort. So you have the openbay. That was like 2014, I think, or something like that. 2015. And then you have 2019, which is the single room. So like, you would hope that the unit also gets better at managing babies every year. So could that be confounding? It's always difficult. The group that's publishing this is is by the way, stellar, stellar group that has done stellar work in neurodevelopment. So I'm not questioning But, you know, this is a discussion that will never end and everybody's going to find the like, you're going to get so much confirmation bias when like, whatever whatever you want to find to sustain your argument one way or another, you will have data for

Daphna 50:14

get it done. Yeah, all right. And we settled our unit is kind of a hybrid.

Ben 50:22

Yeah, yeah.

Daphna 50:27

You got one more force.

Ben 50:28

I got one more for I got one more fireplace. So this was a paper Hold on. So this was also in the archives of diseases in childhood, fetal and neonatal edition. The first author is our friend again, Brett Manley from Australia. The title of the article is trends in the use of non invasive respiratory support for term infants in tertiary neonatal units in Australia and New Zealand. All of our pulmonary that this, this will take. The idea here is that we've been using an IMD much more in recent years, we've gotten very comfortable managing babies on an IV, especially even term infants. And so the question they were asking was, has the use of non invasive respiratory support to treat term infant in Australia, New Zealand, which is the area that we're looking at? Has Has it changed over time? And if so, whether there are parallel changes in short term respiratory outcomes. So they did a retrospective database review of, of data from Australia, New Zealand, from 2010 to 2018, of term infants admitted to the NICU. And the idea is, I forgot to mention that in the background, which I think is a very interesting point that Brett is bringing up saying, we've gotten so comfortable using an IMD that have we now developed a lower threshold to start an iamb on some of these babies, which in turn, might increase separation from the mother. Right. And, and can that be quantified? So I thought I thought that was that was an interesting point. So it involved 21 hospitals, they included any term infants admitted to a tertiary NICU, they had pretty much no exclusion criteria. The modes of non invasive respiratory support were CPAP and nasal high flow. Data on specific setting devices or interface are not available. Again, it's kind of the what you get when you do database review, right? You can't get super granular data. But you do compensate by having large datasets. So it's, you knew that from the get go. The primary outcome was the annual change in hospital specific rates of non invasive respiratory support per 1000 inborn life birth, expressed as a percentage change. They had some secondary outcome, which were the change in rates of mechanical ventilation, the number of pneumothoraces requiring drainage, the number of exogenous surfactant treatment or and the last one was death before hospital discharge. So the data 754,000 term infants over nine years, like I said, you get those large, large numbers, and then you can't have all the like, you can find out whether they were using OptiFLOW RAM cannula, right? It's perfectly fine. Overall, the estimated average change in term inborn was plus 9.4 births per year, so there was more and more birth. They had 14,000 eligible registered from the 21 NICUs. A total of 12,719 infants receive non invasive respiratory support across the period. And the number of infants receiving non invasive respiratory support almost doubled from 2010 to 2018. Going from 980 to 1930. So that's already pretty impressive. So the primary outcome was across the 21 NICUs. Hospitals specific rates of non invasive respiratory support increased by 8.7% per year, from an estimated 10.8 per 1000 live births in 2010 to 20.8 per 1000 births in 2018. And I suggest you look at some of these graphs where the trend lines are pretty much a straight line with a with a positive slope 19 of the 21 NICUs had a statistically significant increase in non invasive respiratory support. Over time no NICU had a statistically significant decrease in non invasive respiratory support over time, the annual rate of non invasive respiratory support dividual NICU, ranged from 3.1 to 22.6 per 1000 live births in 2010 and from 9.7 to 40.9. So even that variability was shifted up significantly. cause the study period. Some of the secondary outcomes were quite interesting as well, there was no change over time in the rates of mechanical ventilation or death. However, there was a some evidence of increasing pneumothorax, requiring drainage 4% per year increasing from an estimate of 0.5 per 1000 live births in 2010 to 0.66 per 1000 live births in 2018. So, you know, not it's never, never risk free. And there was an increase in surfactant use 7.8% per year. So, the conclusion are, that the use of non invasive support to treat term infants in the NICU has increased over time in Australia and New Zealand without any reduction in mechanical ventilation, but a concomitant increase in pneumothorax, requiring drainage and surfactant use. They're concluding in their conclusion, they're mentioning that clinicians should be diligent in selecting newborn infants most likely to benefit from treatment with non invasive respiratory support in this relatively low risk population. And they obviously mentioned that this inter unit variation that we were talking about earlier, warrants further exploration. So we're running out of time, but the discussion was very interesting. They were asking basically, why what are the drivers for this increasing use? And they're saying, Are we taking evidence that has shown that non invasive is very good in preterm infants and just translating that straight to term infants without really having the evidence that this, that this is true? Have we just gotten more comfortable? Do we think that babies that maybe should be monitored in the nursery can't be monitored closely anyway, they have all these different hypotheses that I think are very, very thought provoking and compelling. So I suggest I suggest you read the Yeah. And, and obviously, they're talking about now that we're using this non invasive are we We're doing this to avoid, right, we're doing this this by we're doing this of trying to start non invasive, mechanical ventilation, to reduce complications to reduce the use of surfactant. But in truth, this is not happening. Like we're using more surfactin than before. And we're you have in the morning, more authorities. So anyway, there's a lot there talk about the limitations of their data, obviously, no assessment of maternal factors. And all the other stuff associated with using a dataset. I thought that was a very interesting study.

Daphna 57:41

Yeah, very interesting. I would like, you know, there are so many reasons that babies have respiratory distress, right? And so when we talk about individualizing medicine and phenotypes in the NICU, maybe that is the next step in stratifying babies is by pathology, right? Like it, maybe it matters for why why you need respiratory support. And I think that's why I bore out with the term infants, because their needs are different. Yeah, I

Ben 58:13

thought that was smart. Yeah, just use the term infants and non invasive support. Again, I mentioned that right, that the non invasive supports was CPAP, and nasal high flow. Right. So

Daphna 58:30

all right. All right.

Ben 58:31

I think that's it for Journal Club today. We are very grateful for a lot of the messages that we've received via email, and via the Twitter handle to support the work that we're doing. Were really happy to I mean, these are the messages that keep the spark going. When we're having like the past few weeks that we've had, where we're both on service, and it's just nuts,

Daphna 58:55

lots of late night recording,

Ben 58:57

like tonight, in any case, but yeah, thank you, everybody, for all your support, go register on the neonatal network, and let's get some discussions going on research and stuff like that. It's really exciting. Register and post. Yeah, remember that the neonatal network is a HIPAA protected platform. So we can talk about patient care, we can talk about cases, and it's a platform reserved for physicians and providers. So it's really the perfect place in our opinion, to have meaningful conversation with one another. Doctor, I will see you on Monday for your review.

Daphna 59:34

Sounds good.


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