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#051 - Journal Club 24

NICU journal club the incubator podcast

Hello friends 👋

Journal club is BACK!!!

We have many many articles to go over today. Most notably the recent publication by the neonatal research network in the New England Journal of Medicine looking at the use of prophylactic hydrocortisone to improve BPD-free survival. We even had the pleasure to ask the lead author Dr. Kristi Watterberg about her thoughts on how to interpret the data. She will also join us for a full interview to be released on April 17th. Look out for this interview.

Daphna reviews some interesting articles about provider concordance regarding goals of care discussion in the nicu and reviews an amazing QI project aimed at reducing length of stay by improving time to full oral feeds.

We also chat about probiotics to reduce NEC, use of glycerin suppositories and whether or not they are associated with increased rates of NEC in preterm infants, and review some interesting neurodevelopmental outcomes from our scandinavian colleagues.



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

Provider concordance regarding elements of goals-of-care discussions in neonatal intensive care. Guttmann K, Liu B, Kelley A.Acta Paediatr. 2022 Apr;111(4):776-778. doi: 10.1111/apa.16235. Epub 2021 Dec 29.

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. Watterberg KL, Walsh MC, Li L, Chawla S, D'Angio CT, Goldberg RN, Hintz SR, Laughon MM, Yoder BA, Kennedy KA, McDavid GE, Backstrom-Lacy C, Das A, Crawford MM, Keszler M, Sokol GM, Poindexter BB, Ambalavanan N, Hibbs AM, Truog WE, Schmidt B, Wyckoff MH, Khan AM, Garg M, Chess PR, Reynolds AM, Moallem M, Bell EF, Meyer LR, Patel RM, Van Meurs KP, Cotten CM, McGowan EC, Hines AC, Merhar S, Peralta-Carcelen M, Wilson-Costello DE, Kilbride HW, DeMauro SB, Heyne RJ, Mosquera RA, Natarajan G, Purdy IB, Lowe JR, Maitre NL, Harmon HM, Hogden LA, Adams-Chapman I, Winter S, Malcolm WF, Higgins RD; Eunice Kennedy Shriver NICHD Neonatal Research Network.N Engl J Med. 2022 Mar 24;386(12):1121-1131. doi: 10.1056/NEJMoa2114897

Glycerin Suppositories and Enemas in Premature Infants: A Meta-analysis. Burchard PR, Lay R, Ruffolo LI, Ramazani SN, Walton JM, Livingston MH.Pediatrics. 2022 Apr 1;149(4):e2021053413. doi: 10.1542/peds.2021-053413.

Neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation.Morsing E, Lundgren P, Hård AL, Rakow A, Hellström-Westas L, Jacobson L, Johnson M, Nilsson S, Smith LEH, Sävman K, Hellström A.Acta Paediatr. 2022 Jun;111(6):1167-1175. doi: 10.1111/apa.16316. Epub 2022 Mar 22.

Predictive Ability of 10-Minute Apgar Scores for Mortality and Neurodevelopmental Disability. Shukla VV, Bann CM, Ramani M, Ambalavanan N, Peralta-Carcelen M, Hintz SR, Higgins RD, Natarajan G, Laptook AR, Shankaran S, Carlo WA.Pediatrics. 2022 Apr 1;149(4):e2021054992. doi: 10.1542/peds.2021-054992.

Improving Time to Independent Oral Feeding to Expedite Hospital Discharge in Preterm Infants. Gentle SJ, Meads C, Ganus S, Barnette E, Munkus K, Carlo WA, Salas AA.Pediatrics. 2022 Mar 1;149(3):e2021052023. doi: 10.1542/peds.2021-052023.

Bifidobacteriumlongum subsp. infantis EVC001 Administration Is Associated with a Significant Reduction in the Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants.Tobias J, Olyaei A, Laraway B, Jordan BK, Dickinson SL, Golzarri-Arroyo L, Fialkowski E, Owora A, Scottoline B.J Pediatr. 2022 May;244:64-71.e2. doi: 10.1016/j.jpeds.2021.12.070. Epub 2022 Jan 12.


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

Ben 1:04

Hello, everybody. Welcome back to the podcast Daphna. You're back.

Daphna 1:12

Well, we were still doing some podcasts, you know,

Unknown Speaker 1:15

here. No, but you're back.

Daphna 1:17

I'm back. I'm back. I'm back. But but I'm not. I'm on vacation right now.

Ben 1:23

But I was talking for the purposes of the podcast, you are you are now we have your your full all in,

Unknown Speaker 1:31

you know, how was that test?

Daphna 1:35

You know? You never know, right? Just do the best you can. And we see what's what, when the scores come out. That's what I feel like everybody's like, a little stressed out about it. You know, I think that's normal.

Ben 1:52

I think what people tend to forget is that if you come came out of this test, and you're the only one who said, Yeah, that. That was a tough one. And everybody else says that was a walk in the park. Yeah, you should be concerned. But when you start realizing everybody has that feeling of like, Oh, terrible.

Daphna 2:11

It's hard, because, you know, there's this like, scaled score that like, what does that even mean? You know? So it's hard to, it's hard to see where you landed because you don't know what the goals are. So I you know, doctors are not very, we're not great with uncertainty, even though we have to do it all the time.

Ben 2:32

No. That's right. When I was in college, I didn't do so well with scaled scores, because I used to get like the questions everybody got wrong. I used to get them all right. And they got dropped. And the questions and the questions that were giving me is I used to overcomplicate life for myself and I would get them wrong. And now it's like in this predicament. Yeah. Anyway, we have Journal Club is back. In case you are confused about our new schedule, it's not something crazy. No, we are going to do we have two weeks, where we're going to do journal club back to back. And then we'll resume our new our usual alternating Journal Club interview schedule. And yeah, thank you for everybody who downloaded the episode last week with Dr. Richard Paul. And that was that was a pretty cool interview.

Unknown Speaker 3:21

Very interesting, too, which is cool.

Ben 3:24

Yeah. Yeah. Although all his former fellows came, came out in droves up. Yeah, so without further ado, should we start?

Daphna 3:37

Yeah, you go first. Okay, so

Ben 3:39

then then we have to begin

Daphna 3:40

when we do when we do board review questions. I go first every time so you go first.

Ben 3:45

That's fine. So today, it's an easy one. I mean, today we have the hydrocortisone paper published in the New England Journal of Medicine, in case you are living under a rock and haven't heard of this paper coming out. It is called hydrocortisone to improve survival without bronchopulmonary dysplasia. first author is Christie Waterberg. It is from the neonatal research network. So before we begin, we should be telling people that are coming out upcoming interview so not next week. But the following week, is with Christie Waterberg. We've, we've managed to record an episode with her and we thought it was so timely that this paper came out and that we would bring her on the show. She's such a fascinating individual. And for the people who don't know her, you are practicing neonatology based on a lot of stuff that this lady has published. So she was so humble, it was amazing. Anyway, so and we asked her some questions about this paper that will will get her opinion throughout this this episode. So that's kind of cool. So this paper obviously looks at hydrocortisone, right. So hydrocortisone has a long history of wanting to be used for reducing inflammation, especially in the context of bronchopulmonary dysplasia is it's more specifically and trying to even prevent bronchopulmonary dysplasia. hydrocortisone is is notorious for having both mineral and glucocorticoid. properties. And compared to dexamethasone, in the animal animal studies, it had much less apoptotic effect. And so and so that's, that's that's what originally led investigators to look at this medication. There's a lot of data that came out and we talked to Dr. Waterberg about that on our upcoming show, where, since the 19, the late 1990s. In 1999, we started having papers looking at the use of hydrocortisone and its effect on bronchopulmonary dysplasia. This is what those early studies uncovered this this peculiar association between PDA treatment and hydrocortisone administration that led to spontaneous perforation. But, and more recently, with the publication of the premiere lock trial in The Lancet by the French group, there's been a big, big debate in the community whether we should be using prophylactic hydrocortisone in very small babies at risk of developing BPD to prevent the development of BPD. So this trial, specifically by the research network was undertaken to determine the efficacy of hydrocortisone and increasing survival without BPD. And its long term safety, assessing that rule neurodevelopmental outcome between 20 to 36 months, adjusted for prematurity. So this was a double masked, placebo controlled randomized trial. This was done by the neonatal Research Network in 19. US academic centers, a collected data from 2011 to 2018. And then the follow up for the neurodevelopment was between 2013 and 20 in 2020. So the infants that were eligible were included in the study if they were into 28 days postnatal age. And if they had an estimated gestational age at birth of less than 30 weeks, they had to be born or admitted in a neonatal research network site at no more than 72 hours of postnatal age. And they had to have been on mechanical ventilation through an endotracheal tube tube for at least seven days. And we're receiving mechanical ventilation through that D tube at trial entry. Obviously, some of the exclusion criteria included major congenital anomalies. Any baby that decisions were made to limit intensive life support into medicine or ibuprofen treatment within 48 hours of trial entry, obviously, dating back to these early 2000 studies, trying to prevent sips and previous administration of steroids for treatment or prevention of BPD. So, the intervention were either receiving a saline placebo, or hydrocortisone sodium succinate. The dose basically was a tapering course that started on day one and was tapered over the course of 10 days, started off at four milligrams per kilo per day for two days. Two milligrams per kilo per day for three days, one milligram per kilo per day for three days and point five per kilo per day for two days on the basis of anti inflammatory dosing schedule, which is another article that Dr. Waterberg published. So again, if you are giving hydrocortisone and you're using one milligram per kilo Q eight, right, you are using her her study published in 2007, ebony. In terms of extubation, that was very interesting. I don't know if if you saw that Daphna. But the decision to activate was left to the discretion of the attending. However, an extubation attempt was required within 72 hours after starting hydrocortisone, or placebo within 24 hours after the following criteria had been met. So they had extubation criteria, and the clinician was free to do it or not to do it. But they had to attempt it at least within that three day period. The exhibition criteria were in FIU to have 40% or less to maintain the saturation of 80% Amenia weed pressure of eight or less and hemodynamically stable condition in the opinion of the clinical team. Now, a successful extubation was defined as remaining activated for at least a week, including at least three days after the last dose of hydrocortisone or placebo. The outcomes of these of this study were pretty much expected the primary outcome included both efficacy and safety measures. The efficacy outcome was the improvement in survival without physiologically defined moderate or severe BPD. Measure that 36 weeks post menstrual age. And obviously, if you're not familiar, the physiologic definition here is explained as the use of supplemental oxygen positive pressure ventilation are both to maintain an oxygen saturation more than 90%. And then they did this ambient air challenge for infants estimated to be receiving an FY two of less than point three. So If you're gonna 30% or less by nasal cannula, they try to win you down to remember, the safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months corrected age. And for that they used a pretty standard, barely three measurements and CP stuff that neonatal Research Network has used in the past. So there's nothing really earth shattering. They're all very solid stuff. secondary outcomes were very interesting. growth measures after extremely birth was one of the secondary outcomes. Successful extubation was a secondary outcome. The use of open label dexamethasone was a secondary outcome and the respiratory status at 40 Weeks was a secondary outcome. The use of hydrocortisone after the treatment period was considered a violation of protocol. So if anybody had to receive hydrocortisone, I think they were they were taken out of the trial. The sample size was calculated to be 800 infants for 80% power to detect an increase in survival without moderate or severe BPD by 10 percentage points from a baseline of 35% or less. And Dr. Waterbrook talked to us about that, that we in Unit our expectations pretty high. And it makes the work that we have to do to get these studies done much harder, harder. Yeah. So let's talk about the results. So the mean birth weight of these infants were 715 grams, and the mean gestational age was about 24.9 weeks, the outcome of survival without moderate or severe BPD was known for all the Enrolled infants and for the neurodevelopmental follow up, they had 91% retention rate, the primary outcome at 36 weeks of postmenstrual, age 16.6% of the babies in the hydrocortisone group were alive without moderate or severe BPD. Compare the two, three 13.2% in the placebo group, so better, but not statistically significant. The confidence interval range from point nine three to 1.7 for the results for the components of the primary outcome were similar in the two groups as well as the severity of bronchopulmonary dysplasia and survivor at 22 to 26 months of corrected age survival without moderate or severe neurodevelopmental impairment. Sorry, occurred in 36.9% in the hydrocortisone group, compared to 37% in the placebo group. So slightly worse in in hydrocortisone, but again, not different statistically 95% confidence interval was point eight one to 1.18. So from the primary outcome, basically no, no real difference. Now the secondary outcomes were interesting. So more infants in the hydrocortisone group were successfully activated than in the placebo groups. So 44.7% in the hydrocortisone group were successfully excavated compared to 33.6%. In the placebo group, the hydrocortisone group had fewer days of mechanical ventilation than the placebo group before 36 weeks of postmenstrual age. The open label use of dexamethasone was administered to 39.7% of the infants in the hydro, Corazon group, and 42.1% in the placebo group, so they were less likely to get another round of steroids. And then in terms of adverse events, the main thing that's mentioned is hypertension. The babies were on hydrocortisone required more treatment for self for a short while for hypertension, but no infant was discharged receiving antihypertensive meds.

And when you look, so the interesting thing about this study, obviously, is that if you look at table three, which are already in hospital outcomes, hydrocortisone does pretty well, but it's just never reaches that statistically significant results that we were we were hoping for. And even when it comes to the the efficacy, the numbers tend towards the hydrocortisone but but never in a significant manner. So yeah, definitely. What were your thoughts on the hydrocortisone paper?

Daphna 14:16

Yeah, I think you hit a lot of the big points, which there were still a lot of signals and trends in the in the data that you know, I don't think we can totally ignore and I think that's the big question, right. Like, I think people were hoping we would either lay or lay hydrocortisone to rest one way or another. But I'm, I'm not sure we can do that. Yet. This may have answered this specific question. But I wonder as we learn more and we see more studies on the corticosteroids and the different types of steroids that will get more information about who will respond better to one thing or another. For we talked to Dr. Weinberg about this, that probably there are different phenotypes for babies that will respond and babies that won't. And I just don't I just don't know that we have all the information yet. So some things I super liked about the paper, I told this to Dr. Waterberg, I think her work is so easy to read. Some of the papers we review are actually quite hard to read. So I really appreciated that. They put in the effort that, you know, you really knew what the study design looks like you really knew what the plan was, you really got a lot of details, and it was a long study. So I'm always impressed by these mult big trial, right 19 Big us centers and high volume centers over the course of seven years with over 90% follow up, which is really, really cool. Because that was part of the question, too, is what is the developmental follow up with the use of steroids? So I think that is another piece of the puzzle that if you're going to use hydrocortisone, that the developmental outcomes weren't different, either. And, you know, I mean, we do know that the babies got estimated sooner. So it didn't make a difference about BPD. But we have to talk about what is what is the cost of staying intubated, even without, you know, separate from from BPD. So right, I think there's, there's there's to be done. I guess

Ben 16:40

my point. Yeah. So we did. We did ask a lot of these questions. Dr. Waterbrook, I think there's we had an interesting discussion as to how people are going to view the data. I think many people are going to look at the secondary outcomes and be very enthusiastic. But I wanted to share Let's Let's actually bring in Dr. Waterbrook, herself to answer the question, whether Are we moving towards, we're searching for the silver bullets, and there's an editorial in the New England Journal about like, is the was hydrocortisone supposed to be the silver bullet. And I think what we've learned from neonatology is that there's not a single drug that's going to fix a big disease. It's mostly going to be risk assessment, Bayesian approach. And let's see what Dr. Warburg had to say about that. Do you think we're going to end up with a risk stratification, where chorioamnionitis, for example, would be an important factor, the degree of inflammation soon after birth will be a big factor and based on this risk stratification, then we will decide whether to use or not hydrocortisone?

Speaker 3 17:36

I think so I think people are already trying to do that we're going to present an abstract at this upcoming meeting talking about, you know, is there a differential effect based on the baseline risk? That kind of stuff, I'm certain that that will be true that the problem is that when you get down to 2324, even 22 weekers, the risk for developing chronic lung disease is almost unimaginably high. You know, if you start out being intubated, it's sort of you'd be surprised if they don't end up with some kind of oxygen requirement at 36 weeks or more.

Ben 18:12

And going back to some of the of the, of the, of the secondary findings that you've mentioned, especially shorter invasive ventilation earlier, extubation. Do you think that there, there's going to be a need to study these outcomes as primary outcomes in future studies? Or do you think that there's enough data right now to to use at least hydrocortisone maybe not as a, as a as an agent to reduce survival as an agent to reduce BPD, but maybe to have these outcomes of less time on events and earlier extubation?

Speaker 3 18:47

I think I think people will, will put their own imprint on it. I think some people will say I want to do this to get that baby off the ventilator, I think it's worth it. And we've shown that it doesn't have any adverse neurodevelopmental or growth outcomes, at least at two years, we are following these babies to five to six years in a long term outcome. And we're doing pulmonary, pulmonary function outcomes in a subset of babies at certain centers that have that capability. So we're going to be able to say more about that school age outcome, you know, in a couple of years, but I think everybody's just gonna put their own take on it, depending on what they're actually what their back biases and their background is.

Ben 19:24

I'm super excited that we're starting to think about the problem in with risk stratification. And yeah, I mean, again, stay tuned for the rest of our interview. It was a lot of fun.

Daphna 19:38

I asked, anytime we're studying sorry, to to be, you know, one of this but every time we're talking about anything to do with pharmacology, or medications, I just think there's like so much exciting work being done. And, you know, it's just now trickling down into neonatology about pharmacogenomics and you know, what will we learn about which patients respond to what kind of medication? So I just think I just think we have a long way to go and in terms of that, and so we won't have to do so much trial and error for individual patients. Obviously, we'll have to keep doing trials. Oh, it's my turn. I guess. It is your attorney. I feel like we're doing questions.

Unknown Speaker 20:28

I forgot that it was my turn.

Daphna 20:32

Okay, so this is a brief report in ACTA paediatrica, provider concordance regarding elements of goals of care discussions in neonatal intensive care. So this study comes to us out of the Children's Hospital Philadelphia, done between January 2018, and February 2019. But the research teams predominantly from Mount Sinai with a lead author, Catherine Goodman, Catherine Goodman. And so really what they wanted to do is if you had mixed teams like a multidisciplinary team, participating in a goals of care discussion, did at the end of the discussion, did you agree on how things went, which I think is really interesting, because I think that's something we see all the time that we have a say myself, I'm a neonatologist. I'm a physician, I had a goals of care discussion, I think things went a certain way. And lo and behold, I may find out that not everybody feels it went the same way. So that's what they wanted to look at. They used a survey called the Williams intro instrument. It's an 82 items survey. And it was provided to people after a discussions of care meeting, so they identified discussions by doing weekly email sent out to the staff, social workers notifying the team about goals of care discussion. And then they used the questions from the survey and put things into four different domains communication, quality of care, quality of life, and shared decision making. All of this was done on a Likert scale. And they circulated the survey to as many people as possible nurses, attending physicians, social workers, all involved in patient care within 10 days following a goals of care discussion. In general, their discussions had two or three participants. And when a conversation had three participants, they tried to look at all of the possible combinations for concordance. So overall, the scores on the Williams instrument within it within a discussion. So again, they were looking at concordance, so did everybody agree or moderately concordance it with a median kendal's court correlation coefficient of point four. And most 65% of the coefficients had a p value less than point oh, five, b interest, the most interesting things about the study, though, I think, is actually looking at the separate items. So even when people kind of agreed in a conversation, they had the same level of agreement about the presence or of an absence of an item, they disagreed on on certain items. So even though the conversation as a whole was important, they might have disagreements about the different items. And so for example, providers past value judgments was an example of a statement about which there were low levels of agreement. So people did not feel the same way about how that went. providers were frank and honest, is an example of a statement about which there were high levels of agreement, which I guess is a good thing, depending on how you look at it. Some of the other items that were really had low agreement and adequately explained hospital policies related to the child's care, and I feel like this this is something that gets us tripped up in our own unit all of the time.

Ben 24:20

I don't even know what I was very confused as to what that meant even. So it

Daphna 24:24

it means like, for example, a visitor policy a when is the Touch Time policy, things like that, where somebody may see somebody may say one thing and a different person says something else and I think it's one of the main stress points for families in any given unit. So I'm not surprised by that.

Ben 24:46

I get in trouble for that so often, yeah. I allow way too many things.

Speaker 4 24:52

Do you want to do it? Yeah, sure. Sure. Bring bring that person over. Of course they can see the baby

Daphna 24:59

thing is like recognized when parents felt intimidated by the number of providers. So we do this to families all the time, we have way too many providers in the room. So there was a low agreement about whether people recognize those parental keys, adequate use of aids such as notes and diagrams. So I thought that was really valuable. Lots of our families actually would like to see some of the information in a more visual format. We've talked about passing value judgments, which is always a touchy situation. And then parents feel that the right decision was made regarding withdrawal. 47% agreement, encouraged parents to provide mutual support and trust 52% provide parents with sufficient number of discussions 53% And then things have scored really high. Health care workers were frank and honest, I told you parents were encouraged to ask questions. 89% We almost always get that right. Yeah. Do you have any questions? And they don't even know where to start asking questions. Right? avoided answering parents questions 89% agreement, health care workers were polite, and were respectful 96% respectively. So I thought this was interesting, for a number of reasons. One, I think there's value to debriefing after and family conferences, just like we would do with a code or procedure. I think these are procedures with definitive skills to be learned. So I think that's useful. And I think it saves us trouble in the long run. The other thing, I thought were by looking at these answer and question options, I think there's some tips in there about how to improve our communication with families. So

Ben 26:52

that's, yeah, I mean, this, this will reinforce a lot of the things that I had learned from our episode with Betsy Pilon, right? I mean, I've started to like, put myself whenever I'm having a family discussion, or just try to see like, how does this look from the perspective of the family, and very recently, I was talking to a family, and I was just approaching them, and it was telling them something not meaningless, but they just were talking about reflux, like their babies had a bit of reflux, nothing really crazy. But somehow more nurses showed up around the bed side at the same time. And at some point, I'm realizing that like, now, there's like, seven staff members around and I said, Hey, like, this is gonna sound like we're delivering, like horrible news. So I stopped and I said, Hey, why is there so many people around here now? Like, we didn't need and the dad made the comment said, Yeah, okay, cuz I'm like, I was worried, like, what do you guys gonna tell me? Yeah. And it was so funny how, by just stopping to realize that something was happening, like the father had picked up on the volume, like, the, like, the size of the team, as is mentioned in this article, can be very intimidating. And unless we do something about it, the parents are just going to try to hold their ground and the most of the time won't say anything, but so I resonated with that paper.

Daphna 28:11

And if you if you feel it's like uncomfortable, like, probably the parents were uncomfortable, like a few steps back, right. So props for you for for being attentive.

Ben 28:22

Yeah, I mean, yeah. Betsy pylons interview was great. Like when, when she talks about like, all the things that are happening around her and how she is hyper hypersensitive, she she hears everything because she's apparent under stress in the NICU. And what the President says with the nurse sake, we have to be very careful. Okay. Is it my turn?

Unknown Speaker 28:44

Okay, so, this That's right, back and forth. I wanted

Ben 28:48

to thank you, ma'am. I wanted to go over this article published in pediatrics about glycerin, suppositories and enemas. So when I was a resident, our surgeons liked to use glycerin sponsors like pediatric surgeons often do. And this paper came out in pediatrics at the time, it was 2017 That said, there's a trend toward glycerin enemas in association with NEC. And we teased our surgeons so much because we knew it was not statistically significant, but I remember which is me like, Oh, you're the reason and so that meta analysis that came out in 2017, I remember myself as a resident and this is published in pediatrics, it's called glycerin, suppositories and enemas in premature infants, a meta analysis first author is Paul Burchard. I think it's and in any case, it is basically a revised meta analysis from that same group that published that other study in 2015, sorry, 2015. So, this is a meta analysis where they basically looked at stuff studies that assess infants treated with glycerin, suppositories or enemas. They had specific inclusion criteria for their study number one, it had to include premature infants less than 32 weeks of gestation and or birth weight less than 1500 grams. intervention had to include the intervention with glycerin enemas or suppositories used prophylactically or as rescue therapy. And three, the studies had to be randomized controlled trial, the outcomes that they were looking for was time to full enteral feed. That was their primary outcome measure, and additional outcomes included mortality, necrotizing, enterocolitis, rectal perforation, rectal bleeding, meconium, evacuation and jaundice. So after their search was was completed, they were able to identify and to identify six randomized control trials. And that included a total of 389 premature infants. Four of these trials four out of six included babies less than 32 weeks, one of them 30 to 35. And the other just mentioned premature infants with a birth weight of 500 to 250 grams. All six trials excluded neonates with congenital or gastrointestinal malformation three specifically excluded premature infants with hemodynamic instability or shock, because of the risk obviously associated with that when it comes to to the to the gut. The definition for full enteral feeding vary across two studies. And some of them use the 100 mL per kilo per day 150 mL per kilo per day one ad for a total of 24 hours or tolerance of enteral feeds and discontinuation of TPN for more than 48 hours. The transition to full enteral feeding was defined as the difference in days between the start of enteral feeding and full enteral feeding. So basically how long it took you from the point you started to give the baby some milk and the point where you actually shut off their TPN. That duration was called the transition to full enteral feeding. across the across five of the six rounds, there was no statistical difference in the in the time two to four feeds between treatment groups. When it comes to mortality, the mortality rates ranged from zero to 17%. And they didn't find any statistically significant difference in mortality between infants who were administered cluster in depositories or glycerin enemas compared to control. When it came to NEC. There was no statistical difference between the incidence of neck between the treatment groups and in any of those six trials. The meta analysis demonstrated a non significant trend toward a higher incidence of any C with glycerin suppositories. So again, the p value was point one six, the 95% confidence interval was point six eight to 11.2. However, the mentioned that there were no apparent trends for glycerin enemas, or overall so do I mean, I guess we're we're back exactly where we began. There was no significant difference in the case in the in the incidence of rectal perforation and bleeding. And then when it came to make conium evacuation, they found no difference in the days to initial meconium evacuation between treatment groups. Three trials reported completion of meconium evacuation, and one of those trials reported a non significant trend toward earlier completion of meconium evacuation when clusterings were were used. The main analysis itself revealed significantly earlier completion of meconium evacuation overall. And then finally, when looking at jaundice, two studies reported outcomes related to jaundice. And there was no significant difference in the administration of glycerin suppositories versus control in the peak total serum bilirubin, which is kind of interesting because when, when it should hits the fan would bilirubin sometimes we give glycerin enemas to full term babies to try to stimulate the enterohepatic circulation. So it was interesting to see what

Unknown Speaker 34:24

I've literally never done you've never heard of that. No. Yeah, so

Ben 34:28

so if you have like a baby that comes in for an exchange transfusion and as you're prepping for everything I've seen, okay, I'm going to be honest, I've done it myself too. Like you can give a bit of glycerin pass through it to get the babies to poop so that you can stimulate peristalsis and you can try to get you can theoretically stimulate a bit more enterohepatic circulation. I have no idea if this is evidence based maybe I sound like

Daphna 34:51

all the way down there. What the poops already down.

Ben 34:57

Listen, when when the exchange transfusion threshold is almost met. If somebody says you sprinkle this magic water over the baby, I will do it.

Daphna 35:07

Alright, so tell us about the bilirubin

Ben 35:11

No, so they didn't see any difference in the in the total serum. Now what was interesting so, so so right so there was no so the overall conclusion of the of the meta analysis was that this suggests that the use of glycerin suppositories and MS does not affect mortality, the transition to enteral feeding, and there's not there's does not seem to be any definitive association with NEC, although they're leaving the door open saying that with more evidence this may change. Now they do also state very early on in their discussion that the quality of the of the evidence for the administration of the medication is predominantly low to very low, largely because of underpowered studies and risk of bias due to methodology inadequate binding, frequent protocol violation, incomplete outcome data, possibly selective reporting and possible publication bias. So the data isn't great. But I feel like glycerin suppositories is something that's very ubiquitous in a lot of NICUs. And, and especially for preterm babies. And so I don't know, what were glycerin is yes, no, yeah, changing what you're doing based on this paper

Daphna 36:17

I trained, where I trained. Like, I never, I don't think I ever placed an order for this repository that not once. And then as you know, where we practice together, everybody had it on the MAR. So yeah, and I mean, that's just my NF too. You know, I just think I just think we people feel this is something people feel very strongly one way or another about and I'm not sure we have any data to support one way or another.

Ben 36:50

Yeah, I mean, that's the thing that, to me was asking more questions than giving answers is like the rapid completion of meconium evacuation. Is that necessary? Like, is this a good thing I don't like Right. I mean, it sounds like,

Daphna 37:03

I mean, I think there are some babies right where you're like, I mean, we either gotta get stuff moving, or I'm gonna have to intubate this kid, right? Because of the distension and the CPAP. And you're like, what's, what's what's what, you know, what's, where's the? Where does the balance fall? You know, so, as usual, I think this is an individualized thing. I don't think saying never and, or having it on every baby in the unit is the right is the right choice.

Ben 37:32

I think for now, based on the evidence that we have out there, if you were wanting to use glycerin, you would not have it seems strong evidence to oppose that practice. But it also doesn't seem like you would be supported that practice either. So just like when you go to the ocean, swim at your own risks.

Daphna 37:57

But that's right. That's something else we talked to Dr. Atterberg about are there more answers or more questions or she said both. I wanted to talk about this paper, which gosh, there's been a lot of Twitter buzz about about new articles. So this is this is our push that if you're if you if you have hesitation about being on social media, there's just so much to learn. So I hope I hope this is you will heed heed this advice to join us on via Twitter right so this also is an I was enacted paediatrica, neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation. Lead author Eva morsing. This is a study comprised of a Swedish national cohort of 399 children born before 24 weeks of gestation between the years of 2007 and 2018. All of these infants had survived at least until 40 weeks postmenstrual age, obviously, because we were looking at some of these long term outcomes. But in Sweden, any baby born under 30 weeks, who survives until 40 weeks postmenstrual age are registered in the Swedish National Register for retinopathy of prematurity, or the Swede rock. So that is a nice cohort to have. And then they wanted to look forward. So they have this registry as babies less than 30 weeks, but they were interested in looking specifically at what are like the long term health outcomes of babies born at 24 weeks gestation. So then they looked at the other diagnoses retrieved from the National Board of Health and welfares National Patient register. And in addition, they looked at individual medical charts of the children to validate and complete the diagnoses found in the registries. I've known thought it was important to know what is the parry viable resuscitation look like and they do comment. So in general, they consider as excitation at 22 weeks, it's recommended at 23 weeks. And then their cohort survival rate increased from 20% in this low gestational age in 2013 to 2015, increased to 38%, between 2016 and 2018. So some of the disorders they were looking for, or the long term outcomes they were looking for, they looked at cerebral palsy using the gross motor function classification system. And then they looked at a lot of ICD 10 codes. And again, they cross referenced the charts and the registers. So they made a diagnosis of intellectual disability based on developmental tests and estimated adaptive skills and classified using the IQ scores and the ICD 10 codes. So again, they looked at IQ and then they classified into mild moderate to severe and they looked at any intellectual disability as an ICD 10 code, the epilepsy, hearing impairment was defined as dependence on hearing aids or worse. For example, deafness. Visual Impairment was defined as being referred to a low vision clinic, or at any age having a best corrected visual acuity. That was below the, the lower limit. The other somatic diagnoses they looked at failure to thrive short stature due to endocrine disorder, surgically treated inguinal hernia and gastrostomy, nephrocalcinosis and nephritis. They looked at respiratory diagnoses of asthma and childhood BPB, persistent pulmonary hypertension and vocal cord paralysis. I looked at severe respiratory impairment, which was defined as need for oxygen supplementation up to at least two years of age or more, and or tracheostomy, and or home ventilator during childhood. And then they looked also at referrals to habitation had, let me say, right habilitation centers, which is really about the use of therapy. And they had almost 400 babies, like I said, they plan to follow, and they did have some deaths in the cohort to their final inclusion was 383. And the child's age at last visit was anywhere between two and 13 years, which I thought was interesting. Because, again, some kids were only following up until two years, so it's just something to note of the 383 infants. Go ahead.

Ben 43:02

I was gonna ask the habilitation centers? Uh huh. I'm not familiar with that term.

Unknown Speaker 43:08

It's like habilitation habilitation services. I'm

Ben 43:11

sorry. It's like

Daphna 43:12

therapy services. Oh, I see. Okay, like rehabilitation is where it comes from?

Ben 43:21

Fine, it's okay. That's okay, fine. I just wanted to make sure I there was not like a subtle difference. The Swedish do things kind of neatly sometimes. And so I wanted to make sure that was not missing some cool aspect of what we're doing.

Daphna 43:36

That's what I found in my my review, because I looked it up also. So if that if I'm wrong, people can definitely let us know. Or they will, they'll let us know. So of the infants, they are born in a median age of 23.3 weeks range of 21 weeks to 26 23.9 weeks of gestation here in my notes, doesn't seem like it can be wrecked. The median birth weight was 565 grams, a range of 340 to 874 grams. And they did have two infants born in this 21 week, period. 91 infants born at 22 weeks. And then they did look at so of the 21 weeks they had one male one female 91 infants born at 22 weeks were 54% male, and the 290 infants born at 23 weeks where 51% male. And so yeah, so go ahead. Go ahead.

Ben 44:38

No, I was gonna say this whole thing with the weeks. It's like, either you you say 23.3 It means like, a third of the week, or you're saying 23 and three days, which is an addition, like three days of the week is not 23.9 weeks nine, which is like 90% of a week.

Daphna 44:57

Correct. Thank you. Thank you better. And I did want to they did mention that the two infants born at 21 weeks, they kind of lumped into the 22 week group, so you should know that. So, basically 75% of the children had quote unquote, any neurodevelopmental disorder, and then they went into the different groups. So speech disorders, 52% intellectual disabilities, 40%, ADHD, 30%, Autism Spectrum Disorder, 24%, visual impairment, 22%, cerebral palsy, 17%, epilepsy, 10%, hearing impairment 5%. And they looked at them by week, so not surprisingly, a larger proportion of children born at 21 and 22 weeks compared to those born at 23 weeks had intellectual disability. 49% versus 36%. A larger proportion were referred for habilitation care 64% versus 52%. More males and female infants were diagnosed with intellectual disabilities 46% versus 36%. And this difference was most pronounced in those born at 23 weeks. When they looked at 23 week group, more males and females were visually impaired 25% versus 14%. And then, like I said, they looked at the failure to thrive short stature was diagnosed in 39% of children more frequent in those born at 21 and 22 weeks than those born at 23 weeks 49% versus 36%. severe constipation was found at 29% of the total core heart gastrostomy in 18%, which was actually better than I anticipated for the respiratory outcomes as my childhood BPD 63% pulmonary hypertension 12% vocal cord precice 13%, severe respiratory impairment 12%. So the majority 96% of the children had one or more of the diagnoses selected for the study, there were total 15 children without any diagnoses. 10 of these were female infants and five male infants. And, and those 15 children without any diagnoses included one boy and one girl at 22 weeks. Then again, they verified with the medical records, medical records clearly stated that five of the 15 children were healthy. The data was sporadic for two of those 15 as they did not attend the plan follow up. And there were medical indications of disorders in the remaining eight children, especially in kind of lung problems, allergies and neuro behavioral problems, but no ICD 10 codes diagnosed. They also looked at kind of long term interaction with care. So 193 of the children 50% had further episodes of inpatient care, after they were discharged from the NICU. The median number was two additional admissions, the median number of days in inpatient care was eight and did not differ by gestational age. So I think that this paper does just give us a little bit more information about what do those babies look like when they leave the unit? And we know that parents now instead of the question, mean, there's still the question, right, like, will my baby leave the unit, but really defining what happens when they leave the unit?

Ben 48:33

Yeah, and the Swedish court is always they're always so good, just because of the fact that they can follow so far out. So it's kind of it's kind of nice to have a large cohort that's been followed Well, into two childhood years, you know? Yeah. But it's not obviously there. But the outcomes are not great, though. I mean, I mean, yeah. Go ahead. No, I was saying the outcomes were not fantastic, either. So it's not like it's right. It's good data to have and to be able to present to parents, but definitely is highlighting and underscoring the work that needs to be done.

Daphna 49:12

Yeah, I don't I'm not sure it changes my counseling, but it gives maybe a little more granularity to what to what life potentially looks like. Obviously, the medical system is different. So, you know, I think, I think that matters, potentially. Especially with the social,

Unknown Speaker 49:31

I think, I think, please,

Ben 49:33

yeah, I think it does affect my counseling a little bit because you do see, especially with a lot of our, our outpatient northern mental follow up data, that children have this amazing ability to catch up really well and sometimes you can see that the impairments, whatever whatever they are, they tend to get better as you keep moving forward and for like, you get to like wait two

Speaker 5 49:58

years. Great. Nobody like that. Yeah. Right.

Ben 50:02

And here, it's like, it's not, it's not amazing. So, we have to, it's it may be highlighting this this very vulnerable population that is that is not managing as well to catch up on their, on their impairments as well as older gestations. So yeah, more work to be done for us, I guess.

Daphna 50:24

Yeah, I think it begs the question to, you know, how do we what's the best way to really transition transition those babies to their new medical homes? Is that even something we're, you know, doing? How do we prepare parents for the things that cause readmissions so we can minimize readmissions? I mean, that's, that's ripe for work that needs to be done.

Ben 50:48

Okay, I have two more papers. We're running out

Unknown Speaker 50:50

of time. We're running out of time.

Ben 50:53

I have two more papers. I have to talk about these papers though. Okay. So this is a paper that was published in pediatrics, and it's titled predictive ability of 10 minute Apgar scores for mortality and neurodevelopmental disability. The first author is Vivec Shukla. And there's a bunch of extremely extremely famous neonatologist on this paper, most notably Dr. Susan Heinz, Dr. Rosemary Higgins, Dr. Abbott lab took Dr. Sita Shankar on and none other than our friends as a trailing author, Dr. Weil DeCarlo. So, in the introduction, they do mention how the Apgar score is universally accepted as a measure of assessment of newborns cardio respiratory and your neurologic neuro neuralgic status, and we know that lower 10 Of course, minutes 10 minute Apgar scores are associated with increased risk of adverse neurodevelopmental outcomes. We also know that the 10 Minute Apgar score is an integral part of the assessment used for the initiation of therapeutic hypothermia in cases of infants affected by hypoxic ischemic encephalopathy. However, when we also know from some studies that were quoted in the background that many of the babies who have low 10 minute Apgar score tend to survive and tend to do, surprisingly, okay for such a bleak status at that moment in time. And the two they're mentioning the 2015, American Heart Association and the International Liaison Committee on resuscitation and how their recommendations at the time was that if you had an Apgar of zero after 10 minutes of resuscitation, it was considered reasonable to reevaluate whether you should continue resuscitative efforts, and that this stance was adjusted in 2020, where instead of using the Apgar score of zero, maybe they suggested continuing resuscitative efforts for about 20 minutes. And even then the evidence is considered to be weak, with very low certainty. So the goal of the paper was to take advantage of the optimizing cooling trial, right. And so this was a trial that was published, I think, in 2017. And this was a an a trial that attempted to look at the depth and duration of cooling on death or disability at age 18 months, among neonates with HIV. And they had 364 infants in that trial. And we're not really going to go over this trial right now. I mean, it's been published for a while, I think the outcomes are known, the trial was stopped early, just because the effect of increased depth or duration of cooling did not make much of a difference. But what they thought was that this population presented an interesting group that was quite large to assess the predictive performance of the Apgar score for death or moderate disability disability at 18 to 22 months of age. And so they tested this hypothesis that the Apgar score at 10 minutes is independently predictive for death, or moderate or severe disability. So, as we've said, they took the patients from the optimizing calling trial, and for the sake of, of completion, the inclusion criteria were that the babies had to be 36 weeks or more, they had to be less than six hours after birth, they had to fulfill both biochemical and clinical criteria for the diagnosis of moderate or severe HIV. Biochemical criteria included a first gas with a pH of 7.0 or less or a base deficit of 16 or more millimoles per liter. If the pH was a bit higher, between 7.01 and 7.15. A base deficit between 10 and 15.9, or a blood gas was not available, there are additional criterias, which included like a clear carry needle event, a 10 minute Apgar score of five or less or needing mechanical ventilation for at least 10 minutes. The primary outcome was the composite outcome of death or moderate or severe disability at 18 to 22 months of age. Follow up was completed in 95% of the infants enrolled in the trial, the the neurodevelopmental impairment was defined using the belly three very much neonatal Research Network style, you know, and so, so not, I don't think there was any any, any holes or anything surprising in that. The one thing that was interesting from a statistical standpoint is that they performed this classification and regression tree analysis. And basically what they did was that to determine a cut points for Apgar scores and identify a combination of predictive value variables that were most predictive of the composite outcome. So based on the different 10 minute Apgar score, they wanted to see what level which is going to predict the composite the primary outcome, and then they added more clinical variables to that analysis to see if there was a combination that was the most predictive of the of the desired outcome. Okay, so let's let's get into the results. And so a total of 354 infants had data available on survival. And among these 354 infants 100 347 had 18 to 22 months outcome. Of those babies who did complete follow up to 2218 to 22 months 307 had documented 10 minute Apgar score. They were 26 infants with an Apgar score of zero at 10 minutes, the median 10 minute Apgar score were significantly lower in the infants with the composite outcome of death or moderate or severe impairment or disability I'm sorry. In addition, several variables available during resuscitation were found to be associated with the outcome by bivariate analysis. And we are going to talk about that. So let's talk about the 10 Minute Apgar score. A 10 minute Apgar score of zero was independently predictive of death or moderate slash severe disability the adjusted risk relative risk was 1.7 to 95% confidence interval was 1.11 to 2.68, the p value was 0.016. However, the AUC was low. And that was about 0.56. Half of the infants with a 10 minute Apgar score of zero survived. So that was pretty impressive. So 13 out of 26 infants with an Apgar score of zero survived, and even more impressive was of the survivors with a 10 minute Apgar score of zero 46% had no disability 16% had only mild disability. 38% had moderate or severe disability. Even more interesting, there was no significant interaction between hyperthermia treatment and 10 minute Apgar scores for death and or moderate or severe disability. When they did the cart analysis, this regression, actually, you know what, let me go first into figure one. So you should all look at figure one because it's a bar graph that basically has on the x axis, the 10 Minute Apgar scores, and you have 0123456, and seven or more. And then you have in these bars, different colors based on the babies who either passed away had moderate or severe disability, mild disability or no disability. And it's quite impressive to see that the survival rates for these babies who have very low 10 minute avatars is extremely high. And so that's that's, that's already something quite interesting. So going back to the to the card analysis. The card analysis based prediction model to predict the risk of death or moderate or severe disability identified that it was a 10 minute Apgar score of less than two and no maternal hypertension as the most predictive variable. The AUC of the 10 Minute model to predict the risk of death or moderate or severe disability was improved 2.66 compared to with the AUC of the 10 Minute Apgar score alone of point five, six, and the prediction model to predict the risk of death, identify the 10 Minute Apgar score of less than two and a cord blood pH of less than 6.9 as the most predictive variables. So I guess what was the most striking thing to me obviously, was that the majority and they did discuss that and they talk about that in the discussion is that them majority of surviving infants with a 10 minute Apgar score of zero did not have moderate or severe disability at 18 or 22 months of age, ad indicating that prediction of the outcome at 10 minutes may be very much too early and God knows that we rely on that when when things are unfolding. So I think this paper was was very, very interesting. I'm curious, what were your thoughts Daphna?

Daphna 1:00:25

Yeah, I mean, I think it supports it supports the change to, you know, to saying, you know, 20 minutes is a reasonable, and I

Ben 1:00:35

think the Apgar score is useful. But it's, I think we're trying to overfit a lot of stuff in the Apgar score, trying to make it do so many different things, when in truth, it's not really meant to be really like this one score. Yes, objectively being given by a provider at birth, and then you should be able to tell the whole kids life story. And but yeah, three years of age, I think that maybe a bit too.

Daphna 1:00:57

Yeah. Sounds like when I when we, you know, we still do some newborn coverage. And the parents say, well, just yet, what were the app cars, and I was like, I have literally no idea you're, you're here in the nursery. So I didn't look at the but I can find out for you. But so or, or the opposite is true, you know, you're having a real, real resuscitative effort. And someone at five minutes and 10 minutes, and as you're wheeling the isolette out is begging you for the app cars, and you're like, I I'm gonna have to get back to you. I'm gonna have to think about that for a little bit. So yeah, I'm sorry. And admit the baby to like, tell you the app cars, I will get back to you. So it's also an interesting discussion about studying research around app cars, because so many times you have to go back and assign the anchors. So there is a recall bias with that, too. Anyways, we're really going over but we said last time that we would at least touch on this Qi paper in pediatrics, improving time to independent oral feeding, to expedite hospital discharge and preterm infants. Lead author, Samuel, gentle, and the anchoring authors, Ariel Salas. And then we had Dr. Salas on the podcast as well. So this is coming to us from you. Well, we

Ben 1:02:27

spoke to him his episode is scheduled for

Daphna 1:02:29

it. That's right. You don't know. Guys don't know that. We have. We spoke we've

Ben 1:02:35

had a discussion with him. Yeah, it's scheduled for release. It's just not there yet. Don't start scrolling like maniacs and saying, where's that? Where's that?

Daphna 1:02:42

This is a really good episode. So you guys, that'll give you something for you guys to look forward to. So this is coming to us from UAB, Birmingham. And their real goal was to reduce the the post menstrual age at discharge, and their target intervention was earlier feeding at younger gestational age. So before their project initiation, the average postmenstrual postmenstrual age at discharge was 38 and 830 8.8 weeks, infants born at a gestational age between 25 and zero and 32, and six weeks, and infants born between 25 and zero and 32 and six weeks. Again, their objectives were to increase the proportion of preterm infants initiated on oral feedings before 33 weeks to implement Cubase feeding, and to increase the frequency of oral feeding attempts and infants who were not having independent oral feeding by 36 weeks postmenstrual age. So those really were their three PDSA cycles. And the overall aim was to reduce the gestational age at discharge by one week with a balancing measure of hospital readmission within two weeks of discharge. They included unborn infants born between 25 and zero, like I said to 32 and six, and they excluded babies born in less than 25 weeks, given the higher rates of BPD. And the fact that they would have ongoing likely have ongoing respiratory needs at 36 weeks. Because their thresholds for feeding on respiratory support. Were four liters of high flow. And obviously that's an ongoing thresholds of discussion worldwide, I think. So, to tell you a little bit about each cycle, so the first was really identifying infants approaching the 32 and zero week marks so that they could try to initiate feeds before 33 weeks, so they have these oral feeding huddles To decide which babies were kind of up for that evaluation, that was our first cycle. The second cycle, like I said, Use Cubase feeding. And if you're not familiar with Cubase feeding, that's really, each time you look at the infant, you assess for signs of feeding readiness. Things like routing, flexion, and the arms and legs, a weak status, sucking on a pacifier hands. And that's really looking at each baby each opportunity and saying, Does this baby look ready to eat? I love that. That is, and that is not the case, I think everywhere. So

Speaker 4 1:05:39

it's a constant reassessment. Yeah,

Daphna 1:05:43

absolutely. And then the third PDSA cycle was if the baby was at 36 weeks at that point, they would transition from this Cubase feeding to quote unquote, practitioner driven feeding, where they were provided and attempt to feed. With every touch time, infants were progressed to this feeding strategy, if orally fed for at least three weeks with greater than 50% of daily feedings attempted by mouth, so they still kind of had this queue based feeding. But if you were meeting a certain threshold, then they offered you food every time. The other thing they did, which wasn't exactly its own PDSA cycle was removing the NG tube after 120 mL per kilo per day by mouth. And that was in the third PDSA cycle. So the process measures were oral feeding initiation by 33 weeks bedside, by use of oral feeding logs. They looked at the day of oral feeding initiation, defined as the first day when an infant was fed either by nipple or at the breast, which I thought that was also very cool is that they were pushing to have, you know, breastfeeding count as the first early feed. And the other thing they do, which was not necessarily a PDSA cycle, but I think super important is that they provided their staff with weekly compliance rates. And I think that has a lot to do with how well our staff responds to our QI projects. They had a total of 614 infants between 25 and 32 weeks of gestation, the average institutional age across the three PDSA cycles was about 30 to 31 weeks to differs significantly, the oral feeding baseline by postmenstrual week attempts were 6% at 32 weeks, 50% at 33 weeks, 88% at 34 weeks, 90% at 35 weeks, and 100% of babies had at least a tap, they were at least attempting to feed at 36 weeks. And so they after their first PDSA cycle, they were able to improve that 33 week baseline 33 weeks and last from 47% to 80%. After the first PDSA cycle, which again was just huddles, looking at which babies were falling with within those gestational ages, and after that cycle, they achieved a 90% Q based assessments. And they were able to decrease gestational age at discharge from 38.7 to 37.7 weeks, with eight points below the mean on the run chart by targeting feeding initiation before 33 weeks. So anybody who was recently studying for the boards is very familiar with with read charts, and then an important part of Qi research. So they made a lot of drastic difference really with their first PDSA cycle, which was just identifying which babies were up and making sure that they got that evaluation. But by their third PDSA cycle, one of the major changes they found was reducing this quote unquote extreme length of stay. So babies who were really outliers on like this day, they decreased by implementing that practitioner driven feeding at 36 weeks. The other thing they looked at was what were their terminal barriers to discharge. And before they got to the third PDSA cycle, the terminal barrier discharge in 56.3% of hospitalizations was feeding and that decreased to 33.7. After PDSA cycle three, and then apnea was probably the next most common barrier to discharge and apnea resolution became the predominant terminal barrier to discharge during PDSA cycle to so they basically changed what discharge looks like in their unit, even even after the first PDSA cycle. So they have their rent charts there. I think it's interesting to look at. I think everybody has an ongoing debate about when they're comfortable starting feeds I'm in with what respiratory support. But I think this highlights the fact that we should at least be having the discussion and preparing staff and families for feeding readiness. And I love anytime we can talk about key based feeding. But now it's your turn to tell me what you think.

Ben 1:10:18

Yeah, no, I think I think to me, the takeaways are, they were able to reduce time to discharge number one, which means they were able to get these babies to feed independently sooner. And the crux of their intervention was bring all the involved parties together, to daily reassessment every day is a new day for trying and then have this balance between Cubase and provider based feeding. I think that was very, very smart. So I really liked I really liked it because it's it's a it's not it's a very well done Qi if you are interested in doing Qi, I think it's important to read up on Qi is that were well done and well conducted. That's one of them. And how a little bit of tweaking, right, I mean, all the like they didn't come up with something new and revolutionary, but they took all the ingredients that we all have and just put them together in a very nice blend to get the outcome that they needed. So that was cool. Yeah. Okay, I have one paper. That's all I want. And then we go, yeah, this was recommended to us by one of our audience member it's called by Fito bacterium longum subspecies and fantas EVC 001. Administration is associated with a significant reduction in the incidence of necrotizing enterocolitis, and very low birth weight infants. first author Joseph Tobias, I have to say that this basically is a study looking at the probiotics in vivo is it ie vivo or in vivo? Forgot? No, I think it's easy though. Ie vivo. Right. And, and I know that we are a podcast sponsored by, by record, Johnson, but the person who recommended the paper to us said they had nothing to do with the trial or with the company. And we are not been asked to review this paper by our sponsors. But I thought it was a very interesting paper nonetheless. So the goal of this study was to evaluate the impact of this supplementation with evil probiotic, I'm going to call it evil because I'm not gonna call it like B and Fantasy V zero, C 001. dot m throw on the rates of neck in at risk preterm infant. So this was a non concurrent retrospective cohort design. So if you've taken the board, you know exactly what that means. And it was used to compare clinical outcomes in very low birth weight infants who either received a probiotic or who did not, it is easy for you right to see it, I wrote it down there. The eligibility criteria was that babies had to be weighing less than 1500 grams at birth, they had to have received for resuscitation, they had to have survived for at least the first three days of life. They were fed a human milk based diet consisting of either mother's milk donor milk or a combination thereof. And they were fed according to the institutional guidelines, incorporating the best practices for any prevention, including human milk based diet, an initial period of trophic feeding and gradual feeding advancement. This was a study that was done in the department of neonatology at Oregon in at Oregon, Clinical and Translational Research Institute, so they excluded babies who underwent palliative care on successful resuscitation or who died before day of life for so it's important to go over their feeding protocol. I think everybody is going to be interested in that. So each cohort was fed human milk based diet of mother's milk donor milk or both. There's an initial period of trophic feed daily events meant that thereafter to a goal of 150 to 160 mL per kilo per day, during the milk feeding was continued until at least 34 weeks PMA for a minimum of five days in infants born at 34 weeks or more, after which donor milk was replaced with bovine milk based formula if the mother's milk was not available, a bovine milk based human milk fortifier in this case, they were using the Similac HMF was used to meet the nutrient and energy needs of the very low birth weight infants until September 2017. So in their in their original historical cohort, they were fortifying the milk with a bovine fortifier. And then after 2017 they switched to prolactin, which is human milk based fortification, so there's like nine months in their control sample that actually were switched from bovine to prolactin, and then all the people all the patients who were exposed to EVO probiotic were fortified with prolactin. The use of bovine milk based fortification was continued for infants weighing more than 1000 grams but less than 1500 grams at birth, but as of March 2020, they switch that to birth weight less than 12 50 So, the administration of the probiotic, the received 8 billion colony forming units of activated B infantis EVC 001. suspended in point five milliliters of medium chain triglyceride oil MCT oil daily via gastric tube before morning feed. From June 2018 to 2019, the evil administration was initiated that feeding volume of 80 to 100. And in August 2019, they switch the protocol to begin it on the day of trophic feeds. So initially they were waiting almost like when you taper off the lipids, but now they were giving it really right away. The primary outcome was a diagnosis of neck determined using the bell staging criteria. Cases of spontaneous intestinal perforation were excluded. Spontaneous intestinal perforation was defined as the as a GI perf without signs of neck and the diagnosis of neck was confirmed by an independent review of each case by at least two neonatologist and one pediatric surgeon. secondary outcomes included medical neck separate surgical neck separate associated neck associated mortality and day of life at the diagnosis of neck. So they were able to enroll to include 483 infants who met their inclusion criteria. And 301 infants who 301 infants who were not exposed to the to the probiotic, and 82 infants who were exposed to the illegal probiotics. There's no significant differences in the measured covariance between the two cohorts except for sex and antenatal steroid administration. The mean gestational age at birth for both cohort was 28 weeks and a mean birth weight of 1000 grams and 1045 grams for the for the placebo and then 1048 gram for the vivo group. Regarding the primary outcome, they had 33 cases of NEC. And what they did was they looked at the control group and they said when we switched from the Similac fortifier to the proactive fortifier was there any differences in NEC, and they did see a small reduction from like 20% to 16.7%. But that was not really statistically significant. So they felt it was okay for them to continue to analyze this control group as one single group, even though they had some heterogeneity in terms of the fortify that they received. So when the log binomial models demonstrate that infants with no who didn't receive the probiotic had a 73%, higher cumulative incidence of any see compared with infants in the probiotic group, after adjusting for differences in sex, birth weight, gestational age, and mode of delivery, I encourage you to review the numbers because it's quite impressive, because they basically looked at all the very low birth weight infants, and the rates of neck went down from 11% to 2.7%. And when they looked at less than 1000 grams, it went down from 19.2% to 5.3%. The number needed to treat for the V lb W's was 13 and for ELB W's it was eight is there anything else that I wanted to tell you subgroup analysis was carried out to determine the effect of the evil administration on LBW infant and those with a birth weight of 1000 to 1500 grams. And it demonstrated a statistically significant difference in the neck incidence between cohorts with an adjusted relative risk of point to aid in ER BW infants. In the babies who did develop neck, they didn't find a really significant difference in the incidence of medical versus surgical neck. And then we talked about the difference in the RBW. So very interesting about this very selective probiotic. And this EVO probiotic is consisting of this by fiddle, bacteria Mangum subspecies, infantis, so, b infantis. And it's, they describe it as a mutualistic colonizer of the human gut, worldwide, and that it encodes for the complete gene cluster needed to metabolize the full range of prebiotic human milk oligosaccharides complex sugars in human milk that are otherwise indigestible by the infant. And so that's why they're making the case that this probiotic is really well designed for our preterm population. And they're quoting a

another study in the introduction which looked at the supplementation of eatigo to human milk in preterm infants in the neonatal intensive care unit, and basically, they had done safety and making sure that the, the, the probiotic was well tolerated, and that it colonized the mic. The intestinal microbiota, and that had some positive effect on it, which was one of the big issues in this study. Obviously, it's retrospective. So there's a few holes. But there's also not much analysis of the stool to look at the effect really on the microbiome when this was given. But they're using that that original paper to say that that's already been pretty much discussed. So yeah, thoughts? 2.7% rates of neck?

Daphna 1:20:24

Yeah, I mean, aren't we all looking for something to reduce neck? And it's just it's hard, because there's been, you know, a long, long history of of papers looking at and probiotics. So I'm just happy that we're still looking that we're doing more studies on it, for sure. I think the combinations, right, we always had to decide, like, is this applicable to my population? So I think we have to look specifically like the combinations of things that were giving. So it was really important that they talked about what their fortification was. And can you mix the two groups? I don't know, I don't know what to say about that. But I think I think we're, I think you have to look at what what it is that you give your you know, I think we have to look at everything we give our babies and say is it the same thing as they what they give their babies, instead of just looking at products individually? I think that's going to be the long term problem. I

Ben 1:21:25

have to admit this paper made me hopeful because I do feel like it is now and and these are pretty striking differences. I mean, we started again, we have no no, we're not being paid to say this. But like we started using NVivo in our in our in our unit as well. I think I think this is I think this is this is something that that's coming and we're going to have we're going to ask Abdul Razak we're gonna have on the podcast as well, because I loved his Jama editorial one on the use of probiotics. So anyway, alright, we're way over time. I feel like way over time. We are over time, but that was fun.

Speaker 5 1:21:59

I feel like that journal club so yeah, I miss Journal Club.

Ben 1:22:03

And there's even more papers coming up next week. So stay tuned. Yeah, definitely. This was fun.

Daphna 1:22:09

Bye, everybody.

Unknown Speaker 1:22:10

Take care, guys. Bye.

Ben 1:22:13

Thank you


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